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Telaprevir: Phase 3 Trials in Treatment-Naïve Patients Paris, France 30 January, 2012

Telaprevir: Phase 3 Trials in Treatment-Naïve Patients Paris, France 30 January, 2012. Ira M. Jacobson, M.D. Vincent Astor Professor of Medicine Chief, Division of Gastronterology and Hepatology Medical Director, Center for the Study of Hepatitis C Weill Cornell Medical College.

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Telaprevir: Phase 3 Trials in Treatment-Naïve Patients Paris, France 30 January, 2012

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  1. Telaprevir: Phase 3 Trials in Treatment-Naïve PatientsParis, France 30 January, 2012 Ira M. Jacobson, M.D. Vincent Astor Professor of Medicine Chief, Division of Gastronterology and Hepatology Medical Director, Center for the Study of Hepatitis C Weill Cornell Medical College

  2. The Evolution of HCV Therapy 2002 1986 1998 2001 SVR (%) 54-56 42 39 34 16 6 IFN/RBV 12 mo PEG-IFN /RBV 12 mo IFN 6 mo IFN/RBV 6 mo IFN 12 mo PEG-IFN 12 mo Strader DB, et al. Diagnosis, Management, and Treatment of Hepatitis C. Hepatology 2004;39:1147-1171.

  3. IRES ARFP 5 (U/UC) 3 UTR UTR Hepatitis C Virus GenomeThe Function of the NS3/4A Serine Protease Envelope ProteaseHelicase Polymerase Structural Nonstructural Abbreviations: ARFP, alternate reading frame protein; IRES, internal ribosome entry site; UTR, untranslated region. Glenn JS. Clin Liver Dis. 2005;9:353-369.

  4. Phase 1 Trial of Telaprevir vs PEG IFNvs PEG IFN Alone 1 Sequence analysis Baseline 0 -1 PEG IFN alfa-2a + placebo N=4 HCV RNA Change from Baseline (Log10 IU/mL) -2 • Resistant mutations emerged within 4-7 days; subsequently • suppressed by PEG IFN + RBV • Differences in G1 subtypes -3 Telaprevir N=8 -4 -5 Telaprevir + PEG IFN alfa-2a N=8 -6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Study Time (days) Kieffer T, et al. Hepatology. 2007;46:631-639

  5. Lessons Learned From Phase 2 Trials With Telaprevir + PR in Naïve Patients(PROVE1, PROVE2) • Higher rates of RVR, lower rates of relapse drive higher rates of SVR in G1 • Foundation for exploration of response guided therapy in phase 3 • 12 weeks triple therapy too short to achieve optimal results in overall population • Inability to delete ribavirin from regimen • Side effect profile McHutchison J et al NEJM 2009;Hezode C et al NEJM 2009

  6. Phase 3 Trials of Telaprevir in Treatment-Naïve Patients ADVANCE Pivotal N=1088 ILLUMINATE Supportive N=540

  7. ADVANCE: Treatment Naïve G1 Weeks 0 8 12 24 36 48 72 Randomized, Double-Blind, Placebo-Controlled for Telaprevir 72 weeks SVR eRVR + Follow-up Follow-up T12PR TVR + PR PR SVR Follow-up eRVR- PR . SVR eRVR + Follow-up Follow-up T8PR TVR + PR Pbo + PR PR SVR Follow-up eRVR- PR . SVR PR48 (control) Pbo + PR PR Follow-up eRVR = HCV RNA undetectable at week 4 and week 12 (Taqman v2.0) (T) TVR = telaprevir 750 mg q8h; Pbo = Placebo; (P) Peg-IFN = pegylated interferon alfa-2a (40 kD) 180 µg/wk; (R) RBV = ribavirin 1,000 or 1,200 mg/da Jacobson IM, et al. N Engl J Med 2011;364:2405-16

  8. ADVANCE: Stopping Rules *Applied to telaprevir-treated patients only Jacobson IM, et al. N Engl J Med 2011;364:2405-16

  9. T12PR T8PR PR ADVANCE: SVR Rates P<0.0001 100 P<0.0001 90 75 80 69 70 60 Percent of patients with SVR 44 50 40 30 20 10 0 n/N = 271/363 250/364 158/361 SVR Jacobson IM, et al. N Engl J Med 2011;364:2405-16

  10. Higher SVR Rates From ADVANCE in FDA Approved Label SVR rates in package insert (%) Explanations for change 79 Counted HCV RNA between LLQ and LLD at f/u week 24 as SVR 72 46 Counted SVR12 as SVR

  11. T12PR T8PR PR ADVANCE: Relapse Rates 100 90 80 70 60 Percent of patients with relapse 50 40 27 28 30 20 9 9 7 6 10 0 n/N = 27/314 28/295 64/229 17/264 18/247 51/189 Overall Completed Regimen Overall – patients who had undetectable HCV RNA at the last dose of treatment Completed regimen – patients who completed assigned regimen and had undetectable HCV RNA after the last dose of treatment

