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Psorilax:opinioni |pscurtar crema psoriasi

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Psorilax: prezzo, funziona, recensioni, opinioni, composizione

Mercato globale degli inibitori alfa TNF per classe di farmaci (Adalimumab, Certolizumab Pegol, Etanercept, Golimumab, Infliximab), per analisi pipeline (Fase I, Fase II, Fase III), Per regioni (Nord America, Europa, Asia del Pacifico, Resto del mondo ): Previsioni globali fino al 2025

Accedi all'esempio PDF del rapporto @ https://www.orbisresearch.com/contacts/request-sample/3770666

Questo rapporto di ricerca di mercato include una segmentazione dettagliata del mercato globale degli inibitori del TNF alfa per classe di farmaci (adalimumab, certolizumab pegol, etanercept, golimumab e infliximab), analisi della pipeline (fase I, fase II e fase III) e regioni (Nord America, Europa, Asia-Pacifico e Resto del mondo).

Panoramica delle ricerche di mercato globali sugli inibitori alfa TNF:
Il rapporto di ricerche di mercato di Infoholic prevede che il mercato globale degli inibitori del TNF alfa crescerà ad un CAGR del 3,6% durante il periodo di previsione 2019-2025. Gli inibitori del TNF, noti anche come bloccanti del TNF, farmaci anti-TNF e terapie biologiche, sono un gruppo di farmaci usati per trattare condizioni infiammatorie, tra cui l'artrite reumatoide, l'artrite giovanile, l'artrite psoriasica, la spondilite anchilosante, la malattia infiammatoria intestinale (Croitis e colite ulcerosa ) e la psoriasi. I farmaci riducono l'infiammazione e possono fermare lo sviluppo della malattia prendendo di mira una sostanza che causa l'infiammazione, il fattore di necrosi tumorale (TNF)

Il mercato sta assistendo alla perdita di brevetti in Europa per vari farmaci di successo, con conseguente comparsa di biosimilari. Nell'aprile 2019, Eticovo, un biosimilare tra Samsung Bioepis e Amgen's Enbrel (etanercept), ha ricevuto l'approvazione della FDA. Nel novembre 2018, la FDA ha approvato Hyrimoz sviluppato da Sandoz, un biosimilare del farmaco di successo Humira di AbbVie, che sarà lanciato sul mercato statunitense entro il 2023. Attualmente, solo cinque inibitori del TNF approvati, ad esempio, adalimumab, certolizumab, etanercept, golimumab e infliximab , controlla il mercato. L'ampia applicazione di questi farmaci per numerose malattie autoimmuni garantisce una crescita costante del mercato durante il periodo di previsione 2019-2025.

I principali attori che operano in questo campo, ovvero AbbVie Inc., Amgen Inc., Johnson & Johnson e Celgene Corporation, stanno generando la maggior parte delle entrate nel mercato globale degli inibitori alfa TNF.

Secondo l'analisi di Infoholic Research, il Nord America rappresentava la quota maggiore del mercato globale degli inibitori alfa TNF nel 2018 e manterrà una posizione elevata durante il periodo di previsione. Il Nord America è seguito dall'Europa, con una quota di mercato superiore al 20% nel 2018.

Per classe di farmaci:
• Adalimumab
• Certolizumab Pegol
• Etanercept
• Golimumab
• Infliximab
Nel 2018, il segmento adalimumab ha rappresentato la quota maggiore e si prevede che cresca a un CAGR a metà singola cifra durante il periodo di previsione. L'aumentata efficacia clinica e l'elevata preferenza da parte dei medici per il trattamento di gravi malattie reumatiche hanno reso il segmento il maggiore azionista nel 2018. Si prevede che Golimumab crescerà a un CAGR elevato durante il periodo di previsione 2019-2025.

Analisi della pipeline:
• Fase I
• Fase II
• Fase III
Molte aziende stanno facendo enormi investimenti per sviluppare prodotti ed entrare nel mercato non appena i prodotti biologici perdono i loro brevetti. Tra i vari inibitori del TNF alfa, adalimumab ha il maggior numero di studi clinici in corso, seguiti da certolizumab pegol.
Per regioni:
• Nord America
• Europa
• Asia Pacifico
• Resto del mondo
Basato sulla geografia, il Nord America ha dominato il mercato nel 2018 con una quota di mercato superiore al 60% e si prevede che mantenga questa posizione durante il periodo di previsione. Si prevede che l'Europa crescerà a un CAGR elevato durante il periodo di previsione. La crescente accettazione dei biosimilari e i crescenti investimenti nella ricerca e sviluppo di nuovi farmaci rendono l'Europa la regione in più rapida crescita durante il periodo di previsione.

Analisi competitiva della ricerca di mercato sugli inibitori globali del TNF alfa: Il mercato sta crescendo a un ritmo costante, cioè a un CAGR del 3,6% durante il periodo di previsione 2019-2025. Nuovi lanci di farmaci, approvazioni di prodotti, partnership strategiche e collaborazioni sono tra le strategie significative adottate dai leader di mercato per mantenere la loro posizione di leadership. Ad esempio, a luglio 2019, la FDA statunitense ha approvato HADLIMA di Samsung Bioepis, un riferimento biosimilare HUMIRA, per il trattamento dell'artrite idiopatica giovanile, la malattia di Crohn adulta, l'artrite psoriasica, la spondilite anchilosante, la colite ulcerosa, l'artrite reumatoide e la psoria della placca. Nel marzo 2019, la FDA degli Stati Uniti ha approvato l'iniezione di Cimzia per il trattamento della spondiloartrite assiale non radiografica (nr-axSpA) negli adulti, con segni distinti di gonfiore che lo rendono il primo trattamento approvato dalla FDA che soddisfa i bisogni insoddisfatti di nr-axSpA; e nel maggio 2018, il farmaco è stato approvato per il trattamento della psoriasi a placche da moderata a grave.

La crescente incidenza di malattie autoimmuni croniche ha portato al crescente lancio di biosimilari a livello globale. Nel maggio 2019, Fresenius Kabi ha lanciato l'IDACIO biosimilare IDACIO in Germania. Nel maggio 2019, Janssen ha lanciato Simponi Autoinjector in Giappone e i farmaci sono distribuiti da Mitsubishi Tanabe. Inoltre, altri importanti fornitori si stanno concentrando sull'investimento enorme in attività di ricerca e sviluppo per sviluppare nuovi farmaci per ottenere una quota elevata nel mercato.
Fornitori chiave:
• AbbVie Inc.
• Novartis AG
• Amgen Inc.
• Johnson & Johnson
• Celgene Corporation
• Assistenza sanitaria cellulare
• Samsung Bioepis Co. Ltd.
• Apogenix
• 3SBIO Inc.
• Shanghai CP Guojian Pharmaceutical Co. Ltd.
Fatti competitivi chiave:
• UCB Biopharma S.P.R.L. sta conducendo una sperimentazione clinica di fase 3 in 15 centri in Germania per studiare “Efficacia e sicurezza di certolizumab pegol (CZP) rispetto a un comparatore attivo e placebo in soggetti con psoriasi a placche (PSO) (CIMPACT)”.

• A livello globale, oltre il 95% degli studi clinici su certolizumab è condotto da UCB Pharma.
• Nel luglio 2018, Mylan ha siglato un accordo di licenza di brevetto con AbbVie sul biosimilare Humira proposto da Mylan. Secondo i termini dell'accordo, AbbVie concederà a Mylan le licenze esclusive sulle proprietà intellettuali di Humira il 31 luglio 2023 negli Stati Uniti e in altri paesi esclusa l'Europa.

Vantaggi: il rapporto fornisce dettagli completi sul sottosegmento del mercato globale degli inibitori dell'alfa TNF. Pertanto, le principali parti interessate possono conoscere le principali tendenze, i driver, gli investimenti, le iniziative dei giocatori verticali e le iniziative del governo nei confronti del segmento farmaceutico nei prossimi anni, insieme ai dettagli delle società pureplay che entrano nel mercato. Inoltre, il rapporto fornisce dettagli sulle principali sfide che avranno un impatto sulla crescita del mercato. Inoltre, il rapporto fornisce dettagli completi sulle principali opportunità commerciali per le principali parti interessate al fine di espandere la propria attività e acquisire le entrate in specifici settori verticali e analizzare prima di investire o espandere l'attività in questo mercato.

Key Takeaways:
• Comprendere le potenziali opportunità di mercato con dimensioni precise del mercato e dati previsionali.
• Analisi di mercato dettagliate incentrate sulla crescita del settore degli inibitori dell'alfa TNF.
• Fattori che influenzano la crescita del mercato degli inibitori alfa del TNF.
• Approfondita analisi competitiva di venditori dominanti e di puro gioco.
• Analisi delle previsioni del settore degli inibitori alfa del TNF nelle regioni sviluppate e in via di sviluppo.
• Informazioni chiave relative ai principali segmenti del mercato degli inibitori alfa TNF.
• Le ultime analisi dell'andamento del mercato che incidono sul comportamento di acquisto dei consumatori.

Azionisti principali:
Sfoglia il rapporto completo @ https://www.orbisresearch.com/reports/index/tnf-alpha-inhibitors-market-by-drug-class-adalimumab-certolizumab-pegol-etanercept-golimumab-infliximab-by-pipeline-analysis -da-regioni-nord-america-europa-Asia-Pacifico-resto-of-the-world-global-previsione-up-to-2025
Sommario

1 Outlook del settore 10
1.1 Panoramica del settore 10
1.1.1 Driver globale per la domanda farmaceutica 11
1.1.2 Gasdotto R&S nell'industria farmaceutica 11
1.1.3 Principali farmaci farmaceutici per vendite ($ milioni) 11
1.2 Tendenze del settore 12
1.3 Mercato totale indirizzabile 13
1.4 Tendenze del mercato dei farmaci per immunoterapia 13
2 Schema del rapporto 15
2.1 Ambito del rapporto 15
2.2 Riepilogo report 15
2.3 Metodologia della ricerca 16
2.4 Presupposti per la segnalazione 16
3 Istantanea del mercato 18
3.1 Definizione del mercato – Ricerca Infoholic 18
3.2 Mercato indirizzato segmentato (SAM) 18
3.3 Tendenze del mercato degli inibitori alfa di TNF 18
3.4 Mercati correlati 19
3.4.1 Farmaci oncologici 19
3.4.2 Prodotti biologici 20
3.4.3 Biosimilari 20
4 Prospettive di mercato 22
4.1 Segmentazione del mercato 22
4.2 Analisi PEST 23
4.3 Porter 5 (Five) Forces 24
5 Caratteristiche del mercato 25
5.1 DRO – Dinamiche di mercato globali degli inibitori alfa TNF 25
5.1.1 Driver 25
5.1.1.1 Aumentare la prevalenza della malattia autoimmune cronica 25
5.1.1.2 Ricerca costante per sviluppare prodotti biologici basati sugli obiettivi 26
5.1.2 Opportunità 26
5.1.2.1 Sviluppo continuo di biosimilari 26
5.1.2.2 Aumentare le opportunità nei mercati emergenti 27
5.1.3 Limitazioni 27
5.1.3.1 Processo complesso di sviluppo di farmaci 27
5.1.3.2 Scadenza del brevetto 28
5.2 DRO – Analisi dell'impatto 29
5.3 Principali stakeholder 30
6 Prodotto: dimensioni e analisi del mercato 31
6.1 Panoramica 31
6.2 Adalimumab 32
6.3 Certolizumab Pegol 36
6.4 Etanercept 38
6.5 Golimumab 42
6.6 Infliximab 43
7 Analisi della pipeline: dimensioni e analisi del mercato 47
7.1 Panoramica 47
7.2 Fase I 47
7.3 Fase II 51
7.4 Fase III 54
8 regioni: dimensioni e analisi del mercato 66
8.1 Panoramica 66
8.2 Nord America 67
8.2.1 Panoramica 67
8.2.2 US 72
8.2.3 Canada e altri 75
8.3 Europa 77
8.3.1 Panoramica 77
8.3.2 UK 82
8.3.3 Germania 83
8.3.4 Russia e Ucraina 84
8.3.5 Turchia 85
8.4 Asia Pacifico 86
8.4.1 Panoramica 86
8.4.2 India 91
8.4.3 Pakistan 92
8.4.4 Indonesia 92
8.4.5 Thailandia 93
8.5 Resto del mondo 93
8.5.1 Panoramica 93
8.5.2 Messico 98
8.5.3 Brasile 98
8.5.4 Medio Oriente e Africa 99
9 Paesaggio competitivo 100
10 Profilo del fornitore 102
10.1 AbbVie Inc. 102
10.1.1 Panoramica 102
10.1.2 Entrate geografiche 105
10.1.3 Focus aziendale 105
10.1.4 Analisi SWOT 106
10.1.5 Strategie aziendali 106
10.2 Novartis AG 107
10.2.1 Panoramica 107
10.2.2 Unità di business 112
10.2.3 Entrate geografiche 113
10.2.4 Focus aziendale 113
10.2.5 Analisi SWOT 114
10.2.6 Strategie aziendali 114
10.3 Amgen Inc. 115
10.3.1 Panoramica 115
10.3.2 Entrate geografiche 120
10.3.3 Focus aziendale 120
10.3.4 Analisi SWOT 121
10.3.5 Strategie aziendali 121
10.4 Johnson & Johnson 122
10.4.1 Panoramica 122
10.4.2 Business Unit 126
10.4.3 Entrate geografiche 127
10.4.4 Focus aziendale 127
10.4.5 Analisi SWOT 128
10.4.6 Strategie aziendali 128
10.5 Celgene Corporation 129
10.5.1 Panoramica 129
10.5.2 Entrate geografiche 132
10.5.3 Focus aziendale 132
10.5.4 Analisi SWOT 133
10.5.5 Strategie aziendali 133
11 aziende da tenere d'occhio per 134
11.1 Apogenix 134
11.1.1 Panoramica 134
11.2 Celltrion Healthcare 135
11.2.1 Panoramica 135
11.3 Samsung Bioepis Co. Ltd. 136
11.3.1 Panoramica 136
11.4 3SBio Inc. 138
11.4.1 Panoramica 138
11.5 Shanghai CP Guojian Pharmaceutical Co. Ltd. 139
11.5.1 Panoramica 139
Allegato 140
Abbreviazioni 140

Acquista direttamente il rapporto @ https://www.orbisresearch.com/contact/purchase-single-user/3770666

Riguardo a noi:
Orbis Research (orbisresearch.com) è un aiuto unico per tutte le esigenze di ricerca di mercato. Disponiamo di un vasto database di relazioni dei principali editori e autori in tutto il mondo. Siamo specializzati nella consegna di report personalizzati secondo le esigenze dei nostri clienti. Abbiamo informazioni complete sui nostri editori e quindi siamo sicuri dell'accuratezza delle industrie e dei verticali della loro specializzazione. Questo aiuta i nostri clienti a mappare le loro esigenze e produciamo lo studio di ricerca di mercato richiesto perfetto per i nostri clienti.

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Psorilax:Passo dopo passo |creme efficaci per la psoriasi

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Psorilax: prezzo, funziona, recensioni, opinioni, come si usa

MISSISSAUGA 24 febbraio 2020 (Thomson StreetEvents) – Trascrizione modificata di Bausch Health Companies Inc teleconferenza o presentazione degli utili mercoledì 19 febbraio 2020 alle 13:00:00 GMT

* Arthur J. Shannon

Bausch Health Companies Inc. – Vicepresidente senior e responsabile IR e comunicazioni

* Joseph C. Papa

Bausch Health Companies Inc. – CEO e presidente del consiglio di amministrazione

* Paul S. Herendeen

Bausch Health Companies Inc. – Vicepresidente esecutivo e CFO

* David A. Amsellem

* Terence C. Flynn

Evercore ISI Institutional Equities, Research Division – Senior MD & Senior Analyst of Equity Research

Buona giornata e benvenuti alla teleconferenza sui risultati finanziari del quarto trimestre e dell'intero anno 2019 di Bausch. (Istruzioni per l'operatore) Questo evento è in fase di registrazione.

Vorrei ora rivolgere la conferenza a Arthur Shannon, Senior Vice President Investor Relations e Global Communications. Per favore prosegui.

Arthur J. Shannon, Bausch Health Companies Inc. – Senior VP e Head of IR & Communications (2)

Grazie Alicia. Buongiorno a tutti e benvenuti alla nostra Conference Call sui risultati finanziari del quarto trimestre e dell'intero anno 2019. Alla chiamata odierna partecipano il presidente e l'amministratore delegato, Joe Papa; e Chief Financial Officer, Sig. Paul Herendeen. Oltre a questo webcast live, una copia della presentazione di diapositive di oggi e un replay di questa conference call saranno disponibili sul nostro sito Web nella sezione Investor Relations.

Prima di iniziare, vorremmo ricordarti che la nostra presentazione oggi contiene informazioni previsionali. Ti chiediamo di dedicare un momento alla lettura della legenda delle dichiarazioni previsionali all'inizio della nostra presentazione in quanto contiene informazioni importanti. Questa presentazione contiene misure finanziarie non GAAP. Per ulteriori informazioni su queste misure, fare riferimento alla diapositiva 2 della presentazione.

Le riconciliazioni non GAAP sono riportate nell'appendice della presentazione pubblicata sul nostro sito Web. Infine, l'orientamento finanziario in questa presentazione è efficace solo oggi. La nostra politica è in genere di non aggiornare le linee guida fino al trimestre successivo e di non aggiornare o affermare le linee guida se non attraverso una divulgazione pubblica ampiamente diffusa.

Detto questo, è mio piacere consegnare la chiamata a Joe Papa.

Joseph C. Papa, Bausch Health Companies Inc. – CEO e Chairman of the Board (3)

Grazie Art e grazie a tutti al telefono per esserti unito a noi oggi. Rivediamo rapidamente gli argomenti che tratteremo oggi. Inizierò con un breve riassunto dei punti salienti della nostra azienda del 2019 prima di passare la chiamata a Paul Herendeen, il nostro CFO. Paul ci guiderà attraverso i risultati finanziari del quarto trimestre e dell'intero anno e fornirà la nostra guida per il 2020. Esaminerò quindi i punti salienti e i catalizzatori del segmento prima di aprire la linea per le domande.

A partire dalla diapositiva 4. Nel 2019, il nostro tema era quello di offendere o concentrarci sulla promozione della crescita organica nelle nostre attività principali. Ora abbiamo realizzato 8 trimestri consecutivi di crescita organica e il 2019 è stato il nostro primo anno intero di crescita dei ricavi segnalati dal 2015. Bausch Health è cresciuta organicamente del 4% nel 2019 e i ricavi sono aumentati del 3%.

Il nostro più grande segmento, B + L / International, ha realizzato il suo terzo anno consecutivo di crescita organica dei ricavi a metà singola cifra. Per la prima volta Salix ha registrato ricavi per oltre 2 miliardi di dollari per l'intero anno. Abbiamo generato $ 1,5 miliardi di liquidità dalle operazioni. Abbiamo aumentato gli investimenti in ricerca e sviluppo del 14% rispetto al 2018. E abbiamo utilizzato circa $ 1,1 miliardi di contanti per pagare circa $ 900 milioni di debiti e finanziare circa $ 250 milioni di acquisizioni o prodotti di licenza. Il pivot offensivo includeva anche il lancio di nuovi prodotti e la loro crescita, ei nostri nuovi prodotti continuano a crescere.

In primo luogo, dopo il lancio di Thermage FLX nell'Asia del Pacifico, il franchising Thermage ha registrato una crescita organica del 73% rispetto al 2018. Questo eccezionale tasso di crescita ha reso Thermage una delle 10 migliori franchising di Bausch Health nel 2019. LUMIFY ha raggiunto una quota di mercato settimanale di circa il 43% nel 2019, è il prodotto n. 1 raccomandato dai medici nella categoria allevia il rossore.

TRULANCE TRxs è cresciuto del 31% (sic) (30%) anno su anno e abbiamo migliorato la posizione di accesso al mercato per circa 35 milioni di vite da quando abbiamo acquistato il prodotto nel primo trimestre del 2019.

DUOBRII è stato un altro straordinario. I TRx settimanali sono cresciuti del 25% dal terzo al quarto trimestre del 2019 e ora abbiamo raggiunto un accesso commerciale del 63%.

Nel complesso, l'intero team Bausch Health di 22.000 dipendenti ha mantenuto la nostra promessa di commettere reati nel 2019 e ha dimostrato la durabilità della nostra attività, che è cresciuta sia organicamente che attraverso acquisizioni strategiche. Grande sforzo da parte di tutto il team Bausch Health.

Paul ti guiderà attraverso il quarto trimestre e i risultati dell'intero anno in maggiore dettaglio. Quindi, con quello, lo consegnerò a Paul.

————————————————– ——————————

Paul S. Herendeen, Bausch Health Companies Inc. – Executive VP & CFO (4)

————————————————– ——————————

Grazie Joe. Molto da coprire. Proverò ad andare veloce. Buon trimestre e un buon anno. Un approccio leggermente diverso in questo trimestre. Inizierò con la diapositiva 5, un riepilogo delle variazioni delle entrate per segmento e per le principali unità di business sia per il quarto trimestre che per l'intero anno 2019. Successivamente, scenderò dal conto economico di primo livello per il trimestre e fornirò alcune osservazioni su l'intero anno prima di passare alla nostra guida per il 2020.

Un rapido promemoria, quando parliamo di crescita organica, ciò significa escludere l'impatto delle variazioni dei tassi di cambio, l'impatto delle attività cedute e cessate nei periodi dell'anno precedente e l'impatto delle attività acquisite.

Va bene. Diapositiva 5. Nel trimestre, abbiamo registrato una crescita organica del 4% rispetto al quarto trimestre del 2018. Ricordiamo che lo scorso anno abbiamo preso provvedimenti per ridurre le scorte di canali detenute presso i grossisti e che hanno avuto l'effetto di ridurre le entrate del quarto trimestre del 18 di un stimato $ 76 milioni. Quindi questo è un vento in poppa per noi in questo trimestre. Escludendo l'impatto della contrazione delle scorte, abbiamo comunque registrato una crescita organica dei ricavi di livello superiore di oltre l'1%. C'erano molte parti in movimento, ma molte cose buone all'interno di ciascuno dei nostri segmenti.

Cominciamo con Salix in quanto ha contribuito maggiormente alla crescita organica dei ricavi nel trimestre, con un aumento organico del 17% sulla continua forte performance di XIFAXAN, con un aumento del 29%. RELISTOR, in crescita del 29%, e PLENVU hanno anch'essi contribuito alla crescita. Abbiamo perso l'esclusività per APRISO nel trimestre e questo, combinato con la continua erosione generica di UCERIS, ha compensato parte della crescita. Pur non essendo un fattore di crescita organica, le vendite di TRULANCE sono ammontate a $ 18 milioni nel trimestre e i TRx riempiti sono aumentati del 69% rispetto al quarto trimestre del '18. Un trimestre forte da Salix per concludere un grande anno, registrando una crescita organica del 13% delle entrate per l'intero anno rispetto al 2018 nonostante i LOE.

I ricavi del segmento B + L / International sono aumentati organicamente del 3% nel trimestre, guidati da Global Consumer, più il 7% organicamente in forza di LUMIFY negli Stati Uniti e dei nostri marchi globali di soluzioni per lenti a contatto, renu e Biotrue multiuso. Global Surgical ha registrato un aumento organico del 5% nel trimestre in termini di forza nei materiali di consumo per la parte posteriore dell'occhio e le IOL enVista. Global Vision Care ha registrato un aumento organico del 4% nel trimestre in termini di forza nelle lenti mensili in silicone ULTRA idrogel, le nostre lenti AQUALOX Daily SiHy in Giappone e le lenti Biotrue ONEday. La nostra attività farmaceutica internazionale è stata sostanzialmente piatta rispetto al quarto trimestre del '18, mentre Global Ophtho Rx è diminuita organicamente del 2% poiché la crescita di VYZULTA e PROLENSA è stata più che compensata dal declino della famiglia del marchio LOTEMAX a causa dell'erosione generica.

Per tutto l'anno, B + L / International è cresciuta organicamente del 5%, in linea con la nostra convinzione che questo segmento diversificato e duraturo possa offrire nel tempo una crescita a metà singola cifra. Tutte e 5 le business unit di B + L / International hanno registrato una crescita organica dei ricavi per l'anno, guidata da Global Consumer, in crescita organica del 6% in forza di LUMIFY negli Stati Uniti e delle nostre vitamine per gli occhi a livello globale; seguito da Global Vision Care, in crescita organica del 7%, con contributi delle nostre lenti Biotrue ONEday, delle nostre lenti mensili ULTRA e delle nostre lenti AQUALOX Daily SiHy in Giappone.

La nostra attività farmaceutica internazionale è cresciuta organicamente del 5% in forza in Russia, Egitto e Canada. Global Ophtho Rx ha registrato un aumento organico del 2%. A differenza del trimestre, per l'intero anno, la crescita di VYZULTA, PROLENSA e un portafoglio dei nostri marchi oftalmici internazionali hanno superato la resistenza LOE di LOTEMAX. Il segmento Ortho Dermatologics è diminuito organicamente dell'1% nel quarto trimestre del '19 rispetto al '18, poiché la crescita spettacolare nel nostro settore dell'estetica globale, Solta, che è cresciuta del 42%, ha quasi superato il calo del 18% della dermatologia medica.

Nel settore Solta, la piattaforma Thermage è ora saldamente tra i primi 10 prodotti per l'intera azienda e ha contribuito in modo significativo alla crescita dell'intera azienda. LOE ha svolto un ruolo importante nel declino trimestrale del derma medico, principalmente la crema Elidel e Zovirax. Il saldo dei prodotti promossi nel derma medico, tra cui DUOBRII, JUBLIA, SILIQ e BRYHALI, è cresciuto rispetto al quarto trimestre del 2018. È praticamente la stessa storia per il segmento Ortho Derm per l'intero anno, forte crescita da Global Solta, oltre al 45% organicamente per l'anno, più che compensato dal declino della dermatologia medica.

Per l'intero anno, il derm medico è stato il nostro business più colpito dalle LOE, con un calo di $ 121 milioni in meno rispetto al 2018. Tra i lati positivi, JUBLIA è stato uno dei 15 principali contribuenti alla crescita dei ricavi a livello aziendale nel 2019 rispetto al '18. Poiché l'impatto dei LOE è moderato in questo segmento, JUBLIA, insieme ai nostri marchi in fase di crescita, sono DUOBRII, SILIQ e BRYHALI, costituiscono il nucleo del nostro portafoglio di derm medici e le basi per un ritorno atteso alla crescita in questo settore nel 2020.

Infine, il segmento Diversified, che è diminuito organicamente del 5% nel trimestre, in quanto i LOE sono stati un freno di $ 29 milioni sul business neuro. La nostra attività di generici è cresciuta organicamente del 3% nel trimestre con le versioni generiche autorizzate dei nostri prodotti a marchio che hanno perso l'esclusività, principalmente UCERIS, APRISO, LOTEMAX ed Elidel, fornendo la maggior parte di tale crescita. Per l'intero anno, Diversified è sceso organicamente del 5%, poiché la crescita dell'11% del nostro business dei generici ha compensato parte della resistenza alla crescita LOE di $ 116 milioni nel nostro business neuro. I ricavi totali dell'azienda per l'anno sono cresciuti organicamente del 4%, con il 2% derivante dal miglioramento dei prezzi di vendita netti realizzati e il 2% dall'aumento del volume.

Passa alla diapositiva 6, il sommario P&L per il trimestre. Il nostro margine lordo nel trimestre è stato del 71,4%, in calo di circa 20 punti base rispetto al quarto trimestre del 2018, principalmente a causa delle maggiori cancellazioni di inventario nel quarto trimestre del 19 rispetto al trimestre dell'anno precedente. Si noti che per l'intero anno, il nostro margine lordo è stato del 72,7%, favorevole di 80 punti base rispetto al 2018, con un mix di un grande driver, in particolare ha influenzato la crescita di XIFAXAN ma anche dai miglioramenti associati alle nostre attività di Project CORE. La nostra guida finale per l'intero anno per il margine lordo è stata di circa il 73%.

Le spese di vendita e pubblicità nel trimestre sono aumentate – o sfavorevoli su base valutaria costante del 6% rispetto al 4 ° trimestre 2018 a causa dell'aggiunta di TRULANCE al portafoglio Salix e dei maggiori costi di A&P in Vision Care per supportare i nuovi lanci e nel settore farmaceutico internazionale per lancio di prodotti, in particolare in Canada e Russia. Le spese di G&A rettificate su base valutaria costante sono state sfavorevoli dell'8% nel trimestre rispetto al quarto trimestre del '18, a causa dell'aumento del costo delle iniziative di sviluppo aziendale e dei costi IT più elevati in corso mentre continuiamo a lavorare per migliorare i nostri sistemi operativi globali.

Voglio sottolineare che nel quarto trimestre del 2019, il tasso di esecuzione G&A rettificato è – è al di sopra di quello che mi aspetterei in media che il tasso di gestione trimestrale sarà nel 2020. Il tasso di esecuzione G&A rettificato per il futuro è probabilmente tra i 163 milioni di dollari che ha visto nel quarto trimestre e la media di $ 140 milioni nei primi 3 trimestri del 2019. La ricerca e sviluppo è diminuita nel trimestre, favorevole del 5% su base valutaria costante. Non vorrei leggere molto in questo perché è solo il modo in cui i tempi delle spese sono diminuiti in entrambi i periodi. Per l'intero anno, la ricerca e sviluppo è cresciuta del 15% su base valutaria costante a $ 471 milioni, leggermente al di sotto della nostra guida finale del 2019 per ricerca e sviluppo di $ 480 milioni. Ancora una volta, solo il momento in cui sono diminuite le spese. Come vedremo quando arriverò all'orientamento 2020, intendiamo impegnare più capitale nelle attività di ricerca e sviluppo.

L'EBITDA rettificato nel trimestre è stato di $ 898 milioni, in crescita del 5% rispetto al trimestre dell'anno precedente su base valutaria costante. Un trimestre solido che ci ha permesso di registrare un EBITDA rettificato di $ 3,571 miliardi per l'intero anno, che è stato più il 4% su base valutaria costante dal 2018 e appena al di sotto della fascia alta della nostra gamma di orientamento finale per il 2019.

Passando alla diapositiva 7. Penso che valga la pena dare un'occhiata a come abbiamo fatto nel 2019 rispetto al punto medio della nostra guida originale del 2019, che era di $ 8,4 miliardi di ricavi e $ 3,425 miliardi di EBITDA rettificato. Le nostre entrate effettive per il 2019 sono state di $ 201 milioni al di sopra del punto medio della guida originale con un risultato favorevole in funzione di 4 cose: l'acquisizione di TRULANCE ha aggiunto $ 55 milioni; i ricavi delle attività LOE sono stati più di $ 53 milioni; la nostra attività di base è stata favorevole di $ 115 milioni; e compensando le variazioni dei buoni nei tassi FX, i ricavi hanno ridotto le entrate di circa $ 22 milioni.

L'EBITDA rettificato è stato di $ 146 milioni al di sopra del punto medio della nostra guida originale. FX non ha avuto alcun impatto. TRULANCE non ha avuto alcun impatto. Le migliori entrate LOE hanno generato un profitto di $ 36 milioni. Le migliori prestazioni di base hanno aggiunto $ 71 milioni di profitti, mentre gli investimenti in ricerca in R&S e SG&A sono stati entrambi leggermente superiori alla nostra visione originale. Il principale fattore singolo nel miglioramento dell'EBITDA rettificato è stato il nostro margine lordo che si è attestato a 120 punti base meglio di quanto inizialmente previsto, che ha generato un rialzo di circa $ 100 milioni.

Il punto della storia è che con il passare degli anni abbiamo avuto una buona fortuna con gli asset LOE. Ma la maggior parte dei risultati migliori è arrivata dalle nostre unità commerciali che promuovono prestazioni migliori nelle nostre attività di base, dalle nostre attività di Project CORE per migliorare le reti lorde e dai nostri incessanti sforzi per migliorare l'efficienza della nostra catena di approvvigionamento. Un buon anno

Passando alla diapositiva 8, il riepilogo del flusso di cassa. La nostra liquidità netta fornita dalle attività operative nel 2019 è stata di $ 1,501 miliardi, la fascia bassa della nostra gamma prevista in quanto abbiamo aumentato le scorte di alcuni prodotti chiave e API per garantire un'offerta ininterrotta. Tieni presente che alla fine dell'anno avevamo a disposizione $ 3,244 miliardi di liquidità, poiché alla fine di dicembre abbiamo completato un'offerta di $ 2,5 miliardi di titoli non garantiti e non avevamo ancora applicato tali proventi al pagamento del contenzioso statunitense in materia di titoli, ovvero $ 1,21 miliardi, e il pagamento anticipato di altri debiti per $ 1,24 miliardi. Al netto di tali importi e delle relative commissioni, la nostra liquidità operativa a fine anno era di circa $ 750 milioni.

Analogamente, nella diapositiva 9, la liquidità e il debito sul nostro bilancio a fine anno sono gonfiati a causa dei tempi dell'aumento del debito di $ 2,5 miliardi e dell'utilizzo di tali proventi netti. Ci penso così. Pro forma per la distribuzione di tali fondi, il nostro debito netto a fine anno sarebbe stato di circa $ 24,2 miliardi. La risoluzione del caso dei titoli statunitensi ci ha riportato indietro nei nostri progressi riducendo il quanto del nostro debito e migliorando i nostri rapporti di leva finanziaria, ma era assolutamente la cosa giusta da fare per quantificare e risolvere una significativa incertezza a strapiombo.

A parte un attimo, proprio la scorsa settimana, abbiamo iniziato il processo di richiamo di altri $ 100 milioni di capitale in obbligazioni. Intendiamo continuare a ridurre sistematicamente il nostro debito verso il basso.

Un'ultima cosa in bilancio. Durante il trimestre, ci siamo accumulati per la risoluzione del caso di drop of stock negli Stati Uniti, altri casi correlati e contenziosi e indagini in corso. L'accantonamento totale è stato di $ 1,39 miliardi ed è incluso in GAAP Altre entrate e uscite nel nostro conto economico. A scanso di equivoci, escludiamo questa spesa dal calcolo dell'EBITDA rettificato e dell'utile netto adjusted.

Infine, e alle diapositive per me, a partire dalla diapositiva 10, che mostra la nostra guida per il 2020. La nostra guida alle entrate per il 2020 è un intervallo da $ 8,65 miliardi a $ 8,85 miliardi e ciò rappresenta un intervallo di crescita compreso tra l'1% e il plus 3% alle attuali tariffe FX. Le nostre linee guida sull'EBITDA rettificato sono comprese tra 3,5 e 3,65 miliardi di dollari, il che rappresenta un intervallo di crescita compreso tra meno il 2% e più il 2% ai tassi FX correnti.

Voglio coprire gli altri elementi della nostra guida su questa diapositiva prima di parlare di come pensare a tali ricavi e tassi di crescita degli utili per il 2020. Le spese amministrative e amministrative regolate sono state di $ 2,5 miliardi nel 2019 e stiamo guidando a circa $ 2,6 miliardi per il 2020. L'incremento di circa $ 100 milioni o del 4% è superiore a quello che potrebbe essere dato che guardiamo al 2021 e al 2022.

Nel nostro piano 2020, abbiamo razionalizzato OpEx in diverse unità di business, ma abbiamo anche allocato risorse di vendita, pubblicità e promozionali incrementali ad alcune unità per supportare prodotti e prodotti di lancio nelle fasi di lancio, inclusi obiettivi Daily SiHy, LUMIFY, DUOBRII e Thermage. In G&A, stiamo continuando a costruire la nostra organizzazione e infrastruttura IT globale, e questo ha un costo, aumentando i nostri G&A adeguati nel 2020 rispetto al 2019. Mentre avanziamo nel 2021 e nel 2022, dovremmo essere in grado di sostenere la crescita di SGAV inferiore a quello della crescita dei ricavi.

Stiamo guidando a circa $ 500 milioni in R&S per il 2020, in aumento di circa $ 30 milioni dal 2019. Se torni al 2017, il nostro investimento in ricerca e sviluppo è stato di $ 361 milioni. Negli ultimi anni, abbiamo creato l'organizzazione e le infrastrutture di ricerca e sviluppo per supportare un volume maggiore di prodotti per sostenere ciascuna delle nostre attività principali. Ciò include la riduzione dell'intensità di investimento in alcune aree, aumentando nel contempo gli impegni in altre aree in cui eravamo stati sotto-investiti per un certo numero di anni, e in particolare GI, B + L Surgical e Ophtho Rx. Mentre un aumento del 6% in R&S riduce la nostra crescita degli utili e degli utili a breve termine, è la cosa giusta da fare per migliorare le nostre prospettive per realizzare una crescita organica a lungo termine. Per gli interessi passivi, stiamo guidando a $ 1,55 miliardi, in calo rispetto a $ 1,6 miliardi nonostante l'aggiunta di $ 1,21 miliardi di debito per finanziare il regolamento dell'azione di titoli statunitensi.

