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

The Evolution of HCV Therapy Strader DB, et al. Diagnosis, Management, and Treatment of Hepatitis C. Hepatology 2004;39: SVR (%) IFN 6 mo IFN/RBV 6 mo PEG-IFN /RBV 12 mo IFN 12 mo IFN/RBV 12 mo PEG-IFN 12 mo

Abbreviations: ARFP, alternate reading frame protein; IRES, internal ribosome entry site; UTR, untranslated region. Glenn JS. Clin Liver Dis. 2005;9: CoreE1E2P7P7 NS2NS3NS 4A NS4BNS5ANS5B ARFP UTR IRES 5 3 (U/UC) UTR Protease Helicase Polymerase StructuralNonstructural Hepatitis C Virus Genome The Function of the NS3/4A Serine Protease Envelope

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

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

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

ADVANCE: Treatment Naïve G1 (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 eRVR = HCV RNA undetectable at week 4 and week 12 (Taqman v2.0) Weeks12836 Follow-up PR48 (control) SVR Pbo + PRPR T12PR TVR + PR Follow-up SVR eRVR- PR. eRVR + Follow-up SVR PR Follow-up SVR TVR + PR T8PR eRVR- PR. Pbo + PR Follow-up SVR eRVR + PR 72 weeks Follow-up Randomized, Double-Blind, Placebo-Controlled for Telaprevir Jacobson IM, et al. N Engl J Med 2011;364:

ADVANCE: Stopping Rules TimepointCriteria for StoppingAction Week 4*HCV RNA >1000 IU/mL Discontinue TVR, continue PR Week 12HCV RNA <2 log 10 decline Discontinue all treatment Week 24-40HCV RNA detectable Discontinue all treatment *Applied to telaprevir-treated patients only Jacobson IM, et al. N Engl J Med 2011;364:

ADVANCE: SVR Rates SVR P< /363250/364158/361n/N = Percent of patients with SVR T12PRT8PRPR Jacobson IM, et al. N Engl J Med 2011;364:

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

ADVANCE: Relapse Rates 27/31428/29564/22951/18918/24717/ Percent of patients with relapse OverallCompleted Regimen n/N = 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 T12PRT8PRPR

ADVANCE: RVR and eRVR Rates 246/363242/36434/36129/361207/364212/ Percent of patients with HCV RNA undetectable Week 4 (RVR)Weeks 4 and 12 (eRVR) n/N = Patients eligible to receive 24 weeks of total treatment T12PRT8PRPR Jacobson IM, et al. N Engl J Med 2011;364:

ADVANCE: SVR Rates by eRVR Status 189/212171/20728/29130/33279/15782/ eRVR+ eRVR- n/N = Percent of patients with SVR week regimen 24-week regimen T12PRT8PRPR Jacobson IM, et al. N Engl M Med 2011;364:

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 T12PR Virologic failure 8% Weeks on Treatment Percent of Patients Weeks on Treatment T8PR Virologic failure 13% 3% 5% 3% 10% Jacobson IM et al, N Engl J Med 2011;364: ; Kieffer T et al AASLD 2010

ADVANCE: SVR by Subgroups Male Female Age White Black 1b 1a Genotype 800K HCV RNA

ADVANCE: Most Common Adverse Events % of Patients with T12PR N=363 T8PR N=364 PR (control) N=361 Any Adverse Event*99 98 Fatigue Pruritus Headache Nausea Rash Anemia Insomnia32 31 Diarrhea Influenza-like illness Pyrexia Shaded areas: 10% or greater incidence in either TVR groups vs control

ADVANCE: Discontinuation for Adverse Events D/CT12PRT8PRPR TVR/Placebo only 11%7%1% All therapy (overall study) 10% 7% Jacobson IM, et al. N Engl J Med 2011;364:

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 % of Patients with T12PR N=363 T8PR N=364 PR (control) N=361 Rash events Severe rash events641 Discontinuation of telaprevir/placebo only due to rash events 751 Discontinuation of all study drugs due to rash events Jacobson IM et al. N Engl J Med 2011;364:

Nadir Hemoglobin, Discontinuation for Anemia, and Median Hemoglobin Levels 0 Median Hemoglobin (g/dL) Weeks TVR …. TVR T12PR (n=363) T8PR ( (n=364) PR (control) (n=361) % of Patients with T12PR N=363 T8PR N=364 PR N=361 Hemoglobin <10 g/dL Hemoglobin <8.5 g/dL 992 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 Hemoglobin nadir during TVR/Pbo PhaseMedian Hemoglobin Jacobson IM, et al.N Engl J Med 2011;364:

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

SVR Rates in ADVANCE Patients Genotyped for IL28B T12PR T8PR PR 45/50 38/45 35/5548/68 43/76 20/80 16/22 19/32 6/26 Patients with SVR (%) n/N= CCCTTT Jacobson IM, et al. Poster presented at: EASL: The International Liver Congress 2011; March 30-April 3, 2011; Berlin, Germany. Poster LB1369.

