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(Tofacitinib) for the Treatment of Moderate to Severe Ulcerative Colitis

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(Tofacitinib) for the Treatment of Moderate to Severe Ulcerative Colitis Author: Lou Ferrara Source: FDA AC Notice Letter Slide Coordinators Reviewed Graphics (Crystal Huntoon) Ready for QC QC Coordinator In QC Date Graphics ® (Crystal Huntoon) QC Edits XELJANZ (tofacitinib) for the Treatment of Moderate to Severe QC Coordinator QC Complete Date Ulcerative Colitis Graphics (Crystal Huntoon) Gastrointestinal Drugs Advisory Committee (GIDAC) QC Coordinator In RE-QC March 8, 2018 Date FDA White Oak Campus Silver Spring, MD MA-1 Author: Lou Ferrara Source: Title slides and presenters Overview of Presentation Topic Presenter Lou Ferrara Introduction Director, Regulatory Affairs Pfizer Inc William Sandborn, MD Ulcerative Colitis: Chief, Division of Gastroenterology A Clinician’s Perspective/Unmet Medical Need Director, Inflammatory Bowel Disease Center University of California, San Diego Eric Maller, MD Tofacitinib Ulcerative Colitis Development Program Executive Director, UC Development Program and Efficacy Inflammation and Immunology Pfizer Inc Chinyu Su, MD Safety of Tofacitinib in Ulcerative Colitis Senior Director, Global Clinical Lead UC Development Program Inflammation and Immunology Pfizer Inc Thomas Jones, MD Risk Management Senior Director, Safety Risk Management Pfizer Inc Michael Corbo, PhD Senior VP, Chief Development Officer Benefit:Risk and Conclusion Inflammation and Immunology Pfizer Inc UC=Ulcerative Colitis MA-2 Author: Jim Clark Source: Flanagan ME et al, J Med Chem 2010; 53:8468-8484 Tofacitinib is a New Treatment Approach for Ulcerative Colitis Tofacitinib induces and maintains steroid-free remission Tofacitinib is efficacious in TNF naïve and TNF-experienced patients Oral, reversible, small molecule inhibitor of the Janus family of Kinases (JAKs) Human genetics implicate JAK dependent cytokines in UC (e.g. IL-12/23, INFg, IL-21, OSM, STATs and SOCS) Immune effect extensively studied clinically (e.g. vaccine, immune function and genetics studies) IL=Interleukin; INFg=Interferon gamma; OSM=Oncostatin M; SOCS=Suppressors Of Cytokine Signaling; STAT=Signal Transducers and Activators of Transcription; TNF=Tumor Necrosis Factor MA-3 Author: Jim Clark Source: Flanagan ME et al, J Med Chem 2010; 53:8468-8484 Tofacitinib is a New Treatment Approach for Ulcerative Colitis Tofacitinib induces and maintains steroid-free remission Tofacitinib is efficacious in TNF naïve and TNF-experienced patients Oral, reversible, small molecule No risk of anti-drug inhibitor of the Janus family of antibodies Kinases (JAKs) Direct inhibition readily Human genetics implicate JAK reversible dependent cytokines in UC (e.g. IL-12/23, INFg, IL-21, Tofacitinib modulates OSM, STATs and SOCS) important pathways that Immune effect extensively drive disease studied clinically (e.g. vaccine, immune function and genetics Well characterized and studies) manageable safety profile IL=Interleukin; INFg=Interferon gamma; OSM=Oncostatin M; SOCS=Suppressors Of Cytokine Signaling; STAT=Signal Transducers and Activators of Transcription; TNF=Tumor Necrosis Factor MA-4 Author: Lou Ferrara Source: Approval Letters, RA Team and UC sNDA submission acknowledgement letter XELJANZ® (tofacitinib) US Approval History Rheumatoid Arthritis (RA) – Adult RA 5 mg BID IR NDA Approved – November 6, 2012 – Adult RA 11 mg QD XR NDA Approved – February 23, 2016 – Tofacitinib tablets are approved for RA in more than 85 countries; including US, Canada, EU countries and Japan Psoriatic Arthritis (PsA) – PsA sNDAs (5 mg BID IR and 11 mg XR) Approved – December 14, 2017 Pending Applications – UC sNDA Submitted – May 4, 2017 BID=twice daily; IR=Immediate Release; mg=milligram; NDA=New Drug Application; QD=once daily; RA=Rheumatoid Arthritis; sNDA=supplemental New Drug Application; XR=Extended Release MA-5 Author: Lou Ferrara Source: Key Messages fro presentations Tofacitinib for the Treatment of Moderate to Severe UC Significant medical need for alternate UC treatments with new MoAs Tofacitinib provides clinically meaningful benefit for both induction and maintenance – Rapid onset of induction in many patients – Durable steroid-free benefit in maintenance – Benefit in both TNF naïve and prior TNF failure patients • With tofacitinib 10 mg BID maintenance providing important clinical benefit in TNF failure patients The safety profile of tofacitinib in UC patients is well characterized, manageable and similar between doses – Targeted risk management plan to address risks for UC patients MoA=Mechanism of Action MA-6 Author: Lou Ferrara Source: Dec 14, 2018 IR response sNDA submission ® (eCTD Seq No. 0514) XELJANZ (tofacitinib) for Moderate to Severe UC Proposed USPI: Indication and Dosing Proposed Indication in sNDA (1. INDICATIONS