La nostra aliquota fiscale sugli utili rettificati è stata del 7,8% nel 2019. Prevediamo che tale aliquota sia all'incirca la stessa, all'incirca l'8%, nel 2020. Verso la fine della pagina, notiamo che stiamo guidando le spese in conto capitale nel 2020 di circa $ 300 milioni. In passato, ho affermato che il nostro CapEx allo stato stazionario potrebbe essere compreso tra $ 160 milioni e $ 175 milioni all'anno e che l'aumento nel 2019 è dovuto principalmente agli investimenti in relazione all'iniziativa quotidiana di lenti in silicone idrogel e alla nostra costituzione sistemi IT globali.

Nel corso del tempo, abbiamo stabilito che gli investimenti insufficienti, in particolare nella nostra catena di approvvigionamento, negli ultimi anni richiedono maggiori investimenti nel 2020 e oltre. Riteniamo attualmente che dopo circa 300 milioni di dollari di investimenti nel 2020, probabilmente vedremo diminuire i requisiti di CapEx nel 2021 e di nuovo nel 2022. Il nostro stato stazionario di qualche anno potrebbe essere più vicino a 225 milioni di CapEx all'anno.

Considerazioni potenziali, pietre miliari e accordi di licenza sono stati pari a $ 58 milioni nel 2019 e stiamo guidando a circa $ 100 milioni nel 2020. L'aumento è correlato a una pietra miliare prevista per le vendite su RELISTOR e ai pagamenti relativi ai diritti recentemente acquisiti su XIPERE e NOV03.

Infine, Ristrutturazione e altro. Nel 2019, questi articoli hanno totalizzato $ 52 milioni. Nel 2020, stiamo guidando a $ 75 milioni, sottolineando che questo elemento rappresenta la nostra stima dei costi di ristrutturazione, l'integrazione di alcuni sistemi e il regolamento di casi legali e indagini.

Passando alla diapositiva 11, il ponte dai risultati effettivi del 2019 alla nostra guida per il 2020. Innanzitutto, concentrati sull'impatto LOE. Prevediamo un rallentamento della crescita di $ 275 milioni dal paniere di attività LOE nel 2020. La buona notizia qui è che siamo finalmente vicini a lasciare alle spalle l'impatto del grande secchio di LOE. Nel 27 (sic) (2017) contro il '16, la resistenza alla crescita è stata di $ 486 milioni; nel '18 contro il '17, era $ 289 milioni; nel '19 contro il '18, erano $ 360 milioni. Negli ultimi 3 anni, la nostra crescita dei ricavi è stata trainata da oltre $ 1,1 miliardi di resistenza LOE.

Nel 2020, prevediamo che la resistenza si ridurrà a $ 275 milioni. Ed ecco la parte buona. Ciò si basa sul fatto che realizziamo entrate per il paniere LOE di $ 237 milioni nel 2020. E mentre tale importo diminuirà nel 2021 rispetto al 2020, la resistenza sarà sostanzialmente ridotta. Non abbiamo aggiunto nuovi LOE al paniere LOE nel 2020. E guardando nel periodo dal '21 al '23, prevediamo che l'impatto dei futuri beni LOE sarà abbastanza gestibile.

Le prestazioni di base di oltre 100 – mi scusi $ 415 milioni sono influenzate in modo negativo da alcune cose che ho chiamato durante la nostra ultima chiamata e alcune altre degne di nota. In primo luogo, vi è la parte non ricorrente dei miglioramenti delle reti lorde che abbiamo visto nel 2019, in particolare nel terzo trimestre, che sono un freno alla crescita del 2020. Successivamente, la traiettoria – è la traiettoria di Glumetza. Glumetza era stato un grande performer nei primi 3 trimestri del 2019, prima che ci avvertissimo. È caduto quasi a metà nel quarto trimestre e si prevede che tenderà al ribasso da lì nei prossimi trimestri.

Successivamente, e uno che non avevo precedentemente chiamato per te, abbiamo avuto prestazioni eccezionali nel nostro settore dei farmaci generici nel 2019 con importanti contributi dalle versioni generiche autorizzate di UCERIS ed Elidel. Con il lancio di versioni più generiche di questi prodotti, vedremo un calo significativo delle entrate per le nostre AG nel 2020. Pensa alle AG come a noi che allunghiamo la coda dei marchi che perdono l'esclusività. Va bene, ma sta andando via.

Un altro pezzetto di colore. Le prestazioni di base avrebbero potuto essere migliori, ma la nostra guida include una stima di un significativo vento contrario sulla nostra regione di Asia Pac, in particolare la Cina, associata alla situazione del coronavirus. La nostra guida alle entrate include un impatto di circa 50 milioni di coronavirus. Questa è una stima e vedremo come andrà a finire nel 2020. Ovviamente, ciò ha influito anche sulla nostra guida EBITDA modificata. Pertanto, questi elementi fanno parte del motivo per cui la crescita delle entrate nel 2020 implicita nell'orientamento è compresa tra l'1% e il 3% ai tassi di cambio correnti.

Passando al ponte EBITDA nella parte inferiore della pagina, gli impatti su valuta, LOE e R&S sono autoesplicativi. Nell'ambito delle prestazioni di base, stiamo assorbendo circa $ 100 milioni o un aumento del 4% in SG&A. E l'impatto del coronavirus sulle nostre aspettative di entrate influisce anche sul nostro EBITDA rettificato. Tutti questi elementi insieme sono alla base dei tassi di crescita EBITDA rettificati impliciti che i nostri intervalli di orientamento sono inferiori a quelli del nostro tasso di crescita dei ricavi.

Questo è tutto per me. Di nuovo a te, Joe.

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Joseph C. Papa, Bausch Health Companies Inc. – CEO e presidente del consiglio di amministrazione (5)

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Grazie Paul. Nella diapositiva 12, ci sono molte informazioni, ma il messaggio importante da evidenziare è che ora abbiamo consegnato 3 anni consecutivi di crescita organica delle entrate a metà cifra per B + L / International. B + L / International è cresciuto del 6% nel 2017, del 4% nel 2018 e del 5% nel 2019.

Passando alla diapositiva 13. Global Vision Care è stata una forte performance e voglio evidenziare 2 prodotti che sono stati i driver chiave della crescita in questo settore: le lenti a contatto Biotrue ONEday e ULTRA. Abbiamo mostrato ricavi riportati a 5 anni per ciascuno nel grafico dalla parte inferiore della diapositiva 13. A sinistra, dal 2015 al 2019, le lenti Biotrue ONEday hanno registrato un tasso di crescita annuale composto del 22% e le entrate organiche sono aumentate del 23% nel 2019 A destra, gli obiettivi ULTRA hanno avuto un CAGR del 32% negli ultimi 5 anni e sono cresciuti organicamente del 24% nel 2019. Abbiamo definito le pietre miliari che hanno guidato la crescita incrementale, tra cui il lancio di obiettivi per astigmatismo, presbiopia ed estensione indossare.

Le elevate prestazioni sottolineano la durata di questi prodotti e la forza del marchio Bausch + Lomb. Stiamo assistendo a una maggiore quota di mercato negli Stati Uniti Vision Care. Questa attività ha guadagnato 1,6 punti di condivisione all'11% di quota unitaria per il mese di dicembre 2019 contro una quota del 9,4% a dicembre 2018. Infine, prevediamo di lanciare le nostre lenti giornaliere in idrogel di silicone negli Stati Uniti entro la fine dell'anno. Le lenti in silicone idrogel sono uno dei segmenti in più rapida crescita nel mercato delle lenti a contatto.

Passando alla diapositiva 14 per un aggiornamento su Global Consumer. Voglio evidenziare 2 franchising. In primo luogo, il nostro portafoglio di vitamine dell'occhio più venduto negli Stati Uniti, Ocuvite e PreserVision, è cresciuto organicamente del 4% nel 2019 e ha avuto un CAGR di circa il 7% dal 2015 al 2019. E in secondo luogo, LUMIFY, il primo medico raccomandato dal categoria di alleviamento di arrossamenti, ha registrato vendite per $ 63 milioni nel 2019 e ha raggiunto una quota di mercato settimanale di circa il 43%.

Nella diapositiva 15, abbiamo messo in evidenza le prestazioni di enVista nella nostra attività di chirurgia globale. La famiglia di lenti intraoculari o IOL di enVista sono lenti trasparenti e artificiali che i chirurghi oculari usano per sostituire le lenti naturali di una persona quando diventa troppo torbida a causa di una cataratta. enVista è cresciuto organicamente del 36% nel 2019. Il grafico seguente mostra i ricavi riportati da enVista negli ultimi 5 anni, che sono cresciuti a un CAGR del 22%.

Abbiamo anche lanciato un enVista toric nel 2019, che abbiamo mostrato in basso a destra. Guardando al catalizzatore 2020, prevediamo di lanciare una piattaforma di lenti intraoculari con profondità di messa a fuoco estesa nel 2020. Con l'introduzione di questa piattaforma, entreremo nel segmento IOL premium al di fuori degli Stati Uniti. Infine, prevediamo di lanciare una IOL precaricata piattaforma iniettori per IOL enVista nel secondo trimestre del 2020.

Passiamo ora alla diapositiva 16. Prima di esaminare i punti salienti di Salix, desidero esaminare 2 aggiornamenti.

In primo luogo, dopo aver esaminato il nostro portafoglio IG alla luce delle opportunità di mercato, abbiamo deciso di aumentare l'attenzione promozionale su XIFAXAN e TRULANCE e abbiamo interrotto la promozione di DOPTELET e LUCEMYRA. Inoltre, abbiamo recentemente ricevuto la notifica che Norwich Pharmaceuticals ha presentato un ANDA per compresse rifaximin da 550 milligrammi. Alfasigma e Bausch Health presenteranno denuncia contro Norwich, sostenendo la violazione di brevetti e scateneranno un periodo di approvazione di 30 mesi. Rimaniamo fiduciosi nella forza dei 23 brevetti che coprono XIFAXAN e continueremo a difendere vigorosamente la nostra proprietà intellettuale.

Il grafico a destra mostra la crescita di XIFAXAN TRx negli ultimi 9 trimestri. Come puoi vedere, TRxs è cresciuto del 7% dal 2017 al 2018 e dell'8% dal 2018 al 2019. In particolare per IBS-D, TRxs è cresciuto del 15% nel 2019 rispetto al '18.

Passando ora a RELISTOR, TRxs è cresciuto del 6% nel 2019. E a partire dal 2020, abbiamo recentemente migliorato la posizione di accesso al mercato orale di RELISTOR per oltre 50 milioni di vite.

Finalmente TRULANCE. I TRx sono cresciuti di oltre il 30% nel 2019. E dall'acquisizione, abbiamo migliorato la posizione di accesso al mercato per circa 35 milioni di vite. Stiamo registrando progressi nel mercato a marchio IBS-C, in cui la nuova quota di mercato di TRULANCE Rx è cresciuta – dal 3,9% al 6,4% nel 2019.

Alla diapositiva 17, Ortho Dermatologics. In primo luogo, DUOBRII TRx è aumentato del 25% nel quarto trimestre rispetto al terzo trimestre, e siamo molto soddisfatti di questo lancio. Come mostrato nella tabella in basso a sinistra, entro 2 quarti dal lancio, DUOBRII sta catturando circa il 40% dei nuovi pazienti che iniziano con un prodotto di psoriasi topica o orale con marchio di prima linea. Quando si guarda DUOBRII contro questi 3 concorrenti elencati, riteniamo che offra una prospettiva sull'opportunità di DUOBRII e sui potenziali risparmi che potrebbero derivare dal ritardare la necessità di iniziare i pazienti con un trattamento biologico.

Inoltre, sono lieto di dire che DUOBRII è ora al 63% di accesso commerciale per gli Stati Uniti. E guadagniamo – man mano che otteniamo una copertura incrementale, prevediamo di ridurre il supporto dei coupon e prevediamo che le reti lorde miglioreranno nel tempo. È importante sottolineare che il prezzo medio di vendita è aumentato dal terzo trimestre e abbiamo chiuso l'anno con un ASP più elevato. Ci stiamo chiaramente muovendo nella giusta direzione. Siamo molto entusiasti dell'opportunità per DUOBRII, principalmente perché, per la prima volta, possiamo offrire ai pazienti con psoriasi un prodotto topico con un corticosteroide ad alta potenza che possono trattare fino alla clearance piuttosto che essere limitati per un certo periodo di tempo.

Passando ora a SILIQ. TRxs è cresciuto del 100% nel 2019 rispetto all'anno precedente e abbiamo raggiunto un accesso commerciale del 67%. I BRXHALI TRx sono aumentati del 60% nella seconda metà del 2019 rispetto alla prima metà e BRYHALI ha ora un accesso commerciale del 71%. Riteniamo che tassi di accesso dal 60% al 70% dimostrino che l'assistenza gestita riconosce il valore e l'efficacia dei nostri prodotti per la psoriasi nel contribuire a migliorare la vita dei pazienti.

A destra, evidenziamo un nuovo modello di pagamento in contanti per i nostri prodotti di dermatologia su prescrizione negli Stati Uniti, ora disponibile online su Dermatology.com. Telemedicina ed e-commerce sono disponibili sulla piattaforma da ieri. Prodotti iconici come Retin-A saranno disponibili su Dermatology.com e nuovi prodotti come ALTRENO. La piattaforma è stata lanciata con un portafoglio di 15 prodotti e prevediamo di espandere il numero di prodotti con pagamento in contanti nel tempo. Riteniamo che Dermatology.com abbia il potenziale per soddisfare le esigenze dei pazienti e contribuire a far crescere la nostra attività in dermatologia.

Passando alla diapositiva 18. La nostra attività estetica, Global Solta, è cresciuta organicamente del 42% nel quarto trimestre del 2019 rispetto al quarto trimestre del 2018 e del 45% nell'intero anno, guidata dall'espansione globale di Thermage FLX. Thermage è una terapia a radiofrequenza non invasiva che può affrontare la scienza dell'invecchiamento della pelle. Puoi vedere la tendenza nel grafico a sinistra con un CAGR del 46% dal 2017. Guardando al 2020 oltre, prevediamo di vedere una continua espansione globale per Thermage FLX, compresa l'espansione geografica nell'UE.

Nella diapositiva 19, puoi vedere che abbiamo un buon numero di programmi di sviluppo in fase avanzata in ciascuno dei nostri 4 segmenti di business. Abbiamo aumentato gli investimenti in R&S nel 2019 rispetto al 2018 e abbiamo assegnato una percentuale maggiore del nostro budget in R&S a Bausch + Lomb e Salix su base annuale. Il lancio di nuovi prodotti guiderà la nostra crescita futura e siamo lieti di avere una pipeline attiva in fase avanzata di nuovi programmi innovativi con il potenziale per espandere il nostro portafoglio di salute degli occhi, IG e dermatologia.

Ho parlato di alcuni dei programmi lungo la strada, ma voglio evidenziarne un paio in modo più dettagliato. Prima di passare alla Slide 20, all'inizio del 2018, abbiamo identificato i Significant Seven come fattori chiave per la crescita futura. Questi 7 prodotti sono cresciuti collettivamente del 68% nel 2019. Mentre siamo soddisfatti di quella crescita, limitandoci a 7 prodotti ed escludendo prodotti di crescita come Biotrue, ULTRA, PreserVision, enVista IOL, Thermage, Aplenzin, TRULANCE e XIFAXAN non ci dà quadro completo dei driver attesi della nostra crescita futura delle entrate. Di conseguenza, continueremo a registrare i ricavi per i nostri primi 10 prodotti per ogni azienda e in generale per Bausch Health, ma non segnaleremo più i ricavi combinati per i Significant Seven.

Let's turn to Slide 20 for additional detail on our promising late-stage programs in GI and eye health. Amiselimod is a late-stage oral compound that targets the S1P receptor, which plays an important role in autoimmune diseases such as inflammatory bowel disease. Approximately 1.6 million Americans currently suffer from IBD and as many as 70,000 new patients are diagnosed in the U.S. annually. We entered into an exclusive licensing agreement with Mitsubishi to develop and commercialize amiselimod in April 2019.

In January 20, we completed an FDA-approved cardiovascular clinical trial protocol that compared amiselimod to placebo and moxifloxacin. The primary endpoint demonstrated that amiselimod had no effect on QT interval prolongation and no other secondary safety signals were identified. We expect to initiate a multi-arm, randomized, placebo-controlled Phase II study in 2020 in ulcerative colitis for amiselimod.

On Slide 21, we highlight NOV03, which we recently licensed in for the U.S. and Canada. NOV03 is a nonaqueous eye drop for the treatment of Dry Eye. The prescription Dry Eye market represents a great opportunity with 6.8% of the U.S. adult population projected to have diagnosed Dry Eye disease, and prevalence will increase with age.

If approved, NOV03 will be the first new prescription treatment for Dry Eye disease with a mechanism of action that is different from currently available products. A Phase II study has already been completed, which showed significant and clinically meaningful improvements in both signs and symptoms of Dry Eye disease. There's a Phase III study underway, and we expect to initiate a second Phase III study later this year.

To wrap up, on Slide 22, we have provided an overview of the 2020 vision for our 3 core businesses which includes both a look back and what has driven performance and a look ahead to what is coming into focus for 2020.

First, Bausch + Lomb. We expect mid-single-digit growth to continue for 2020 based on 5 years of organic revenue growth for ULTRA, Biotrue and Ocuvite and PreserVision and new products like LUMIFY and VYZULTA. Looking ahead, we see significant opportunities in the SiHy launch in the U.S., in EU and the rest of the world, the ramp-up of our enVista IOL platform and the expected launch of an extended depth of focus for the IOL platform.

Next, in Salix, while absorbing the headwinds from APRISO and Glumetza in 2020, our GI business will be based on 2 years of high single TRx growth for XIFAXAN, increased market share for TRULANCE and double-digit growth driven by market access for our RELISTOR oral business. In 2020, we are planning to look forward to also PLENVU ramp-up, continued development of new formulations and indications for rifaximin and pipeline expansions, including dolcanatide and amiselimod.

Third, Ortho Dermatologics, we expect this business to return to growth in 2020 based on a 73% organic revenue growth for Thermage franchise, weekly DUOBRII TRx growth and increased commercial access, driving improved gross-to-nets and the continued ramp of launch products, including SILIQ, BRYHALI and ALTRENO.

Looking ahead, we seek opportunity in building out the cash pay model with more products, telemedicine and e-commerce and the launch of ARAZLO. Finally, we continue to expect to deliver on our 3-year CAGRs on a constant currency basis. And for the midpoint of 2019 guidance, we expect revenue to grow at 4% to 6% CAGR and adjusted EBITDA to grow at 5% to 8% CAGR.

With that, operator, let's open up the line for questions.

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Questions and Answers

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Operator (1)

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(Operator Instructions) The first question today comes from Terence Flynn of Goldman Sachs.

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Terence C. Flynn, Goldman Sachs Group Inc., Research Division – MD (2)

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Maybe 2 for me. Just wondering, at a high level, what's embedded in your 2020 guidance for net pricing across the portfolio. How that compares to 2019?

And then on SiHy, the launch in Japan. I was wondering any details you can share on market share. And then how we should think about pricing and positioning as you approach the U.S. launch?

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Joseph C. Papa, Bausch Health Companies Inc. – CEO & Chairman of the Board (3)

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Okay. Let me start on our pricing — net pricing. Our expectation is that we'll have somewhere in that 2% range, approximately. That's very consistent with what we saw in our 2019 information. Net pricing was approximately 2%. We expect it to be something comparable to that. Now there will be some variation between the product A and product B, but on balance there.

In terms of the SiHy market share, again in Japan, we're pleased with our initial launch in Japan. There were some issues that we had to deal with as we launched a new product, but on balance, we're pleased with what we've seen in terms of that launch. And as Paul said in previous quarters, importantly, as we looked at the Japan market, we believe the SiHy market as a percentage of Japan is about 15% and is growing by about 31%, so — the SiHy market that is. So we think it's an important contributor to growth and will be an important contributor for a long time and also as we launch here in the U.S. later this year. The U.S. is a little smaller percentage of total market in the U.S. It's less than, I think, 13%, but we also see it growing quickly. So we're excited about what that means for us.

We probably aren't going to say anything about pricing yet on the SiHy Daily, but I think you can think that will be competitive with the other products out in the marketplace in the U.S. SiHy Daily business.

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Operator (4)

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(Operator Instructions) The next question comes from David Amsellem of Piper Sandler.

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David A. Amsellem, Piper Sandler & Co., Research Division – MD & Senior Research Analyst (5)

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I wanted to focus on XIFAXAN. And looking at the IQVIA retail data is in January, it looks like the growth trajectory of prescriptions is a little more muted compared to 2019. So I'm wondering if there's any indication that the franchise is maturing in any way. And how should we think about the trajectory of volumes for both IBS and AG as we move more into 2020?

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Joseph C. Papa, Bausch Health Companies Inc. – CEO & Chairman of the Board (6)

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Sicuro. I'll start with that one. We always see some normal variation in the early year, especially as patients have the donut hole questions and different reimbursement challenges as we start the year. So we don't see anything specifically happening there that is unusual relative to what we've seen in the past.

I think as you think about trajectory, I mean if you — one of the comments I made was talking about XIFAXAN specifically relative to IBS-D. I remind you that within IBS-D, we were growing, I think, it was mid-double digits. Somewhere around 15%. And importantly, we believe the opportunity there is still very significant for us with XIFAXAN.

Remember that the IBS-D category, for example, has about 9 — I'm sorry, has about 12 million antispasmodic prescriptions. And as we've looked at that, we're less than, let's call it, 10% of that business. Therefore, we believe we've got a great product for IBS-D patients, where, with an episodic treatment, you can potentially get these patients to just move off of these products like the antispasmodics like BENTYL dicyclomine and actually get relief from — long-term relief for use of XIFAXAN. So we're going to continue to promote that area, and we continue to expect to see that growth going on into the future to be clear.

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Operator (7)

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The next question comes from Ken Cacciatore of Cowen and Company.

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Kenneth Charles Cacciatore, Cowen and Company, LLC, Research Division – MD & Senior Research Analyst (8)

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Congratulations on all the progress. I know from time to time, you're asked about splitting or selling some of the businesses. But I was wondering, as you get more credit for your performance and the underlying value of all the entity and everything that you're doing, your equity is clearly responding. So I just wanted to know, strategically, how do you view your equity? Is this something that you would think about using to deleverage? Is it something you're thinking about in terms of maybe larger acquisitions? Just wanted to get your thoughts on that.

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Paul S. Herendeen, Bausch Health Companies Inc. – Executive VP & CFO (9)

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Sì. Thanks for the question, Ken. It's Paul. Sì. Our equity has responded. It kind of opens the door to potentially using that equity in some way. I'd say that, for now, I mean, we have a great deal of runway to continue to run our businesses and using equity to reduce our leverage and just be — based on the quantum of our debt and what it would take in order to make a meaningful change, probably not the path we go down.

Now using equity in the context of a value generative transaction, obviously, would have to be the right transaction and something we were incredibly excited about, but we would indeed consider that. I want to touch on because it's interesting. We haven't heard the question as often about splitting the company up over the last, I'd say, several months as the stock has performed better. But I think when you look longer term, the trend — the overall trend in financial markets is for a preference on the part of investors for pure plays. And we own a bunch of great businesses that are today together, and I think that they are stronger — we are stronger with those businesses together today in light of our capital structure.

But as we look down the road, some day down the road, there may be opportunities to pursue more pure plays with respect to one or more of our businesses. But that's just something that's down the road.

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Operator (10)

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The next question comes from Umer Raffat of Evercore.

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Umer Raffat, Evercore ISI Institutional Equities, Research Division – Senior MD & Senior Analyst of Equity Research (11)

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I have 2, if I may. One for you, Joe — maybe both for you, Joe. Okay. So you clearly characterize the pivot to be offense and the EBITDA growth of 5% to 8%. But in light of the guidance for this year and in light of our raising investor debate on whether the base business is truly a growth business in the first place, I'm curious, do you feel strongly that the 5% to 8% CAGR is achievable? Especially this year, tracks at the midpoint of the guidance?

And secondly, I was very curious about the S1P1 press release you guys put out in January, not only because I could still never find the trial online anywhere. So I was curious where it was actually done. And — but also, it seemed to me that the issue with the drug was cardiovascular adverse events and not exactly a QT signal. So I was curious that FDA asked you to do a QT study as a clearing event for larger trials.

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Joseph C. Papa, Bausch Health Companies Inc. – CEO & Chairman of the Board (12)

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Okay. So I'll start on the first part of the question of what we're thinking about pivot to offense and guidance, but I'm going to also turn it over to Paul who's worked his way through that. And then I'll comment on the S1P modulator.

So the simple answer to your question on the CAGRs, are we confident? The answer is yes. We continue to look at that revenue guidance of 4% to 6% growth and then the 5% to 8% on the EBITDA as something that is achievable, and I'm going to let Paul comment more about that specifically. But the simple answer is yes. And Paul, do you want to make some specific comments, and then I'll come back on the amiselimod?

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Paul S. Herendeen, Bausch Health Companies Inc. – Executive VP & CFO (13)

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Yes, sure. I mean — and thanks for the question because we — Umer, because we do get this question a fair amount. Joe said in his remarks, so let's refresh what we meant when we said 4% to 6% and 5% to 8%. It was off the midpoint of our original 2019 guidance at constant currency. If you adjust that, you would could come up with a range of targets for 2022 in order to meet that CAGR in the range of, say, circa $9.4 billion to $9.95 billion in revenue, $3.9 billion to $4.29 billion for adjusted EBITDA. Yes, we continue to believe that we can and will produce revenue and adjusted EBITDAs in that range. I mean, that's our current belief. Obviously, not a forecast or a bit of guidance that we take lightly. It is fully supported by our bottoms-up long-term view of what we think we can do with each of our businesses.

I want to point out because people lose sight of this, and say it was off the midpoint of 2019 guidance. I spent some time in my prepared remarks talking about how we did in 2019 relative to that original midpoint. We did better so that helps us along the road. I think people are going to look at our revenue — forecast revenue off of our guidance range of plus 1% to plus 3% and adjusted EBITDA minus 2% to plus 2%, say, gee, you're not on track. And say, first of all, we've said this a million times, it's not linear. And we are focused on where we need to be in 2022 in order to be able to achieve those targets that we set for ourselves, and we remain confident that we can achieve those targets.

The good news is we had a great 2019. The bad news is part of that was through LOEs that continued on. We're delighted to have earned the profit and have generated the cash from those LOEs, but that goes away. And so that's a bit of a growth track for us in 2020. Net-net, we are on track.

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Joseph C. Papa, Bausch Health Companies Inc. – CEO & Chairman of the Board (14)

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On the second part of your question, Umer, on the S1P modulator, amiselimod, the trial that we did was an FDA-approved protocol that we had gone and had the FDA approve the protocol. So we had that in place. We wanted to solve that question or answer that question so that we were assured that there was no QT elongation issue. As you know, other products in this category have had that problem. And we wanted to make sure that, that was not going to happen with this product.

We had belief that it wasn't, but we finished — we wanted to finish the definitive trial for amiselimod to get to that answer. So that is the reason we did it. There was no request or anything. It was just — we had asked and had that as part of the information that we acquired when we received the product from Mitsubishi on amiselimod. So I think that answers that part of the question.

On the rest of it, we will publish this trial. It has not been published yet, but it will be published and presented in a poster session in the not-too-distant future. And I think that was the other part of the question.

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Operator (15)

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The next question comes from Gregg Gilbert of SunTrust.

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Gregory Daniel Fraser, SunTrust Robinson Humphrey, Inc., Research Division – Research Analyst (16)

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It's Greg Fraser on for Gregg Gilbert. On XIFAXAN, can you comment on payer coverage for the IBS indication and whether there's any room for improvement there? And can you also please comment on your initiatives to drive higher growth for the HE indication?

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Joseph C. Papa, Bausch Health Companies Inc. – CEO & Chairman of the Board (17)

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Sicuro. We have very strong coverage for XIFAXAN. Overall, it's 98.7%. HE is a little bit stronger, but at that level, it's essentially universal coverage. I mean, we've got very strong coverage on XIFAXAN. There is some variation from plan A to plan B, but we're very pleased with that.

On the question of HE, our view is that we are going to continue to try to improve the compliance and adherence to the product. We have great data that says that if a patient stays compliant with XIFAXAN, you can reduce rehospitalization for hepatic encephalopathy. And if we're able to do that, obviously, we could save the healthcare system a tremendous amount of dollars. So that's our plan and our focus, and we continue to go out and share that data with plans so that they can help lower the cost.

Our fundamental belief, though, is that as healthcare plans, and there's mergers where the medical and the pharmaceutical comes together, we believe we're going to have even more traction on that as we look at the opportunity to not only lower the total cost of the patient from the point of view of both the drug cost and the cost of rehospitalization, et cetera.

So that's our plan, and that's how we've been working on it. We think it's going to be important for patients going into the future with hepatic encephalopathy. And you may recall from our previous comments, we're even looking at trying to get to some of these patients before the actual hepatic encephalopathy by going after some clinical trial evidence that we see in patients who have cirrhosis. So a lot more work. Stay tuned to that for the future.

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Operator (18)

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The next question comes from Jason Gerberry of Bank of America.

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Jason Matthew Gerberry, BofA Merrill Lynch, Research Division – MD in US Equity Research (19)

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So a quick question on XIFAXAN. I think previously, in September, you communicated around a 10% to 12% range of growth with minimal contribution from Project CORE. I just wanted to confirm if that's still the fundamental outlook.

And then just on the Significant Seven, is the change in disclosure more or less, hey, this isn't indicative of our broader pipeline value? Or is there a diminished outlook as it pertains to the $1 billion target end of 2022?

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Joseph C. Papa, Bausch Health Companies Inc. – CEO & Chairman of the Board (20)

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Paul, why don't you take the first part of that?

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Paul S. Herendeen, Bausch Health Companies Inc. – Executive VP & CFO (21)

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Sì. Sì. On the first part of that, I think what we said was we kind of continue to believe that XIFAXAN would — in 2020 versus 2019 that the way — best way to forecast that would be to think about TRxs in growth and use as a proxy for unit growth. And I think we continue to believe that, that can be in the high single digits. And to that, you need to add a couple hundred basis points of net price increase. And the reason it's only a couple hundred basis points is that nonrecurring part of the revenue that we saw in 2019 related to the nondurable part of the improvements in gross-to-nets. Some of it is reflected in absolutely improved net selling price increases that we've realized in '19, but some of it is — it just goes away and becomes kind of a growth headwind.

So net-net, I think we pretty much said high single-digits units and a couple hundred basis points of growth, so circa 10%.

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Joseph C. Papa, Bausch Health Companies Inc. – CEO & Chairman of the Board (22)

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On the second part of your question on Significant Seven, the way we looked at it is if you go back historically, in 2018 — early 2018, we identified 7 products that we felt were the key growth drivers for us. And as we thought about that, we had great success. This year, it was up 68%, achieved $269 million and expect to see it continue to grow to be clear going forward.

But what we felt is that that's going to leave out some really important growth drivers like XIFAXAN, like TRULANCE, like Thermage, like Biotrue, ULTRA, PreserVision, enVista, Aplenzin. And we really came up with a group of not 7, but actually, I could be fair to say, so close to 15 products that are clear drivers for our future. Now we're not going to comment specifically about those. But my point was that there are some big opportunities there for the future relative to where we saw the future of this business.

And specifically, you get a product like XIFAXAN, our largest product growing double digits, it really is a meaningful contributor. And you can't leave that out of the equation as you're thinking about the future for our business. So that was really the issue. It was — no concerns about our expectations for the future on that one.

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Operator (23)

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The next question comes from Chris Schott of JP Morgan.

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Christopher Thomas Schott, JP Morgan Chase & Co, Research Division – Senior Analyst (24)

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Maybe — first question was maybe one for Paul and just following up with the potential for a split and some of those comments you made on investor appetite for pure plays. I think you mentioned that's a trend to think about down the road. But just maybe a little more color on what you'd need to see to enable a split. Is this simply just a matter of getting leverage to a lower level? Or is there something fundamentally we need to think about in the businesses before you would consider maybe separating out into individual kind of units as compared to the portfolio you have today?

My second question was just a quick one on the second XIFAXAN filer. Just any color about this filer relative to Sandoz as you think about the defense of that franchise over time?

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Paul S. Herendeen, Bausch Health Companies Inc. – Executive VP & CFO (25)

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Sì. Chris, thanks for the question. I'll obviously take the first one. Leverage, I would say our level of leverage today is a — makes — it would make it challenging to pursue something where we spin out one of our entities or whatever. It's not impossible, but it would make it a fairly significant challenge. That is the primary thing that we'd sit there and say, it becomes more clear for us with the passage of time. And again, I don't think I'm saying anything here that's groundbreaking.

A pure play is a thing. I mean, people love pure play. We get it. We own businesses that are very attractive and very attractive in their own right. As we're sitting here today and for the near term, we continue to believe that we are, based on our cap structure, stronger together. And we'll continue to evaluate opportunities for providing that pure play as we go forward.

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Joseph C. Papa, Bausch Health Companies Inc. – CEO & Chairman of the Board (26)

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On the second part of your question, new XIFAXAN filer, as I mentioned in my comments, that company is Norwich. My understanding, although we don't have all the information yet, is they filed specifically on both the IBS-D and HE. Our belief is that we have 23 patents. So when we initially settled with the largest generic company, Teva, we had 22 patents. We have now supplemented that with another patent. So we have 23 patents. So we feel very strong about our intellectual property position relative to this filing. And we don't see anything specifically different from this — from what they filed versus what Teva filed.

So we continue to believe we've got a strong intellectual property position. So no other specifics — any differences that we've observed.

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Operator (27)

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The last question comes from Akash Tewari of Wolfe Research.

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Akash Tewari, Wolfe Research, LLC – Director of Equity Research & Senior Research Analyst (28)

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So look, if we take into account the $275 million LOE impact, the roughly $160 million kind of inventory true-up accrual benefit you had in 2019 that we might not necessarily carry over, it looks like you need over $500 million in new product sales year-over-year to kind of hit the midpoint of your guidance on reps. Can you walk us through where that growth is coming from?

I'm assuming maybe like $150 million is on XIFAXAN, but what's the contribution on the Significant Seven? What's the contribution on Thermage, et cetera, et cetera? Any color would be really appreciated.

And then just a bit on the cash flow. There was a bit of dip in Q4. I'd love a bit more color on what happened. And then how we should think about it in 2020. It looks like your 2020 cash flow from operations is $1.5 billion, which is a bit lower than what I had expected. So if there's any color on that, we'd really appreciate it.

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Joseph C. Papa, Bausch Health Companies Inc. – CEO & Chairman of the Board (29)

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Okay. I'm going to start, but Paul — we're going to — there were quite a few questions there. We're going to have to take pieces here.

I think the fundamental first question is, where can we grow and how can we grow in 2020 and beyond? And what I would simply go back to is that as we look at our business, we think the overall B + L/International business is going to grow at that mid-single-digit rate. I think your characterization of XIFAXAN growing ballpark 10%, I think that's a fair characterization. Solta, I think you saw the growth that we experienced with Solta in 2019. We clearly think that, that's a great opportunity. And then the final area I'd say is the derm returning to growth is a really important message. If you think about our business, the B + L business, the Salix business have been important to us, but we've had a headwind with dermatology.

As that dermatology grows, especially with some of the new programs, new products like DUOBRII plus the Derm.com — Dermatology.com contribution to our business, we think are all going to be important parts of that growth for the future. And obviously, we got less LOEs versus we had in the past. But Paul, anything you want to add to that portion or talk a little bit about cash flow with them?

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Paul S. Herendeen, Bausch Health Companies Inc. – Executive VP & CFO (30)

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Well, sure. I mean, I actually — I do want to talk about the kind of the growth, where is it going to come from. First is, I think you stated a number on the kind of an inventory issue that was well above what it really was. In 2019, the '18, the aggregate amount that it was kind of a onetimer, if you will, of us taking those wholesale inventories down was $76 million. A big number in the quarter, a couple of hundred basis points of volume growth that was based on that relative — basically what was a relative expansion, although it was not an expansion at all. And for the year, yes, it was also baked into our year versus 2018, but not as big a factor on a total revenue base of $8.6-odd billion.

If you look at the bridge on Slide 11 of our presentation, that $415 million of increase in coming from what we call base performance is obviously net of any pipeline things that would have come up. So that bridge shows you, I think, how we will get to in the aggregate at a company-wide basis, how we'll get to within our revenue guidance.

With respect to cash flow, I mean, I don't want to start with 2019 because, as I said in my prepared remarks, we were at $1.501 billion. So just at the low end of our guidance range. And to be super clear, that is for cash generated from operations, and that's on a GAAP basis.

The primary difference between us at being $1.5 billion and being $1.55 billion or $1.6 billion was that we did at the end of the year have more inventory than we had perhaps been thinking about when we started the year. And that was based on specific decisions that we took to increase inventories, both finished goods and of API for key products to ensure that we had consistency of supply. You'll get our balance sheet later this year. You'll see the increase in our inventory at the end of the year, and that was a primary driver.