  12. T12PR T8PR PR ADVANCE: RVR and eRVR Rates 100 Patients eligible to receive 24 weeks of total treatment 90 80 68 70 66 58 60 57 Percent of patients with HCV RNA undetectable 50 40 30 20 9 8 10 0 n/N = 246/363 242/364 34/361 212/363 207/364 29/361 Week 4 (RVR) Weeks 4 and 12 (eRVR) Jacobson IM, et al. N Engl J Med 2011;364:2405-16

  13. T12PR T8PR PR ADVANCE: SVR Rates by eRVR Status 97 100 89 90 83 80 70 60 54 50 Percent of patients with SVR 50 39 40 30 20 10 0 n/N = 189/212 171/207 28/29 82/151 79/157 130/332 24-week regimen 48-week regimen eRVR- eRVR+ Jacobson IM, et al. N Engl M Med 2011;364:2405-16

  14. 20 T12PR Virologic failure 8% 20 T8PR Virologic failure 13% 16 16 12 10% 12 Percent of Patients 8 8 5% 3% 3% 4 4 0 0 4 12 24 28 36 40 48 4 12 24 28 36 40 48 Weeks on Treatment Weeks on Treatment Overall On-treatment Virologic Failure is Lower in Patients Receiving 12 Weeks of Telaprevir • Criteria for virologic failure: • Met stopping rule • HCV RNA > 1000 IU/ml at week 12 even with HCV RNA decline > 2 log (TVR arms only) • HCV RNA detectable at end of treatment Jacobson IM et al, N Engl J Med 2011;364:2405-16; Kieffer T et al AASLD 2010

  15. ADVANCE: SVR by Subgroups 83 78 78 75 75 74 74 71 70 62 White Black Male Female <45 >45-65 1b 1a <800K >800K Age Genotype HCV RNA

  16. ADVANCE: Most Common Adverse Events Shaded areas: 10% or greater incidence in either TVR groups vs control

  17. ADVANCE: Discontinuation for Adverse Events Jacobson IM, et al. N Engl J Med 2011;364:2405-16

  18. Rash Events During Telaprevir/Placebo Phase Rash was primarily eczematous and resolved upon cessation of therapy Severe/worsening moderate rash was managed by sequentially discontinuing telaprevir, followed by ribavirin and, if indicated, peginterferon for continued progression Anorectal symptoms in ~29% with telaprevir Jacobson IM et al. N Engl J Med 2011;364:2405-16

  19. T12PR (n=363) T8PR ( (n=364) PR (control) (n=361) Nadir Hemoglobin, Discontinuation for Anemia, and Median Hemoglobin Levels Hemoglobin nadir during TVR/Pbo Phase Median Hemoglobin TVR TVR …. 15 14 Median Hemoglobin (g/dL) • Per protocol, anemia was to be managed with RBV dose modifications and ESAs were not allowed • 1%, 3% and 1% of patients in T12PR, T8PR and PR, respectively discontinued all drugs due to anemia events • 4%, 2% and 0% of patients in T12PR, T8PR and PR, respectively discontinued telaprevir/placebo only 13 12 11 0 0 4 8 12 16 24 20 Weeks Jacobson IM, et al.N Engl J Med 2011;364:2405-16

  20. IL28B Allele Distribution in ADVANCE was Consistent With Previous Reports for Treatment-Naïve Patients • Samples from 42% (454/1088) of ADVANCE patients were available in the IL28B dataset Jacobson IM et al, EASL 2011; DDW 2011

  21. T12PR T8PR 100 90 PR 84 73 80 71 64 59 57 60 Patients with SVR (%) 40 25 23 20 0 16/22 19/32 6/26 45/50 38/45 35/55 48/68 43/76 20/80 n/N= CC CT TT SVR Rates in ADVANCE Patients Genotyped for IL28B Jacobson IM, et al. Poster presented at: EASL: The International Liver Congress 2011; March 30-April 3, 2011; Berlin, Germany. Poster LB1369.

  22. RVR and eRVR in ADVANCE Patients Genotyped for IL28B eRVR (%) RVR (%) 84 78 71 64 62 57 60 59 51 50 50 45 16 16 2 2 0 0 50 45 55 68 76 80 22 32 26 50 45 55 68 76 80 22 32 26 CC CT TT eRVR patients received 24 weeks of treatment Jacobson IM, et al. Poster presented at: EASL 2011 Poster LB1369.