AND USAGE) For the treatment of adult patients with moderately to severely active ulcerative colitis (UC) with an inadequate response, loss of response or intolerance to corticosteroids, azathioprine, 6-mercaptopurine (6-MP) or TNF inhibitor therapy Proposed Dosage in sNDA (2. DOSAGE AND ADMINISTRATION) The recommended dose of XELJANZ for adult patients with moderately to severely active ulcerative colitis is 10 mg twice daily for induction for 8 weeks and 5 mg twice daily for maintenance Adult patients with moderately to severely active UC with an inadequate response, loss of response, or intolerance to TNF blocker therapy: 10 mg BID for maintenance may be considered in order to maintain therapeutic benefit For patients who do not achieve adequate therapeutic benefit by Week 8, the induction dose of 10 mg BID can be extended for an additional 8 weeks (16 weeks total), followed by 5 mg BID for maintenance. Discontinue therapy in patients who do not achieve adequate therapeutic benefit by Week 16 USPI=United States Package Insert MA-7 Author: Mike Corbo? Source: Benefit Risk and Conclusion section Patient Population Map Core Treatment Population: Moderate to Severe UC Tofacitinib 10 mg BID Induction for 8 weeks Tofacitinib 5 mg BID Maintenance TNF Treatment Failure Subpopulation Tofacitinib 10 mg BID Maintenance Extended Induction Subpopulation Tofacitinib 10 mg BID Induction for 16 weeks MA-8 Author: Mike Corbo? Source: Benefit Risk and Conclusion section Patient Population Map Core Treatment Population: Moderate to Severe UC Tofacitinib 10 mg BID Induction for 8 weeks Tofacitinib 5 mg BID Maintenance TNF Treatment Failure Subpopulation Tofacitinib 10 mg BID Maintenance Extended Induction Subpopulation Tofacitinib 10 mg BID Induction for 16 weeks MA-9 Author: Lou Ferrara Source: Title slides and presenters Overview of Presentation Topic Presenter Lou Ferrara Introduction Director, Regulatory Affairs Pfizer Inc William Sandborn, MD Ulcerative Colitis: Chief, Division of Gastroenterology A Clinician’s Perspective/Unmet Medical Need Director, Inflammatory Bowel Disease Center University of California, San Diego Eric Maller, MD Tofacitinib Ulcerative Colitis Development Program Executive Director, UC Development Program and Efficacy Inflammation and Immunology Pfizer Inc Chinyu Su, MD Safety of Tofacitinib in Ulcerative Colitis Senior Director, Global Clinical Lead UC Development Program Inflammation and Immunology Pfizer Inc Thomas Jones, MD Risk Management Senior Director, Safety Risk Management Pfizer Inc Michael Corbo, PhD Senior VP, Chief Development Officer Benefit:Risk and Conclusion Inflammation and Immunology Pfizer Inc MA-10 Author: Chudy Nduaka Source: Experts Additional Experts in Sponsor Section Expert Area of Expertise Bruce Sands, MD Professor of Medicine Gastroenterology Icahn School of Medicine at Mount Sinai Phil Schein, MD Oncology President, The Schein Group Robert Schooley, MD Professor of Medicine Infectious Disease University of California, San Diego MA-11 KOL Slide No QC Needed Ulcerative Colitis: A Clinician’s Perspective/ Unmet Medical Need William Sandborn, MD Chief, Division of Gastroenterology Director, Inflammatory Bowel Disease Center University of California, San Diego MA-12 Footnotes: IBD=inflammatory bowel disease; UC=ulcerative colitis. KOL Slide No QC Needed Ulcerative Colitis is a Chronic Inflammatory References: 1. Ordas I, Eckmann L, Talamini M, Bowel Disease with an Unpredictable Course Baumgart DC, Sandborn WJ. Ulcerative colitis. Lancet. 2012;380:1606-1619. Idiopathic, incurable chronic 2. Danese S, Fiocchi C. Ulcerative colitis. inflammatory disorder of the N Engl J Med. 2011;365:1713-1725. 3. da Silva BC, Lyra AC, Rocha R, Santana 1,2 colon GO. Epidemiology, demographic – Diarrhea, rectal bleeding, urgency, characteristics and prognostic predictors of tenesmus, profound fatigue, pain ulcerative colitis. World J Gastroenterol. 2014;20:9458-9467. Early age of onset 4. Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. Incidence and prevalence 2014;14:329-342. on the rise3,4 5. Martini FH, Ober WC, Garrison CW, – Affects as many as 907,000 Welch K, Hutchings RT, Ireland K. In: Americans3,4 Anatomy & Physiology. Philippine ed. de Chambrun GP et al. Nat Rev Gastroenterol. 2010;7:15-29. Jurong, Singapore: Pearson Education South Asia Pte. Ltd.; 2007:571, 683. 6. Feuerstein JD, Cheifetz AS. Ulcerative colitis: epidemiology, diagnosis, and 1. Ordas I et al. Lancet. 2012;380:1606-1619. 2. Danese S et al. N Engl J Med. 2011;365:1713-1725. management. Mayo Clin Proc. 3. Shivashankar R et al. Clin Gastroenterol Hepatol. 2017 Jun;15(6): 857-863. 2014;89:1553-1563. 4. Molodecky NA et al. Gastroenterology. 2012 Jan;142(1):46-54. MA-13 Shivashankar R, Tremaine W, Harmsen W, Loftus E. Clin Gastroenterol Hepatol. 2017 Jun; 15(6): 857–863. Molodecky NA1, Soon
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