Looking ahead to 2020, we have all the factoids that you essentially need to make — come up with a forecast for cash flow from ops. You've got our adjusted EBITDA from the guidance range. You've got our interest expense. You've got restructuring and other. You've got recent milestones and license agreements. You have a pretty good idea what our taxes will be based on our guidance there. And the 1 wildcard is working capital. We will grow in 2020, 2019. And accordingly, that growth, if you assume we're currently at the right level of adjusted working capital, which I would comment on in a minute, that you would add some working capital.

So you'll do that math and you're going to come out somewhere near $1.5 billion. That's the way the math works out. I mean, the pieces that you can't see or can't forecast as well as we can is the interaction or the impact of accruals and other things that are very difficult to forecast. But I think the length — the $1.5 billion will be consistent. I mean, interesting if you look at the history, in 2018, it was $1.501 billion. In 2019, it was $1.501 billion. And we're guiding to $1.5 billion in 2020. It's what we expect today. It could be more than that, but we'll just have to wait and see how that year plays out.

On my last comment, I said about inventory and working capital. I want to provide additional texture. Over time, we are going to drive our inventory balance down. We made some progress, and we've now taken some strategic steps that have moved us in the opposite direction. Longer term, we will be able to unlock cash from our balance sheet by better managing our inventory balances. It's — we're not seeing it in 2019. And I'm essentially telling you we're not going to see it in a significant way in 2020. Stop there.

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Joseph C. Papa, Bausch Health Companies Inc. – CEO & Chairman of the Board (31)

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Okay. Let me just thank everyone for joining us, and we'll see you soon as we will be on the road for the next few months at the various healthcare conferences. Thank you, everyone, for joining. Have a great day, everyone.

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Operator (32)

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The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

Psorilax:Cura |nizoral crema psoriasi

0

Psorilax: prezzo, funziona, recensioni, opinioni, ingredienti

Bene, si scopre che non solo abbiamo bisogno di alimenti ricchi di nutrienti per avere corpi sani, ma dobbiamo anche mangiarli per capelli sani. Mentre le pubblicità televisive ti dicono che una formula speciale in un certo tipo di shampoo o olio lo farà, mangiare vitamine è l'opzione migliore per una crescita più rapida dei capelli. È molto più facile da integrare nella tua routine (a meno che tu non sia un orso in letargo che non mangia quotidianamente).

Che aspetto ha una dieta ricca di nutrienti? Dovrebbe essere composto da tutte le 13 vitamine essenziali che possono aiutare a mantenere la salute dei capelli. Le vitamine essenziali includono vitamina A, C, D, E, nonché il gruppo del complesso B.

Ci sono alcuni avvertimenti quando si tratta di una crescita più rapida dei capelli. Inutile dire che non esiste un trattamento “taglia unica per tutti” per la caduta dei capelli. Se il tuo bestie può far crescere i capelli più velocemente di te, non significa che dovrebbe essere lo stesso per te. In secondo luogo, nessuna prova supporta l'idea di singole vitamine che incoraggiano i capelli a crescere più velocemente.

Il segreto per risolvere ENTRAMBE questi problemi è includere una combinazione di aggiunta di integratori e regolazione della dieta per garantire che includa le giuste dosi di nutrienti essenziali come il ferro. I ricercatori hanno condotto una serie di studi su come le vitamine D ed E potrebbero supportare la crescita dei capelli, insieme alle vitamine del complesso B. Quando non mangi queste vitamine, le carenze causano la caduta dei capelli, quindi è importante consumarne abbastanza per ridurre la possibilità di perdere i capelli.

Quanto tempo ci vuole per vedere i risultati dalle vitamine dei capelli?

Prima di iniziare, sappi che possono essere necessari circa 3 mesi per iniziare a vedere i risultati o fino a 6 mesi per vedere i risultati completi. Infatti, potresti riscontrare carenze nel presentarsi come spargimento eccessivo. Ma poi quando le cellule ciliate iniziano a crescere con buone vitamine, di solito inizierai a vedere i risultati entro 6-12 settimane, che è il periodo di tempo di un ciclo di crescita naturale dei capelli.

In questo articolo, forniamo informazioni sulle migliori vitamine per capelli per una crescita più rapida dei capelli per prevenire il diradamento e la caduta dei capelli.

Le migliori vitamine per capelli per una crescita più rapida dei capelli:

Vitamina A

Tutte le cellule del corpo hanno bisogno di vitamina A per la crescita, compresi i capelli. La vitamina A, è una vitamina di fondamentale importanza per la salute dei capelli.

La vitamina A aiuta anche le ghiandole della pelle a produrre sebo che è una secrezione oleosa della nostra pelle che idrata il cuoio capelluto e mantiene sani i follicoli piliferi. Il sebo favorisce la circolazione dell'ossigeno sul cuoio capelluto e rafforza i follicoli piliferi migliorando la crescita dei capelli e prevenendone la rottura. Non sorprende quindi che una carenza di vitamina A possa portare a A) capelli secchi e B) perdita di capelli.

Tuttavia, una recensione del 2017 ha mostrato che l'assunzione di quantità in eccesso può avere effetti negativi, inclusa la perdita di capelli. Quindi, consuma solo la quantità raccomandata perché di più non è meglio quando si tratta di vitamina A.

Gli alimenti ricchi di vitamina A includono: carote, zucca, patate dolci, spinaci, olio di fegato di merluzzo, peperone rosso dolce, piselli dagli occhi neri, albicocche, cavolo e cavolo, mentre prodotti animali come latte, uova e yogurt inoltre sono ricchi di vitamina A.

Vitamina B7

La vitamina B7 o la biotina scompone le proteine ​​per espellere gli aminoacidi essenziali per rafforzare i capelli. Carenze di biotina o vitamina B7, in particolare, possono portare alla caduta dei capelli. Secondo una recensione del 2019, i ricercatori hanno esaminato 18 studi su persone con carenza di biotina. In otto di questi studi, l'integrazione della vitamina biotina ha combattuto la maggior parte dei sintomi di perdita di capelli.

La biotina è una vitamina del complesso B ed è importante per la crescita dei capelli. Mentre la ricerca mostra che una carenza di biotina è una delle cause della perdita di capelli, l'attuale relazione tra biotina e crescita dei capelli è ancora un po 'un mistero. Le vitamine del gruppo B sono ben note per aiutare a creare i globuli rossi, che svolgono un ruolo importante nella crescita dei capelli perché trasportano ossigeno e sostanze nutritive al cuoio capelluto e ai follicoli piliferi.

L'uso e il consumo di alimenti ricchi di biotina per la crescita dei capelli inverte i danni causati da acconciature, acqua clorata e sole. Il consumo regolare di compresse di vitamine della biotina per la crescita dei capelli provoca anche capelli voluminosi e lucenti.

La biotina si trova naturalmente in molti alimenti, tra cui: spinaci, cereali integrali, broccoli, mandorle, patate dolci, cavolfiore, funghi, formaggio, arachidi, noci, carne, frutti di mare, tuorli d'uovo, cereali, latte, sardine, avocado, lamponi, banane, mandorle e verdure a foglia verde scure.

Vitamina C

La vitamina C è una vitamina per la crescita dei capelli che crea una proteina chiamata collagene che è parte integrante della struttura dei capelli poiché produce antiossidanti e combatte i radicali liberi. Inoltre, la vitamina C previene l'invecchiamento dei capelli. La vitamina C aiuta anche il corpo ad assorbire il ferro, un minerale essenziale per la crescita dei capelli. Alcuni dei benefici positivi della vitamina C è che agisce come antiossidante e previene i danni dei radicali liberi. Lo stress da radicali liberi colpisce le cellule del follicolo pilifero, l'invecchiamento precoce e il conseguente danno (inclusa la caduta dei capelli) possono iniziare a manifestarsi con l'età.

La vitamina C è diffusa in una varietà di alimenti tra cui: cavoletti di Bruxelles, broccoli, cavolfiori, agrumi, fragole, peperoni, spinaci, cime di rapa, cavoli, pomodori, zucca invernale, guaiave, ribes nero, timo, limone e prezzemolo.

Vitamina D

La perdita dei capelli è collegata a carenze di vitamine legate alla crescita come la vitamina D. Nel 2019, una recensione ha trovato un legame tra la mancanza di vitamina D nel corpo e l'alopecia. L'alopecia, un nome scientifico per la perdita di capelli, è una condizione che può portare a una grave perdita di capelli e i sondaggi condotti nella revisione del 2019 hanno mostrato che le persone con alopecia areata avevano livelli più bassi di vitamina D nel sangue.

Tuttavia, in uno studio del 2016 sui dati del sondaggio dello studio sulla salute degli infermieri, sono stati raccolti dati di 55.929 donne negli Stati Uniti, ma i ricercatori non hanno trovato una connessione diretta tra l'assunzione totale di vitamina D e la caduta dei capelli. Oltre a ciò, c'erano meno prove che suggeriscono persino che la vitamina D può portare alla ricrescita dei capelli. Pertanto, sono necessarie ulteriori ricerche per confermare la verità sulla vitamina D per la crescita dei capelli.

Sebbene la vitamina D possa non avere collegamenti diretti con la crescita dei capelli, sicuramente previene gli effetti dei bassi livelli di vitamina D. L'Ufficio degli integratori alimentari raccomanda agli adulti di assumere 600 unità internazionali o 15 microgrammi (mcg) di vitamina D al giorno. Tuttavia, molte persone non rientrano in questo requisito. Infatti, statisticamente alcuni studi dimostrano che oltre 1 miliardo di persone in tutto il mondo ha una carenza di vitamina D, quindi assicurati di assumere la dose giornaliera di vitamina D.

Vitamina D dal sole:

Soprannominata la “vitamina del sole o del sole”, la vitamina D può creare nuovi follicoli piliferi e alcuni pensano che abbiano un ruolo nella produzione dei capelli. Il tuo corpo produce vitamina D attraverso il contatto con i raggi del sole, oppure puoi ottenerlo da pesci grassi, olio di fegato di merluzzo e alcune varietà di funghi. Tuttavia, molte persone non ricevono abbastanza vitamina D su base giornaliera.

Quindi, l'esposizione al sole può anche aiutare. Il corpo umano produce vitamina D quando entriamo in contatto diretto con i raggi del sole. Indossare la protezione solare per la protezione della pelle è fondamentale se si prevede di assumere la vitamina D in questo modo.

Vitamina D dai supplementi:

Le persone che assumono un integratore dovrebbero farlo con un pasto che contenga un buon grasso. Questo assorbirà parte della vitamina D. Sì, le vitamine sono importanti ma, alcuni minerali sono importanti anche per la crescita dei capelli, tra cui ferro, zinco e iodio. La mancanza di ferro è la carenza nutrizionale più comune in tutto il mondo e più connessa alla caduta dei capelli in numerosi studi. Quindi puoi assumere integratori di ferro anche con una dieta a base di pesce grasso.

Alcuni modi naturali per ottenere più vitamina D includono il consumo: formaggio, latte fortificato a basso contenuto di grassi, succo d'arancia, mandorla, pesce come salmone o pesce spada, olio di fegato di merluzzo, ostriche, tuorlo d'uovo, funghi, latte di soia, farina d'avena, cereali.

In tutti i casi, quando si integra con vitamina D, è necessario prestare attenzione. La vitamina D è liposolubile e si accumula nei tessuti adiposi a livelli pericolosi. L'ingestione di vitamina D in eccesso può portare a troppo calcio nel sangue, che può causare affaticamento e problemi ai reni.

Vitamina E

La vitamina E fa circolare l'ossigeno sul cuoio capelluto rafforzando i follicoli piliferi. Aspira l'umidità, evitando che il fusto del capello si asciughi e appaia opaco. Ecco perché la vitamina E è vista come una delle migliori vitamine per capelli per una crescita più rapida dei capelli. Alcune persone persino strofinano l'olio di vitamina E direttamente sulla pelle o sul cuoio capelluto, credendo che accelererà la rigenerazione cellulare, ma la scienza non lo supporta ancora.

Ma questo è ciò che la scienza supporta quando si tratta di vitamina E: in una recensione del 2019, le persone con alopecia avevano concentrazioni significativamente più basse di vitamina E nel sangue rispetto a quelle senza la condizione. I risultati di uno studio clinico del 2010 hanno anche scoperto che l'uso di integratori di tocotrienolo presenti nella vitamina E ha migliorato la salute dei capelli delle persone con alopecia. Questi integratori hanno anche contribuito a prevenire la caduta dei capelli.

Ottenere la vitamina E dagli integratori:

La vitamina E può essere acquistata in forma di capsule e come liquido.

I prodotti alimentari che contengono vitamina E includono: germe di grano, cavolo, spinaci, semi di girasole, avocado, mandorle, arachidi, nocciole, broccoli, olio di semi di girasole, olio di semi di soia, mango, kiwi, pistacchio, olive e albicocche sott'aceto

Altri rimedi per la caduta dei capelli:

Sì, le vitamine e altri nutrienti del cibo sono importanti per la salute dei capelli, ma puoi anche seguire questi cambiamenti nello stile di vita:

  • Ridurre l'uso di gel per capelli, asciugare e raddrizzare i capelli e spazzolare i capelli quando sono bagnati.
  • Ridurre lo stress impegnandosi in almeno 150 minuti di esercizio da moderato a intenso a settimana, cioè solo 30 minuti di esercizio ogni 5 giorni della settimana, secondo le raccomandazioni dell'American Heart Association (AHA). Ridurre lo stress può anche aiutare a migliorare la forza e l'aspetto dei capelli.
  • Bevi da sei a otto bicchieri d'acqua ogni giorno.
  • Guarda la tua dieta.
  • Tirare costantemente indietro i capelli per una coda di cavallo o un panino alto o usando alcune tecniche di acconciatura può aggravare l'alopecia.

Cose da considerare prima di acquistare vitamine e integratori per la crescita dei capelli:

1. Scopri le vitamine per la crescita dei capelli e cosa fanno

Le vitamine e i minerali chiave che agiscono per la crescita dei capelli sono le vitamine A, B, C, E, D, oltre a minerali e proteine ​​come acido folico, niacina, ferro, zinco, acidi grassi omega-3, tiamina, riboflavina, calcio e pochi altri.

Nel regno delle vitamine per la crescita dei capelli, molti si chiedono se dovrebbero sprecare soldi per così tante vitamine. Le persone chiedono anche: “Non posso ottenere gli stessi risultati con un multivitaminico?”

La risposta è che ci sono molti integratori per la crescita dei capelli, pillole e vitamine sul mercato. Ma i multivitaminici non sono progettati per la crescita di capelli (e unghie) in genere per includere la giusta quantità di vitamine e minerali ritenuti essenziali per i capelli sani. Tuttavia, fai attenzione ai prodotti inferiori che non fanno altro che sovraccaricarti di determinate vitamine e minerali senza fare molto per i capelli.

2. Leggi l'etichetta

È facile dire che dovremmo leggere l'etichetta di tutto ciò che acquistiamo, ma in realtà è un'altra cosa farlo quando si è di fretta. Fai del tuo meglio per leggere l'etichetta di qualsiasi integratore per la crescita dei capelli prima di acquistare. Per uno, potrebbe esserci un ingrediente a cui sei allergico o che altrimenti non ti fa bene. Dovresti evitare integratori non naturali o prodotti chimicamente. Anche le fonti organiche e gli integratori a base vegetale sono buoni, perché le cellule li assorbono più facilmente.

3. Leggi anche gli ingredienti

Dopo aver letto l'etichetta, sapere quali ingredienti sono buoni per te. Abbiamo già discusso importanti vitamine per la crescita dei capelli, ma dovresti anche cercare estratti come biotina, bacche di palmetto, neem, olio di ricino, gambo e foglia di bambù, olio di semi di lino, olio di borragine, alghe e altri. Non che questi ingredienti debbano essere presenti in ogni bottiglia esaminata, ma sappi solo che sono utili per la crescita dei capelli. Una grande proteina presente nei capelli è la cheratina che è ottima per la crescita dei capelli.

4. Parla con il tuo medico

Alcune carenze nutrizionali sono comuni, come ferro, calcio, vitamina A, vitamina B12, magnesio, quindi consulta il tuo medico per scoprire se potresti averne uno. Inoltre, può fornirti utili informazioni sulla caduta dei capelli. Ad esempio, quando stavo perdendo i capelli come un cane, il mio dermatologo mi ha chiesto se avevo la febbre virale? Quando ho detto di sì, mi ha immediatamente assicurato che la mia perdita di capelli era il risultato della ricostruzione del mio corpo. Sono cresciuto di nuovo capelli lunghi e spessi in 4 mesi.

5. Costo

Costoso non significa necessariamente meglio per qualsiasi prodotto, compresi gli integratori per la crescita dei capelli. L'importante è trovare un integratore che funzioni e si adatti al tuo budget.

6. Leggi le recensioni, sia buone che cattive

Quindi, se non sai già che ci sono molte persone che rivendicano grandi cose su un prodotto, ma è solo perché vengono pagate per farlo. Ecco perché è importante leggere anche quelli negativi. Dopo aver letto una recensione, hai una buona idea di quali prodotti producono risultati e quali persone usano da un po 'di tempo.

Pensieri finali

La caduta dei capelli può o meno essere grave. Se si verificano capelli che cadono a chiazze, può essere un segno di una condizione di salute di base come la psoriasi, la dermatite e il cancro della pelle, l'alopecia areata, lo stress e alcuni trattamenti medici. D'altra parte, potrebbe essere la mancanza di un buon cibo ricco di vitamine equilibrato. Quindi, se sei preoccupato per la perdita dei capelli, visita un dermatologo per determinare cosa sta causando i loro problemi di crescita dei capelli.

Inoltre, tieni presente che il taglio regolare dei capelli può mantenerlo sano. Il taglio dei capelli elimina le doppie punte e alleggerisce il peso dei capelli, riducendo così l'impatto sulle radici, che crescono dal cuoio capelluto. Quindi, un cuoio capelluto sano è fondamentale per la crescita dei capelli sani.

Alla fine, due fattori tendono ad influenzare la maggior parte dei casi di caduta dei capelli: ormoni e genetica. Anche se acquisti le migliori vitamine per capelli per una crescita più rapida dei capelli, non puoi superare la genetica e i tuoi ormoni. Ma queste vitamine sono state studiate per promuovere la crescita dei capelli in coloro che sono carenti.

Psorilax:Gratuito |crema psoriasi labbra

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Psorilax: prezzo, funziona, recensioni, opinioni, come si usa

The following is a discussion and analysis of the financial condition of
AbbVie Inc. (AbbVie or the company) as of December 31, 2019 and 2018 and results
of operations for each of the three years in the period ended December 31, 2019.
This commentary should be read in conjunction with the consolidated financial
statements and accompanying notes appearing in Item 8, "Financial Statements and
Supplementary Data."
EXECUTIVE OVERVIEW
Company Overview
AbbVie is a global, research-based biopharmaceutical company formed in 2013
following separation from Abbott Laboratories (Abbott). AbbVie uses its
expertise, dedicated people and unique approach to innovation to develop and
market advanced therapies that address some of the world's most complex and
serious diseases. AbbVie's products are focused on treating conditions such as
chronic autoimmune diseases in rheumatology, gastroenterology and dermatology;
oncology, including blood cancers; virology, including hepatitis C virus (HCV)
and human immunodeficiency virus (HIV); neurological disorders, such as
Parkinson's disease; metabolic diseases, including thyroid disease and
complications associated with cystic fibrosis; pain associated with
endometriosis; as well as other serious health conditions. AbbVie also has a
pipeline of promising new medicines in clinical development across such
important medical specialties as immunology, oncology and neuroscience, with
additional targeted investment in cystic fibrosis and women's health.
AbbVie's products are generally sold worldwide directly to wholesalers,
distributors, government agencies, health care facilities, specialty pharmacies
and independent retailers from AbbVie-owned distribution centers and public
warehouses. In the United States, AbbVie distributes pharmaceutical products
principally through independent wholesale distributors, with some sales directly
to pharmacies and patients. Outside the United States, AbbVie sells products
primarily to customers or through distributors, depending on the market served.
Certain products are co-marketed or co-promoted with other companies. AbbVie has
approximately 30,000 employees. AbbVie operates in one business
segment-pharmaceutical products.
On June 25, 2019, AbbVie announced that it entered into a definitive transaction
agreement under which AbbVie will acquire Allergan plc (Allergan). See Note 5 to
the Consolidated Financial Statements for additional information regarding the
proposed acquisition.
2019 Financial Results
AbbVie's strategy has focused on delivering strong financial results, advancing
and investing in its pipeline and returning value to shareholders while ensuring
a strong, sustainable growth business over the long term. The company's
financial performance in 2019 included delivering worldwide net revenues of
$33.3 billion, operating earnings of $13.0 billion, diluted earnings per share
of $5.28 and cash flows from operations of $13.3 billion. Worldwide net revenues
grew by 3% on a constant currency basis, primarily driven by revenue growth
related to IMBRUVICA and VENCLEXTA as well as the continued strength of HUMIRA
in the U.S. and newly launched immunology assets SKYRIZI and RINVOQ, offset by
international HUMIRA biosimilar competition.
Diluted earnings per share in 2019 was $5.28 and included the following
after-tax costs: (i) $3.2 billion for the change in fair value of contingent
consideration liabilities; (ii) $1.3 billion related to the amortization of
intangible assets; (iii) a Stemcentrx-related impairment charge of $823 million
net of the related fair value adjustment to contingent consideration
liabilities; (iv) $364 million for acquired in-process research and development
(IPR&D); and (v) $338 million of expenses related to the proposed Allergan
acquisition. These costs were partially offset by the following after-tax
benefits: (i) $414 million from litigation matters primarily due to the
settlement of an intellectual property dispute with a third party; (ii)
$400 million due to the favorable resolution of various tax positions; and (iii)
$297 million from an amended and restated license agreement between AbbVie and
Reata Pharmaceuticals, Inc. (Reata). Additionally, financial results reflected
continued funding to support all stages of AbbVie's emerging pipeline assets and
continued investment in AbbVie's on-market brands.
In November 2019, AbbVie's board of directors declared a quarterly cash dividend
of $1.18 per share of common stock payable in February 2020. This reflects an
increase of approximately 10.3% over the previous quarterly dividend of $1.07
per share of common stock.

26 ((Immagine rimossa: abbvieimage2a14.gif)) | 2019 Modulo 10-K

————————————————– ——————————



2020 Strategic Objectives
AbbVie's mission is to be an innovation-driven, patient-focused specialty
biopharmaceutical company capable of achieving top-tier financial performance
through outstanding execution and a consistent stream of innovative new
medicines. AbbVie intends to continue to advance its mission in a number of
ways, including: (i) growing revenues by diversifying revenue streams, ensuring
strong commercial execution of new product launches and driving late-stage
pipeline assets to the market; (ii) continuing to invest and expand its pipeline
in support of opportunities in immunology, oncology and neuroscience, with
additional targeted investment in cystic fibrosis and women's health as well as
continued investment in key on-market products; (iii) expanding operating
margins; and (iv) returning cash to shareholders via a strong and growing
dividend while also reducing incremental debt. In addition, AbbVie anticipates
several regulatory submissions and key data readouts from key clinical trials in
the next 12 months.
AbbVie expects to achieve its strategic objectives through:
• Completion and successful integration of the proposed Allergan acquisition.


• Crescita dei ricavi dell'oncologia ematologica sia da IMBRUVICA che da VENCLEXTA.

• Crescita dei ricavi dell'immunologia guidata da lanci commerciali di successo

SKYRIZI e RINVOQ, nonché HUMIRA NOI. crescita delle vendite.

• Gestione efficace dell'erosione biosimilare internazionale HUMIRA.


•         The favorable impact of pipeline products and indications recently
          approved or currently under regulatory review where approval is
          expected in 2020. These products are described in greater detail in the
          section labeled "Research and Development" included as part of this
          Item 7.


AbbVie remains committed to driving continued expansion of operating margins and
expects to achieve this objective through continued leverage from revenue
growth, productivity initiatives in supply chain and ongoing efficiency programs
to optimize manufacturing, commercial infrastructure, administrative costs and
general corporate expenses.
The combination of AbbVie and Allergan will create a diverse entity with
leadership positions across immunology, hematologic oncology, aesthetics,
neuroscience, women's health, eye care and virology. AbbVie's existing product
portfolio and pipeline will be enhanced with numerous Allergan assets and
Allergan's product portfolio will benefit from AbbVie's commercial strength,
expertise and international infrastructure.
Research and Development
Research and innovation are the cornerstones of AbbVie's business as a global
biopharmaceutical company. AbbVie's long-term success depends to a great extent
on its ability to continue to discover and develop innovative pharmaceutical
products and acquire or collaborate on compounds currently in development by
other biotechnology or pharmaceutical companies.
AbbVie's pipeline currently includes approximately 60 compounds or indications
in clinical development individually or under collaboration or license
agreements and is focused on such important medical specialties as immunology,
oncology and neuroscience along with targeted investments in cystic fibrosis and
women's health. Of these programs, approximately 30 are in mid- and late-stage
development.
The following sections summarize transitions of significant programs from
Phase 2 development to Phase 3 development as well as developments in
significant Phase 3 and registration programs. AbbVie expects multiple Phase 2
programs to transition into Phase 3 programs in the next 12 months.
Significant Programs and Developments
Immunology
RINVOQ
•         In February 2019, the U.S. Food and Drug Administration (FDA) accepted

per revisione prioritaria New Drug Application (NDA) di AbbVie per

upadacitinib, un inibitore selettivo del JAK1 orale sperimentale, per la

          treatment of adult patients with moderate to severe rheumatoid
          arthritis (RA).

• Nel Febbraio 2019, AbbVie ha avviato uno studio clinico di fase 3 per valutare

          the efficacy and safety of upadacitinib in subjects with giant cell
          arteritis.



    2019 Form 10-K  | ((Image Removed: abbvieimage2a14.gif))  27



————————————————– ——————————


•         In August 2019, the FDA approved RINVOQ (upadacitinib) for the
          treatment of adults with moderately to severely active RA who have had
          an inadequate response or intolerance to methotrexate.

• Nel Ottobre 2019, AbbVie ha annunciato i migliori risultati della sua prima fase

3 studi clinici su RINVOQ in pazienti adulti con psoriasica attiva

artrite (PsA). Risultati dello studio SELECT-PsA 2, che ha valutato

RINVOQ rispetto al placebo in pazienti che non hanno risposto adeguatamente

il trattamento con uno o più DMARD biologici ha mostrato che entrambe le dosi di

RINVOQ (15 mg e 30 mg) ha raggiunto gli endpoint primari e secondari chiave a

          week 12. The safety profile was consistent with that of previous
          studies across indications, with no new safety risks detected.


•         In November 2019, AbbVie announced data from the Phase 2/3
          SELECT-AXIS 1 trial in which twice as many adult patients with
          ankylosing spondylitis treated with RINVOQ achieved the primary

endpoint alla settimana 14 rispetto al placebo. Il profilo di sicurezza era coerente

          with that of previous studies across indications, with no new safety
          risks detected.

• Nel Novembre 2019, AbbVie ha avviato uno studio clinico di fase 3 per valutare

          the efficacy and safety of RINVOQ in adult patients with axial
          spondyloarthritis.

• Nel Dicembre 2019, il Commissione europea (CE) ha concesso la commercializzazione

          authorization for RINVOQ for the treatment of adult patients with
          moderate to severe active rheumatoid arthritis who have had an
          inadequate response or intolerance to one or more DMARDs.

• Nel Febbraio 2020, AbbVie ha annunciato i migliori risultati dalla sua seconda

Studio clinico di fase 3 di RINVOQ in pazienti adulti con PsA attiva.

Risultati dello studio SELECT-PsA 1, che ha valutato RINVOQ rispetto a

          placebo in patients who did not adequately respond to treatment with
          one or more non-biologic DMARDs, showed that both doses of RINVOQ (15

mg e 30 mg) hanno soddisfatto gli endpoint primari e secondari chiave. La sicurezza

profilo era coerente con quello di studi precedenti in tutto

indicazioni, senza che siano stati rilevati nuovi rischi per la sicurezza.

SKYRIZI

• Nel Marzo 2019, AbbVie ha avviato due studi clinici di fase 3 per valutare

l'efficacia e la sicurezza di risankizumab, uno studio sperimentale

inibitore dell'interleuchina-23 (IL-23), in soggetti con artrite psoriasica.


•         In April 2019, the FDA approved SKYRIZI (risankizumab) for the
          treatment of moderate to severe plaque psoriasis in adults who are
          candidates for systemic therapy or phototherapy.

• Nel Aprile 2019, la CE ha rilasciato l'autorizzazione all'immissione in commercio per SKYRIZI per

il trattamento della psoriasi a placche da moderata a grave nei pazienti adulti

che sono candidati per la terapia sistemica.

Oncologia

IMBRUVICA

• Nel Gennaio 2019, approvato dalla FDA IMBRUVICA, in combinazione con GAZYVA

          (obinutuzumab), for adult patients with previously untreated chronic
          lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).


•         In June 2019, AbbVie announced results from the Phase 3 CLL12 trial,
          evaluating IMBRUVICA in patients with previously untreated CLL, which
          demonstrated that IMBRUVICA significantly improved event- and
          progression-free survival.

• Nel Novembre 2019, AbbVie ha presentato una nuova domanda di droga supplementare

          (sNDA) to the FDA for IMBRUVICA in combination with rituximab for the
          first-line treatment of younger patients with CLL or SLL.

VENCLEXTA

• Nel Marzo 2019, AbbVie ha annunciato che la FDA ha posto una clinica parziale

          hold on all clinical trials evaluating VENCLEXTA for the
          investigational treatment of multiple myeloma (MM). The partial
          clinical hold followed a review of data from the ongoing Phase 3
          BELLINI trial, a study in relapsed/refractory MM, in which a higher
          proportion of deaths was observed in the VENCLEXTA arm compared to the
          control arm of the trial. In June 2019, AbbVie announced that the FDA
          lifted the partial clinical hold placed on the Phase 3 CANOVA trial,
          evaluating VENCLEXTA for the investigational treatment of
          relapsed/refractory MM positive for the translocation (11;14)
          abnormality, based upon agreement on revisions to the CANOVA study

protocollo, comprese le nuove misure di mitigazione del rischio, specificato dal protocollo

          guidelines and updated futility criteria. This action does not impact
          any of the approved indications for VENCLEXTA, such as CLL or acute
          myeloid leukemia (AML).



28  ((Image Removed: abbvieimage2a14.gif)) | 2019 Form 10-K


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• Nel Maggio 2019, il VENCLEXTA approvato dalla FDA, in combinazione con

obinutuzumab, per pazienti adulti con CLL / SLL non precedentemente trattati. Il

l'approvazione si basava sui dati dello studio di fase 3 CLL14, valutando il

efficacia e sicurezza di VENCLEXTA più obinutuzumab rispetto a obinutuzumab

          plus chlorambucil in previously untreated patients with CLL, which
          demonstrated that VENCLEXTA plus obinutuzumab prolonged
          progression-free survival and achieved higher rates of complete

risposta e minima negatività residua della malattia rispetto al comune

standard di cura usato obinutuzumab più clorambucile.

• Nel Gennaio 2020, AbbVie ha annunciato che il comitato per i medicinali

          Products for Human Use (CHMP) of the European Medicines Agency (EMA)
          granted a positive opinion for VENCLYXTO in combination with
          obinutuzumab for patients with previously untreated CLL.

Depatux-M

• Nel Maggio 2019, AbbVie ha annunciato la decisione di interrompere la Fase 3

Studio INTELLANCE-1 sulla depatuxizumab mafodotin (Depatux-M, precedentemente

noto come ABT-414) in pazienti con glioblastoma di nuova diagnosi, di cui

i tumori hanno amplificazione dell'EGFR (recettore del fattore di crescita epidermico), a

          an interim analysis. An Independent Data Monitoring Committee
          recommended stopping enrollment in INTELLANCE-1 due to lack of survival
          benefit for patients receiving Depatux-M compared with placebo when

aggiunto al regime standard di radiazioni e temozolomide. Iscrizione

è stato sospeso in tutti gli studi Depatux-M in corso.

Veliparib

• Nel Luglio 2019, AbbVie ha annunciato che i risultati di punta della Fase 3

Studio BROCADE3 che valuta veliparib, un poli orale sperimentale

(adenosina difosfato-ribosio) inibitore della polimerasi (PARP), in

la combinazione con carboplatino e paclitaxel ha raggiunto il suo endpoint primario di

          progression-free survival in patients with HER2 negative germline
          BRCA-mutated advanced breast cancer.

• Nel Luglio 2019, AbbVie ha annunciato che i risultati di punta della Fase 3

Studio VELIA, condotto in collaborazione con il GOG Foundation, Inc.,

valutazione di veliparib con carboplatino e paclitaxel seguiti da

la terapia di mantenimento con veliparib ha raggiunto il suo endpoint primario di

sopravvivenza libera da progressione in pazienti con ovaia di nuova diagnosi

cancro, indipendentemente dallo stato dei biomarcatori.

Rova-T

• Nel Agosto 2019, AbbVie ha annunciato la decisione di chiudere il MERU

prova, uno studio di Fase 3 che valuta rovalpituzumab tesirina (Rova-T) come a

terapia di mantenimento di prima linea per carcinoma polmonare avanzato a piccole cellule

(SCLC). Si raccomanda un comitato indipendente di monitoraggio dei dati

la conclusione dello studio dopo che i risultati non hanno dimostrato alcun beneficio in termini di sopravvivenza a

          a pre-planned interim analysis for patients receiving Rova-T as
          compared with placebo. With the closing of the MERU trial, AbbVie
          announced the termination of the Rova-T research and development
          program.


Virology/Liver Disease
•         In August 2019, the EC granted marketing authorization for MAVIRET
          (glecaprevir/pibrentasvir) to shorten the once-daily treatment duration
          from 12 to 8 weeks in treatment-naïve, compensated cirrhotic, chronic
          HCV patients with genotype (GT)1, 2, 4, 5 and 6 infection.

• Nel Settembre 2019, il MAVYRET approvato dalla FDA (glecaprevir / pibrentasvir)

ridurre la durata del trattamento una volta al giorno da 12 a 8 settimane in

pazienti con cirrosi, HCV cronici, naïve al trattamento, compensati in tutto

genotipi (GT1-6).

• Nel Gennaio 2020, AbbVie ha annunciato che il CHMP dell'EMA ha

ha raccomandato una modifica dell'autorizzazione all'immissione in commercio per MAVIRET a

ridurre la durata del trattamento una volta al giorno da 12 a 8 settimane in

pazienti con HCV cronica, cirrotica, compensata, naïve al trattamento con GT 3

          infection.


Neuroscienza

• Nel Maggio 2019, AbbVie ha avviato uno studio clinico di Fase 3 per valutare la

sicurezza e tollerabilità di ABBV-951, una levodopa / carbidopa sottocutanea

          delivery system, in subjects with Parkinson's disease.


•         In July 2019, AbbVie announced the decision to discontinue the Phase 2

Studio ARISE che ha valutato ABBV-8E12, un anticorpo sperimentale anti-tau,

          in patients with progressive supranuclear palsy, after an Independent
          Data



    2019 Form 10-K  | ((Image Removed: abbvieimage2a14.gif))  29


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Monitoring Committee recommended stopping the trial for futility after the trial
showed that ABBV-8E12 did not provide efficacy.
Other
•         In July 2019, AbbVie submitted an NDA to the FDA for elagolix in
          combination with estradiol/norethindrone acetate (E2/NETA) daily
          add-back therapy for the management of heavy menstrual bleeding
          associated with uterine fibroids.


