New Therapies on the Horizon in Hepatitis C Patients Paul Y. Kwo, MD

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1 Viral Targets for HCV New Therapies on the Horizon in Hepatitis C Patients Paul Y. Kwo, MD Sites for development of inhibitors Metalloproteinase Serine protease (trans) Core E E2 NS2 NS3 NS4a/NS4b NS5a/NS5b 5 UTR 3 UTR Helicase Serine protease (cis) RNA polymerase The Three Phases in the Evolution of HCV Therapy 99s and beyond The Empiric Phase The Refinement Phase Viral kinetics Optimal dosing Challenging populations Nonresponders Modifed from : Weisberg IW, Sigal SH, Jacobson IM. Current Hepatitis Reports 27;6:75-82 The Phase of Direct Acting Anti-virals (DAA) Or Specifically Targeted Antiviral Therapy For HCV (STAT-C) Two protease inhibitors show promise in therapy for genotype HCV infection Telaprevir and Boceprevir specifically inhibit the NS3/4A protease of genotype hepatitis C virus Inhibition of NS3/4a blocks polyprotein processing interfering with HCV replication Phase 2 results show both have the potential improve SVR rates Phase 3 results to be presented at AASLD /2 Both therapies will be added to peg interferon and ribavirin HCV Infection and Replication: Targets for Therapy Cell infection Receptormediated binding HCV Entry & uncoating Replication: Majority of new agents in development Translation & post-translational Processing (NS3 protease) polyprotein Nucleus Ribosome structural Nonstructural 5' 3' Replicase HCV RNA (RDRP-Helicase) polymerase 3' 5' Assembly 5' 3' Figure modified from Davis GL. Hepatitis C. In: Schiff s Disease of the Liver, 22. Membrane fusion & secretion Assembly & Secretion Direct Viral Enzyme Inhibitors Potently Suppress Viral Replication: Protease Inhibition HCV RNA Change from Baseline (Log IU/mL) B Study Time (days) Forestier N, et al. Hepatology. 27;46(3): Baseline PEG-IFN alfa-2a + placebo Telaprevir (VX-95) Telaprevir (VX-95) + PEG-IFN alfa-2a

2 Median HCV RNA (Log IU/mL) Resistance Develops Rapidly with Monotherapy Median HCV RNA Over Time Resistance profiles established Study Time (Days) PR48 (control) (n=75) T2/PR2 (n=7) T2/PR24 (n=79) T2/PR48 (n=79) PROVE: Phase II Study Design U.S., Genotype, Treatment Naive Placebo + TVR + TVR + TVR + Peg-IFN Weeks Subjects in the 2- and 24-week TVR-based treatment arms needed to achieve RVR at Week 4 and maintain undetectable HCV RNA (< IU/mL) through the end of their assigned dosing, to end of treatment at Weeks 2 and 24, respectively Placebo Telaprevir 45 mg q8h Telaprevir 75 mg q8h Telaprevir 25 mg q2h Reesink HW, et al. Gastroenterology. 25;28(suppl 2):A-697. Abstract 527. Dosing: Peg-IFN = Peg-IFN alfa-2a 8 µg/week, RBV = RBV, or,2 mg/day, TVR = TVR 75 mg q8h; RVR = rapid virologic response McHutchison. EASL 28 In Vitro Resistance to Protease Inhibitors Cross Resistance Will Occur PROVE : SVR Rates (ITT) C E E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Telaprevir Boceprevir ITMN-9 BILN-26 V36A/M T54A R55K/T. Lu L, et al. Antimicrob Agents Chemother. (6), Mo H, et al. 25;49 (): Lin C, et al. J Biol Chem 4. Lin C, et al. J Biol Chem. 25;28, Sarrazin C, et al. AASLD. 25. A56S/V/T D68A/V/E V7A S489L 6. Yi M, et al.. 26;28(2): Malcolm BA, et al. 2 th International Symposium on HCV Zeuzem S, et al. AASLD Seiwert SD, et al. DDW Keiffer T, et al. Hepatology, 27;46(3): SVR rate (%) / /7 PR48 T2/PR2 T2/PR24 T2/PR48 One subject in the T2/PR24 arm did not meet RVR criterion, completed 48 weeks of treatment and had an SVR, but was not counted as a responder in this analysis McHutchison. EASL 28 p=.2 p=. 6 48/ /79 Protease (NS3/4A) Inhibitors: Genotype 5 PROVE: Relapse Rates BILN 26 Boehringer Ingelheim Phase Stop- Heart Tox Telaprevir Vertex/Tibotec Phase 3 Boceprevir Schering-Plough Phase 3 ACH-86 Achillion/Gilead Phase Stop- Renal tox ITMN 9/R7227 InterMune/Roche Phase 2 TMC43535 Medivir/Tibotec JJ Phase 2 BI 2335 Boehringer Ingelheim Phase 2 MK79 Merck Phase 2 Relapse rate (%) /35 PR48 33* 3/9 T2/PR2 TVR drives high rates of RVR and low rates of relapse /4 3/5 6 2* T2/PR24 T2/PR48 In the T2/PR48 arm, including only subjects who had an RVR, the relapse rate was % Denominator is the number of subjects with undetectable HCV RNA at completion of assigned treatment duration *Includes subjects who met the RVR criterion and stopped at 2 or 24 total weeks of treatment McHutchison.NEJM 29 2