RVR and eRVR in ADVANCE Patients Genotyped for IL28B RVR (%) eRVR (%) eRVR patients received 24 weeks of treatment Jacobson IM, et al. Poster presented at: EASL 2011 Poster LB1369. CCCTTT

ILLUMINATE Study: 24 vs 48 Weeks After eRVR With Telaprevir Phase 3 Treatment-naïve Genotype 1 Week T12/ PR 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: Telaprevir (750 mg q8h) PegIFN + RBV SVR Follow-Up PegIFN + RBV SVR Follow-Up With eRVR SVR Follow-Up SVR Follow-Up PegIFN + RBV Without eRVR

SVR Rates: ILLUMINATE ITT eRVR+ T12PR24 eRVR+ T12PR48 eRVR- T12PR48 Other (D/C pre-wk 20)  4.5% (2-sided 95% CI = -2.1% to +11.1%) /540149/162140/160n/N=76/11823/100 Patients With SVR (%) Sherman KE, et al. N Engl J Med 2011;365:

ILLUMINATE: Relapse Rates 9/1594/154n/N=37/469 T12PR24T12PR48ITT Patients with Relapse (%)

Effect of Shortening Therapy in Cirrhotics with eRVR: ILLUMINATE /1811/12,Telaprevir package insert,2011

Adverse Events Leading to Study Drug Discontinuations Total N=540 Discontinuation of All Study Drugs during Telaprevir Treatment Phase, % Any Adverse Event7 Rash events1 Anemia events1 Discontinuation of Telaprevir during Telaprevir Treatment Phase, % Any Adverse Event12 Rash events7 Anemia events2 Overall treatment phase 17% of patients in ITT discontinued all study drugs due to AEs

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

Effect of Fibrosis in Pooled ADVANCE and ILLUMINATE Studies Marcellin P, et al. AASLD 2011, San Francisco, #2105 Liver fibrosis stage Treatment eRVR, n (%) EOT, n (%) SVR, n (%) Relapse, n/N (%) VF, n (%) F0–F2T12PR (n=681) 444 (65)563 (83)539 (79)16/563 (3)40 (6) PR (n=288) 25 (9)183 (64)140 (49)42/183 (23)78 (27) F3–F4T12PR (n=222) 121 (55)158 (71)144 (65)11/158 (7)28 (13) PR (n=73) 4 (5)37 (51)26 (36)11/37 (30)27 (37)

Telaprevir Safety Data: Cirrhosis vs No Cirrhosis Cirrhosis N=82 No cirrhosis N=821 Cirrhosis N=21 No cirrhosis N=340 Anemia Grade 355 (67%)377 (46%)5 (24%)85 (25%) Grade 4 2 (2%) 11 (1%)0 (0%) Neutropenia Grade 38 (10%)72 (9%)4 (19%)39 (11%) Grade 42 (2%)11 (1%)0 (0%)10 (3%) Thrombopenia Grade 310 (12%)12 (2%)0 (0%)1 (<1%) Grade 4 1 (1%) 0 (0%)1 (5%)0 (0%) T12 PR(ADVANCE, ILLUMINATE) PR (ADVANCE) Treatment Naive Kaufman R et al, HepDart December 2011

Stopping Rules for Telaprevir Treatment 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

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)

Contraindicated Drugs With Telaprevir & Boceprevir 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 Interaction with CYP3A4 May occur via inhibition OR induction

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 Sullivan J, et al. EASL 2011, Berlin, O8 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 No RVs Median time after EOT, months V36A/M68% (115/169) 10 T54A/S84% (27/32) 4 R155I/K/M/T59% (100/170) 11 A156S/T/V86% (19/22) 4 V36M + R155K 52% (65/124) 14

Summary: Telaprevir and Treatment-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