RESULTS OF OPERATIONS
Net Revenues
The comparisons presented at constant currency rates reflect comparative local
currency net revenues at the prior year's foreign exchange rates. This measure
provides information on the change in net revenues assuming that foreign
currency exchange rates had not changed between the prior and the current
periods. AbbVie believes that the non-GAAP measure of change in net revenues at
constant currency rates, when used in conjunction with the GAAP measure of
change in net revenues at actual currency rates, may provide a more complete
understanding of the company's operations and can facilitate analysis of the
company's results of operations, particularly in evaluating performance from one
period to another.
                                                                                        Percent change
                                                                  At actual currency rates        At constant currency rates
years ended (dollars in
millions)                   2019         2018         2017           2019             2018           2019             2018
United States            $ 23,907$ 21,524$ 18,251           11.1  %          17.9 %         11.1  %          17.9 %
International               9,359       11,229        9,965          (16.7 )%          12.8 %        (13.6 )%          10.4 %
Net revenues             $ 33,266$ 32,753$ 28,216            1.6  %          16.1 %          2.6  %          15.2 %




30 ((Immagine rimossa: abbvieimage2a14.gif)) | 2019 Modulo 10-K

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La tabella seguente descrive i ricavi netti mondiali di AbbVie:

                                                                                                   Percent change
                                                                             At actual currency rates        At constant currency rates
years ended December 31 (dollars
in millions)                           2019         2018         2017          2019             2018            2019             2018
Immunology
HUMIRA          United States       $ 14,864$ 13,685$ 12,361           8.6  %          10.7  %          8.6  %           10.7  %
                International          4,305        6,251        6,066         (31.1 )%           3.1  %        (27.8 )%            0.6  %
                Total               $ 19,169$ 19,936$ 18,427          (3.9 )%           8.2  %         (2.9 )%            7.4  %
SKYRIZI         United States       $    311     $      -     $      -           n/m              n/m             n/m               n/m
                International             44            -            -           n/m              n/m             n/m               n/m
                Total               $    355     $      -     $      -           n/m              n/m             n/m               n/m
RINVOQ          United States       $     47     $      -     $      -           n/m              n/m             n/m               n/m
                International              -            -            -           n/m              n/m             n/m               n/m
                Total               $     47     $      -     $      -           n/m              n/m             n/m               n/m
Hematologic Oncology
IMBRUVICA       United States       $  3,830$  2,968$  2,144          29.1  %          38.4  %         29.1  %           38.4  %
                Collaboration
                revenues                 844          622          429          35.8  %          45.0  %         35.8  %           45.0  %
                Total               $  4,674$  3,590$  2,573          30.2  %          39.5  %         30.2  %           39.5  %
VENCLEXTA       United States       $    521$    247$     89       >100.0%          >100.0%         >100.0%           >100.0%
                International            271           97           33       >100.0%          >100.0%         >100.0%           >100.0%
                Total               $    792$    344$    122       >100.0%          >100.0%         >100.0%           >100.0%
HCV
MAVYRET         United States       $  1,473$  1,614$    277          (8.8 )%       >100.0%            (8.8 )%        >100.0%
                International          1,420        1,824          213         (22.1 )%       >100.0%           (19.6 )%        >100.0%
                Total               $  2,893$  3,438$    490         (15.9 )%       >100.0%           (14.6 )%        >100.0%
VIEKIRA         United States       $      -     $      3$     61        (100.0 )%         (96.7 )%       (100.0 )%          (96.7 )%
                International             36          175          723         (79.2 )%         (75.6 )%        (77.2 )%          (74.8 )%
                Total               $     36$    178$    784         (79.6 )%         (77.2 )%        (77.6 )%          (76.5 )%
Other Key Products
Creon           United States       $  1,041$    928$    831          12.2  %          11.7  %         12.2  %           11.7  %
Lupron          United States       $    720$    726$    669          (0.8 )%           8.6  %         (0.8 )%            8.6  %
                International            167          166          160           0.8  %           3.4  %          6.0  %            4.7  %
                Total               $    887$    892$    829          (0.5 )%           7.6  %          0.5  %            7.9  %
Synthroid       United States       $    786$    776$    781           1.3  %          (0.6 )%          1.3  %           (0.6 )%
Synagis         International       $    718$    726$    738          (1.2 )%          (1.6 )%          0.9  %           (2.8 )%
Duodopa         United States       $     97$     80$     61          20.4  %          31.4  %         20.4  %           31.4  %
                International            364          350          294           4.2  %          19.1  %          9.8  %           14.8  %
                Total               $    461$    430$    355           7.2  %          21.2  %         11.7  %           17.7  %
Sevoflurane     United States       $     74$     74$     78           2.0  %          (6.2 )%          2.0  %           (6.2 )%
                International            274          317          332         (13.8 )%          (4.4 )%         (9.5 )%           (4.3 )%
                Total               $    348$    391$    410         (10.9 )%          (4.7 )%         (7.4 )%           (4.6 )%
Kaletra         United States       $     38$     55$     71         (31.0 )%         (22.1 )%        (31.0 )%          (22.1 )%
                International            245          281          352         (12.9 )%         (20.2 )%         (9.5 )%          (20.1 )%
                Total               $    283$    336$    423         (15.8 )%         (20.5 )%        (12.9 )%          (20.4 )%
AndroGel        United States       $    172$    469$    577         (63.3 )%         (18.8 )%        (63.3 )%          (18.8 )%
ORILISSA        United States       $     91$     11     $      -       >100.0%              n/m         >100.0%               n/m
                International              2            -            -           n/m              n/m             n/m               n/m
                Total               $     93$     11     $      -       >100.0%              n/m         >100.0%               n/m
All other                           $    511$    308$    876          66.1  %         (64.9 )%         73.0  %          (73.2 )%
Total net revenues                  $ 33,266$ 32,753$ 28,216           1.6  %          16.1  %          2.6  %           15.2  %



n / m – Non significativo

2019 Modulo 10-K | ((Immagine rimossa: abbvieimage2a14.gif)) 31

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The following discussion and analysis of AbbVie's net revenues by product is
presented on a constant currency basis.
Global HUMIRA sales decreased 3% in 2019 and increased 7% in 2018. The sales
decrease in 2019 was primarily driven by direct biosimilar competition in
certain international markets, partially offset by market growth across
therapeutic categories. The sales increase in 2018 was primarily driven by
market growth across therapeutic categories and geographies as well as favorable
pricing in certain geographies. In the United States, HUMIRA sales increased 9%
in 2019 and 11% in 2018. The sales increases in 2019 and 2018 were primarily
driven by market growth across all indications and favorable pricing.
Internationally, HUMIRA revenues decreased 28% in 2019 and increased 1% in 2018.
The sales decrease in 2019 was primarily driven by direct biosimilar competition
in Europe following the expiration of the European Union composition of matter
patent for adalimumab in October 2018. The sales increase in 2018 was primarily
driven by market growth across indications partially offset by direct biosimilar
competition. Biosimilar competition for HUMIRA is not expected in the United
States until 2023. AbbVie continues to pursue strategies intended to further
differentiate HUMIRA from competing products and add to the sustainability of
HUMIRA.
Net revenues for SKYRIZI were $355 million in 2019 following the April 2019
regulatory approvals for the treatment of moderate to severe plaque psoriasis.
Net revenues for RINVOQ were $47 million in 2019 following the August 2019 FDA
approval for the treatment of moderate to severe rheumatoid arthritis.
Net revenues for IMBRUVICA represent product revenues in the United States and
collaboration revenues outside of the United States related to AbbVie's 50%
share of IMBRUVICA profit. AbbVie's global IMBRUVICA revenues increased 30% in
2019 and 39% in 2018 as a result of continued penetration of IMBRUVICA for
patients with CLL as well as favorable pricing.
Net revenues for VENCLEXTA increased by more than 100% in 2019 and 2018
primarily due to market share gains following additional regulatory approvals of
VENCLEXTA for the treatment of patients with relapsed/refractory CLL and
first-line AML in 2018 and first-line CLL in 2019.
Global MAVYRET sales decreased by 15% in 2019 primarily driven by lower patient
volumes in certain international markets and competitive dynamics in the U.S.
Global MAVYRET sales increased more than 100% in 2018 as a result of market
share gains following the FDA and EMA approvals of MAVYRET in the second half of
2017 as well as further geographic expansion. Global VIEKIRA sales decreased by
78% in 2019 and 76% in 2018 primarily due to lower market share following the
launch of MAVYRET.
Net revenues for Creon increased 12% in 2019 and 12% in 2018, primarily driven
by continued market growth and favorable pricing. Creon maintains market
leadership in the pancreatic enzyme market.
Net revenues for Duodopa increased 12% in 2019 and 18% in 2018, primarily driven
by increased market penetration.
Gross Margin
                                                                                 Percent change
years ended December 31 (dollars
in millions)                        2019          2018          2017           2019            2018
Gross margin                     $  25,827$  25,035$  21,174            3 %             18 %
as a percent of net revenues            78 %          76 %          75 %


Gross margin as a percentage of net revenues in 2019 increased from 2018
primarily due to the full year effect of the expiration of HUMIRA royalties,
partially offset by the IMBRUVICA profit sharing arrangement and unfavorable
impact from higher intangible asset amortization.
Gross margin as a percentage of net revenues in 2018 increased from 2017
primarily due to the expiration of HUMIRA royalties and a 2017 intangible asset
impairment charge of $354 million partially offset by the IMBRUVICA profit
sharing arrangement.

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Vendita, generale e amministrativa

                                                                                 Percent change
years ended December 31 (dollars
in millions)                        2019          2018          2017           2019            2018
Selling, general and
administrative                   $   6,942$   7,399$   6,295           (6 )%            18 %
as a percent of net revenues            21 %          23 %          22 %


Selling, general and administrative (SG&A) expenses as a percentage of net
revenues in 2019 decreased from 2018 primarily due to the favorable impacts of
international HUMIRA expense reductions and lower litigation reserve charges
that decreased by $326 million. This favorability was partially offset by new
product launch expenses, higher restructuring charges and $103 million of
transaction expenses associated with the proposed Allergan transaction.
Additionally, SG&A expenses in 2018 included non-recurring philanthropic
contributions of $350 million to certain U.S. not-for-profit organizations.
SG&A expenses as a percentage of net revenues in 2018 increased from 2017
primarily due to new product launch expenses and non-recurring philanthropic
contributions to certain U.S. not-for-profit organizations partially offset by
continued leverage from revenue growth.
Research and Development and Acquired In-Process Research and Development
                                                                                Percent change
years ended December 31 (dollars
in millions)                        2019          2018          2017           2019          2018
Research and development         $   6,407$  10,329$   5,007          (38 )%       >100%
as a percent of net revenues            19 %          32 %          18 %
Acquired in-process research and
development                      $     385$     424$     327

(9)% 30%



Research and Development (R&D) expenses decreased in 2019 and increased in 2018
principally due to impairment charges related to IPR&D acquired as part of the
2016 Stemcentrx acquisition. In 2019, the company recorded a $1.0 billion
intangible asset impairment charge which represented the remaining value of the
IPR&D acquired following the decision to terminate the Rova-T R&D program. In
2018, the company recorded a $5.1 billion intangible asset impairment charge
following the decision to stop enrollment in the TAHOE trial, which lowered the
probabilities of success of achieving regulatory approval across Rova-T and
other early-stage assets obtained in the acquisition. See Note 7 to the
Consolidated Financial Statements for additional information regarding these
impairment charges.
Acquired IPR&D expenses reflect upfront payments related to various
collaborations. There were no individually significant transactions or cash
flows during 2019 or 2018. Acquired IPR&D expense in 2017 included a charge of
$205 million as a result of entering into a global strategic collaboration with
Alector, Inc. (Alector) to develop and commercialize medicines to treat
Alzheimer's disease and other neurodegenerative disorders. See Note 5 to the
Consolidated Financial Statements for additional information regarding the
Alector agreement.
Other Operating Expenses and Income
Other operating income in 2019 included $550 million of income from a legal
settlement related to an intellectual property dispute with a third party and
$330 million of income related to an amended and restated license agreement
between AbbVie and Reata. See Note 5 to the Consolidated Financial Statements
for additional information on the Reata agreement.
Other operating expenses in 2018 included a $500 million charge related to the
extension of the previously announced Calico collaboration to discover, develop
and bring to market new therapies for patients with age-related diseases,
including neurodegeneration and cancer. See Note 5 to the Consolidated Financial
Statements for additional information regarding the Calico agreement.

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Other Non-Operating Expenses
years ended December 31 (in millions)     2019        2018        2017
Interest expense                        $ 1,784$ 1,348$ 1,150
Interest income                            (275 )      (204 )      (146 )
Interest expense, net                   $ 1,509$ 1,144$ 1,004

Net foreign exchange loss               $    42$    24$   348
Other expense, net                        3,006          18         466


Interest expense in 2019 increased compared to 2018 primarily due to $363
million of incremental interest and debt issuance costs associated with
financing the proposed acquisition of Allergan, as well as the unfavorable
impact of higher interest rates on the company's debt obligations. Interest
expense in 2018 increased compared to 2017 primarily due to the unfavorable
impact of higher interest rates on the company's debt obligations and a higher
average outstanding debt balance during 2018.
Interest income in 2019 increased compared to 2018 primarily due to a higher
average cash and cash equivalents balance during 2019, partially offset by
decreased investments in debt securities. Interest income in 2018 increased
compared to 2017 primarily due to higher interest rates.
Net foreign exchange loss in 2017 included $316 million of historical currency
translation losses that were reclassified from accumulated other comprehensive
income (AOCI) related to the liquidation of certain foreign entities following
the enactment of U.S. tax reform.
Other expense, net included charges related to the change in fair value of the
contingent consideration liabilities of $3.1 billion in 2019, $49 million in
2018 and $626 million in 2017. The fair value of contingent consideration
liabilities is impacted by the passage of time and multiple other inputs,
including the probability of success of achieving regulatory/commercial
milestones, discount rates, the estimated amount of future sales of the acquired
products still in development and other market-based factors. In 2019, the
Boehringer Ingelheim (BI) contingent consideration liability increased due to
higher probabilities of success, higher estimated future sales, declining
interest rates and passage of time. The higher probabilities of success
primarily resulted from the April 2019 regulatory approvals of SKYRIZI for the
treatment of moderate to severe plaque psoriasis. These changes were partially
offset by a $91 million decrease in the Stemcentrx contingent consideration
liability due to the termination of the Rova-T R&D program during the third
quarter of 2019. In 2018, the BI contingent consideration liability increased
due to the passage of time and higher estimated future sales partially offset by
the effect of rising interest rates. This increase in the BI contingent
consideration liability was primarily offset by a $428 million decrease in the
Stemcentrx contingent consideration liability recorded during the fourth quarter
of 2018 due to a reduction in probabilities of success of achieving regulatory
approval across Rova-T and other early-stage Stemcentrx assets. In 2017, the
change in fair value represented mainly higher probabilities of success, the
passage of time and declining interest rates. Other expense, net for 2017 also
included realized gains on available-for-sale investment securities of $90
million.
Income Tax Expense
The effective income tax rate was 6% in 2019, negative 9% in 2018 and 31% in
2017. The effective tax rate in each period differed from the statutory tax rate
principally due to the allocation of the company's taxable earnings among
jurisdictions, the benefit from foreign operations which reflects the impact of
lower income tax rates in locations outside the United States, tax incentives in
Puerto Rico and other foreign tax jurisdictions and business development
activities. The increase in the effective tax rate for 2019 over the prior year
was principally due to the timing of provisions of the Tax Cuts and Jobs Act
(the Act) related to the earnings from certain foreign subsidiaries. The
increase is also attributable to changes in the jurisdictional mix of earnings,
including a change in fair value of contingent consideration liabilities. These
increases were partially offset by the favorable resolution of various tax
positions in the current year.
The effective tax rate for 2018 also included the effects of Stemcentrx
intangible impairment related expenses.
The effective tax rate in 2017 included tax expense of $4.5 billion on the
one-time mandatory repatriation of previously untaxed earnings of foreign
subsidiaries, partially offset by a $3.6 billion net tax benefit for the
remeasurement of deferred taxes related to the Act and foreign tax law changes.

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The Act significantly changed the U.S. corporate tax system. The Act reduced the
U.S. federal corporate tax rate from 35% to 21% and created a territorial tax
system that included new taxes on certain foreign sourced earnings. See Note 14
to the Consolidated Financial Statements for additional information regarding
the Act.
FINANCIAL POSITION, LIQUIDITY AND CAPITAL RESOURCES
years ended December 31 (in millions)   2019         2018        2017
Cash flows from:
Operating activities                  $ 13,324$ 13,427$ 9,960
Investing activities                       596      (1,006 )      (274 )
Financing activities                    18,708     (14,396 )    (5,512 )


Operating cash flows in 2019 decreased slightly from 2018 primarily due to
higher payments for income taxes offset by improved results of operations
resulting from an increase in operating earnings. Operating cash flows in 2018
increased from 2017 primarily due to improved results of operations from revenue
growth and a decrease in income tax payments. Operating cash flows also
reflected AbbVie's contributions to its defined benefit plans of $727 million in
2019, $873 million in 2018 and $246 million in 2017.
Investing cash flows in 2019 included net sales and maturities of investments
totaling $2.1 billion resulting from the sale of substantially all of the
company's investments in debt securities, payments made for other acquisitions
and investments of $1.1 billion and capital expenditures of $552 million.
Investing cash flows in 2018 included payments made for other acquisitions and
investments of $736 million and capital expenditures of $638 million, partially
offset by net sales and maturities of investment securities totaling
$368 million. Investing cash flows in 2017 included capital expenditures of
$529 million and payments made for other acquisitions and investments of
$308 million, partially offset by net sales and maturities of investment
securities totaling $563 million.
Financing cash flows in 2019 included the issuance of $30.0 billion aggregate
principal amount of floating rate and fixed rate unsecured senior notes at
maturities ranging from 18 months to 30 years. AbbVie expects to use the net
proceeds of $29.8 billion to fund a portion of the aggregate cash consideration
due to Allergan shareholders in connection with the proposed acquisition and to
pay related fees and expenses. Pending the consummation of the proposed Allergan
acquisition, the net proceeds from the offering are permitted to be invested
temporarily in short-term investments. All of the notes are subject to special
mandatory redemption at a redemption price equal to 101% of the aggregate
principal amount of the notes plus accrued and unpaid interest if the proposed
acquisition of Allergan is not completed by January 30, 2021 or the company
notifies the trustee in respect of the notes that it will not pursue the
consummation of the proposed Allergan acquisition.
Additionally, financing cash flows in 2019 included the issuance of €1.4 billion
aggregate principal amount of unsecured senior Euro notes which the company used
to redeem €1.4 billion aggregate principal amount of 0.38% senior Euro notes
that were due to mature in November 2019, as well as the repayment of a
$3.0 billion 364-day term loan credit agreement that was scheduled to mature in
June 2019.
Financing cash flows in 2018 included proceeds from the issuance of $3.0 billion
drawn under the term loan in June 2018. In September 2018, the company issued
$6.0 billion aggregate principal amount of unsecured senior notes. Of the
$5.9 billion net proceeds, $2.0 billion was used to repay the company's
outstanding three-year term loan credit agreement in September 2018 and $1.0
billion was used to repay the aggregate principal amount of 2.00% senior notes
at maturity in November 2018. Financing cash flows in 2018 also included the May
2018 repayment of $3.0 billion aggregate principal amount of the company's 1.80%
senior notes at maturity.
In 2019, 2018 and 2017, the company issued and redeemed commercial paper. There
were no commercial paper borrowings outstanding as of December 31, 2019 and
there was $699 million outstanding as of December 31, 2018. AbbVie may issue
additional commercial paper or retire commercial paper to meet liquidity
requirements as needed.
Cash dividend payments totaled $6.4 billion in 2019, $5.6 billion in 2018 and
$4.1 billion in 2017. The increase in cash dividend payments was primarily
driven by an increase in the dividend rate. On November 1, 2019, AbbVie
announced that its board of directors declared an increase in the quarterly cash
dividend from $1.07 per share to $1.18 per share beginning with the dividend
payable on February 14, 2020 to stockholders of record as of January 15, 2020.
This reflects an increase of approximately 10.3% over the previous quarterly
rate. The timing, declaration, amount of and payment of any dividends by AbbVie
in the future is within the discretion of its board of directors and will depend
upon many factors, including AbbVie's financial condition, earnings, capital
requirements of its operating subsidiaries, covenants associated with certain of
AbbVie's

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debt service obligations, legal requirements, regulatory constraints, industry
practice, ability to access capital markets and other factors deemed relevant by
its board of directors.
On February 15, 2018, AbbVie's board of directors authorized a new $10.0 billion
stock repurchase program, which superseded AbbVie's previous stock repurchase
program. On December 13, 2018, AbbVie's board of directors authorized a $5.0
billion increase to the existing $10.0 billion stock repurchase program. The
company's stock repurchase authorization permits purchases of AbbVie shares from
time to time in open-market or private transactions at management's discretion.
The program has no time limit and can be discontinued at any time. Under this
authorization, AbbVie repurchased 4 million shares for $300 million in 2019 and
109 million shares for $10.7 billion in 2018. AbbVie cash-settled $201 million
of its December 2018 open market purchases in January 2019. AbbVie's remaining
stock repurchase authorization was $4.0 billion as of December 31, 2019.
Under previous stock repurchase programs, AbbVie made open market share
repurchases of 11 million shares for $1.3 billion in 2018 and 13 million shares
for $1.0 billion in 2017. AbbVie cash-settled $285 million of its December 2016
open market purchases in January 2017.
In 2019, AbbVie made contingent consideration milestone and royalty payments to
BI totaling $234 million following the commercial launch of SKYRIZI in certain
geographies. $163 million of these payments were included in financing cash
flows and $71 million of the payments were included in operating cash flows. In
2018, AbbVie paid $100 million of contingent consideration to BI related to BLA
and MAA acceptance milestones. $78 million of these payments were included in
financing cash flows and $22 million of the payments were included in operating
cash flows. In 2017, AbbVie paid $305 million of contingent consideration to BI
related to a Phase 3 enrollment milestone. $268 million of this milestone was
included in financing cash flows and $37 million was included in operating cash
flows.
In connection with the proposed acquisition of Allergan, on June 25, 2019,
AbbVie entered into a $38.0 billion 364-day bridge credit agreement and on July
12, 2019, AbbVie entered into a $6.0 billion term loan credit agreement. The
company incurred a total of $242 million of debt issuance costs related to the
two agreements. On October 25, 2019, AbbVie commenced offers to exchange any and
all outstanding notes of certain series issued by Allergan for up to $15.5
billion aggregate principal amount and €3.7 billion aggregate principal amount
of new notes to be issued by AbbVie and cash, subject to conditions including
the closing of the proposed acquisition. See Note 10 to the Consolidated
Financial Statements for additional information. In February 2020, the remaining
commitments under the bridge credit agreement were reduced to $0 as a result of
cash on hand at AbbVie. AbbVie subsequently terminated the bridge credit
agreement in its entirety as permitted under its terms.
Credit Risk
AbbVie monitors economic conditions, the creditworthiness of customers and
government regulations and funding, both domestically and abroad. AbbVie
regularly communicates with its customers regarding the status of receivable
balances, including their payment plans and obtains positive confirmation of the
validity of the receivables. AbbVie establishes an allowance against accounts
receivable when it is probable they will not be collected. AbbVie may also
utilize factoring arrangements to mitigate credit risk, although the receivables
included in such arrangements have historically not been a significant amount of
total outstanding receivables.
Credit Facility, Access to Capital and Credit Ratings
Credit Facility
In August 2019, AbbVie entered into an amended and restated $4.0 billion
five-year revolving credit facility that matures in August 2024. This amended
facility enables the company to borrow funds on an unsecured basis at variable
interest rates and contains various covenants. At December 31, 2019, the company
was in compliance with all its credit facility covenants. Commitment fees under
the credit facility were insignificant. No amounts were outstanding under the
company's credit facilities as of December 31, 2019 and 2018.
Access to Capital
The company intends to fund short-term and long-term financial obligations as
they mature through cash on hand, future cash flows from operations, or by
issuing additional debt. The company's ability to generate cash flows from
operations, issue debt or enter into financing arrangements on acceptable terms
could be adversely affected if there is a material decline in the demand for the
company's products or in the solvency of its customers or suppliers,
deterioration in the company's key financial ratios or credit ratings, or other
material unfavorable changes in business conditions. At the current time, the
company believes it has sufficient financial flexibility to issue debt, enter
into other financing arrangements and attract long-term capital on acceptable
terms to support the company's growth objectives.

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Credit Ratings
Following the announcement of the proposed acquisition of Allergan and the
$30.0 billion senior notes issuance, Moody's Investor Service affirmed its Baa2
senior unsecured long-term rating and Prime-2 short-term rating with a stable
outlook. S&P Global Ratings revised its ratings outlook to negative from stable
and expects to lower the issuer credit rating by one notch to BBB+ from A- and
the short-term rating to A-2 from A-1 when the acquisition is complete.
Unfavorable changes to the ratings may have an adverse impact on future
financing arrangements; however, they would not affect the company's ability to
draw on its credit facility and would not result in an acceleration of scheduled
maturities of any of the company's outstanding debt.
Contractual Obligations
The following table summarizes AbbVie's estimated contractual obligations as of
December 31, 2019:
                                                     Less than          One to           Three to          More than
(in millions)                           Total         one year        three years        five years        five years
Long-term debt, including current
portion                              $  67,233$     3,750$       14,150$       7,625$      41,708
Interest on long-term debt(a)           30,494           2,146              4,087             3,479            20,782
Non-cancelable operating and finance
lease payments(f)                          774             129                224               125               296
Purchase obligations and other(b)        3,532           3,295                186                45                 6
Other long-term liabilities (c) (d)
(e)                                     11,544             166              1,395             2,123             7,860
Total                                $ 113,577$     9,486$       20,042$      13,397$      70,652

(a) Include i pagamenti di interessi futuri stimati sul debito a lungo termine. Interesse

i pagamenti sul debito sono calcolati per periodi futuri utilizzando gli interessi previsti

tassi in vigore alla fine del 2019. I pagamenti di interessi previsti comprendono il

effetti correlati degli accordi di swap su tassi di interesse. Alcuni di questi proiettati

i pagamenti di interessi potrebbero differire in futuro in base alle variazioni del floating

tassi di interesse o altri fattori o eventi. I pagamenti degli interessi previsti

riguardano solo gli obblighi e gli accordi in essere presso 31 dicembre 2019.

Per ulteriori informazioni, consultare la Nota 10 del bilancio consolidato

informazioni relative agli strumenti di debito della società e alla nota 11 per

ulteriori informazioni sugli accordi di swap su tassi di interesse in essere presso

31 dicembre 2019.

(b) Include i significativi obblighi di acquisto incondizionati della società. Questi

gli impegni non superano i requisiti previsti dalla società e vengono assunti

nel normale corso degli affari.

(c) Esclude le passività associate ai benefici fiscali non riconosciuti della società

in quanto non è possibile stimare in modo affidabile i tempi della liquidità futura

deflussi relativi a tali passività. Vedi nota 14 al testo consolidato

Bilanci per ulteriori informazioni su tali imposte non riconosciute

benefici.

(d) Include $ 7,3 miliardi delle passività per corrispettivo potenziale che sono

registrato al valore equo nel bilancio consolidato. Potenziale

pagamenti di corrispettivi potenziali che eccedono il valore equo registrato nel

    consolidated balance sheet are not included in the table of contractual
    obligations. See Note 11 to the Consolidated Financial Statements for
    additional information regarding these liabilities.

(e) Include un'obbligo fiscale di transizione una tantum su un obbligo ritenuto

conseguente rimpatrio di utili precedentemente non tassati di filiali estere

a partire dal NOI. riforma fiscale attuata nel 2017. L'imposta di transizione una tantum è

generalmente pagabile in otto rate annuali. Vedi nota 14 al

Bilancio consolidato per ulteriori informazioni al riguardo

passività fiscali.

(f) I pagamenti per il leasing includono circa $ 350 milioni del minimo contrattuale

pagamenti per contratti di locazione eseguiti ma non ancora iniziati. Questi contratti di locazione lo faranno

iniziare nel 2020 con un contratto di locazione di circa 11 anni.



AbbVie enters into R&D collaboration arrangements with third parties that may
require future milestone payments to third parties contingent upon the
achievement of certain development, regulatory, or commercial milestones.
Individually, these arrangements are insignificant in any one annual reporting
period. However, if milestones for multiple products covered by these
arrangements would happen to be reached in the same reporting period, the
aggregate charge to expense could be material to the results of operations in
that period. From a business perspective, the payments are viewed as positive
because they signify that the product is successfully moving through development
and is now generating or is more likely to generate future cash flows from
product sales. It is not possible to predict with reasonable certainty whether
these milestones will be achieved or the timing for achievement. As a result,
these potential payments are not included in the table of contractual

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obligations. See Note 5 to the Consolidated Financial Statements for additional
information on these collaboration arrangements.
CRITICAL ACCOUNTING POLICIES AND ESTIMATES
The preparation of financial statements in accordance with generally accepted
accounting principles in the United States requires the use of estimates and
assumptions that affect the reported amounts of assets and liabilities and the
reported amounts of revenue and expenses. A summary of the company's significant
accounting policies is included in Note 2 to the Consolidated Financial
Statements. Certain of these policies are considered critical as these most
significantly impact the company's financial condition and results of operations
and require the most difficult, subjective, or complex judgments, often as a
result of the need to make estimates about the effect of matters that are
inherently uncertain. Actual results may vary from these estimates.
Revenue Recognition
AbbVie recognizes revenue when control of promised goods or services is
transferred to the company's customers, in an amount that reflects the
consideration AbbVie expects to be entitled to in exchange for those goods or
services. Sales, value add and other taxes collected concurrent with
revenue-producing activities are excluded from revenue. AbbVie generates revenue
primarily from product sales. For the majority of sales, the company transfers
control, invoices the customer and recognizes revenue upon shipment to the
customer.
Rebates
AbbVie provides rebates to pharmacy benefit managers, state government Medicaid
programs, insurance companies that administer Medicare drug plans, wholesalers,
group purchasing organizations and other government agencies and private
entities.
Rebate and chargeback accruals are accounted for as variable consideration and
are recorded as a reduction to revenue in the period the related product is
sold. Rebates and chargebacks totaled $18.8 billion in 2019, $16.4 billion in
2018 and $12.9 billion in 2017. Rebate amounts are typically based upon the
volume of purchases using contractual or statutory prices, which may vary by
product and by payer. For each type of rebate, the factors used in the
calculations of the accrual for that rebate include the identification of the
products subject to the rebate, the applicable price terms and the estimated lag
time between sale and payment of the rebate, which can be significant.
In order to establish its rebate and chargeback accruals, the company uses both
internal and external data to estimate the level of inventory in the
distribution channel and the rebate claims processing lag time for each type of
rebate. To estimate the rebate percentage or net price, the company tracks sales
by product and by customer or payer. The company evaluates inventory data
reported by wholesalers, available prescription volume information, product
pricing, historical experience and other factors in order to determine the
adequacy of its reserves. AbbVie regularly monitors its reserves and records
adjustments when rebate trends, rebate programs and contract terms, legislative
changes, or other significant events indicate that a change in the reserve is
appropriate. Historically, adjustments to rebate accruals have not been material
to net earnings.

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The following table is an analysis of the three largest rebate accruals and
chargeback allowances, which comprise approximately 94% of the total
consolidated rebate and chargebacks recorded as reductions to revenues in 2019.
Remaining rebate provisions charged against gross revenues are not significant
in the determination of operating earnings.
                               Medicaid
                                  and        Managed
                               Medicare        Care       Wholesaler
(in millions)                   Rebates       Rebates     Chargebacks

Saldo a 31 dicembre 2016$ 1,167$ 1,167$ 383
disposizioni

                        2,909        3,990           5,026
Payments                         (2,736 )     (3,962 )        (4,887 )
Balance at December 31, 2017      1,340        1,195             522
Provisions                        3,493        4,729           6,659
Payments                         (3,188 )     (4,485 )        (6,525 )
Balance at December 31, 2018      1,645        1,439             656
Provisions                        4,035        5,772           7,947
Payments                         (3,915 )     (5,275 )        (7,917 )

Saldo a 31 dicembre 2019$ 1,765$ 1.936$ 686



Cash Discounts and Product Returns
Cash discounts and product returns, which totaled $1.6 billion in 2019, $1.6
billion in 2018 and $1.3 billion in 2017, are accounted for as variable
consideration and are recorded as a reduction to revenue in the same period the
related product is sold. The reserve for cash discounts is readily determinable
because the company's experience of payment history is fairly consistent.
Product returns can be reliably estimated based on the company's historical
return experience.
Pension and Other Post-Employment Benefits
AbbVie engages outside actuaries to assist in the determination of the
obligations and costs under the pension and other post-employment benefit plans
that are direct obligations of AbbVie. The valuation of the funded status and
the net periodic benefit cost for these plans are calculated using actuarial
assumptions. The significant assumptions, which are reviewed annually, include
the discount rate, the expected long-term rate of return on plan assets and the
health care cost trend rates, and are disclosed in Note 12 to the Consolidated
Financial Statements.
The discount rate is selected based on current market rates on high-quality,
fixed-income investments at December 31 each year. AbbVie employs a yield-curve
approach for countries where a robust bond market exists. The yield curve is
developed using high-quality bonds. The yield-curve approach reflects the plans'
specific cash flows (i.e. duration) in calculating the benefit obligations by
applying the corresponding individual spot rates along the yield curve. AbbVie
reflects the plans' specific cash flows and applies them to the corresponding
individual spot rates along the yield curve in calculating the service cost and
interest cost portions of expense. For other countries, AbbVie reviews various
indices such as corporate bond and government bond benchmarks to estimate the
discount rate. AbbVie's assumed discount rates have a significant effect on the
amounts reported for defined benefit pension and other post-employment plans as
of December 31, 2019. A 50 basis point change in the assumed discount rate would
have had the following effects on AbbVie's calculation of net periodic benefit
costs in 2020 and projected benefit obligations as of December 31, 2019:
                                                  50 basis point
(in millions) (brackets denote a reduction)  Increase       Decrease
Defined benefit plans
Service and interest cost                   $    (76 )$       92
Projected benefit obligation                    (723 )            825
Other post-employment plans
Service and interest cost                   $    (11 )$       14
Projected benefit obligation                    (101 )            117

Il tasso di rendimento atteso a lungo termine si basa sull'allocazione delle attività,
performance storica e visione attuale dei rendimenti futuri attesi. Abbvie
considera questi input con un focus a lungo termine per evitare il mercato a breve termine
influenze. Il


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current long-term rate of return on plan assets for each plan is supported by
the historical performance of the trust's actual and target asset allocation.
AbbVie's assumed expected long-term rate of return has a significant effect on
the amounts reported for defined benefit pension plans as of December 31, 2019
and will be used in the calculation of net periodic benefit cost in 2020. A
one percentage point change in assumed expected long-term rate of return on plan
assets would increase or decrease the net period benefit cost of these plans in
2020 by $71 million.
The health care cost trend rate is selected by reviewing historical trends and
current views on projected future health care cost increases. The current health
care cost trend rate is supported by the historical trend experience of each
plan. Assumed health care cost trend rates have a significant effect on the
amounts reported for health care plans as of December 31, 2019 and will be used
in the calculation of net periodic benefit cost in 2020. A one percentage point
change in assumed health care cost trend rates would have the following effects
on AbbVie's calculation of net periodic benefit costs in 2020 and the projected
benefit obligation as of December 31, 2019:
                                                   One percentage point
(in millions) (brackets denote a reduction)       Increase           Decrease
Service and interest cost                   $      40$    (28 )
Projected benefit obligation                      244                   (186 )


Income Taxes
AbbVie accounts for income taxes under the asset and liability method.
Provisions for federal, state and foreign income taxes are calculated on
reported pretax earnings based on current tax laws. Deferred taxes are provided
using enacted tax rates on the future tax consequences of temporary differences,
which are the differences between the financial statement carrying amount of
assets and liabilities and their respective tax bases and the tax benefits of
carryforwards. A valuation allowance is established or maintained when, based on
currently available information, it is more likely than not that all or a
portion of a deferred tax asset will not be realized.
Litigation
The company is subject to contingencies, such as various claims, legal
proceedings and investigations regarding product liability, intellectual
property, commercial, securities and other matters that arise in the normal
course of business. See Note 15 to the Consolidated Financial Statements for
additional information. Loss contingency provisions are recorded for probable
losses at management's best estimate of a loss, or when a best estimate cannot
be made, a minimum loss contingency amount within a probable range is recorded.
Accordingly, AbbVie is often initially unable to develop a best estimate of loss
and therefore, the minimum amount, which could be zero, is recorded. As
information becomes known, either the minimum loss amount is increased,
resulting in additional loss provisions, or a best estimate can be made, also
resulting in additional loss provisions. Occasionally, a best estimate amount is
changed to a lower amount when events result in an expectation of a more
favorable outcome than previously expected.
Valuation of Goodwill and Intangible Assets
AbbVie has acquired and may continue to acquire significant intangible assets in
connection with business combinations that AbbVie records at fair value.
Transactions involving the purchase or sale of intangible assets occur with some
frequency between companies in the pharmaceuticals industry and valuations are
usually based on a discounted cash flow analysis incorporating the stage of
completion. The discounted cash flow model requires assumptions about the timing
and amount of future net cash flows, risk, cost of capital, terminal values and
market participants. Each of these factors can significantly affect the value of
the intangible asset. IPR&D acquired in a business combination is capitalized as
an indefinite-lived intangible asset until regulatory approval is obtained, at
which time it is accounted for as a definite-lived asset and amortized over its
estimated useful life, or discontinuation, at which point the intangible asset
will be written off. IPR&D acquired in transactions that are not business
combinations is expensed immediately, unless deemed to have an alternative
future use. Payments made to third parties subsequent to regulatory approval are
capitalized and amortized over the remaining useful life.
AbbVie reviews the recoverability of definite-lived intangible assets whenever
events or changes in circumstances indicate the carrying value of an asset may
not be recoverable. Goodwill and indefinite-lived intangible assets are reviewed
for impairment annually or when an event occurs that could result in an
impairment. See Note 2 to the Consolidated Financial Statements for further
information.
Annually, the company tests its goodwill for impairment by first assessing
qualitative factors to determine whether it is more likely than not that the
fair value is less than its carrying amount. Some of the factors considered in
the assessment include general macro-economic conditions, conditions specific to
the industry and market, cost factors, the overall financial

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performance and whether there have been sustained declines in the company's
share price. If the company concludes it is more likely than not that the fair
value of the reporting unit is less than its carrying amount, a quantitative
impairment test is performed. AbbVie tests indefinite-lived intangible assets
for impairment by first assessing qualitative factors to determine whether it is
more likely than not that the fair value is less than its carrying amount. If
the company concludes it is more likely than not that the fair value is less
than its carrying amount, a quantitative impairment test is performed.
For its quantitative impairment tests, the company uses an estimated future cash
flow approach that requires significant judgment with respect to future volume,
revenue and expense growth rates, changes in working capital use, the selection
of an appropriate discount rate, asset groupings and other assumptions and
estimates. The estimates and assumptions used are consistent with the company's
business plans and a market participant's views. The use of alternative
estimates and assumptions could increase or decrease the estimated fair value of
the assets and could potentially impact the company's results of operations.
Actual results may differ from the company's estimates.
Contingent Consideration
The fair value measurements of contingent consideration liabilities are
determined as of the acquisition date based on significant unobservable inputs,
including the discount rate, estimated probabilities and timing of achieving
specified development, regulatory and commercial milestones and the estimated
amount of future sales of the acquired products. Contingent consideration
liabilities are revalued to fair value at each subsequent reporting date until
the related contingency is resolved. The potential contingent consideration
payments are estimated by applying a probability-weighted expected payment model
for contingent milestone payments and a Monte Carlo simulation model for
contingent royalty payments, which are then discounted to present value. Changes
to the fair value of the contingent consideration liabilities can result from
changes to one or a number of inputs, including discount rates, the
probabilities of achieving the milestones, the time required to achieve the
milestones and estimated future sales. Significant judgment is employed in
determining the appropriateness of certain of these inputs. Changes to the
inputs described above could have a material impact on the company's financial
position and results of operations in any given period. At December 31, 2019, a
50 basis point increase/decrease in the assumed discount rate would have
decreased/increased the value of the contingent consideration liabilities by
approximately $280 million. Additionally, at December 31, 2019, a five
percentage point increase/decrease in the assumed probability of success across
all potential indications would have increased/decreased the value of the
contingent consideration liabilities by approximately $150 million.
Recent Accounting Pronouncements
See Note 2 to the Consolidated Financial Statements for additional information
on recent accounting pronouncements.