  23. ILLUMINATE Study: 24 vs 48 WeeksAfter eRVR With Telaprevir SVR SVR Follow-Up Follow-Up PegIFN + RBV Telaprevir (750 mg q8h) PegIFN + RBV Phase 3 Treatment-naïve Genotype 1 PegIFN + RBV T12/ PR With eRVR SVR Follow-Up PegIFN + RBV SVR Without eRVR Follow-Up PegIFN + RBV Week 0 12 20 24 48 72 eRVR (extended rapid virologic response): HCV RNA <25 IU/mL at weeks 4 and week 20. Sherman KE, et al. N Eng J Med 2011;365:1014-24

  24. 100 80 60 40 20 0 SVR Rates: ILLUMINATE  4.5% (2-sided 95% CI = -2.1% to +11.1%) 92 88 72 64 Patients With SVR (%) 23 n/N= 388/540 149/162 140/160 76/118 23/100 eRVR+ T12PR24 eRVR+ T12PR48 eRVR- T12PR48 ITT Other (D/C pre-wk 20) Sherman KE, et al. N Engl J Med 2011;365:1014-24

  25. 20 15 Patients with Relapse (%) 10 8 6 5 3 0 n/N= 37/469 9/159 4/154 ITT T12PR24 T12PR48 ILLUMINATE: Relapse Rates

  26. Effect of Shortening Therapy in Cirrhotics with eRVR: ILLUMINATE 92 67 12/18 11/12 ,Telaprevir package insert,2011

  27. Adverse Events Leading to Study Drug Discontinuations • Overall treatment phase • 17% of patients in ITT discontinued all study drugs due to AEs

  28. ADVANCE and ILLUMINATE Studies: SVR Rates by Anemia and Ribavirin Dosing Status Ribavirin Dose Reduction Status Anemia Status T12/PR PR T12/PR PR T12/PR24 T12/PR48 T12/PR24 T12/PR48 78% 77% 76% 76% 75% 74% 73% 73% 72% 72% 70% 69% 54% 50% Patients With SVR (%) Patients With SVR (%) 41% 41% Dose Reduction (n=172/148/320/89) No Dose Reduction (n=293/272/565/285) Anemia (n=196/165/361/92) No Anemia (n=269/259/324/262) Retrospective pooled analysis. Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S195. Abstract 477.

  29. Effect of Fibrosis in Pooled ADVANCE and ILLUMINATE Studies Marcellin P, et al. AASLD 2011, San Francisco, #2105

  30. Telaprevir Safety Data:Cirrhosis vs No Cirrhosis Treatment Naive T12 PR(ADVANCE, ILLUMINATE) PR (ADVANCE) Kaufman R et al, HepDart December 2011

  31. Stopping Rules for TelaprevirTreatment Naïve & Experienced Week 4 HCV RNA >1000 IU/ml Week 12 HCV RNA >1000 IU/ml Week 24 HCV RNA detectable Stop all therapy Stop all therapy Stop all therapy Telaprevir Package Insert, 2011

  32. Response-Guided Therapy:Telaprevir • Naives (and relapsers) • eRVR+ • 24 weeks (TPR12/PR12) • eRVR- • 48 weeks (TPR12/PR36) “Treatment-naïve patients with cirrhosis and eRVR may benefit from additional 36 weeks of PR” (package insert)

  33. Contraindicated Drugs With Telaprevir & Boceprevir • Interaction with CYP3A4 • May occur via inhibition OR induction • Rifampin • Alfuzosin • Ergot derivatives • Cisapride • St. John’s wort • Lovastatin, simvastatin, atorvastatin • Sildefnafil or tadalafil for PA hypertension • Oral midazolam, triazolam Many other drugs with established or potential drug-drug interactions that require caution Telaprevir Package insert

  34. Evaluation of Treatment-Emergent Resistant Variants in TVR Phase III trials • 74% of treatment-failure pts had RV • 255 pts with RVs were followed from Phase III trials • ADVANCE/ILLUMINATE: 151 • REALIZE: 104 • Median follow-up: 11 months • Population sequencing • 60% lost RVs during follow-up • RVs were different in G1a and G1b, and cleared more rapidly in G1b • Long-term analysis of RV after PI failure provides encouragement that • re-treatment with PIs will be possible • Reconstitution rates of wt virus are more rapid for G1b than G1a. • Re-treatment studies will be needed for definitive assessment Sullivan J, et al. EASL 2011, Berlin, O8

  35. Summary: Telaprevir andTreatment-Naïve HCV Patients • Telaprevir + peginterferon + ribavirin for 12 weeks, then peginterferon + ribavirin for an additional 12 or 36 weeks • Response-guided therapy is non-inferior to 48 weeks of treatment in patients with an eRVR (undetectable at week 4 and 24) • May be possible in nearly two-thirds of treatment-naïve patients • Rash common; seldom results in overall treatment discontinuation • Anemia requires monitoring; potential RBV reductions, epo, transfusions • Sustained virologic responses • Significantly improved over standard of care for overall population and those with impaired response: black, cirrhotic patients • Ribavirin dose reduction for anemia does not appear to impact response • IL28B may “refine the discussion”, but not decisive in most

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