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© Edgar Online, fonte scorci

Psorilax:Ridurre |crema grassa x psoriasi

0

Psorilax: prezzo, funziona, recensioni, opinioni, originale

This approval is based on the Phase 3 ATTRACTION-3 trial, which evaluated Opdivo versus chemotherapy (docetaxel or paclitaxel) for the treatment of patients with unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC) refractory or intolerant to combination therapy with fluoropyrimidine and platinum-based drugs. For the primary endpoint of overall survival (OS), Opdivo demonstrated a 23% reduction in the risk of death (Hazard Ratio (HR) 0.77; 95% Confidence Interval (CI): 0.62 to 0.96; p=0.019) and a 2.5-month improvement in median OS (10.9 months (95% CI: 9.2 to 13.3)) compared with chemotherapy (8.4 months (95% CI: 7.2 to 9.9)). The safety profile of Opdivo in this trial was consistent with previously reported studies in solid tumors. The ATTRACTION-3 trial was sponsored by Ono Pharmaceutical Co. Ltd. of Japan, Bristol-Myers Squibb’s development partner for Opdivo.

“Alongside our partner, Ono Pharmaceutical, we are proud to offer Opdivo as an alternative to chemotherapy for patients in Japan with esophageal cancer, regardless of their PD-L1 status,” said Fouad Namouni, M.D., head, Oncology Development, Bristol-Myers Squibb. “This first-ever approval of Opdivo in esophageal cancer exemplifies our commitment to advancing treatment options with the potential to extend survival for patients with difficult-to-treat gastrointestinal cancers.”

About ATTRACTION-3

ATTRACTION-3 (ONO-4538-24/CA209-473; NCT02569242) is a Phase 3, multi-center, randomized, open-label global study, evaluating Opdivo versus chemotherapy (docetaxel or paclitaxel) for patients with esophageal cancer refractory or intolerant to first-line combination therapy with fluoropyrimidine and platinum-based drugs. Patient enrollment occurred predominantly in Asia, with the remainder in the United States and Europe. Patients were treated until disease progression or unacceptable toxicity. The primary endpoint of the trial was OS. Secondary endpoints include investigator-assessed objective response rate, progression-free survival, disease control rate, duration of response and safety.

Patients treated in the Opdivo arm showed 12- and 18-month OS rates of 47% (95% CI: 40 to 54) and 31% (95% CI: 24 to 37), respectively, versus 34% (95% CI: 28 to 41) and 21% (95% CI: 15 to 27) among patients in the chemotherapy arm. Survival benefit with Opdivo was observed regardless of tumor PD-L1 expression levels. An exploratory analysis of patient-reported outcomes showed significant overall improvement in quality of life with Opdivo versus chemotherapy.

Fewer treatment-related adverse events (TRAEs) were reported with Opdivo versus chemotherapy, with a rate of 66% of any grade TRAEs for patients receiving Opdivo compared to 95% for patients receiving chemotherapy. Patients in the Opdivo arm also experienced a lower incidence of Grade 3 or 4 TRAEs compared to those in the chemotherapy arm (18% versus 63%), and the percentage of patients experiencing TRAEs leading to discontinuation was the same in both arms (9%).

Data from the study were featured in a Presidential Symposium during the European Society for Medical Oncology 2019 Annual Congress and simultaneously published in The Lancet Oncology.

About Esophageal Cancer

Esophageal cancer is the seventh most common cancer and the sixth most common cause of death from cancer worldwide. The five-year relative survival rate is 8% or less for patients diagnosed with metastatic disease. Globally, an estimated 572,000 new cases of esophageal cancer are diagnosed each year, nearly 80% of which occur in Asia. In Japan, approximately 20,000 cases are diagnosed and 12,000 deaths are caused by esophageal cancer every year. The two most common types of esophageal cancer are adenocarcinoma and squamous cell carcinoma, the latter accounting for approximately 90% of all esophageal cancer cases diagnosed in Japan. The majority of cases are diagnosed in the advanced setting and impact a patient’s daily life, including their ability to eat and drink.

Bristol-Myers Squibb: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. The focus of our research is to increase quality, long-term survival for patients and make cure a possibility. Through a unique multidisciplinary approach powered by translational science, we harness our deep scientific experience in oncology and Immuno-Oncology (I-O) research to identify novel treatments tailored to individual patient needs. Our researchers are developing a diverse, purposefully built pipeline designed to target different immune system pathways and address the complex and specific interactions between the tumor, its microenvironment and the immune system. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines, like I-O, a reality for patients.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology, and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO®

OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO® (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO® (nivolumab) is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC).

OPDIVO® (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO® (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO® (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy, and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests, at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6% (25/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 1.7% (2/119) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 7% (8/119) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 8% (10/119) of patients.

In Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hypophysitis occurred in 3.4% (4/119) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 5% (21/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 5.9% (7/119) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving this dose of OPDIVO with YERVOY. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 15% (18/119) of patients. Hyperthyroidism occurred in 12% (14/119) of patients. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 1.7% (2/119) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16% (90/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 14% (17/119) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of exposure. Encephalitis occurred in one RCC patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of exposure. Encephalitis occurred in one MSI-H/dMMR mCRC patient (0.8%) receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg after 15 days of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.

If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 4.2% (5/119) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue breastfeeding during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 032, serious adverse reactions occurred in 45% of patients receiving OPDIVO (n=245). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, pneumonitis, pleural effusions, and dehydration. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib. The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in ≥2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia. In Checkmate 238, Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. Serious adverse reactions occurred in 18% of OPDIVO-treated patients.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 032, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=245) were fatigue (45%), decreased appetite (27%), musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea (21%), constipation (20%), and cough (20%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), decreased appetite (21% vs 29%), dyspnea (20% vs 21%), and vomiting (20% vs 28%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO (n=236) were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent, the most common adverse reactions (≥20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, the most common adverse reactions (≥20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Recommended Dose Modifications

Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Discontinue in patients with severe or life-threatening infusion reactions.

Endocrine: Withhold YERVOY for symptomatic endocrinopathy. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for symptomatic reactions lasting 6 weeks or longer or an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.

Ophthalmologic: Permanently discontinue YERVOY for Grade 2-4 reactions not improving to Grade 1 within 2 weeks while receiving topical therapy or requiring systemic treatment.

All Other Organ Systems: Withhold YERVOY for Grade 2 adverse reactions. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for Grade 2 reactions lasting 6 weeks or longer, an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day, and Grade 3 or 4 adverse reactions.

Immune-Mediated Enterocolitis

Immune-mediated enterocolitis, including fatal cases, can occur with YERVOY. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent). Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Consider adding anti-TNF or other immunosuppressant agents for management of immune-mediated enterocolitis unresponsive to systemic corticosteroids within 3-5 days or recurring after symptom improvement, if other causes are excluded. In patients receiving YERVOY 3 mg/kg in MDX010-20, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 YERVOY-treated patients (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 YERVOY-treated patients (5%). Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis. Infliximab was administered to 5 (8%) of the 62 patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3-5 immune-mediated enterocolitis occurred in 76 patients (16%) and Grade 2 enterocolitis occurred in 68 patients (14%). Seven (1.5%) developed intestinal perforation and 3 patients (0.6%) died as a result of complications.

Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered in corticosteroid-refractory immune-mediated colitis if other causes are excluded.

Immune-Mediated Hepatitis

Immune-mediated hepatitis, including fatal cases, can occur with YERVOY. Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution. Withhold YERVOY in patients with Grade 2 hepatotoxicity. Permanently discontinue YERVOY in patients with Grade 3-4 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids. In patients receiving YERVOY 3 mg/kg in MDX010-20, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5× the ULN or total bilirubin elevations >3× the ULN; Grade 3-5) occurred in 8 YERVOY-treated patients (2%), with fatal hepatic failure in 0.2% and hospitalization in 0.4%. An additional 13 patients (2.5%) experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5× but ≤5× the ULN or total bilirubin elevation >1.5× but ≤3× the ULN; Grade 2). In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3-4 immune-mediated hepatitis occurred in 51 patients (11%) and moderate Grade 2 immune-mediated hepatitis occurred in 22 patients (5%). Liver biopsy performed in 6 patients with Grade 3-4 hepatitis showed evidence of toxic or autoimmune hepatitis.

Immune-Mediated Dermatitis

Immune-mediated dermatitis, including fatal cases, can occur with YERVOY. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically; administer topical or systemic corticosteroids if there is no improvement within 1 week. Withhold YERVOY in patients with moderate to severe signs and symptoms. Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. In patients receiving YERVOY 3 mg/kg in MDX010-20, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 YERVOY-treated patients (2.5%); 1 patient (0.2%) died as a result of toxic epidermal necrolysis and 1 additional patient required hospitalization for severe dermatitis. There were 63 patients (12%) with moderate (Grade 2) dermatitis. In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3-4 immune-mediated dermatitis occurred in 19 patients (4%). There were 99 patients (21%) with moderate Grade 2 dermatitis.

Immune-Mediated Neuropathies

Immune-mediated neuropathies, including fatal cases, can occur with YERVOY. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities). Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities), such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management for severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. In patients receiving YERVOY 3 mg/kg in MDX010-20, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported. In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3-5 immune-mediated neuropathy occurred in 8 patients (2%); the sole fatality was due to complications of Guillain-Barré syndrome. Moderate Grade 2 immune-mediated neuropathy occurred in 1 patient (0.2%).

Immune-Mediated Endocrinopathies

Immune-mediated endocrinopathies, including life-threatening cases, can occur with YERVOY. Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated. Monitor clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY in symptomatic patients and consider referral to an endocrinologist. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. In patients receiving YERVOY 3 mg/kg in MDX010-20, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 YERVOY-treated patients (1.8%). All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 patients (2.3%) and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 2.5 months and ranged up to 4.4 months after the initiation of YERVOY. In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3-4 immune-mediated endocrinopathies occurred in 39 patients (8%) and Grade 2 immune-mediated endocrinopathies occurred in 93 patients (20%). Of the 39 patients with Grade 3-4 immune-mediated endocrinopathies, 35 patients had hypopituitarism (associated with 1 or more secondary endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary hypothyroidism. The median time to onset of Grade 3-4 immune-mediated endocrinopathy was 2.2 months (range: 2 days-8 months). Twenty-seven (69.2%) of the 39 patients were hospitalized for immune-mediated endocrinopathies. Of the 93 patients with Grade 2 immune-mediated endocrinopathy, 74 had primary hypopituitarism (associated with 1 or more secondary endocrinopathy, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 9 had primary hypothyroidism, 3 had hyperthyroidism, 3 had thyroiditis with hypo- or hyperthyroidism, 2 had hypogonadism, 1 had both hyperthyroidism and hypopituitarism, and 1 subject developed Graves’ ophthalmopathy. The median time to onset of Grade 2 immune-mediated endocrinopathy was 2.1 months (range: 9 days-19.3 months).

Other Immune-Mediated Adverse Reactions

Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions. Monitor patients for signs or symptoms of ocular toxicity, which may include blurred vision and reduced visual acuity. Immune-mediated ocular toxicity may be associated with retinal detachment or permanent vision loss. Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving YERVOY and may require treatment with systemic steroids to reduce the risk of permanent vision loss. Fatal or serious graft-versus-host disease (GVHD) can occur in patients who receive a CTLA-4 receptor blocking antibody either before or after allogeneic hematopoietic stem cell transplantation (HSCT). Follow patients closely for evidence of GVHD and intervene promptly. Consider the benefit versus risks of treatment with a CTLA-4 receptor blocking antibody after allogeneic HSCT. In MDX010-20, the following clinically significant immune-mediated adverse reactions were seen in <1% of YERVOY-treated patients: cytopenias, nephritis, pneumonitis, meningitis, pericarditis, uveitis, and iritis. In CA184-029, the following clinically significant immune-mediated adverse reactions were seen in <1% of YERVOY-treated patients unless specified: cytopenias, eosinophilia (2.1%), pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis, pericarditis, uveitis, and fatal myocarditis. Across 21 dose-ranging trials administering YERVOY at doses of 0.1 to 20 mg/kg (n=2478), the following likely immune-mediated adverse reactions were also reported with <1% incidence unless specified: angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, ocular myositis, cytopenias (2.5%), and nephritis.

Embryo-Fetal Toxicity

Based on its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for 3 months after the last dose.

Lactation

It is not known whether YERVOY is secreted in human milk. Advise women not to breastfeed during treatment with YERVOY and for 3 months after the last dose.

Common Adverse Reactions

The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%). The most common adverse reactions (≥5%) in patients who received YERVOY at 10 mg/kg were rash (50%), diarrhea (49%), fatigue (46%), pruritus (45%), headache (33%), weight loss (32%), nausea (25%), pyrexia (18%), colitis (16%), decreased appetite (14%), vomiting (13%), and insomnia (10%).

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.

Checkmate Trials and Patient Populations

Checkmate 037–previously treated metastatic melanoma; Checkmate 066–previously untreated metastatic melanoma; Checkmate 067–previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 017–second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057–second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 032–small cell lung cancer; Checkmate 025–previously treated renal cell carcinoma; Checkmate 214–previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 205/039–classical Hodgkin lymphoma; Checkmate 141–recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275–urothelial carcinoma; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 040–hepatocellular carcinoma; Checkmate 238–adjuvant treatment of melanoma.

About the Bristol-Myers Squibb and Ono Pharmaceutical Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol-Myers Squibb further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram.

Celgene and Juno Therapeutics are wholly owned subsidiaries of Bristol-Myers Squibb Company. In certain countries outside the U.S., due to local laws, Celgene and Juno Therapeutics are referred to as, Celgene, a Bristol-Myers Squibb company and Juno Therapeutics, a Bristol-Myers Squibb company.

Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on historical performance and current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, Opdivo may not receive regulatory approval from the U.S. Food and Drug Administration or other regulatory authorities for the additional indication described in this release and whether such product candidate for such additional indication described in this release will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol-Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2018, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol-Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

Psorilax:Piano |creme per psoriasi glande

0

Psorilax: prezzo, funziona, recensioni, opinioni, quanto costa

Azienda Bristol-Myers Squibb (NYSE: BMY) ha annunciato oggi che il Ministero della salute, del lavoro e del welfare (MHLW) del Giappone ha approvato Opdivo (nivolumab) per il trattamento di pazienti con carcinoma esofageo avanzato o ricorrente non resecabile che è progredito a seguito di chemioterapia. “data-reagid =” 20 “> Bristol-Myers Squibb Company (NYSE: BMY) ha annunciato oggi il Ministero della salute, del lavoro e del benessere del Giappone (MHLW) ha approvato Opdivo (nivolumab) per il trattamento di pazienti con carcinoma esofageo avanzato o ricorrente non resecabile che è progredito dopo la chemioterapia.

Opdivo come alternativa alla chemioterapia per i pazienti in Giappone con carcinoma esofageo, indipendentemente dal loro stato di PD-L1 “, ha affermato Fouad Namouni, M.D., responsabile dello sviluppo dell'oncologia, Bristol-Myers Squibb.” Questa prima approvazione Opdivo nel carcinoma esofageo esemplifica il nostro impegno nel far progredire le opzioni terapeutiche con il potenziale di estendere la sopravvivenza per i pazienti con tumori gastrointestinali difficili da trattare. “” data-reagid = “22”> “Accanto al nostro partner, Ono Pharmaceutical, siamo orgogliosi di offrire Opdivo come alternativa alla chemioterapia per i pazienti in Giappone con carcinoma esofageo, indipendentemente dal loro stato di PD-L1 “, ha affermato Fouad Namouni, M.D., responsabile dello sviluppo dell'oncologia, Bristol-Myers Squibb.” Questa prima approvazione Opdivo nel carcinoma esofageo è un esempio del nostro impegno a far progredire le opzioni terapeutiche con il potenziale di estendere la sopravvivenza per i pazienti con tumori gastrointestinali difficili da trattare “.

Il cancro esofageo è il settimo tumore più comune e la sesta causa più comune di morte per cancro in tutto il mondo. Il tasso di sopravvivenza relativa a cinque anni è dell'8% o inferiore per i pazienti con diagnosi di malattia metastatica. A livello globale, ogni anno vengono diagnosticati circa 572.000 nuovi casi di carcinoma esofageo, quasi l'80% dei quali si verificano in Asia. In Giappone, vengono diagnosticati circa 20.000 casi e 12.000 decessi sono causati ogni anno dal cancro esofageo. I due tipi più comuni di carcinoma esofageo sono l'adenocarcinoma e il carcinoma a cellule squamose, che rappresentano circa il 90% di tutti i casi di carcinoma esofageo diagnosticati in Giappone. La maggior parte dei casi viene diagnosticata in un ambiente avanzato e ha un impatto sulla vita quotidiana di un paziente, inclusa la sua capacità di mangiare e bere.

Bristol-Myers Squibb: Advancing Oncology Research“data-reactionid =” 34 “>Bristol-Myers Squibb: Advancing Oncology Research

Alla Bristol-Myers Squibb, i pazienti sono al centro di tutto ciò che facciamo. L'obiettivo della nostra ricerca è aumentare la qualità, la sopravvivenza a lungo termine per i pazienti e rendere possibile la cura. Attraverso un approccio multidisciplinare unico basato sulla scienza traslazionale, sfruttiamo la nostra profonda esperienza scientifica nella ricerca oncologica e di immuno-oncologia (I-O) per identificare nuovi trattamenti su misura per le esigenze dei singoli pazienti. I nostri ricercatori stanno sviluppando una pipeline diversificata, appositamente costruita, progettata per colpire diverse vie del sistema immunitario e affrontare le interazioni complesse e specifiche tra il tumore, il suo microambiente e il sistema immunitario. Forniamo innovazione internamente e in collaborazione con il mondo accademico, il governo, i gruppi di difesa e le società di biotecnologia, per contribuire a rendere la promessa di medicinali trasformazionali, come l'I-O, una realtà per i pazienti.

Di Opdivo“data-reactionid =” 36 “>Di Opdivo

INDICAZIONI APPROVATE DALLA FDA USA PER OPDIVO®“data -eagido =” 40 “>INDICAZIONI APPROVATE DALLA FDA USA PER OPDIVO®

IMPORTANTI INFORMAZIONI SULLA SICUREZZA“data-reactionid =” 54 “>IMPORTANTI INFORMAZIONI SULLA SICUREZZA

OPDIVO può causare polmonite immuno-mediata. Sono stati segnalati casi fatali. Monitorare i pazienti per segni con imaging radiografico e per sintomi di polmonite. Somministrare corticosteroidi per polmonite di grado 2 o più grave. Interrompere permanentemente per il Grado 3 o 4 e sospendere fino alla risoluzione per il Grado 2. Nei pazienti in trattamento con monoterapia OPDIVO si sono verificati casi fatali di polmonite immuno-mediata. La polmonite immunomediata si è verificata nel 3,1% (61/1994) dei pazienti. Nei pazienti trattati con OPDIVO 1 mg / kg con YERVOY 3 mg / kg, la polmonite immuno-mediata si è verificata nel 6% (25/407) dei pazienti. Nei pazienti con carcinoma a cellule renali trattati con OPDIVO 3 mg / kg con YERVOY 1 mg / kg, la polmonite immuno-mediata si è verificata nel 4,4% (24/547) dei pazienti. Nei pazienti con mCRC MSI-H / dMMR trattati con OPDIVO 3 mg / kg con YERVOY 1 mg / kg, la polmonite immuno-mediata si è verificata nell'1,7% (2/119) dei pazienti.

In Checkmate 205 e 039, la polmonite, inclusa la malattia polmonare interstiziale, si è verificata nel 6,0% (16/266) dei pazienti trattati con OPDIVO. La polmonite immunomediata si è verificata nel 4,9% (13/266) dei pazienti trattati con OPDIVO: Grado 3 (n = 1) e Grado 2 (n = 12).

OPDIVO può causare colite immuno-mediata. Monitorare i pazienti per segni e sintomi di colite. Somministrare corticosteroidi per grado 2 (di durata superiore a 5 giorni), 3 o 4 coliti. Sospendere la monoterapia con OPDIVO per il grado 2 o 3 e interrompere definitivamente per il grado 4 o la colite ricorrente al momento del riavvio di OPDIVO. Quando somministrato con YERVOY, sospendere OPDIVO e YERVOY per il grado 2 e interrompere definitivamente per il grado 3 o 4 o colite ricorrente. Nei pazienti in terapia con OPDIVO in monoterapia, la colite immuno-mediata si è verificata nel 2,9% (58/1994) dei pazienti. Nei pazienti trattati con OPDIVO 1 mg / kg con YERVOY 3 mg / kg, la colite immuno-mediata si è verificata nel 26% (107/407) dei pazienti, inclusi tre casi fatali. Nei pazienti con carcinoma renale in trattamento con OPDIVO 3 mg / kg con YERVOY 1 mg / kg, si è verificata una colite immuno-mediata nel 10% (52/547) dei pazienti. Nei pazienti con mCRC MSI-H / dMMR trattati con OPDIVO 3 mg / kg con YERVOY 1 mg / kg, la colite immuno-mediata si è verificata nel 7% (8/119) dei pazienti.

In uno studio di fase 3 separato su YERVOY 3 mg / kg, si è verificata enterocolite immuno-mediata grave, grave, pericolosa per la vita o fatale (diarrea di ≥7 feci al di sopra del basale, febbre, ileo, segni peritoneali; grado 3-5) 7%) pazienti. In tutti i pazienti trattati con YERVOY in quello studio (n = 511), 5 (1%) hanno sviluppato perforazione intestinale, 4 (0,8%) sono deceduti a causa di complicanze e 26 (5%) sono stati ricoverati in ospedale per grave enterocolite.

In Checkmate 040, l'epatite immuno-mediata che richiede corticosteroidi sistemici si è verificata nel 5% (8/154) dei pazienti trattati con OPDIVO.

In uno studio di fase 3 separato su YERVOY 3 mg / kg, sono stati riportati 1 caso di sindrome di Guillain-Barré fatale e 1 caso di neuropatia motoria periferica grave (grado 3).

OPDIVO può causare ipofisite immuno-mediata, insufficienza surrenalica immuno-mediata, disturbi autoimmuni della tiroide e diabete mellito di tipo 1. Monitorare i pazienti per segni e sintomi di ipofisite, segni e sintomi di insufficienza surrenalica, funzionalità tiroidea prima e periodicamente durante il trattamento e iperglicemia. Somministrare la sostituzione ormonale come indicato clinicamente e corticosteroidi per ipofisite di grado 2 o superiore. Trattenere per Grado 2 o 3 e interrompere definitivamente per ipofisite di Grado 4. Somministrare corticosteroidi per insufficienza surrenalica di grado 3 o 4. Trattenere per il grado 2 e interrompere definitivamente per l'insufficienza surrenalica di grado 3 o 4. Somministrare la terapia ormonale sostitutiva per l'ipotiroidismo. Avviare la gestione medica per il controllo dell'ipertiroidismo. Sospendere OPDIVO per Grado 3 e interrompere definitivamente per iperglicemia di Grado 4.

Nei pazienti in terapia con OPDIVO in monoterapia, l'ipofisite si è verificata nello 0,6% (12/1994) dei pazienti. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hypophysitis occurred in 3.4% (4/119) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 5% (21/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 5.9% (7/119) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving this dose of OPDIVO with YERVOY. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 15% (18/119) of patients. Hyperthyroidism occurred in 12% (14/119) of patients. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies.

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 1.7% (2/119) of patients.

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16% (90/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 14% (17/119) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of exposure. Encephalitis occurred in one RCC patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of exposure. Encephalitis occurred in one MSI-H/dMMR mCRC patient (0.8%) receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg after 15 days of exposure.

Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.

If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 4.2% (5/119) of patients.

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

In clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue breastfeeding during treatment with YERVOY and for 3 months following the final dose.

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 032, serious adverse reactions occurred in 45% of patients receiving OPDIVO (n=245). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, pneumonitis, pleural effusions, and dehydration. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib. The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in ≥2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia. In Checkmate 238, Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. Serious adverse reactions occurred in 18% of OPDIVO-treated patients.

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 032, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=245) were fatigue (45%), decreased appetite (27%), musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea (21%), constipation (20%), and cough (20%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), decreased appetite (21% vs 29%), dyspnea (20% vs 21%), and vomiting (20% vs 28%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO (n=236) were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent, the most common adverse reactions (≥20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, the most common adverse reactions (≥20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Discontinue in patients with severe or life-threatening infusion reactions.

Endocrine: Withhold YERVOY for symptomatic endocrinopathy. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for symptomatic reactions lasting 6 weeks or longer or an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.

Ophthalmologic: Permanently discontinue YERVOY for Grade 2-4 reactions not improving to Grade 1 within 2 weeks while receiving topical therapy or requiring systemic treatment.

All Other Organ Systems: Withhold YERVOY for Grade 2 adverse reactions. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for Grade 2 reactions lasting 6 weeks or longer, an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day, and Grade 3 or 4 adverse reactions.

Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered in corticosteroid-refractory immune-mediated colitis if other causes are excluded.

Immune-mediated dermatitis, including fatal cases, can occur with YERVOY. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically; administer topical or systemic corticosteroids if there is no improvement within 1 week. Withhold YERVOY in patients with moderate to severe signs and symptoms. Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. In patients receiving YERVOY 3 mg/kg in MDX010-20, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 YERVOY-treated patients (2.5%); 1 patient (0.2%) died as a result of toxic epidermal necrolysis and 1 additional patient required hospitalization for severe dermatitis. There were 63 patients (12%) with moderate (Grade 2) dermatitis. In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3-4 immune-mediated dermatitis occurred in 19 patients (4%). There were 99 patients (21%) with moderate Grade 2 dermatitis.

Immune-mediated neuropathies, including fatal cases, can occur with YERVOY. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities). Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities), such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management for severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. In patients receiving YERVOY 3 mg/kg in MDX010-20, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported. In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3-5 immune-mediated neuropathy occurred in 8 patients (2%); the sole fatality was due to complications of Guillain-Barré syndrome. Moderate Grade 2 immune-mediated neuropathy occurred in 1 patient (0.2%).

Immune-mediated endocrinopathies, including life-threatening cases, can occur with YERVOY. Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated. Monitor clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY in symptomatic patients and consider referral to an endocrinologist. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. In patients receiving YERVOY 3 mg/kg in MDX010-20, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 YERVOY-treated patients (1.8%). All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 patients (2.3%) and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing's syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 2.5 months and ranged up to 4.4 months after the initiation of YERVOY. In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3-4 immune-mediated endocrinopathies occurred in 39 patients (8%) and Grade 2 immune-mediated endocrinopathies occurred in 93 patients (20%). Of the 39 patients with Grade 3-4 immune-mediated endocrinopathies, 35 patients had hypopituitarism (associated with 1 or more secondary endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary hypothyroidism. The median time to onset of Grade 3-4 immune-mediated endocrinopathy was 2.2 months (range: 2 days-8 months). Twenty-seven (69.2%) of the 39 patients were hospitalized for immune-mediated endocrinopathies. Of the 93 patients with Grade 2 immune-mediated endocrinopathy, 74 had primary hypopituitarism (associated with 1 or more secondary endocrinopathy, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 9 had primary hypothyroidism, 3 had hyperthyroidism, 3 had thyroiditis with hypo- or hyperthyroidism, 2 had hypogonadism, 1 had both hyperthyroidism and hypopituitarism, and 1 subject developed Graves’ ophthalmopathy. The median time to onset of Grade 2 immune-mediated endocrinopathy was 2.1 months (range: 9 days-19.3 months).

Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions. Monitor patients for signs or symptoms of ocular toxicity, which may include blurred vision and reduced visual acuity. Immune-mediated ocular toxicity may be associated with retinal detachment or permanent vision loss. Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving YERVOY and may require treatment with systemic steroids to reduce the risk of permanent vision loss. Fatal or serious graft-versus-host disease (GVHD) can occur in patients who receive a CTLA-4 receptor blocking antibody either before or after allogeneic hematopoietic stem cell transplantation (HSCT). Follow patients closely for evidence of GVHD and intervene promptly. Consider the benefit versus risks of treatment with a CTLA-4 receptor blocking antibody after allogeneic HSCT. In MDX010-20, the following clinically significant immune-mediated adverse reactions were seen in <1% of YERVOY-treated patients: cytopenias, nephritis, pneumonitis, meningitis, pericarditis, uveitis, and iritis. In CA184-029, the following clinically significant immune-mediated adverse reactions were seen in <1% of YERVOY-treated patients unless specified: cytopenias, eosinophilia (2.1%), pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis, pericarditis, uveitis, and fatal myocarditis. Across 21 dose-ranging trials administering YERVOY at doses of 0.1 to 20 mg/kg (n=2478), the following likely immune-mediated adverse reactions were also reported with <1% incidence unless specified: angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, ocular myositis, cytopenias (2.5%), and nephritis.

Based on its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for 3 months after the last dose.

It is not known whether YERVOY is secreted in human milk. Advise women not to breastfeed during treatment with YERVOY and for 3 months after the last dose.

The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%). The most common adverse reactions (≥5%) in patients who received YERVOY at 10 mg/kg were rash (50%), diarrhea (49%), fatigue (46%), pruritus (45%), headache (33%), weight loss (32%), nausea (25%), pyrexia (18%), colitis (16%), decreased appetite (14%), vomiting (13%), and insomnia (10%).

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Psorilax:Sano |crema psoriasi lidl

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PRINCETON, N.J.–(BUSINESS WIRE)–Bristol-Myers Squibb Company (NYSE: BMY) today announced Japan’s Ministry of Health, Labor and Welfare (MHLW) has approved Opdivo (nivolumab) for the treatment of patients with unresectable advanced or recurrent esophageal cancer that has progressed following chemotherapy.

This approval is based on the Phase 3 ATTRACTION-3 trial, which evaluated Opdivo versus chemotherapy (docetaxel or paclitaxel) for the treatment of patients with unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC) refractory or intolerant to combination therapy with fluoropyrimidine and platinum-based drugs. For the primary endpoint of overall survival (OS), Opdivo demonstrated a 23% reduction in the risk of death (Hazard Ratio (HR) 0.77; 95% Confidence Interval (CI): 0.62 to 0.96; p=0.019) and a 2.5-month improvement in median OS (10.9 months (95% CI: 9.2 to 13.3)) compared with chemotherapy (8.4 months (95% CI: 7.2 to 9.9)). The safety profile of Opdivo in this trial was consistent with previously reported studies in solid tumors. The ATTRACTION-3 trial was sponsored by Ono Pharmaceutical Co. Ltd. of Japan, Bristol-Myers Squibb’s development partner for Opdivo.

“Alongside our partner, Ono Pharmaceutical, we are proud to offer Opdivo as an alternative to chemotherapy for patients in Japan with esophageal cancer, regardless of their PD-L1 status,” said Fouad Namouni, M.D., head, Oncology Development, Bristol-Myers Squibb. “This first-ever approval of Opdivo in esophageal cancer exemplifies our commitment to advancing treatment options with the potential to extend survival for patients with difficult-to-treat gastrointestinal cancers.”

About ATTRACTION-3

ATTRACTION-3 (ONO-4538-24/CA209-473; NCT02569242) is a Phase 3, multi-center, randomized, open-label global study, evaluating Opdivo versus chemotherapy (docetaxel or paclitaxel) for patients with esophageal cancer refractory or intolerant to first-line combination therapy with fluoropyrimidine and platinum-based drugs. Patient enrollment occurred predominantly in Asia, with the remainder in the United States and Europe. Patients were treated until disease progression or unacceptable toxicity. The primary endpoint of the trial was OS. Secondary endpoints include investigator-assessed objective response rate, progression-free survival, disease control rate, duration of response and safety.

Patients treated in the Opdivo arm showed 12- and 18-month OS rates of 47% (95% CI: 40 to 54) and 31% (95% CI: 24 to 37), respectively, versus 34% (95% CI: 28 to 41) and 21% (95% CI: 15 to 27) among patients in the chemotherapy arm. Survival benefit with Opdivo was observed regardless of tumor PD-L1 expression levels. An exploratory analysis of patient-reported outcomes showed significant overall improvement in quality of life with Opdivo versus chemotherapy.

Fewer treatment-related adverse events (TRAEs) were reported with Opdivo versus chemotherapy, with a rate of 66% of any grade TRAEs for patients receiving Opdivo compared to 95% for patients receiving chemotherapy. Patients in the Opdivo arm also experienced a lower incidence of Grade 3 or 4 TRAEs compared to those in the chemotherapy arm (18% versus 63%), and the percentage of patients experiencing TRAEs leading to discontinuation was the same in both arms (9%).

Data from the study were featured in a Presidential Symposium during the European Society for Medical Oncology 2019 Annual Congress and simultaneously published in The Lancet Oncology.

About Esophageal Cancer

Esophageal cancer is the seventh most common cancer and the sixth most common cause of death from cancer worldwide. The five-year relative survival rate is 8% or less for patients diagnosed with metastatic disease. Globally, an estimated 572,000 new cases of esophageal cancer are diagnosed each year, nearly 80% of which occur in Asia. In Japan, approximately 20,000 cases are diagnosed and 12,000 deaths are caused by esophageal cancer every year. The two most common types of esophageal cancer are adenocarcinoma and squamous cell carcinoma, the latter accounting for approximately 90% of all esophageal cancer cases diagnosed in Japan. The majority of cases are diagnosed in the advanced setting and impact a patient’s daily life, including their ability to eat and drink.

Bristol-Myers Squibb: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. The focus of our research is to increase quality, long-term survival for patients and make cure a possibility. Through a unique multidisciplinary approach powered by translational science, we harness our deep scientific experience in oncology and Immuno-Oncology (I-O) research to identify novel treatments tailored to individual patient needs. Our researchers are developing a diverse, purposefully built pipeline designed to target different immune system pathways and address the complex and specific interactions between the tumor, its microenvironment and the immune system. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines, like I-O, a reality for patients.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology, and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO®

OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO® (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO® (nivolumab) is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC).

OPDIVO® (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO® (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO® (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy, and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests, at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6% (25/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 1.7% (2/119) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 7% (8/119) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 8% (10/119) of patients.

In Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hypophysitis occurred in 3.4% (4/119) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 5% (21/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 5.9% (7/119) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving this dose of OPDIVO with YERVOY. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 15% (18/119) of patients. Hyperthyroidism occurred in 12% (14/119) of patients. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 1.7% (2/119) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16% (90/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 14% (17/119) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of exposure. Encephalitis occurred in one RCC patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of exposure. Encephalitis occurred in one MSI-H/dMMR mCRC patient (0.8%) receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg after 15 days of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.

If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 4.2% (5/119) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue breastfeeding during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 032, serious adverse reactions occurred in 45% of patients receiving OPDIVO (n=245). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, pneumonitis, pleural effusions, and dehydration. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib. The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in ≥2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia. In Checkmate 238, Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. Serious adverse reactions occurred in 18% of OPDIVO-treated patients.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 032, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=245) were fatigue (45%), decreased appetite (27%), musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea (21%), constipation (20%), and cough (20%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), decreased appetite (21% vs 29%), dyspnea (20% vs 21%), and vomiting (20% vs 28%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO (n=236) were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent, the most common adverse reactions (≥20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, the most common adverse reactions (≥20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Recommended Dose Modifications

Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Discontinue in patients with severe or life-threatening infusion reactions.

Endocrine: Withhold YERVOY for symptomatic endocrinopathy. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for symptomatic reactions lasting 6 weeks or longer or an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.

Ophthalmologic: Permanently discontinue YERVOY for Grade 2-4 reactions not improving to Grade 1 within 2 weeks while receiving topical therapy or requiring systemic treatment.

All Other Organ Systems: Withhold YERVOY for Grade 2 adverse reactions. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for Grade 2 reactions lasting 6 weeks or longer, an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day, and Grade 3 or 4 adverse reactions.

Immune-Mediated Enterocolitis

Immune-mediated enterocolitis, including fatal cases, can occur with YERVOY. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent). Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Consider adding anti-TNF or other immunosuppressant agents for management of immune-mediated enterocolitis unresponsive to systemic corticosteroids within 3-5 days or recurring after symptom improvement, if other causes are excluded. In patients receiving YERVOY 3 mg/kg in MDX010-20, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 YERVOY-treated patients (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 YERVOY-treated patients (5%). Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis. Infliximab was administered to 5 (8%) of the 62 patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3-5 immune-mediated enterocolitis occurred in 76 patients (16%) and Grade 2 enterocolitis occurred in 68 patients (14%). Seven (1.5%) developed intestinal perforation and 3 patients (0.6%) died as a result of complications.

Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered in corticosteroid-refractory immune-mediated colitis if other causes are excluded.

Immune-Mediated Hepatitis

Immune-mediated hepatitis, including fatal cases, can occur with YERVOY. Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution. Withhold YERVOY in patients with Grade 2 hepatotoxicity. Permanently discontinue YERVOY in patients with Grade 3-4 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids. In patients receiving YERVOY 3 mg/kg in MDX010-20, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5× the ULN or total bilirubin elevations >3× the ULN; Grade 3-5) occurred in 8 YERVOY-treated patients (2%), with fatal hepatic failure in 0.2% and hospitalization in 0.4%. An additional 13 patients (2.5%) experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5× but ≤5× the ULN or total bilirubin elevation >1.5× but ≤3× the ULN; Grade 2). In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3-4 immune-mediated hepatitis occurred in 51 patients (11%) and moderate Grade 2 immune-mediated hepatitis occurred in 22 patients (5%). Liver biopsy performed in 6 patients with Grade 3-4 hepatitis showed evidence of toxic or autoimmune hepatitis.

Immune-Mediated Dermatitis

Immune-mediated dermatitis, including fatal cases, can occur with YERVOY. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically; administer topical or systemic corticosteroids if there is no improvement within 1 week. Withhold YERVOY in patients with moderate to severe signs and symptoms. Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. In patients receiving YERVOY 3 mg/kg in MDX010-20, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 YERVOY-treated patients (2.5%); 1 patient (0.2%) died as a result of toxic epidermal necrolysis and 1 additional patient required hospitalization for severe dermatitis. There were 63 patients (12%) with moderate (Grade 2) dermatitis. In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3-4 immune-mediated dermatitis occurred in 19 patients (4%). There were 99 patients (21%) with moderate Grade 2 dermatitis.

Immune-Mediated Neuropathies

Immune-mediated neuropathies, including fatal cases, can occur with YERVOY. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities). Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities), such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management for severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. In patients receiving YERVOY 3 mg/kg in MDX010-20, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported. In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3-5 immune-mediated neuropathy occurred in 8 patients (2%); the sole fatality was due to complications of Guillain-Barré syndrome. Moderate Grade 2 immune-mediated neuropathy occurred in 1 patient (0.2%).

Immune-Mediated Endocrinopathies

Immune-mediated endocrinopathies, including life-threatening cases, can occur with YERVOY. Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated. Monitor clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY in symptomatic patients and consider referral to an endocrinologist. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. In patients receiving YERVOY 3 mg/kg in MDX010-20, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 YERVOY-treated patients (1.8%). All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 patients (2.3%) and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 2.5 months and ranged up to 4.4 months after the initiation of YERVOY. In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3-4 immune-mediated endocrinopathies occurred in 39 patients (8%) and Grade 2 immune-mediated endocrinopathies occurred in 93 patients (20%). Of the 39 patients with Grade 3-4 immune-mediated endocrinopathies, 35 patients had hypopituitarism (associated with 1 or more secondary endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary hypothyroidism. The median time to onset of Grade 3-4 immune-mediated endocrinopathy was 2.2 months (range: 2 days-8 months). Twenty-seven (69.2%) of the 39 patients were hospitalized for immune-mediated endocrinopathies. Of the 93 patients with Grade 2 immune-mediated endocrinopathy, 74 had primary hypopituitarism (associated with 1 or more secondary endocrinopathy, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 9 had primary hypothyroidism, 3 had hyperthyroidism, 3 had thyroiditis with hypo- or hyperthyroidism, 2 had hypogonadism, 1 had both hyperthyroidism and hypopituitarism, and 1 subject developed Graves’ ophthalmopathy. The median time to onset of Grade 2 immune-mediated endocrinopathy was 2.1 months (range: 9 days-19.3 months).

Other Immune-Mediated Adverse Reactions

Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions. Monitor patients for signs or symptoms of ocular toxicity, which may include blurred vision and reduced visual acuity. Immune-mediated ocular toxicity may be associated with retinal detachment or permanent vision loss. Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving YERVOY and may require treatment with systemic steroids to reduce the risk of permanent vision loss. Fatal or serious graft-versus-host disease (GVHD) can occur in patients who receive a CTLA-4 receptor blocking antibody either before or after allogeneic hematopoietic stem cell transplantation (HSCT). Follow patients closely for evidence of GVHD and intervene promptly. Consider the benefit versus risks of treatment with a CTLA-4 receptor blocking antibody after allogeneic HSCT. In MDX010-20, the following clinically significant immune-mediated adverse reactions were seen in <1% of YERVOY-treated patients: cytopenias, nephritis, pneumonitis, meningitis, pericarditis, uveitis, and iritis. In CA184-029, the following clinically significant immune-mediated adverse reactions were seen in <1% of YERVOY-treated patients unless specified: cytopenias, eosinophilia (2.1%), pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis, pericarditis, uveitis, and fatal myocarditis. Across 21 dose-ranging trials administering YERVOY at doses of 0.1 to 20 mg/kg (n=2478), the following likely immune-mediated adverse reactions were also reported with <1% incidence unless specified: angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, ocular myositis, cytopenias (2.5%), and nephritis.

Embryo-Fetal Toxicity

Based on its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for 3 months after the last dose.

Lactation

It is not known whether YERVOY is secreted in human milk. Advise women not to breastfeed during treatment with YERVOY and for 3 months after the last dose.

Common Adverse Reactions

The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%). The most common adverse reactions (≥5%) in patients who received YERVOY at 10 mg/kg were rash (50%), diarrhea (49%), fatigue (46%), pruritus (45%), headache (33%), weight loss (32%), nausea (25%), pyrexia (18%), colitis (16%), decreased appetite (14%), vomiting (13%), and insomnia (10%).

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.

Checkmate Trials and Patient Populations

Checkmate 037–previously treated metastatic melanoma; Checkmate 066–previously untreated metastatic melanoma; Checkmate 067–previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 017–second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057–second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 032–small cell lung cancer; Checkmate 025–previously treated renal cell carcinoma; Checkmate 214–previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 205/039–classical Hodgkin lymphoma; Checkmate 141–recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275–urothelial carcinoma; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 040–hepatocellular carcinoma; Checkmate 238–adjuvant treatment of melanoma.

About the Bristol-Myers Squibb and Ono Pharmaceutical Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol-Myers Squibb further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram.

Celgene and Juno Therapeutics are wholly owned subsidiaries of Bristol-Myers Squibb Company. In certain countries outside the U.S., due to local laws, Celgene and Juno Therapeutics are referred to as, Celgene, a Bristol-Myers Squibb company and Juno Therapeutics, a Bristol-Myers Squibb company.

Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on historical performance and current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, Opdivo may not receive regulatory approval from the U.S. Food and Drug Administration or other regulatory authorities for the additional indication described in this release and whether such product candidate for such additional indication described in this release will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol-Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2018, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol-Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

Psorilax:opinioni |pso crema dermaffine recensioni forum psoriasi

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Psorilax: prezzo, funziona, recensioni, opinioni, dove si compra

Bruxelles, 23 febbraio 2020 (Thomson StreetEvents) – Trascrizione modificata della teleconferenza o presentazione degli utili della UCB SA giovedì 20 febbraio 2020 alle 13:00:00 GMT

UCB SA – Chief Medical Officer, Head of Development & Medical Patient Value Practices e Executive VP

Redburn (Europe) Limited, Divisione Ricerca – Analista di ricerca lato vendita biofarmaceutica

Jefferies LLC, Divisione Ricerca – Senior Equity Analyst & European Pharmaceuticals Analyst

* Richard J. Parkes

Sanford C. Bernstein & Co., LLC., Divisione Ricerca – Analista di ricerca

Benvenuti alla teleconferenza UCB. (Istruzioni per l'operatore) Si noti che questa teleconferenza verrà registrata e che un replay del webcast sarà disponibile più tardi oggi sul sito Web della UCB, nella sezione Investitori.

Sono lieto di presentare la signora Antje Witte, responsabile delle relazioni con gli investitori, che sarà moderatrice di questa conferenza. Signora Witte, il pavimento è tuo.

Grazie mille (Qayyum). Buon pomeriggio e buongiorno anche da parte mia. Grazie per esserti unito a noi per la nostra conference call sui risultati dell'intero anno 2019. Prima di passare a Jean-Christophe Tellier, il nostro CEO, che presenterà anche a te i relatori, vorrei ricordarti che questa presentazione, la sessione di domande e risposte e le diapositive della presentazione sono sotto il nostro disclaimer e dichiarazioni di sicurezza, trovi sulla diapositiva 2, che ti chiedo gentilmente di leggere attentamente.

E con ciò, vorrei consegnare a Jean-Christophe, CEO di UCB.

Grazie Antje. Buon pomeriggio, buongiorno a tutti e grazie per aver aderito alla nostra call sui risultati dell'intero anno. Come avrete visto nel comunicato stampa già questa mattina, siamo lieti della nostra performance del 2019. Questi buoni progressi nel nostro percorso di crescita strategica hanno rafforzato la nostra capacità di garantire una crescita sostenibile. Come indicato da Antje, vorrei esaminare l'ordine del giorno di questa chiamata. Ma prima di ciò, forse menzionando che con questo obiettivo in mente, stiamo rafforzando il nostro modello operativo per garantire più agilità e collaborazioni all'interno dell'organizzazione. E questa evoluzione si riflette nella nuova composizione del Comitato Esecutivo che abbiamo comunicato anche questa mattina nel comunicato stampa. Il Comitato Esecutivo, che è diventato più piccolo con ruoli più trasversali tra le imprese e le regioni, e hai alcune delle illustrazioni di ciò nell'agenda che è sullo schermo in questo momento.

Quindi prendendo la parola dopo di me, Emmanuel Caeymaex commenterà la nostra attività di immunologia. Ora abbiamo incluso Evenity nel nostro pilastro dell'immunologia e nel suo nuovo ruolo, Emmanuel sarà anche responsabile degli Stati Uniti, quindi Charl Van Zyl parlerà del franchise di neurologia, concentrandosi sull'epilessia. Charl era in precedenza responsabile della nostra operazione ed è ora responsabile del nostro pilastro di neurologia e delle nostre geografie europee e internazionali. E infine, Detlef ti guiderà attraverso i finanziari come al solito. Commenterà le prospettive per il 2020 e il nostro medio termine: nuove indicazioni a medio termine. Come sapete, e come precedentemente annunciato dopo un mandato di grande successo, Detlef si ritirerà da UCB nella prima metà del 2020. E come avrete visto nel comunicato stampa, stiamo continuando a cercare un successore e fiduciosi di poter – saremo in grado di farlo entro la fine della prima metà di quest'anno.

Quindi, come sapete, la nostra ambizione per i pazienti è di consentire loro di vivere la vita che desiderano e di non avere la vita definita da una malattia. Questa è l'ancora di ciò che facciamo, il nostro principale senso dello scopo e la giustificazione della nostra strategia di valore per il paziente. Rafforziamo costantemente il nostro senso dello scopo al fine di riflettere l'impegno per uno sviluppo sostenibile, e questo è lo scopo di questa diapositiva. Innanzitutto, vogliamo concentrarci sulle innovazioni in R&S, il che significa per noi, e questa è la nostra ambizione per il valore del paziente. Significa per noi offrire una soluzione differenziata con esiti unici per aiutare specifiche popolazioni di pazienti a raggiungere i loro obiettivi. Ma crea anche per loro la migliore esperienza individuale possibile.

Inoltre, significa anche ampliare l'accesso, e questo è il secondo pilastro che vedete qui in questa diapositiva. Accesso ai pazienti che potrebbero aver bisogno delle soluzioni che possiamo proporre loro in un modo che sia praticabile per loro, per la comunità, la società e per UCB. Ma valore per i pazienti, e questo è il terzo pilastro, valore per i pazienti significa anche offrire ai dipendenti della UCB il miglior ambiente per loro di essere al meglio, e in particolare in termini di salute, sicurezza e benessere. E infine, vogliamo fornire ciò minimizzando la nostra impronta ambientale su tutta la catena del valore.

Quindi, partendo da questo viaggio, dove siamo oggi? Come ricorderete, nel 2019 siamo entrati nella nostra seconda fase del nostro percorso strategico, la fase di spesa accelerata. Volevamo accelerare il nostro ciclo e sviluppare agilità. Volevamo espanderci in nuove popolazioni di pazienti e volevamo anche sfruttare la nostra flessibilità strategica identificando e agendo su potenziali opportunità. Quindi cosa abbiamo consegnato nel 2019. Innanzitutto, abbiamo aggiunto 2 nuovi prodotti nel nostro portafoglio per la nuova popolazione di pazienti. L'uniformità con il nostro partner, Amgen, nell'osteoporosi, è stata lanciata negli Stati Uniti e in Giappone e approvata in Corea del Sud, Australia, Canada e Europa. Questa è una terapia innovativa di prima classe per la costruzione di ossa nell'osteoporosi. Secondo nuovo prodotto che abbiamo aggiunto al nostro portafoglio, Nazolam, abbiamo lanciato a dicembre negli Stati Uniti, uno spray nasale per i cluster convulsivi. Abbiamo anche – e questo è il secondo elemento che vedi sulla diapositiva, abbiamo anche continuato ad accelerare e rafforzato significativamente la nostra pipeline con già 3 studi clinici di fase III positivi per bimekizumab nella psoriasi.

E 5 nuovi programmi di Fase III in – iniziati nel 2019: Bimekizumab nell'artrite psoriasica e nella spondiloartrite assiale; padsevonil nell'epilessia refrattaria; e rozanolixizumab nella miastenia grave e nella porpora trombocitopenica immune. E, ultimo ma non meno importante, abbiamo anche sfruttato la nostra flessibilità strategica che avevamo nelle nostre priorità. Lo scorso ottobre, abbiamo annunciato di aver raggiunto un accordo per l'acquisizione di Ra Pharma. Volevamo unire le forze per migliorare la nostra opzione per il trattamento delle persone che soffrono di miastenia grave e altre malattie rare. Charl ne commenterà più avanti. Tuttavia, poiché abbiamo condiviso con te e vogliamo confermare che siamo fiduciosi che saremo in grado di chiudere questo accordo nel primo trimestre 2020. Ma agire sulle potenziali opportunità e collegarci con diversi partner possibili, è anche raggiunto attraverso altri elementi e tu hai alcuni esempi qui.

Abbiamo creato una collaborazione pionieristica di ricerca e sviluppo di genomica di 5 anni con la società dell'epilessia per comprendere meglio la malattia, creare una nuova tassonomia e potenzialmente comprendere meglio i biomarcatori e come sviluppare un trattamento più appropriato per la popolazione di pazienti (impercettibili). Con SeizeIT, abbiamo concesso un accordo di progetto del consorzio per sviluppare un dispositivo di rilevazione delle crisi epilettiche discreto e personalizzato. E con il King's College di Londra, abbiamo firmato una collaborazione di ricerca e sviluppo di 3 anni. Quindi puoi vedere che non stiamo solo guardando alle opportunità esterne dal punto di vista delle fusioni e acquisizioni, ma stiamo anche rafforzando le nostre potenziali collaborazioni con altre parti interessate chiave nelle aree di nostro interesse. Quindi stiamo procedendo bene sui nostri percorsi e stiamo costruendo il nostro futuro.

Ma, naturalmente, siamo in grado di farlo, principalmente perché stiamo offrendo i nostri driver chiave per la crescita, ed è grazie al risultato di oggi, è grazie alle prestazioni di oggi che possiamo continuare a rafforzare un futuro sostenibile. Basandoci sul sesto anno consecutivo di crescita, in alto e in basso con un CAGR delle entrate dell'8% e un CAGR dell'EBITDA del 19% nel periodo che vedete nelle diapositive, abbiamo creato una piattaforma molto forte per il futuro. Quindi – e qui hai i principali risultati per prodotto in termini di crescita e numeri assoluti, allora Charl ed Emmanuel commenteranno ulteriormente. Ciò ci ha guidato e migliorato la nostra guida a medio termine.

Quindi siamo soddisfatti delle forti prestazioni del '19. Siamo lieti di essere stati in grado di continuare a crescere, che ci consentono di accelerare la nostra pipeline, ci consentono di costruire e rafforzare il nostro futuro e fornire valore sostenibile per i pazienti.

Quindi, con questo in mente, vorrei passare ora a Emmanuel.

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Emmanuel Caeymaex, UCB SA – Executive VP of Immunology Solutions & Head of US (4)

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Grazie, Jean-Christophe, e grazie a tutti per esservi uniti. Sono molto lieto di commentare le prestazioni e lo stato di avanzamento delle nostre 3 risorse immunologiche, tra cui Cimzia e i suoi driver di crescita, un aggiornamento su progressi e contesto per bimekizumab e anche sul lancio di Evenity. Partiamo quindi da Cimzia e dai componenti della forte crescita valutaria costante del 14% che avete visto e anche da come questo ci sta portando ad aumentare la nostra guida di vendita di punta per il marchio a 2 miliardi di euro. Quindi il primo punto, è importante notare che la crescita del 2019 è interamente guidata dal volume. Quindi non vi è alcun contributo positivo del prezzo netto. Tutte le aree geografiche hanno contribuito a questa crescita, come puoi vedere, e negli Stati Uniti, sia la formulazione liofilizzata che la presentazione (PFS) sono in crescita. Quindi, come sapete, lyo è destinato all'iniezione in ufficio e abbiamo ottenuto notevoli guadagni di quote di mercato grazie all'ottimo accesso in prima linea.

Ma anche una proposta di valore molto forte con un prodotto a temperatura ambiente che può essere iniettato rapidamente, rispetto alla maggior parte dei prodotti infusi nella categoria. È importante notare anche che l'uso e la copertura della formulazione liofilizzata non è puramente Medicare Parte B. In effetti, il 40% di questa formulazione è coperto da assicuratori commerciali, e questa è la parte in più rapida crescita del 2. Ciò che è stato eccezionale in Il 2019 vedrà crescere nuovamente la nostra siringa preriempita, che è stata alimentata dal nostro lancio nella psoriasi e dal lancio anticipato di axSpA non radiografico. Abbiamo aperto molto accesso a quei pazienti. E non vedo l'ora che arrivi il prossimo anno a vederlo completamente tradotto nella nostra crescita delle vendite.

È interessante notare anche che l'Europa è cresciuta nonostante la concorrenza indiretta dei biosimilari, incidendo sia sul prezzo netto sia sui volumi. Quella crescita è davvero ridotta ad alcuni punti. Il primo è la resilienza e l'aumento delle quote nelle donne in età fertile, che viene sempre più riconosciuto come un segmento di pazienti che necessitano di soluzioni specifiche. E il secondo sono i primi giorni del lancio della nostra psoriasi in Europa.

Quindi i mercati internazionali sono stati forti, come puoi vedere, ne siamo molto soddisfatti, ed è per le stesse ragioni dell'Europa. Quindi, se ora guardiamo sul lato destro, puoi vedere che i driver di crescita in termini di popolazioni di pazienti oltre alle donne in età fertile che ho menzionato e che tagliano la nostra psoriasi con circa 4 punti, come una nuova voce. E poi anche axSpA, che è sia axSpA non radiografico negli Stati Uniti, ma anche un effetto alone generale con i grandi dati che siamo stati in grado di comunicare: generare e comunicare l'anno scorso in tutto il mondo.

In prospettiva, siamo fiduciosi che Cimzia raggiungerà o supererà il picco delle vendite di 2 miliardi di euro. Riteniamo che i driver della crescita multipla compenseranno più che altro l'erosione del volume e dei prezzi legata alla concorrenza sottocutanea in tutto il TNF simile al di fuori degli Stati Uniti e anche per le nuove modalità di azione che entrano nelle varie indicazioni. E così solo per ricapitolare Cimzia, abbiamo la psoriasi, in cui Europa e Giappone contribuiranno alle vendite in contanti in futuro. Abbiamo axSpA, dove ci sono molte passerelle, molte esigenze insoddisfatte e un sacco di market shaping da fare, specialmente negli Stati Uniti. Ulteriori guadagni e certamente, resilienza nelle donne in età fertile, in cui Cimzia non è facilmente sostituibile , rappresenta una terza fonte di crescita futura e credo che il segmento di iniezione in ufficio negli Stati Uniti abbia anche spazio per ulteriori guadagni di quote di mercato e per la nostra espansione geografica con un inizio molto promettente in Cina, che oggi è un piccolo mercato , ma un mercato di importanza strategica a più lungo termine.

Quindi tutto ciò è una buona preparazione e una solida base su cui basarci mentre ci prepariamo a presentare e infine, si spera, a commercializzare bimekizumab sia in dermatologia che in reumatologia. Come puoi vedere qui, bimekizumab è ora in 4 programmi di sviluppo clinico in fase avanzata, per un totale di 10 studi in fase III e IIIb. E stiamo aggiungendo l'idradenite suppurativa come indicazione target per bimekizumab, e ci tornerò un po 'più tardi. Ma forse, per prima cosa, come promemoria, il bimekizumab è un anticorpo monoclonale, che inibisce in modo importante e selettivo 2 citochine: interleuchina-17A e interleuchina-17F. E quindi sappiamo che nella biologia IL-17 umana, sia il 17A che il 17F hanno una funzione pro-infiammatoria e che entrambi si sinergizzano con altre citochine pro-infiammatorie, come ad esempio il TNF.

Pertanto, il blocco di A e F dovrebbe portare a un maggior numero di pazienti che ottengono risposte sostenute e clinicamente adeguate, raggiungendo i loro obiettivi. E questo è ciò che ha suggerito lo studio di Fase II, ed è quello che intendiamo confermare con gli studi di Fase III in corso. Quindi la psoriasi sta avanzando molto bene con il 3 su 3 nel quarto trimestre dell'anno scorso. Quindi siamo molto entusiasti di questo. E siamo anche molto lieti di condividere con voi che i risultati dettagliati dei primi 2 studi, BE VIVID ed BE READY, saranno condivisi in presentazioni orali in ritardo presso l'American Academy of Dermatology il 21 marzo di quest'anno.

E quindi questo include lo studio di superiorità rispetto a Stelara e uno studio placebo che valuta il dosaggio sul prodotto. I risultati completi del terzo studio di Fase III BE SURE sono diventati disponibili dopo la scadenza per la presentazione dei DAE, e quindi abbiamo in programma di condividere questi risultati nella seconda metà dell'anno durante un'importante conferenza medica di dermatologia. Posso anche confermare che ci aspettiamo i risultati dello studio BE READY e di superiorità rispetto a Cosentyx entro la fine del secondo trimestre, che dovrebbe essere appena prima di presentare il bimekizumab con i regolatori americani ed europei in estate. I programmi PsA e axSpA, che sono iniziati l'anno scorso, stanno reclutando per pianificare e ci aspettiamo i migliori risultati entro la fine del prossimo anno. Siamo lieti che i risultati della Fase IIb di PsA siano stati pubblicati all'inizio di questo mese su The Lancet. È già disponibile online. È chiaramente una pubblicazione medica di alto profilo e di grande impatto e questo riconoscimento del potenziale della rilevanza clinica della doppia neutralizzazione di 17A e 17F nell'artrite psoriasica è molto incoraggiante.

Quindi ora una breve parola sull'idradenite suppurativa. Chiamiamolo HS. Quindi è un'area di profonda necessità insoddisfatta del paziente. E quindi non vediamo l'ora di fare la differenza per questi pazienti e i loro fornitori. È davvero una malattia infiammatoria cronica debilitante della pelle del follicolo pilifero con lesioni dolorose e spesso ascessi sotto le ascelle, l'area genitale, l'inguine, i glutei e il seno. In realtà non è raro. Si stima che la prevalenza globale sia vicina all'1%. E così questa malattia in genere inizia nei primi anni '20, prevalentemente nelle donne ed è associata a molteplici comorbidità, tra cui ansia, depressione, imbarazzo e altre condizioni infiammatorie. Quindi i pazienti non sono ben serviti dal sistema sanitario e nemmeno farmacologicamente, dove è approvato un solo farmaco per questa condizione, e questo è HUMIRA.

Quindi è davvero un'area emergente, ma un'area di necessità insoddisfatte molto elevate. E così la base per il nostro programma di Fase III è il riuscito studio di prova di concetto di Fase II, che abbiamo condotto con bimekizumab. I risultati sono stati chiaramente positivi. Li abbiamo condivisi alla recente riunione di hidradenitis suppurativa, la riunione della Fondazione europea HS, all'inizio di febbraio. E sulla base di questi risultati molto incoraggianti, stiamo iniziando 2 studi identici, controllati con placebo da 1 anno, mentre parliamo. E stiamo testando 3 regimi di dose di bimekizumab e per consentire l'inclusione di pazienti precedentemente esposti a HUMIRA.

Quindi la domanda potrebbe essere, ovviamente, in uno spazio ampio, in crescita e competitivo, come potremmo valutare il potenziale di bimekizumab? E ci sono probabilmente fattori importanti che dovremmo considerare quando selezioniamo i medicinali per questi pazienti in tutte queste malattie. Quindi ti invitiamo a esaminare 4 fattori. Il primo è che c'è una significativa intersezione e progressione tra le malattie, certamente, tra la psoriasi e la PsA, che è ben riconosciuta. Ma anche tra l'artrite psoriasica e axSpA, c'è l'intersezione. E c'è una serie emergente di articoli scientifici che indicano pazienti axSpA che soffrono di SA e viceversa, forse non in grandi proporzioni, ma certamente nell'intervallo del 10%. E questo forse indica una comune patobiologia, che dovrebbe essere incoraggiante per un farmaco come il bimekizumab con i suoi risultati di fase IIb axSpA. Quindi, se i dati di Fase III e IIIb confermano i nostri risultati di Fase II, il bimekizumab può essere considerato un'opzione molto interessante attraverso gli spettri di queste malattie dagli operatori sanitari, ma anche dai pagatori.

Quindi accanto a questo, ovviamente, e pensando alla prima indicazione che speriamo colpisca la psoriasi del mercato, stiamo anche cercando velocità per una risposta significativa. Molto spesso per i pazienti, ci vogliono mesi prima di sapere se le iniezioni che stanno facendo funzionano davvero. C'è anche una profondità di risposta. Quindi possiamo eliminare completamente i sintomi e consentire ai pazienti di dimenticare completamente la loro malattia. E quindi il quarto criterio potrebbe essere la durata dell'effetto clinico desiderato perché c'è molta ansia dei sintomi che ritornano, e questa è sicuramente un'area, di cui i clinici si lamentano costantemente, è la perdita di efficacia con molti degli agenti disponibili . Quindi questo tipo di arrotondamento per bimekizumab. Vorrei forse condividere brevemente alcuni punti su Evenity, che potresti anche aver sentito nella chiamata di Amgen se hai partecipato. Così, come ha affermato Jean-Christophe, Evenity è un innovativo trattamento di formazione ossea per le donne in postmenopausa con osteoporosi e ad alto rischio di fratture.

Colpisce 75 milioni di persone negli Stati Uniti, in Europa e in Giappone e 1 donna su 3 con più di 50 anni subirà una frattura. Quindi, nonostante ciò sia comune, solo il 20% dei pazienti con frattura attualmente riceve qualsiasi tipo di trattamento post-frattura. Quindi c'è un enorme bisogno insoddisfatto qui. E la domanda, ovviamente, è chi è il più alto rischio di una grave frattura osteoporotica. E chiaramente, è – quelle donne che hanno avuto una frattura che hanno una probabilità 5 volte superiore di soffrire di una seconda frattura entro il prossimo anno o 2. Quindi questo è un indicatore abbastanza importante. Ed è anche qui che posizioniamo Evenity insieme ai nostri partner, Amgen e Astellas. Queste fratture possono essere eventi che cambiano la vita. Quindi, quindi, è davvero necessario agire, non solo in termini di trattamento, ma anche nello screening dei pazienti e nell'assicurarsi che i pazienti vengano inviati ai medici appropriati.

Quindi, con Evenity, si tratta più di far identificare e curare i pazienti che di spostare altri medicinali. Pensiamo che con i suoi risultati di costruzione ossea rapidi e senza precedenti e la riduzione del rischio di fratture, Evenity possa essere visto come un trattamento di 12 mesi prima di passare alla terapia cronica, e siamo molto soddisfatti dell'approvazione EMEA di dicembre e del successo del lancio finora. Circa 55.000 pazienti sono già stati trattati con Evenity nel 2019 in Giappone e negli Stati Uniti, e abbiamo pianificato e siamo pronti a lanciare Evenity in Germania a marzo con il supporto di Amgen e di ottenere l'accesso in tutta Europa durante il resto di questo anno.

Quindi, per concludere sul portafoglio di immunologia, abbiamo una forte crescita con Cimzia. Non vediamo l'ora di un'ulteriore crescita negli anni a venire sulla base di più driver. Con bimekizumab abbiamo un modo d'azione unico che si sta traducendo in interessanti risultati clinici. E quindi non vediamo l'ora di condividere i risultati della Fase III e scoprire i risultati della Fase III mentre procediamo. E Evenity inizia in modo molto forte nei mercati sottosviluppati. E quindi è davvero un importante impegno a lungo termine che abbiamo nei confronti di questi pazienti.

E con questo, vorrei consegnare il mio collega, Charl.

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Charl Van Zyl, UCB SA – Executive VP of Neurology Solutions & Head of EU / International (5)

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Grazie Emmanuel. Quindi, prima di tutto, buongiorno, buon pomeriggio a tutti e partecipare alla chiamata oggi. Farò alcune osservazioni di apertura rapida prima di entrare in alcuni dettagli più specifici. E prima di tutto, voglio esprimere la mia fiducia su come stiamo costruendo un franchising neurologico molto diversificato nel breve e medio termine. E ci sono 3 messaggi importanti che voglio solo trasmettere e 3 elementi fondamentali per il nostro franchising di neurologia. Prima di tutto, stiamo iniziando con una solida base nell'epilessia e vediamo che la crescita a breve termine a medio termine continua ad essere alimentata da alcuni dei nostri marchi principali nel nostro franchising di epilessia.

In secondo luogo, a medio termine, vediamo anche una piacevole espansione nella neuroinfiammazione, che è un'area di malattie rare, con un alto grado di bisogno insoddisfatto. E qui, abbiamo 2 risorse molto forti in questo caso, il rozimab e la nostra acquisizione di Ra Pharma con 2 modalità che potrebbero darci alcune posizioni forti nelle malattie rare e una varietà di aree insoddisfatte per la crescita futura in quest'area in il medio termine. E infine, a lungo termine, abbiamo una base molto solida nella neurodegenerazione. Chiaramente, abbiamo un'eredità in Neupro e una profonda comprensione del Parkinson, ma abbiamo anche una forte competenza scientifica e comprensione di quest'area, che ci porta ad alcuni nuovi trattamenti potenzialmente qui con lo studio di conferma anche per l'anti-tau in PSP .

Quindi, su questi 3 orizzonti, vediamo una posizione molto ben bilanciata nella crescita sia a breve che a medio e lungo termine, e sono molto fiducioso di essere in una posizione forte nei prossimi anni nel nostro franchising di neurologia.

Quindi, se andiamo un po 'più a fondo nella discussione sull'epilessia, e voglio solo qui esprimere nuovamente la mia fiducia sulla nostra posizione che abbiamo nell'epilessia, e stiamo davvero qui vedendo un portafoglio molto forte di scelte per i pazienti e per i medici per trattare le diverse fasi dell'epilessia. Abbiamo una posizione molto forte nell'area controllata con marchi come Vimpat, il nostro retaggio di Keppra e anche una forte crescita emergente di Briviact. Poi abbiamo un nuovo lancio, come aveva detto Jean-Christophe, nell'area della ricaduta convulsiva con Nazolam in un'area di necessità insoddisfatta molto elevata, e vediamo alcune prestazioni molto forti e primi risultati lì che ci danno la fiducia che abbiamo un vero vincitore in questa particolare area chiamata recidiva convulsiva.

E infine, durante quest'anno, primo trimestre 2020, riveleremo anche ulteriori approfondimenti su padsevonil, che, riteniamo, affronterà un'importante area di pazienti refrattari dove c'è anche un alto bisogno insoddisfatto. Quindi, quando pensiamo alla nostra posizione epilettica oggi, abbiamo un portafoglio forte che sta generando per noi opzioni e soluzioni per molti pazienti in un ampio spettro. Oltre a una posizione molto forte a livello geografico, di cui parlerò tra poco, dove vedremo anche le basi della nostra crescita in tutte le nostre aree geografiche chiave. E quindi, con questa posizione abbiamo, essendo un leader di fiducia, una base molto solida che abbiamo in eredità e nelle nostre offerte future, siamo molto fiduciosi di essere in grado di continuare ad alimentare la crescita nel breve a medio termine dal nostro franchise di epilessia.

Quindi, se passiamo un po 'di tempo ad andare su Vimpat, che è uno dei nostri driver di crescita chiave, voglio esprimere 3 motivi per cui sono molto fiducioso di poter continuare a vedere questo bel percorso di crescita per Vimpat nel breve termine. Prima di tutto, il profilo di Vimpat è molto ampio in termini di mono e componente aggiuntivo. Oggi è davvero la scelta più affidabile per molti medici. Hanno un – vediamo un'ampia prescrizione per un gran numero di medici. Quindi è davvero il loro primo passo per il trattamento nella fase iniziale ed è davvero un marchio di fiducia basato sul suo profilo tollerabile molto favorevole. E chiaramente, ovviamente, anche l'efficacia che offre.

Il secondo motivo per cui siamo fiduciosi è quando pensiamo al nostro motore attraverso le nostre diverse aree geografiche, vedi che sul lato destro, abbiamo un'ampia posizione di presenza in tutte le aree geografiche con i nostri numeri di pazienti illustrati lì. E vediamo ancora una volta una crescita molto forte in tutte le nostre regioni e siamo molto chiari su come realizzare tale crescita con una base molto forte. Prevalentemente, la nostra crescita è guidata dal volume con un certo prezzo, ma riteniamo che sia una delle basi per una crescita continua. Il fatto che possiamo generare una nuova crescita attraverso nuovi volumi e nuovi pazienti con le nostre offerte che abbiamo oggi. E infine, la terza ragione di questa continua crescita è la gestione del ciclo di vita che vediamo l'espansione in nuove aree geografiche, Giappone, Cina e anche nuove indicazioni che abbiamo elencato lì per quanto riguarda le comunicazioni che avremo nella prima metà del 2020 .

Quindi, sono quindi molto fiducioso in questa fase con ciò che abbiamo nelle nostre mani per poter continuare a vedere questa crescita andare avanti. Pertanto, siamo molto fiduciosi di poter aumentare il picco delle vendite da 1,4 a 1,5 miliardi di EUR in base alle nostre attuali prove. Quindi, se poi concludessimo sull'epilessia. E solo per darti una conclusione molto rapida, ancora una volta, vediamo che questo è il 50% oggi delle nostre vendite nette di UCB. E abbiamo un track record di crescita molto forte, come vedi lì, del 14% o su base costante, del 10%, ed è molto guidato dai nostri marchi leader di Vimpat e Briviact. E quelle 2 offerte continuano a mostrare una crescita molto forte mentre le vediamo a medio termine. E continueremo a vedere l'esecuzione di ciascuno di quelli in tutte le aree geografiche che producono quella crescita che desideriamo nel breve termine di una crescita da singola a doppia cifra almeno elevata.

Ma come hai sentito anche da Emmanuel, oggi abbiamo il 50% delle nostre attività in epilessia, ma vediamo anche la nostra posizione diversificarsi a medio termine con, naturalmente, l'ulteriore crescita in Cimzia, il lancio di Bimab e anche la nostra posizione nella neuroinfiammazione con i lanci in arrivo su rozimab e Ra Pharma, quindi quei 7 lanci di cui hai sentito parlare Jean-Christophe, diversificheranno molto la nostra posizione nel medio termine. Ma a breve termine, siamo molto fiduciosi sulla crescita che possiamo offrire e contribuire dal franchise di epilessia.

Quindi, con ciò, vorrei fare alcune osservazioni su rozimab. E ancora, qui, come ho accennato nelle mie osservazioni introduttive, questo è il nuovo – o diciamo, il futuro vettore di crescita per noi nella neuroinfiammazione. È una risorsa chiara che vediamo come un potenziale per affrontare un gran numero di popolazioni di pazienti. Abbiamo iniziato lo sviluppo in 3 di questi, come vedi lì. E – ma crediamo che ci sia potenziale per ulteriori popolazioni di pazienti che potrebbero essere affrontate con rozimab sulla base di un'ampia piattaforma che abbiamo di malattie mediate da IgG. A completare questa è la nostra seconda modalità, che è l'acquisizione di Ra Pharma che ci darà una molecola diversa, non un anticorpo monoclonale, ma un peptide che avrà un diverso modo di erogazione e anche un diverso modo di agire per integrare l'inibizione. E quando metti insieme questi 2, ci sentiamo molto fiduciosi quando guardiamo alla nostra piattaforma che abbiamo su rozimab e Ra Pharma che possiamo diversificare la nostra impronta neurologica e la nostra posizione in malattie rare in aree ad alto bisogno insoddisfatto e anche dove c'è competizione più bassa.

E solo per darti un senso di rozimab, chiaramente, siamo concentrati sullo sviluppo in una vasta gamma di pazienti. Ma vediamo, certamente, nel mercato della plasmaferesi, che è oggi, un'area in cui la maggior parte dei pazienti sta ricevendo il loro trattamento che vi è un alto bisogno insoddisfatto lì. Preferenze del paziente per modi alternativi di consegnare potenzialmente sottocutaneo nel luogo in cui scelgono, e vediamo rozimab all'altezza delle loro promesse e in grado di rivolgersi a quel mercato, che oggi è stimato intorno a 11 miliardi di euro in plasmaferesi. Quindi una forte potenziale opportunità per noi in futuro lì.

E infine, vorrei concludere su Ra Pharma, solo per dire alcune parole su Ra Pharma. Come avresti saputo da noi prima quando abbiamo firmato l'accordo, vediamo una motivazione molto forte per questa acquisizione. Ci sentiamo componenti importanti per noi nella nostra crescita a lungo termine in urologia. Innanzitutto, colma una lacuna molto chiara nel darci il potenziale di condurre nella miastenia grave con un'opzione che consente ai pazienti di essere trattati in una fase più di mantenimento o in una fase controllata con zilucoplan, e vediamo che anche molto ben integrato con rozimab nelle fasi in cui le esigenze dei pazienti sono più in una fase refrattaria, dove hanno bisogno di un trattamento più intermittente. E vediamo che queste 2 opzioni forniscono davvero molte soluzioni ai pazienti per poter trattare la miastenia grave nel modo più efficace per il futuro.

In secondo luogo, con, come ho accennato in precedenza, il franchising e la piattaforma rozimab insieme a Ra Pharma, ci offre 2 modalità di malattie rare e ci dà davvero l'opportunità di espanderci in nuove popolazioni di pazienti che non siamo stati in grado di trattare prima. E la terza componente importante di questo accordo è che ci fornisce una piattaforma scientifica molto forte. Siamo molto soddisfatti delle fondamenta scientifiche di Ra Pharma e davvero la capacità della piattaforma di peptidi macrociclici di essere un potenziale motore di scoperta per noi, sarà anche un elemento importante di questo accordo. E infine, ci consente un'impronta strategica più forte nel nostro spazio di Boston Healthcare, che è un'ambizione importante che dobbiamo anche essere presenti in quell'importante spazio negli Stati Uniti.

Quindi, prima di passare a Detlef, concluderò di nuovo e ti lascerò con i 3 messaggi importanti sul perché siamo molto fiduciosi sul nostro franchising di neurologia: in primo luogo, l'epilessia rimane una crescita fondamentale molto forte. Siamo molto fiduciosi riguardo alla nostra posizione di leadership fidata in molte aree geografiche per essere in grado di garantire una crescita sostenuta nel breve termine; in secondo luogo, la neuroinfiammazione con rozimab e anche l'acquisizione di Ra Pharma ci danno una posizione molto forte per ampliare le nostre popolazioni di pazienti in malattie rare; and finally, our longer-term position with our strong scientific base in neurodegeneration and with the tau — anti-tau molecule going into confirmatory stage, we believe, we also have a strong position in neurodegeneration in the mid- to long term.

So with that, I'm going to hand over to Detlef to take us through some of the financial positions.

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Detlef Thielgen, UCB SA – Executive VP, CFO & Corporate Development (6)

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Thank you, Charl. I have to say that the financials are very good despite that a bit boring when you compare it to what Charl and Emmanuel were able to display in terms of what we are doing at the moment, but what we can do also in the future. Let me lead you to — through the main topics here, just for completeness. We achieved revenues of more than EUR 4.9 billion, as promised earlier this year, which is 6% growth, 7% on a constant base. So very nice and mainly driven by core products. And when you saw the presentations, I think, you got a sense of this and got a sense of the strong growth that we have been experiencing and that also have led to a very strong year finish.

When you look at the operating expenses, it is not a surprise in the situation that we are in with launching, with preparing launches but also having a broad pipeline in Phase III, that our expenses are going up. We have 10% more R&D expenses within our guidance. We have 15% increase in marketing and selling, which makes sense in terms of what you've heard of the launches and also the impact that these launches had. And we have taken the opportunity of a good year also to invest in all the growth pockets that we could see to really take advantage of our strong offerings. That has left us still with a very positive rEBITDA, recurring EBITDA, of 29.1%, which is slightly above the corridor and slightly above what we have guided. And it is over proportionally on the constant rate, which is the more telling variable here.

When you look to profit, one thing that might have surprised you a bit was the tax rate. This is also very easy to explain. We have been talking to you about our tech strategy and being prepared to take advantage of the different patent boxes, R&D credits and with a bit of luck of tax reforms like they happened in the U.K. and Switzerland this year. And that is exactly what has happened. And with more profit, more opportunities of these tax opportunities come in. That is why, as these incentives were given also by the different countries to spur innovation. Core earnings per share then are more or less a result of that, over proportional growth, same like profits, with EUR 5.2 per share.

I'd like to bridge to really 2020 with 2 slides. The first one is about the growth that we have been experiencing consistently over the years, and Jean-Christophe has referred to it, so I will make only one point on that. We have been telling you that we will have to invest more. We have invested more, but we have also managed well, and therefore, have been able, despite increasing R&D and despite increasing sales and marketing, to still keep the — our rEBITDA percentages high.

The next slide is more about investing in through the right things. And what we have been trying to tell you is that we are very conscious about that we have to reallocate the moneys to the right things. And when you look to the left side of the graph, then you see that cost of goods have been going down. R&D has been going down until 2 years ago, when we start into the preparation of our acceleration and expand phase with this broad pipeline that you see today and marketing and selling is more or less 1 year later where we are taking advantage of these products now coming to market. And you have seen the launches in that year.

So when you see G&A, we see no peaks there because we are getting more and more efficient and with more sales, this can also be achieved. So we want to leave you with this impression, I hope that you anyway have, that we are managing towards impact, and this is a good investment for the future. On the right side of the graph, it is something to be celebrated, at least, internally. We have reached net cash this year after long, long years of being in net debt position. We'll change that quickly with the expected Ra acquisition, a substantial part of that firepower that is created out of that is going away, but there is a bit of firepower left that can be used for the right things. Also here, investment into the right things and preparing yourself so that you can do that by real good reallocation.

Leaves me with the midterm guidance and the 2020 guidance. Let's start with 2020. Before we forget that this does not include the Ra Pharma acquisition, as we have not closed on it, this would not be opportune. So the revenue that we are foreseeing is EUR 5.05 billion to EUR 5.15 billion. It has continued strong core product growth, which you might not feel all the time when you look to the number, but there is more than these core products. There's established brands, there's supply in terms of manufacturing for the divested products, there's divested products, and there's also Keppra that is starting to erode more. So don't let yourself be tricked into — this would not be ambitious. This is a good guidance with the parameters that I just offered.

In terms of our rEBITDA, we're expecting 28% to 29% of revenue. When you have in mind that we are close to 26% today, in 2019, we're now thinking that it will be 28%, plus/minus 1% for R&D in the coming year, which already explains to you that we are making still good progress on the reallocation and keeping the profitability. Core EPS is a resulting number more or less out of this, and we are expecting EUR 4.80 to EUR 5.20. The tax ratio should be staying somewhat around the mid-teens for next year. And I would also encourage you to see this as a good number, a good range for your mid-term models, there will be fluctuations up and down. But when you want to model, this would be not bad to do, which brings me to the midterm guidance. rEBITDA revenue ratio of 31% will be 2021. Don't forget, we said it will move to 2022 when Ra will be closed, but we have given these numbers without Ra. Therefore, we are also moving back for this time.

Peak sales will be more or less the same for Briviact and Neupro, and Charl and Emmanuel were already talking about Cimzia being at the level of more than EUR 2 billion and Vimpat at the level of more than EUR 1.5 billion as peak sales.

With that, I would like to conclude, leave you with the feeling and hopefully, also your impression that these are very strong numbers and that we have delivered in the different things that we did want to deliver and hand over back to Jean-Christophe.

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Jean-Christophe Tellier, UCB SA – CEO & Executive Director (7)

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Thank you, Detlef. So we are now at the end of this presentation. I hope you have seen through the different presentations from Charl, Emmanuel and Detlef, the strong results in '19, and also the confidence in the future. The future starts tomorrow, and you see here for 2020, the different trigger points that we have. It will be a rich year in terms of continuation of acceleration of the pipeline, with the various step for rozanolixizumab, bimekizumab and padsevonil. You see also here the closing of Ra Pharma at Q1, the submission of bimekizumab in psoriasis at the midyear, as Emmanuel mentioned. And also, another Phase III starting in lupus with dapirolizumab in first half of the year. And our anti-tau UCB0107 Phase III that will start in Q2 that we have not mentioned yet. So you see strong year, good performance delivered, confidence in the future.

This year, a continuation of the acceleration of the pipeline and important trigger point as we continue to strengthen our future. You know that our plan is to launch up to 7 products by 2025. This notion of 6 or 7 is, of course, linked also to the acquisition and the closing of Ra Pharma, that's the reason of the 6. We have already 2 launches done with Evenity and Nazolam. This will help us to fulfill our missions to deliver sustainable patient value for the patient that you can see here as an example, (Anikere), Christophe, Wendy, Victoria, Lloyd and Kelly and so many others, who aspire to live the life that they want, which is also our aspiration to be able to deliver that for them.

And with that, this closes the session, and I would like to open now for the — for your questions. And just before opening to the questions, I would like to let you know that Iris have also joined us and will be available to answer your questions.

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Antje Witte, UCB SA – VP of IR (8)

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Thank you very much, Jean-Christophe. Qayyum, if you can start the question-and-answer session, please.

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Questions and Answers

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Operator (1)

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(Operator Instructions) We already have a question from Peter Verdult from Citi.

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Peter Verdult, Citigroup Inc, Research Division – Director (2)

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Peter Verdult, Citi. Three questions, please. For Detlef or Emmanuel, just on understanding the profitability flow-through to UCB on Evenity, especially in light of the drug sales ramp far exceeding expectations. You booked roughly about $10 million of other operating income on $150 million-odd of sales. So look, just the drug is on track to do more than $500 million. I mean, our back of the envelope calculations implies that that could flow through to at least $100 million of other operating income coming through. I realize you're not going to talk exact numbers, but anything you're willing to share and help us just better understand sort of the flow-through on profitability there would be very helpful.

Moving to the pipeline for Charl, JC or Iris, padsevonil data coming out next month, I believe. I think historically, this drug has been positioned as treatment-refractory epilepsy. When we speak to the docs, the profile that sort of was hinted at, as the Phase IIa comes through without any big issues with cognitive disorder. The message we're getting is that this could be a sort of add-on of choice or second add-on of choice. So I just want to understand from a UCB positioning, is padsevonil a sort of Briviact sort of niche product? Or could this blue sky be a sort of (impact) replacement?

And then lastly, Detlef, it's sad to think this might be the last time we hear your dulcet tones on the conference call, you've built a good reputation over the years guiding conservatively at the start of the year and always coming up with higher EBITDA and a tax rate way below guidance by the end of the year. Is it safe to assume with your successor yet to be announced that the spirit in which you've approached giving the guidance for 2020 is particularly conservative this year?

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Emmanuel Caeymaex, UCB SA – Executive VP of Immunology Solutions & Head of US (3)

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Peter, Emmanuel here. I'll start with answering the Evenity question and invite Detlef to jump in. So our partnership with Amgen is a 50-50 profit split partnership. And we have a partner in Japan, namely, Astellas, and so the costs and the rewards that go to Astellas for the piece of work they do is subtracted from the profit pool before we share it. So that's what I can tell you at this point. And in terms of future, of course, it will depend on the ramp-up as well. And the price point for this agent is different than for biologics in autoimmune, for example. So relatively, the COGS is a little higher than you would see with biologics. Detlef, anything to add here?

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Detlef Thielgen, UCB SA – Executive VP, CFO & Corporate Development (4)

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No, I think you made it perfectly clear.

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Jean-Christophe Tellier, UCB SA – CEO & Executive Director (5)

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So on padsevonil, maybe…

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Charl Van Zyl, UCB SA – Executive VP of Neurology Solutions & Head of EU/International (6)

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I can start and…

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Jean-Christophe Tellier, UCB SA – CEO & Executive Director (7)

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You can start and then…

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Charl Van Zyl, UCB SA – Executive VP of Neurology Solutions & Head of EU/International (8)

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Sì. So thank you, Peter, for your questions as well. The inclusion of criteria for padsevonil is really in refractory today. And we see, as I showed in my slides, 25% to 30% of patients are in this refractory segment where there's a high unmet need. So that will be our core initial positioning. I think we will learn more as we understand the data over the next months, if there is a potential broader usage. But certainly, today, we see it strongly in the refractory space where there is a very high unmet need. So Iris please add, if you would like as well?

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Iris Löw-Friedrich, UCB SA – Chief Medical Officer, Head of Development & Medical Patient Value Practices and Executive VP (9)

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No, there's not much to add. Peter, as you remember, padsevonil combines 2 of the most potent mechanisms of action in epilepsy, synaptic vesicle blockage plus a GABA-A receptor interaction. So it's only natural that we have selected those patients who are in most need for the initial treatment opportunity with padsevonil. You might also remember that the International League Against Epilepsy defines patients who have tried more than 2 antiepileptics and have no satisfactory treatment response as drug resistant, and we are enrolling in our clinical studies patients who have tried at a minimum 4 antiepileptic medicines and still are not controlled. So we are really, in the clinical trial, studying a highly drug refractory patient population. And that, in combination with a very potent mechanism of action, should give us unique outcomes that have not been demonstrated before. We will see results before the end of this quarter, and that will give us a basis for a discussion in a data-driven way, and that's the next big step.

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Jean-Christophe Tellier, UCB SA – CEO & Executive Director (10)

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Thank you, Iris. And Peter, if I may say, you have asked your questions about the spirit of the guidance in a very elegant way. And so Detlef, I will be curious to hear what is your perspective on it.

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Detlef Thielgen, UCB SA – Executive VP, CFO & Corporate Development (11)

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Peter, thank you very much for your perspective. I appreciate that. I have approached the guidance more or less, as always. So not a lot of change. As you know, we are giving, in this guidance, the benefit of taking the risk on FX rates. We are taking the risk on very volatile interest rates and therefore, we are approaching it with what we believe (in this guidance) can be delivered. For sure, and our track record shows that, the company has always delivered. And I would expect also that we will deliver this guidance. And if things are a good one, as well as we saw that in 2019, which was a bit better than we were expecting, otherwise, we would not have had to do the financial guidance update, then possibilities.

However, we are in an investment phase. And that also means that — I mentioned that before that we try to take any opportunity that we have throughout the year also to reinvest. So in that regard, I feel, to date, very comfortable that this is a guidance that we can achieve as we have achieved the others. And that our product portfolio is strong, therefore, we hope to have a bit of opportunity to reallocate in opportunities when they are coming.

I mentioned before, just — perhaps it might have been lost, that the top line, I read in some of your comments and it's very understandable, from (technical difficulty) looks a bit cautious. But when you think that we probably have to see each for Keppra established brands, the other revenues, royalty lines and divestments, an impact of roughly, let's say, around 1%, then I think (that's what I) mentioned. Then you are — I think it was quoted 2.5% to 4.5% is moving up to something that looks much more in line with what you would expect from our core products. So in that regard, no, I'm very happy to also leave a guidance that can be achieved, but that is also not one that isn't given under oath.

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Operator (12)

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We have another question from Richard Parkes from Deutsche Bank.

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Richard J. Parkes, Deutsche Bank AG, Research Division – Director (13)

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Let me have a few questions. And I'd also like to say best of luck to Detlef and I certainly don't remember you missing the guidance in 13, 14 years, I've been following the stock. It's been very helpful. So my question, firstly on Evenity performance. I'm just wondering if you could talk about to what degree we're seeing a bolus of sales in the most severe patients. Can you talk about how new patient starts have continued to evolve since the launch? So that's the first one.

Secondly, on the anti-tau antibody. Obviously, there's other drugs that have failed in PSP. I wondered if you could talk about how your compound compares and what evidence you have on brain penetration and target engagement based on the data you've seen so far? And I know you were looking at partnering in Alzheimer's disease and just wondered if that was still ongoing.

Third question is on bimekizumab. Obviously, we'll see the Phase III data at AAD, but — and you've outlined where you see the points of differentiation. But could you talk about, based on the data you've seen internally, does that continue to support your optimism of demonstrating superiority to Cosentyx on PASI 100?

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Emmanuel Caeymaex, UCB SA – Executive VP of Immunology Solutions & Head of US (14)

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So Richard, Emmanuel here. I'll take your 2 questions, and my answers might be a bit disappointing. But on the first one, Evenity, I'll have to guide you to Amgen. We've agreed with them that the commentary on the markets that they are (territory leasing) is going to be for them to make. And obviously, you're right to ask the question. It's a 12-month treatment. So we will need to renew the patients very regularly, and that's why we're investing across the world in ensuring that more patients are seen and are treated.

In terms of bimekizumab, I'm afraid we have to wait for the AAD detailed results.

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Iris Löw-Friedrich, UCB SA – Chief Medical Officer, Head of Development & Medical Patient Value Practices and Executive VP (15)

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Richard, this is Iris, and I would like to respond to you to your question regarding our tau antibody and our confidence for efficacy in PSP. And you mentioned the failures of competitor developmental assets. So as you know, the pathology in PSP are tau-tangles and we have designed our tau antibody in biological experiments with human material. And we have learned from these experiments that addressing a central epitope results in different efficacy in terms of preventing the spread than when you address peripheral epitopes. And the 2 molecules that you mentioned that just announced phased clinical studies are addressing peripheral epitopes, while our antibody is addressing a central epitope. So if you talk to our researchers, it was expected to see that failure in other molecules, and it's kind of a validation of our approach. Of course, we still have to demonstrate that the blockage of the central epitope will be efficacious.

You also asked about target engagement, and please rest assured that we have almost complete target engagement at the doses that we are taking into our confirmatory study. And I think while we all agree, this is, of course, a high-risk program, we have confidence in our data that has led us to go from Phase I directly into a single confirmatory trial. So based on everything that we have seen so far, we believe we have an antibody that holds high potential of being efficacious in this patient population who are very desperate and actually confronted with a death verdict when they get their diagnosis.

I would like to leave the question on Alzheimer's partnering to Charl, if I may.

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Charl Van Zyl, UCB SA – Executive VP of Neurology Solutions & Head of EU/International (16)

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Sì. Thank you, Iris. And actually, yes, we will continue to look at partnering in Alzheimer's. But our primary focus, as Iris had stated also, is in really the development in PSP where we see the primary value of this asset. And that's where we will focus. However, broadening the opportunity with a partnership would be something that we continue to talk to different possible interested parties as well. Va bene?

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Operator (17)

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Next question comes from Trung Huynh from Crédit Suisse.

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Trung Chuong Huynh, Crédit Suisse AG, Research Division – Research Analyst (18)

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I have 2 product ones and one modeling question. So firstly, on padsevonil, can you clarify the definition of refractory on Slide 16. In that chart, you show 25% of people living with epilepsy are refractory. Is this segment of patients that have failed 4-plus antiepileptics? And when it comes to labeling, will you try and get a label for refractory patients or given both your late-stage trials are in 4-plus failures, would this be the population?

Secondly, I might be reading too much into this, but the zilucoplan myasthenia gravis data, that's posted as 1H '21, you previously said the data should be expected early '21. Is there a slight delay there?

And then finally, to Detlef, thank you very much for your help over the years. I appreciate you're leaving, but can you help me one last time on your midterm cost levers, given we're 1 year closer to your 31% margin target. So on COGS, is there any opportunity for gross margin improvement here? You did 80% to 82% in 2 years. Does 82% represent a ceiling before your patent expiries? On SG&A, can you help with the growth of your marketing spend as you launch Evenity and (bime)? And then finally, on R&D. Thanks for the 28% ratio for 2020. But as we move forward, you're going to have higher marketing. What sort of R&D growth should we see, given you expect to have margin leverage going forward?

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Jean-Christophe Tellier, UCB SA – CEO & Executive Director (19)

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Va bene. So thank you for your question. On — so I'll start with padsevonil. So as Iris had mentioned earlier on the call, refractory definition is really failure on 2 antiepileptic drugs. In this case, for padsevonil, we are setting a very high hurdle of efficacy with inclusion criteria for patients that have failed on 4 antiepileptic drugs. So clearly, our label today and our intended label will be very much focused on refractory. We see that as essentially 1/3 of the market, of patients that are still — have a high unmet need. And so our focus there will be to position padsevonil on the initial label to treat these refractory population. And then I think your second question on Ra Pharma and the timing. This is consistent with what Ra Pharma has publicly stated. So we have not changed that position in terms of readout of zilucoplan.

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Detlef Thielgen, UCB SA – Executive VP, CFO & Corporate Development (20)

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So then back to the modeling. I think you got it right, both on the cost of goods and G&A, we have still a little bit to go, which it's just also the composition of the portfolio. However, I have to say, and it's not a surprise that our R&D expenses in the next 1 to 2 years will still go up, which leaves us then also, leaves us also understanding why we shifted the year from '21 to '22 because this potentially additional, let's say, 2% to 3% in R&D that is coming on top of what we need for our own late-stage pipeline could not be compensated. And that would then also bring it down a bit in the years in between.

However, the marketing and selling, there is a ramp-up that is crystal clear that we are seeing — have seen already now. We will see that going into the next 1 to 2 years for the key products. But we are also starting to see some opportunity with the overall product portfolio to reallocate. And that will take some of the edge-out of this. So we are comfortable on the 31%, whether it's '21 or '22, depending on without or with Ra Pharma. And I think I have the feeling, we'll make it again.

By the way, for the ones that already did that, thanks all the very kind words. I will keep them with me and have them in mind, always a pleasure.

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Operator (21)

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Our next question comes from Wimal Kapadia from Bernstein.

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Wimal Kapadia, Sanford C. Bernstein & Co., LLC., Research Division – Research Analyst (22)

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Wimal Kapadia from Bernstein. Just following up again on padsevonil. How much importance should we actually place on the Phase II data ahead of the Phase III next year, just given that the trial design size actually looks quite similar. Is there any possibility of filing on Phase IIb data just given the high unmet medical need? And just tied to that, you're clearly going after refractory population. Is it fair to assume high share, high price, because I think it's around 10% of epilepsy patients actually have failed for antiepileptics. So could we assume a relatively high share in that population?

And my second question is just on the upcoming — well, in 2 years' time the Vimpat genericization. Just to get a sense of whether we should really be using Keppra as a good benchmark. Given that it was a true gold standard at a larger installed base, was approved across multiple indications, so is it actually a good benchmark for how to model Vimpat genericizations? Or should we expect the decline to be somewhat faster?

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Iris Löw-Friedrich, UCB SA – Chief Medical Officer, Head of Development & Medical Patient Value Practices and Executive VP (23)

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Sì. Thank you very much. I'll start with your padsevonil, and you're absolutely right. But the Phase IIb study that will read out towards the end of this quarter is a very substantial study, 500 patients across different doses of padsevonil versus placebo. And the study is indeed quite similar to the Phase III study, similar patient population, fewer doses that we are testing in that study. So it's 2 adequate and well-controlled clinical trials. It is very clear that regulatory authority will insist on 2 of these studies to accept submission. Our very early proof-of-concept study, you might remember, was very small, just 50 patients, so that would not qualify in the eyes of the regulators as an adequate and well controlled study. And so we are very clear that we will need both studies for an acceptable filing to the regulators. I have a lot of empathy for your statement that the unmet medical need might lead us to believe differently, but we know very clear from agency feedback that that's not the case.

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Charl Van Zyl, UCB SA – Executive VP of Neurology Solutions & Head of EU/International (24)

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Perfect. And just to follow on to that. At this point, I think it's a little early to comment on price until we learn more about the profile, which we will certainly evaluate over the next months as we go forward.

Then onto your second question on the, how would you model the LOE of Vimpat? There is obviously some differences. Keppra had a lower competition at the stage of when it went off patent. Today, we see with Vimpat and the environment that we face with increased cost containment that you would probably see a slightly higher erosion of Vimpat than of Keppra. So that's how we would give you that guidance at this point.

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Operator (25)

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We have another question from Richard Vosser from JPMorgan.

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Richard Vosser, JP Morgan Chase & Co, Research Division – Senior Analyst (26)

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A few questions, please. Firstly, just thinking about your 31% guidance in 2021, which is the same as last year. You have upgraded the Cimzia guidance, and the Vimpat guidance since then has clearly more sales. I obviously understand that there is things to invest in, but they sound relatively limited in terms of R&D, and you'll be finishing some trials. So just a question why that 31% margin, why the need to clarify Ra Pharma into 2022, why that hasn't actually gone up? So that's the first question.

Second question, and apologies if this has already been batted back. But I think I heard that Evenity in Europe, where you will be in charge of the marketing, you might be able to comment on. So perhaps you could give us an idea of the opportunity you think there for 2020 and also a few years out. And then the final question is on hedging losses within the sales line. Just could you give us an idea of the hedging, maybe plans for 2020 and how to think about it. Clearly, there's not much of a currency benefit in 2020 at current rates. So we should be expecting lower losses, perhaps. So just some thoughts there and more detailed thoughts there.

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Detlef Thielgen, UCB SA – Executive VP, CFO & Corporate Development (27)

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I can take the 2 questions that are more financial in nature. There is this trick. When you look at absolute numbers, and they are rising and you keep the percentage equal that you are tricked into believing the absolute number is also equal but this is rising with it. So that is the first part of it. But the more important part is, it's a very fair point to say it is this overall going up, there should be more money and that is coming down. On the other hand, we also know much more than before in terms of what we have to do. We have additional clinical studies that we are starting that might not have been involved before. But we are feeling that we can compensate that by the improving top line and the profits that are coming by that. So it has not gotten easier due to the success of the portfolio but we are compensating by what I would believe good management and increasing top line.

On the FX, I think you're absolutely right. The FX at this moment is a little better than what we saw end of the year and what we saw throughout 2019. So at this point in time, from a hedging perspective, we are running slightly ahead of the game. However, this will be very marginal when — if it would stay this way. So I would not focus on that. We'll take that throughout the year, seeing what fluctuations will be there and if there's something that can be added, we will add it, as usual.

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Emmanuel Caeymaex, UCB SA – Executive VP of Immunology Solutions & Head of US (28)

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And Richard, on Evenity in Europe. As you know, access and pricing and reimbursement needs to be obtained in Europe. And so for 2020, the only sizable market to which we will have full access to is Germany. Now Germany is also the most underdeveloped bone builder market in Europe. So my guidance would say that contribution this year will be rather incremental in comparison with Japan and the U.S. and over time, of course, Evenity has significant potential in Europe, but it is something that will take a number of years to play out to an extent that would be really significant in light of a much more developed Japanese market and a U.S. market with different characteristics.

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Operator (29)

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Next question comes from Peter Welford from Jefferies.

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Peter James Welford, Jefferies LLC, Research Division – Senior Equity Analyst & European Pharmaceuticals Analyst (30)

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Just a few questions. Firstly, with regards to roza, looking on ClinicalTrials.gov, it looks as though there are now 2 ITP studies. I don't know if this is just a sort of error in the website. But I'm just curious, it does look as though you've also slightly delayed the ITP readout timeline relative to prior expectations. So just comment at all as what's going on there?

And secondly, then just on bimekizumab, I'm curious whether or not in HS — HS, sorry, did you consider doing the head-to-head versus HUMIRA? And if not, why not, I guess, given, obviously, you've done that in other indications, and it would seem like perhaps an obvious choice, given that they're obviously only approved therapy, you could then be the clear winner.

Thirdly, then looking at the Evenity, going back to Europe, I wonder if you can comment at all, presumably, you had some initial thoughts already on Germany with regards to price. If you could give us any sort of insights there, that will be much appreciated.

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Iris Löw-Friedrich, UCB SA – Chief Medical Officer, Head of Development & Medical Patient Value Practices and Executive VP (31)

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So Peter, on rozanolixizumab in ITP, I want to confirm that one Phase III study has started, and that's so far our plan. So I will go back to ClinicalTrials.gov and see what ambiguity there might be, but the confirmation is one study in ITP.

And to your question about data readout as it just has started, I'm not sure that we have given any date already…

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Antje Witte, UCB SA – VP of IR (32)

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Second half 2022.

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Iris Löw-Friedrich, UCB SA – Chief Medical Officer, Head of Development & Medical Patient Value Practices and Executive VP (33)

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'23.

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Antje Witte, UCB SA – VP of IR (34)

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'22. Second half, '22.

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Iris Löw-Friedrich, UCB SA – Chief Medical Officer, Head of Development & Medical Patient Value Practices and Executive VP (35)

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Second half 2022.

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Emmanuel Caeymaex, UCB SA – Executive VP of Immunology Solutions & Head of US (36)

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And on bimekizumab, thank you for your question. So there's actually several factors here. The first one is that we aim to reach the market rapidly. And quite a few patients in our proof-of-concept study would not be included because they had been exposed to HUMIRA. So we've decided to let those patients in because this will probably represent the state of the field by the time we get there. The second reason is that we actually included a HUMIRA reference arm in the proof-of-concept study, which was reported recently in a conference.

And so we were quite encouraged by the potential for a deeper response on certain endpoints with bimekizumab, which is not unlike what's been seen in other indications. So seeing 75% or 90% symptom reduction score DLQI01, and we believe that getting to the market rapidly with an asset that has a significant level of — a rate of deep responders is going to be sufficient in such an area of unmet need to gain access and to be successful commercially.

In terms of Evenity, the way it works in Germany is you are launching at the list price and then within a year or so, you have your AMNOG price. And so I don't really wish to comment on the list price to start with because it's not really going to be meaningful long term.

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Operator (37)

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Next question comes from Charles Pitman from Redburn.

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Charles Pitman, Redburn (Europe) Limited, Research Division – Biopharmaceutical Sell Side Research Analyst (38)

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Charles Pitman from Redburn. Firstly, if we assume the BE RADIANT study shows bimekizumab with superior efficacy to Cosentyx, what would be the hurdle to achieving standard of care status in psoriasis? And in that case, would you need to partner to commercialize it? And could peak sales grow to be larger than Cimzia in the long term?

Secondly, could you just help us with any color on initial physician uptake of Nazolam.

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Emmanuel Caeymaex, UCB SA – Executive VP of Immunology Solutions & Head of US (39)

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So Charles, thank you for your question on BE RADIANT. Sì. I mean, clearly, the reason why we've picked Cosentyx as a comparator is that it is a drug with a high market share and it's the most used of the IL-17A inhibitors. So at a very minimum, the asset would then be regarded as a superior option to what has almost become a standard of care in the field. Would we need to partner bimekizumab? I think the advantage we have with our focused entry with (Xeljanz) psoriasis is that we've established a capability in psoriasis, which we can easily scale across the U.S., Europe and Japan. We have a lot of experience also in terms of the clinical development and medical affairs angle, and I believe that our access capabilities, in particular, in the U.S. are strong now. As you've seen also from the increased Xeljanz) results and (guidance. So I wouldn't say that that should be a base case scenario at all.

And then you had another question related to — sorry…

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Jean-Christophe Tellier, UCB SA – CEO & Executive Director (40)

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Peak sales.

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Emmanuel Caeymaex, UCB SA – Executive VP of Immunology Solutions & Head of US (41)

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Peak sales, yes, it's way too early. But thanks for asking.

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Charl Van Zyl, UCB SA – Executive VP of Neurology Solutions & Head of EU/International (42)

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And Charles, to your question on Nazolam. So it's a little early to get a new prescription data as yet, given that we launched just recently essentially 2 months ago. But I can give you just a couple of points. Estimated patients in the U.S. that have a risk of seizure relapse is around 120,000 patients. We have today an estimate of around 1,000 patients in the first 2 months. What's driving a lot of the early success is unrestricted access. Between 40% and 50% of our accounts have unrestricted access, and we see that trending upward very quickly. So a very promising start and it's obviously, first-in-class and the broad adoption that we see within the community is very promising. But too early to really give you a clear read yet on the peak view of this, okay?

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Operator (43)

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Next question comes from Sandra Cauwenberghs from KBC Securities.

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Sandra Cauwenberghs, KBC Securities NV, Research Division – Director Research for Biotech and Pharma (44)

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First, my sincere congrats to the whole team for the nice progress that you made in 2019. I still have 3 small questions left. First on bimekizumab. So you will start a Phase III trial for a fourth indication? And this is still in the skin inflammation space, so I was wondering if outside of dermatology and rheumatology, do you see any additional benefit of this drug in other inflammatory areas? Or will you stay focused for now on these 2 segments in inflammation?

The second question is on zilucoplan. So you've mentioned earlier the plasma fractionation market or the apheresis market. Can you elaborate a little bit on the potential positioning of this drug. And will you limit yourself potentially to these orphan disease indications? Or do you see broader applications?

And then the last one is with regard to Neupro. So I think this is already on the market since about 14 years. Do you still see an interest in continuing to pursue this particular market?

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Emmanuel Caeymaex, UCB SA – Executive VP of Immunology Solutions & Head of US (45)

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Thank you, Sandra, and thank you for your question. On bimekizumab, we intend to focus indeed on rheumatology and dermatology indications. And with the strong position of Cimzia in spondylarthritis as well as RA, and our entry in psoriasis, I think we'll be in a good position to make the most of bimekizumab's impact for patients.

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Charl Van Zyl, UCB SA – Executive VP of Neurology Solutions & Head of EU/International (46)

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To your question on zilucoplan and the positioning. So typically, what our learning is of the MG patient today is that they start on normal steroids. And then as they lose control, they would go into a situation where they need other interventions. We see zilucoplan being very much the follow-on from steroids to a stage where they need greater control and that we see rozimab playing a strong role where there is periods where they are out of control or in refractory or exacerbations where they would need to have rozimab. And in that space, where we talk about rozimab is really where patients are today on IVIG, and that's the opportunity that we see to potentially provide alternative solutions for patients, and the preference for patients there, at least from our learnings, is to have a subcutaneous infusion at the place where they would like to have that at home or in the office. So we see the 2, zilucoplan and rozimab, coexisting very nicely on that continuum of care for patients with MG.

Then your second question on Neupro. So today, the treatment modality for Parkinson's really mostly symptomatic to address the motor symptoms. We are clearly in our future view of neurodegeneration, want to address potential of disease modification. So our science and our focus on research is really in that area of really trying to intervene earlier to have a better outcome for patients. And that's where we will continue to focus in that space.

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Operator (47)

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Next question comes from Jean-Jacques Le Fur from Bryan Garnier.

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Jean-Jacques Le Fur, Bryan Garnier & Co Ltd, Research Division – Analyst (48)

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A quick one on Cimzia and the peak sales. You mentioned EUR 2 billion regularly during your comments. But it's still just EUR 300 million more than you achieved last year. And last year, you already achieved 3 — close to EUR 300 million more in just 1 year. So isn't it a bit conservative to have this EUR 2 billion as a peak sales? Or is it fair to assume you have some chances, even great chances to beat this EUR 2 billion peak sales, let's say, by 2024, 2026?

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Emmanuel Caeymaex, UCB SA – Executive VP of Immunology Solutions & Head of US (49)

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Thank you, Jean-Jacques. So between '19 and '18, we had cash growth of a little more than EUR 200 million. Now the FX rate played a part in, not a predominant part, but at least 20%. And so this can always reverse, of course. So that's one thing to bear in mind. The second one is that, whilst we are growing in the number of segments, we're also decelerating in some others. And so it's really in those areas that we're differentiated that we're going to grow and so all of that should more than make up for the difference by EUR 300 million. So I think that — with that, the FX rate, we're offering you something that we're confident we can achieve, and that should also be meaningful enough for you to significantly update your models.

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Operator (50)

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Our next question comes from Emily Field from Barclays.

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Emily Field, Barclays Bank PLC, Research Division – Research Analyst (51)

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So at the beginning of the year, there was a lot of enthusiasm around the Momenta M254 hypersialyzed IVIg (sic) (Momenta M254 Hyper-Sialylated IVIg) proof-of-concept data in ITP, and thereby, the effects that that could have to competition for FcRns and IVIg as well in ITP and CIDP. I was just wondering if you could make any comments on that data? Or perhaps, more generally, just on anything that you've seen in the indications outside of MG, which you've obviously spoken a lot about for rozanolixizumab.

And then just secondarily, also, just on the upgrade to the Cimzia peak sales guidance. Have you changed at all any of your assumptions in terms of what you would be seeing regarding the U.S. biosimilar landscape? Or is the sales increase really more predicated on just continuation of trends that you're seeing in Cimzia with sort of the same underlying base assumptions on how bio — HUMIRA biosimilars will play out or if anything has changed regarding those assumptions?

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Charl Van Zyl, UCB SA – Executive VP of Neurology Solutions & Head of EU/International (52)

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Va bene. So on the Momenta question you had, we don't comment on competition. At this point, I would just say that there's a high unmet need in the plasmapheresis space and so we welcome more innovations there for a large number of patients. So to this point, we would not like to comment on that particular question.

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Jean-Christophe Tellier, UCB SA – CEO & Executive Director (53)

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And Emily, thank you for the Cimzia question. It's a good question. (Are you similar) assumption as to the entry of adalimumab remains 2023. So the upgraded guidance is independent of this. So no change to our assumptions there.

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Operator (54)

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Our last question comes from Tom Murillo from Degroof Petercam.

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Tomas Murillo Rodriguez, Degroof Petercam Asset Management – Director (55)

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I have a couple just on bimekizumab and Cimzia. Could you maybe elaborate a bit on the synergies you see in terms of SG&A for both products? And what midterm impact should we expect although in terms of cannibalization potential between both products? That's my first question.

My second question is on the oral zilucoplan or extended release version of zilucoplan, when should we see that on clinical development?

And last question, in terms of design of your ITP trial versus your peer competitor, efgartigimod. Maybe could you elaborate a bit on the potential difference you see in terms of targeted population.

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Emmanuel Caeymaex, UCB SA – Executive VP of Immunology Solutions & Head of US (56)

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Thank you, Tomas. Perhaps to frame the question on potential synergies between bimekizumab and Cimzia, I should first clarify that there's going to be a more or less, at least 2 years gap between our entry in dermatology and rheumatology, if everything goes well. And we would probably expand our dermatology coverage to be able to successfully launch bimekizumab. So I wouldn't factor in too many synergies as far as the launch in psoriasis is concerned. Perhaps there can be some later when bimekizumab gets introduced in axSpA and PsA. But frankly, we haven't really looked into that in great detail, and I don't think it should be a driver. So hopefully, that answers your question in terms of the costs.

And then in terms of co-positioning, I think it's a little early. We first would like to look at the totality of our clinical results across indications before deciding how we might possibly co-position both agents. But of course, you know that Cimzia is associated with advantages for the women of childbearing age population, which are linked to its molecular structure and specific trials we have done, which are unlikely to be reproduced in the same way for bimekizumab. So that's giving you something. Thank you, Tomas.

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Charl Van Zyl, UCB SA – Executive VP of Neurology Solutions & Head of EU/International (57)

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And Tomas, to your question on oral zilucoplan. Obviously, we are very happy that the Ra Pharma organization has the ambition to develop an oral. And this is, obviously, will be a great choice for patients. But today, it's too early to really comment on that until we have joined forces after closing.

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Iris Löw-Friedrich, UCB SA – Chief Medical Officer, Head of Development & Medical Patient Value Practices and Executive VP (58)

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And Tomas, to your question about the ITP study design. I think it's a kind of classical study design. We are recruiting patients with confirmed ITP, who, despite standard of care have a low platelet count. And we believe that rozanolixizumab in this patient population will be able to unfold a sustainable treatment effect, meaning bringing their platelets above count of 50,000, which would be the threshold for reduced bleeding risk. So that's kind of in a nutshell the patient population that's being enrolled.

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Antje Witte, UCB SA – VP of IR (59)

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Va bene. Grazie. I would like to close this Q&A session with 2 questions from the web. The first one from (Alex Pope) from (inaudible). Do you have any proof-of-concept data in humans in any of the indications you are pursuing with bimekizumab that bimekizumab is clinically superior to other IL-17?

And the second question is from Alex (inaudible). I hope I pronounced that correct, from (inaudible). How will you fund Ra Pharma acquisition? What is your net leverage goal after the acquisition, kind of a mid-term to long-term goal?

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Emmanuel Caeymaex, UCB SA – Executive VP of Immunology Solutions & Head of US (60)

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So on bimekizumab, no, we don't have proof-of-concept studies in humans. So it's based on reading across and significant work with statistics and modeling.

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Detlef Thielgen, UCB SA – Executive VP, CFO & Corporate Development (61)

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So concerning the leverage, as we are net cash at this moment in time, if you are just taking EUR 2 billion, you're ending up somewhere at around 1.5x. When you are taking the guidance in consideration, there's — as I mentioned already last year, there's also some extraordinary cash-outs that we will have for our manufacturing and R&D footprint, probably more than EUR 600 million in the coming years. So that will add to it. And we still reserve the opportunity to do the one or other smaller topic. The general idea is to stay below 2x, which doesn't mean that, that has to be all of the time. In that phase that we have just in, and from a very long-term perspective, a 1:1 would be very nice. However, it always depends on the opportunities. And I think we have been showing that we are willing to go up to 3.5x, 4x if that is really needed, and we have a short-term opportunity to bring it back. And we have no problem to be cash positive for some time if we are not seeing the right opportunities. So somewhat in between, it will be. And the 2x is probably a good one to keep in mind as an overall wish that we would have.

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Antje Witte, UCB SA – VP of IR (62)

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So with this, we conclude today's call with a Q&A session. Thank you very much for your interesting questions and for your interactions. Looking forward to see you out there in London, Paris, Brussels, wherever we go in the next couple of months, and I hope you have a great day and a great afternoon. Thank you very much, indeed.

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Operator (63)

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Ladies and gentlemen, this concludes today's conference call. Thank you all for your participation. You may now disconnect.

Psorilax:Offerta |crema per la cura della psoriasi

0

Psorilax: prezzo, funziona, recensioni, opinioni, dove si compra

Il sondaggio sulla consegna di farmaci topici di Global Rx Dermatology fornisce informazioni chiave sul settore, compresi fatti e cifre molto utili e importanti, opinioni di esperti e gli ultimi sviluppi in tutto il mondo. Il rapporto sul mercato globale è un documento importante per ogni appassionato di mercato, decisore politico, investitore e giocatore. Il rapporto fornisce fluttuazioni del valore CAGR durante il periodo di previsione 2019-2026 per il mercato. I rapporti di mercato di Rx Dermatology Topical Drug Delivery forniscono dati su modelli e miglioramenti e indirizzano settori e materiali aziendali, limiti e avanzamenti. In questo rapporto, viene fornita un'analisi SWOT e un'analisi degli investimenti approfondite che prevedono opportunità imminenti per gli operatori del mercato di Rx Dermatology Topical Drug Delivery.

Il mercato globale della consegna di farmaci per dermatologia Rx globale dovrebbe raggiungere 40.646,26 milioni di USD entro il 2026 da 29.475,18 milioni di USD nel 2018, con un CAGR del 4,2% nel periodo di previsione dal 2019 al 2026.

Scarica PDF gratuito Copia di esempio del rapporto @ https://databridgemarketresearch.com/request-a-sample/?dbmr=global-rx-dermatology-topical-drug-delivery-market

Analisi competitiva:

Alcuni dei principali attori che operano in questo mercato sono Galderma Laboratories, LP, Hisamitsu Pharmaceutical Co., Inc., Pfizer Inc., LEO Pharma A / S, GlaxoSmithKline plc., ALLERGAN, Bayer AG, 3M, Bausch Health Companies Inc., The Lubrizol Corporation, Cipla Inc., Kaken Pharmaceutical Co., Ltd. tra gli altri.

I farmaci topici svolgono un ruolo importante nella terapia delle malattie dermatologiche. I farmaci per dermatologia topica incorniciano una grande percentuale di prodotti nel mercato dei farmaci. Questi prodotti sono fabbricati attraverso processi di produzione specializzati come riempimento di volume preciso, miscelazione su larga scala, riscaldamento e imballaggio.

La somministrazione topica di farmaci può essere effettuata nel corpo attraverso percorsi oftalmici, rettali, vaginali e cutanei come vie topiche. Nel settore della dermatologia, la pelle svolge un ruolo importante nella somministrazione di farmaci topici per il trattamento delle malattie della pelle nei pazienti. I preparati topici vengono applicati sulla pelle per effetti superficiali, locali o sistemici. Le formulazioni topiche includono ingredienti terapeuticamente attivi che aiutano a trattare le malattie della pelle nei pazienti.

Il rilascio topico di farmaci è uno dei modi più efficaci di rilascio di farmaci in quanto fornisce risultati terapeutici ottimali. A poco a poco, il sistema topico di consegna dei farmaci è diventato sempre più importante nell'industria farmaceutica. La risposta farmacologica, sia l'effetto terapeutico desiderato sia l'effetto indesiderato indesiderato di un farmaco dipendono dalla concentrazione del farmaco nel luogo di azione, che a sua volta dipende dalla forma di dosaggio e dall'entità dell'assorbimento del farmaco nel sito di azione. Nel settore della dermatologia, molecola di farmaco applicata sulla pelle che penetra principalmente attraverso il percorso intercellulare tortuoso e continuo. Questi prodotti sono disponibili in diverse forme come unguenti, creme, lozioni, gel e altri che hanno la capacità di essere assorbiti nel corpo e mostrano rispettivamente la risposta positiva nella guarigione della ferita.

Mercato globale di consegna di farmaci topici dermatologici per tipo di prodotto (semisolido, liquido, solido), applicazione (infezioni della pelle, dermatite, antiaging, acne, iperpigmentazione, rosacea, cancro della pelle, psoriasi, onicomicosi, altri), categoria (marchiato, generico ), Geografia (Nord America, Europa, Asia-Pacifico, Sud America, Medio Oriente e Africa) – Tendenze e previsioni del settore fino al 2026

Segmentazione: Mercato globale della consegna di farmaci per dermatologia Rx globale

Il mercato globale della consegna di farmaci topici dermatologici Rx è segmentato in base al tipo di prodotto, all'applicazione e alla categoria.

  • Sulla base del tipo di prodotto, il mercato è segmentato in solido, liquido e semisolido. Il solido è sottosegmentato in polvere e altri. Il liquido viene suddiviso in soluzione, emulsione, sospensione, lozione e altri. Semisolid è sottosegmentato in creme, gel, unguenti, pasta, altri.
    • Nel dicembre 2016, Pfizer Inc. ha ricevuto l'approvazione da parte della Food and Drug Administration (FDA) statunitense per il prodotto chiamato EUCRISATM (crisaborole) unguento al 2%. È un nuovo inibitore topico non steroideo della fosfodieterasi-4 (PDE-4). È usato per il trattamento della dermatite atopica da lieve a moderata (AD). Con questo lancio del prodotto l'azienda ha costruito un patrimonio nel settore dell'infiammazione e dell'immunologia.
  • Sulla base dell'applicazione, il mercato è segmentato in acne, dermatite, psoriasi, infezioni della pelle, antiaging, cancro della pelle, iperpigmentazione, onicomicosi, rosacea, altri.
    • Nel marzo 2017, Galderma Laboratories, L.P., produttori del marchio Cetaphil hanno lanciato sette nuovi prodotti per la cura della pelle del viso. Con questo lancio dei prodotti il ​​portafoglio Cetaphil dell'azienda è aumentato. La società ha ora un'ampia gamma di soluzioni specializzate per i pazienti con problemi di pelle, tra cui idratazione e altri.
  • Sulla base della categoria, il mercato è segmentato in generico e marchiato.
    • Nel febbraio 2016, Allergan plc ha ricevuto un'approvazione per il suo prodotto ACZONE (dapsone) Gel, 7,5% dalla Food and Drug Administration (FDA) degli Stati Uniti. Questo prodotto è un nuovo trattamento topico di prescrizione che è utile per il trattamento dell'acne nei pazienti di età pari o superiore a 12 anni. Il prodotto ha aiutato il paziente a trattare facilmente l'acne che alla fine ha contribuito ad aumentare le entrate.

Richiedi questo rapporto dal nostro esperto @ https://databridgemarketresearch.com/inquire-before-buying/?dbmr=global-rx-dermatology-topical-drug-delivery-market

Recenti sviluppi:

  • Nell'aprile 2016, Allergan plc ha acquisito Topokine Therapeutics, Inc. con un pagamento anticipato di 85,8 milioni di USD ed è stato idoneo a ricevere pietre miliari potenziali di sviluppo e commercializzazione fino a 260,0 milioni di USD.
  • Nel febbraio 2019, Kaken Pharmaceutical Co., Ltd. ha concluso un accordo di licenza e distribuzione esclusiva per la formulazione topica di onicomicosi nella Repubblica popolare cinese. Secondo l'accordo Kaken Pharmaceutical Co., Ltd., ha fornito il diritto esclusivo per lo sviluppo e la commercializzazione del Prodotto in RPC e questo ha portato a un'elevata generazione di entrate.
  • Nell'aprile 2019, The Lubrizol Corporation ha lanciato il suo nuovissimo modificatore di reologia 2 in 1 multifunzionale, polimero Carbopol Style 2.0. Il prodotto ha i benefici per la cura della pelle come l'aspetto liscio lucido, le texture uniche e altro. Con questo lancio è aumentato il portafoglio di prodotti dell'azienda che ha comportato una maggiore generazione di entrate.
  • Nell'agosto 2018, Cipla INC. Ha ricevuto l'approvazione finale per la nuova domanda abbreviata di farmaci (ANDA) per Diclofenac Sodium Topical Gel, 1% dalla Food and Drug Administration degli Stati Uniti (US FDA). Per questo motivo l'azienda ha aumentato il proprio portafoglio di prodotti e una forte posizione sul mercato, specialmente nel campo della dermatologia.
  • Nel novembre 2010, 3M ha rilanciato la linea Cavilon Professional Skin Care. Questo prodotto ha aiutato a prevenire danni alla pelle da umidità, attrito e traumi adesivi. Il portafoglio di prodotti dell'azienda è aumentato per quanto riguarda la dermatologia archiviata e quindi le entrate sanitarie.

Opportunità:

BASSA PENETRAZIONE BIOLOGICA:

I biologici sono i farmaci che sono fatti da proteine ​​animali o umane che hanno la capacità di trattare rispettivamente le malattie. Hanno la capacità di trattare il numero di malattie come la psoriasi, l'artrite psoriasica, altri tipi di artrite e malattie infiammatorie intestinali. A causa della bassa attività dei farmaci biologici nel trattamento di eventuali malattie del derma, i farmaci topici stanno superando il mercato a fini terapeutici e quindi la sua domanda è in aumento sul mercato.

AUMENTO DEL CONCORSO CHE GUIDA AD ALTI INVESTIMENTI IN R&S PER INNOVARE NUOVI PRODOTTI:

La malattia della pelle negli ultimi tempi è una delle principali malattie tra le persone per le quali sono disponibili trattamenti. Uno dei trattamenti avanzati è il sistema topico di rilascio del farmaco in cui la pelle svolge un ruolo importante poiché il farmaco viene applicato sulla pelle che ha la capacità di trattare le aree colpite. Numero di aziende ha preso l'iniziativa nel fornire alta qualità di prodotti o farmaci per il trattamento delle malattie della pelle. Ciò comporta il processo di innovazione nella ricerca farmaceutica. L'aumento del numero di malattie richiede un trattamento adeguato per il quale i farmaci topici svolgono attualmente un ruolo importante. Di conseguenza, molte aziende hanno aumentato le proprie strutture di ricerca e sviluppo al fine di fornire i farmaci che saranno ritenuti un fattore importante per guidare il mercato in futuro.

AUMENTO DI FUSIONI E ACQUISIZIONI:

Le industrie farmaceutiche probabilmente subiscono la maggior parte delle attività di fusione e acquisizione (M&A) rispetto a qualsiasi altra industria che coinvolge il numero di operazioni e la spesa in denaro. Questa attività è necessaria a causa dell'aumento dello sviluppo di un nuovo farmaco nell'industria farmaceutica. Ad esempio, a luglio 2018, Leo Pharma ha acquisito un'unità globale di dermatologia su prescrizione di Bayer AG (Germania) a un prezzo non divulgato. Lo scopo di questa acquisizione era di espandere il loro prodotto nei farmaci per la pelle. Leo Pharma sviluppa ulteriormente l'attività di dermatologia su prescrizione con questa acquisizione. L'aumento delle acquisizioni e delle fusioni aiuta le aziende a rafforzare i propri ricavi insieme a strutture di ricerca e sviluppo e produzione e questo ultimo aiuto nella crescita di un particolare mercato.

MERCATO EMERGENTE:

L'elevata accessibilità per i pazienti sta portando a maggiori investimenti da parte del settore privato. Molte aziende si stanno concentrando sull'intraprendere sviluppi strategici per aumentare la loro presenza nelle economie emergenti. Insieme a questo, l'invecchiamento della popolazione e l'aumento del reddito disponibile contribuiranno alla crescita del mercato. Il mercato di consegna di farmaci topici ha una grande opportunità in quanto questa piattaforma ha nuovi elementi che sono stati incorporati per il trattamento di malattie della pelle e delle mucose. Le condizioni della pelle stanno aumentando in tutto il mondo, che alla fine richiede un trattamento. Aumentare la consapevolezza delle malattie della pelle è anche un fattore che sta aiutando il mercato a crescere in futuro.

sfide:

EFFETTI COLLATERALI:

L'effetto collaterale dei farmaci si verifica nell'uomo a causa dell'uso a lungo termine dei farmaci. Ci sono alcuni effetti collaterali che possono verificarsi nel corpo del paziente dopo aver consumato farmaci topici. Ad esempio, il consumo a lungo termine di corticosteroidi può causare difetti alla nascita nel feto. I farmaci topici possono fornire un trattamento migliore ma a parte questo anche il prodotto ha effetti collaterali. Ciò accade a causa dell'uso eccessivo di trattamenti topici che aumentano il rischio di effetti collaterali sia cutanei che sistemici e quindi ostacolano la crescita del mercato.

RICHIAMO DEL PRODOTTO:

Negli ultimi anni, il numero di richiami di prodotti nel mercato topico della consegna di droghe è aumentato enormemente. Questi richiami di prodotti possono verificarsi a causa di inadempienza della conformità, come difetti di progettazione o di fabbricazione che possono essere negoziati con la sicurezza, l'efficacia e la purezza del farmaco o dei dispositivi di consegna del farmaco da parte di un'azienda produttrice di farmaci. Ad esempio, a luglio 2016, GlaxoSmithKline (Regno Unito) ha annunciato il richiamo dell'unguento Bactroban e della crema Bactroban a causa della presenza di contaminazione durante la produzione; queste formulazioni sono state usate localmente per le infezioni della pelle. Inoltre, a giugno 2016, il cerotto per emicrania di Teva Phamaceutical chiamato Zecuity è stato ricordato per aver riportato gravi ustioni e potenziali cicatrici permanenti. Il richiamo dei prodotti influisce sui ricavi dell'azienda e, in definitiva, sul mercato particolare.

Nota: se hai esigenze particolari, faccelo sapere e ti offriremo il rapporto come desideri.

Informazioni sulla ricerca di mercato di Data Bridge:

Data Bridge Market Research si è affermata come una società di ricerca e consulenza di mercato non convenzionale e neoterica con un livello di resilienza senza precedenti e approcci integrati. Siamo determinati a scoprire le migliori opportunità di mercato e promuovere informazioni efficienti per far prosperare il tuo business sul mercato. Data Bridge si impegna a fornire soluzioni adeguate alle complesse sfide aziendali e avvia un processo decisionale senza sforzo.

Contatto:

Ricerche di mercato di Data Bridge

Tel: + 1-888-387-2818

E-mail: Corporatesales@databridgemarketresearch.com

Psorilax:commenti |crema lenitiva per psoriasi

0

Psorilax: prezzo, funziona, recensioni, opinioni, ingredienti

BRUXELLES, 20 febbraio 2020 / PRNewswire / – 7:00 (CET) – informazioni regolamentate – “data-reagente =” 12 “>BRUXELLES, 20 febbraio 2020 / PRNewswire / – 7:00 (CET) – informazioni regolamentate –

  • I ricavi hanno raggiunto € 4,9 miliardi (+ 6%, + 7% CER(1)) le vendite nette sono aumentate a 4,7 miliardi di euro (+ 6%)
  • Redditività sottostante (rEBITDA(2)) è stato di 1,4 miliardi di euro (+ 2%, + 11% CER) o del 29,1% delle entrate
  • Aggiornamento R&S: bimekizumab con tre risultati positivi di Fase 3 nella psoriasi e iniziato un nuovo programma di Fase 3 nell'idradenite suppurativa; Cimzia® con approvazioni in Cina e Giappone
  • Previsioni finanziarie per il 2020: le entrate dovrebbero raggiungere € 5,05 – 5,15 miliardi,
    REBITDA(2) 28 – 29% delle entrate, core EPS(3) di € 4,80 – 5,20 previsto
  • Nuova guida alle vendite di punta per Cimzia® 2,0 miliardi di euro entro il 2024 e per Vimpat® 1,5 miliardi di euro entro il 2022
  • Nuova composizione del comitato esecutivo di UCB nel 2020

Jean-Christophe Tellier, CEO UCB. “In base alla nostra promettente pipeline in fase avanzata e all'acquisizione di Ra Pharma in sospeso, potremmo potenzialmente lanciare fino a 7 prodotti entro il 2025 per creare valore per il paziente per popolazioni specifiche ora e in futuro. Inoltre, ci concentriamo su quattro aree di sostenibilità che sono fondamentali al nostro successo a lungo termine e al nostro contributo alla società. “” data -eagid = “21”> “Il 2019 è stato un anno di forte crescita e crescita. Pertanto, abbiamo aggiornato la guida alle vendite di punta per Cimzia® e Vimpat® e continuiamo ad accelerare i nostri investimenti in futuri fattori di crescita “, ha affermato Jean-Christophe Tellier, CEO UCB. “In base alla nostra promettente pipeline in fase avanzata e all'acquisizione di Ra Pharma in sospeso, potremmo potenzialmente lanciare fino a 7 prodotti entro il 2025 per creare valore per il paziente per popolazioni specifiche ora e in futuro. Inoltre, ci concentriamo su quattro aree di sostenibilità che sono fondamentali al nostro successo a lungo termine e al nostro contributo alla società “.

Il Consiglio di amministrazione di UCB propone un dividendo di € 1,24 per azione (lordo), + 2%.

Gennaio 2020, è iniziato lo studio di fase 3 su pazienti con trombocitopenia immunitaria (ITP), i primi risultati attesi sono attesi in H 2 2022. “data-reagid =” 29 “> In Gennaio 2020, è iniziato lo studio di fase 3 su pazienti con trombocitopenia immunitaria (ITP), i primi risultati attesi sono attesi in H 2 2022.

Maggio 2019. “data-reactionid =” 32 “> A dicembre è stato lanciato UCB Nayzilam® (midazolam) Spray nasale CIV, il primo e unico trattamento di salvataggio nasale per i gruppi epilettici negli Stati Uniti Nayzilam® spray nasale è stato approvato negli Stati Uniti a Maggio 2019.

Cina.
A dicembre, Cimzia® è stato approvato per il trattamento della psoriasi e dell'artrite psoriasica in Giappone. “data-reactionid =” 33 “>Immunologia
Nel mese di luglio, Cimzia® (certolizumab pegol) è stato approvato in associazione con metotrexato per il trattamento dell'artrite reumatoide attiva da moderata a grave in pazienti adulti in Cina.
A dicembre, Cimzia® è stato approvato per il trattamento della psoriasi e dell'artrite psoriasica in Giappone.

  • Nel mese di ottobre, lo studio BE VIVID, che valuta l'efficacia e la sicurezza di bimekizumab negli adulti con psoriasi a placche cronica da moderata a grave ha raggiunto tutti gli endpoint primari e secondari, compresa un'efficacia significativamente maggiore rispetto a ustekinumab.
  • A novembre, lo studio BE READY, che valuta l'efficacia e la sicurezza di bimekizumab rispetto al placebo negli adulti con psoriasi a placche cronica da moderata a grave, hanno incontrato tutti gli endpoint primari e secondari classificati.
  • A dicembre, lo studio SIA SICURO, a confronto bimekizumab per adalimumab per il trattamento di adulti con psoriasi a placche da moderata a grave, ha soddisfatto tutti gli endpoint secondari e classificati, ottenendo un'efficacia significativamente maggiore rispetto a adalimumab.
  • Giappone, gli Stati Uniti., Corea del Sud, Canada e Australia nonché nell'UE. “data -eagid =” 41 “>Evenity® (romosozumab) è ora approvato in Giappone, gli Stati Uniti., Corea del Sud, Canada e Australia così come nell'UE.

    In ottobre, a seguito della procedura di riesame, il comitato per i medicinali per uso umano (CHMP) dell'Agenzia europea per i medicinali (EMA) ha adottato un parere positivo raccomandando l'autorizzazione all'immissione in commercio.

    La storia continua

    Europa, Le vendite nette di Keppra® sono state influenzate da un adeguamento locale degli sconti una tantum nella prima metà del 2019 “data-reazioni” = “53”>Keppra® (Levetiracetam) per l'epilessia, ha riportato un fatturato netto di 770 milioni di euro, che riflette sia il marchio forte e affidabile che la maturità del prodotto. Negli Stati Uniti le vendite nette sono state influenzate dalla concorrenza generica. Nel Europa, Le vendite nette di Keppra® sono state influenzate da un adeguamento locale degli sconti una tantum nella prima metà del 2019

    Europa sono stati quasi compensati dalla buona crescita dei mercati internazionali. “data -eagid =” 55 “>Neupro® (Rotigotina), la patch per il morbo di Parkinson, ha mostrato una leggera riduzione delle vendite nette a 319 milioni di euro. Riduzioni minori negli Stati Uniti, dovute all'ambiente di mercato generico – e Europa sono stati quasi compensati da una buona crescita nei mercati internazionali.

    Germania e il supplemento di ferro Niferex® nel primo trimestre del 2019, e prima che le 'coperture designate riclassificate nelle vendite nette' fossero cresciute del + 13% (+ 9% CER). Questa crescita è stata trainata dalla continua forte performance positiva dei prodotti core di UCB.
    Le entrate e le commissioni delle royalties sono diminuite a € 78 milioni da € 92 milioni. Le altre entrate sono aumentate a € 155 milioni dopo € 128 milioni. “Data-reazioni =” 57 “> Nel 2019, entrate e vendite nette aumentato del 6% (+ 7% CER) a 4 913 milioni di euro e rispettivamente a 4 680 milioni di euro (+ 6%; + 7% CER). Le vendite nette prima delle “coperture designate riclassificate in vendite nette” sono aumentate dell'11% (+ 7% CER) a 4 784 milioni di euro. Aggiustato per cessioni nel 2018, principalmente “Innere Medizin” /Germania e il supplemento di ferro Niferex® nel primo trimestre del 2019, e prima che le 'coperture designate riclassificate nelle vendite nette' fossero cresciute del + 13% (+ 9% CER). Questa crescita è stata trainata dalla continua forte performance positiva dei prodotti core di UCB.
    Le entrate e le commissioni delle royalties sono diminuite a € 78 milioni da € 92 milioni. Gli altri ricavi sono aumentati a € 155 milioni dopo € 128 milioni.

    Europa e nella spondiloartrite assiale non radiografica attiva (nr-axSpA) negli Stati Uniti, nonché i preparativi per il lancio di Evenity® nel Europa, Spese di ricerca e sviluppo superiori del 10% di € & nbsp; 1 & nbsp; 272 & nbsp; milioni – trainate da maggiori investimenti in R & amp; D e risultanti in un rapporto di R & amp; D del 26% nel 2019 dopo il 25% nel 2018 e dell'8% in più in generale e amministrativo spese per € 195 milioni, principalmente in relazione al nuovo modello organizzativo implementato nel 2019. Gli altri ricavi operativi sono stati € 48 milioni dopo spese di € 24 milioni nel 2018. I ricavi sono composti da contributi agli investimenti, utili su cessioni , liberazione di accantonamenti e entrate derivanti dalla collaborazione con Amgen in relazione a Evenity®. Ciò ha comportato un rapporto spese operative (in relazione ai ricavi) del 51% dopo il 50% nel 2018. “data-reazioni” = “59”>Spese operative ha raggiunto 2 527 milioni di euro (+ 9%; + 6% CER) riflettendo un aumento del 15% delle spese di marketing e vendita di 1 108 milioni di euro – guidato dal lancio di Cimzia® nella psoriasi negli Stati Uniti e Europa e nella spondiloartrite assiale non radiografica attiva (nr-axSpA) negli Stati Uniti, nonché i preparativi per il lancio di Evenity® nel Europa, Il 10% in più di spese di ricerca e sviluppo di 1 272 milioni di euro – trainati da maggiori investimenti in ricerca e sviluppo e risultante in un rapporto di ricerca e sviluppo del 26% nel 2019 dopo il 25% nel 2018 e 8% in più di spese generali e amministrative di 195 milioni di euro, principalmente connessione con il nuovo modello organizzativo implementato nel 2019. Gli altri ricavi operativi sono stati pari a 48 milioni di euro dopo spese di 24 milioni di euro nel 2018. I proventi sono composti da contributi agli investimenti, utili da cessione, liberazione di accantonamenti e proventi derivanti dalla collaborazione con Amgen in relazione con uniformità®. Ciò ha comportato un rapporto spese operative (in relazione ai ricavi) del 51% dopo il 50% nel 2018.

    Sei anni consecutivi di crescita hanno sottolineato nel tempo le solide prestazioni di UCB. UCB è pronta ad accelerare ulteriormente e ad espandersi per soddisfare le sue ambizioni di valore per il paziente, potenzialmente lanciando sei o sette nuovi prodotti entro il 2025.

    Jean-Christophe Tellier, CEO di UCB “data -eagid =” 70 “>” Per supportare le nostre ambizioni, abbiamo evoluto la nostra organizzazione e i nostri modi di lavorare per assicurarci di diventare più agili e collaborare più trasversalmente all'interno della nostra organizzazione. Riteniamo che questa organizzazione evoluta aumenterà la nostra chiarezza operativa ed efficienza e ci preparerà per lanci incentrati sul valore per il paziente “, ha affermato Jean-Christophe Tellier, CEO di UCB

    Questa evoluzione si riflette nella nuova composizione del Comitato Esecutivo UCB che è diventato più piccolo, con ruoli più trasversali tra le imprese e le regioni e con una maggiore attenzione alle aree di attività principali dell'azienda.

    1o febbraio 2020 la nuova composizione del Comitato Esecutivo di UCB è la seguente: “data -eagid =” 72 “> Da 1o febbraio 2020 la nuova composizione del Comitato esecutivo di UCB è la seguente:

    • Jean-Christophe Tellier, Amministratore delegato
    • Emmanuel Caeymaex, Vicepresidente esecutivo per le soluzioni immunologiche e capo degli Stati Uniti
    • Jean-Luc Fleurial, Vicepresidente esecutivo e direttore delle risorse umane
    • Iris Löw-Friedrich, Vicepresidente esecutivo e Chief Medical Officer
    • Kirsten Lund-Jurgensen, Vicepresidente esecutivo, Soluzioni di approvvigionamento e tecnologia
    • Dhaval Patel, Vicepresidente esecutivo e Direttore scientifico
    • Bill Silbey, Vicepresidente esecutivo e consigliere generale
    • Detlef Thielgen, Vicepresidente esecutivo, Direttore finanziario e Sviluppo aziendale
    • Charl van Zyl, Executive Vice President Neurology Solutions e Head of EU / International

    Alexander Moscho, Pascale Richetta, Bharat Tewarie e Jeff Wren hanno lasciato il Comitato Esecutivo e UCB è molto grato per i loro contributi passati. Bill Silbey e Kirsten Lund-Jurgensen è entrato a far parte del Comitato esecutivo nel 2019.
    Inoltre, UCB ha annunciato in Luglio 2019 che il Chief Financial Officer dell'azienda, Detlef Thielgen, uscirà da UCB nel primo semestre 2020. È in corso la ricerca di un successore. “data -eagid =” 83 “>Alexander Moscho, Pascale Richetta, Bharat Tewarie e Jeff Wren hanno lasciato il Comitato Esecutivo e UCB è molto grato per i loro contributi passati. Bill Silbey e Kirsten Lund-Jurgensen è entrato a far parte del Comitato esecutivo nel 2019.
    Inoltre, UCB ha annunciato in Luglio 2019 che il Chief Financial Officer dell'azienda, Detlef Thielgen, uscirà da UCB nel primo semestre 2020. È in corso la ricerca di un successore.

    https://www.ucb.com/investors/UCB-Governance#book-CMP_B_55790“data -eagid =” 84 “> Ulteriori informazioni sul Comitato esecutivo di UCB sono disponibili sul sito Web di UCB: https://www.ucb.com/investors/UCB-Governance#book-CMP_B_55790

    http://www.ucb.com/investors/Download-center& nbsp; “data -eagid =” 85 “> Trova i rapporti finanziari FY sul sito Web UCB: http://www.ucb.com/investors/Download-center

    Oggi UCB ospiterà una teleconferenza / webcast video alle 08.00 (EST) / 13.00 (GMT) / 14.00 (CET).

    https://www.ucb.com/investors/UCB-financials/Full-year-financial-results“data -eagid =” 87 “> I dettagli sono disponibili su https://www.ucb.com/investors/UCB-financials/Full-year-financial-results

    Bruxelles, Belgio (www.ucb.com) è una società biofarmaceutica globale focalizzata sulla scoperta e lo sviluppo di farmaci e soluzioni innovativi per trasformare la vita delle persone che vivono con gravi malattie del sistema immunitario o del sistema nervoso centrale. Con oltre 7 persone in circa 40 paesi, la società ha generato ricavi per € 4,9 miliardi nel 2019. UCB è quotata su Euronext Bruxelles (simbolo: UCB). Seguiteci su Twitter: @UCB_news “data -eagid =” 88 “>Informazioni su UCB
    UCB, Bruxelles, Belgio (www.ucb.com) è una società biofarmaceutica globale focalizzata sulla scoperta e lo sviluppo di farmaci e soluzioni innovativi per trasformare la vita delle persone che vivono con gravi malattie del sistema immunitario o del sistema nervoso centrale. Con oltre 7 600 persone in circa 40 paesi, la società ha generato ricavi per € 4,9 miliardi nel 2019. UCB è quotata su Euronext Bruxelles (simbolo: UCB). Seguiteci su Twitter: @UCB_news

    Given these uncertainties, you should not place undue reliance on any of such forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labelling in any market, or at any particular time, nor can there be any guarantee that such products will be or will continue to be commercially successful in the future.

    UCB is providing this information, including forward-looking statements, only as of the date of this press release and expressly disclaims any duty to update any information contained in this press release, either to confirm the actual results or to report or reflect any change in its forward-looking statements with regard thereto or any change in events, conditions or circumstances on which any such statement is based, unless such statement is required pursuant to applicable laws and regulations.

    Additionally, information contained in this document shall not constitute an offer to sell or the solicitation of an offer to buy any securities, nor shall there be any offer, solicitation or sale of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of such jurisdiction.

    (1) CER = constant exchange rates

    (3) Core EPS = core earnings per share

    (4) Due to rounding, some financial data may not add up in the tables.

    (5) Due to rounding, some financial data may not add up in the tables.

    (6) rEBITDA = recurring Earnings Before Interest, Taxes, Depreciation and Amortization charges

    http://www.prnewswire.com/news-releases/ucb-full-year-report-2019-301007945.html” data-reactid=”111″>View original content:http://www.prnewswire.com/news-releases/ucb-full-year-report-2019-301007945.html

    SOURCE UCB