3 Control SPRINT- Study Design Week 4 Week 28 Week 48 Peg-IFNα2b.5 μg/kg 8-4 mg for 48 wks N=4 PROVE 3: Telaprevir (TVR) + PegIFN ± RBV in Previous Nonresponders/Relapsers Week 2 Week 24 Week 48 PART PART 2 a Lead-in 8-4 mg Peg-IFNα2b 8-4 mg No Lead-in Low Dose RBV Peg-IFNα2b Peg-IFNα2b.5 μg/kg + RBV 8-4mg + Boceprevir 8 mg TID for Peg-IFNα2b.5 μg/kg 8-4 mg + Boceprevir 8 mg TID for Peg-IFNα2b.5 μg/kg 8-4 mg + Boceprevir 8 mg TID for 28 wks Peg-IFNα2b.5 μg/kg 8-4 mg + Boceprevir 8 mg TID for 48 wks Peg-IFNα2b.5 μg/kg 8-4 mg + Boceprevir 8 mg TID for 48 wks Peg-IFNα2b.5 μg/kg 4- mg + Boceprevir 8 mg TID for 48 wks a Part two consisted of 75 patients in US sites, :4 randomization. N=3 N=3 N=7 N=3 N=6 N=59 Patients with HCV GT infection and nonresponse, breakthrough, or relapse with previous peg/ifn therapy (N = 453) Manns et al EASL PegIFN alfa-2a 8 µg/week + RBV -2 mg/day + Placebo (n = 4) TVR 75 mg TID + PegIFN PegIFN (n = 5) TVR 75 mg TID + PegIFN (n = 3) TVR 75 mg TID + PegIFN (n = ) PegIFN PegIFN 24-wk follow-up Nonresponse HCV RNA positive throughout treatment and at end of treatment Relapse HCV RNA negative at end of treatment, but HCV RNA positive during follow-up Breakthrough Initially HCV RNA negative during treatment, but HCV RNA positive by end of treatment All with adequate previous course of PEG/RBV What is the Potential Role of a Lead-in Phase? Achieve steady-state drug levels for Peginterferon and ribavirin May suppress the expansion of pre-existent or selected resistant strains May allow to individualize treatment with PIs High PEG-IFN sensitivity: no PI required Minimum PEG-IFN sensitivity to avoid functional monotherapy % with SVR Prove 3: SVR rates by treatment group and prior response 4/7 and 4/8 with prior breakthrough achieved SVR in T2/PR24 and T24/PR48 groups McHutchison et al NEJM 29 % Patients HCV Negative SPRINT- SVR rates Part 54 b 56 c 67d P/R Control P/R/B P/R/B 48 wks 28 wks f P/R 4 wks P/R/B 48 wks N=4 N=7 N=3 N=3 P/R 4 wks P/R/B N=3 Part 2 a Roche COBAS TaqMan LLD <5 IU/mL; b P =.3; c P =.5; d P <.; e P <. compared to P/R Control f late relapser after follow-up week 24, not included n SVR. 75 e P/R/B P/low dose R/B 48 wks 48 wks N=6 N=59 SPRINT-: Boceprevir + PegIFN/RBV in Null Responders to SOC IDEAL study found log decrease in HCV RNA at Wk 4 of pegifn alfa-2b associated with ~ 2 log decrease at Wk 2 [] Two 4-wk lead-in arms of pegifn alfa-2b allowed determination of likely virologic response to SOC [2] Definition of a null response to pegifn alfa-2b : < log decrease at Wk 4 <.5 log drop at Wk 4 of pegifn/rbv lead-in to <. log 6 drop at Wk 4 of 44 pegifn/rbv lead-in /7 5/2 4/9 8/3 PegIFN/RBV 4 wks PegIFN/RBV 4 wks PegIFN/RBV/Boceprevir PegIFN/RBV/Boceprevir SVR (%). McHutchison JG, et al. N Engl J Med. 29;36: Kwo PY, Lancet 2 3

4 Treatment of previous PEG/RBV nonresponders with protease inhibitors Those who are previously interferon sensitive have high chance of achieving SVR (relapsers) Null responders will have opportunity for SVR but with significant risk of developing resistance Treating clinicians will need to counsel genotype infected individuals about risks benefits Advanced fibrosis Stopping rules to minimize resistance More Drugs = More Toxicity Cardiotoxicity Optic neuritis Rash Anemia Neutropenia Lymphopenia Liver test abnormalities DC rates x 2-4 fold Phase 3 Results to be reported at AASLD Telaprevir Advance trial: 75%; Illuminate: 72% treatment naïve Realize: 66% treatment failures Boceprevir Sprint 2: 66% treatment naïve Respond 2: 66% treatment failures HCV RNA Polymerase Nucleoside and Non-nucleoside Inhibition Fingers NNI Allosteric GTP-binding sites Flap Thumb Thumb inhibitors Catalytic site Nucleoside analogs Palm NNI Adapted from Butcher. Nature. 2;4:235. Reprinted with permission. Can We Dispense with Ribavirin? R728 (Nucleoside Polymerase Inhibitor) demonstrated 2.7 log (>99%) Mean HCV RNA Decrease with 5 mg BID Dose Prove 2 (n = 334) Prove 3 (n = 453) All studies showed Sprint (n = 595) Lower response rates w/o ribavirin Higher viral breakthrough rates Mean HCV RNA Change from Baseline N=8 interferon failures per cohort Treatment Period Placebo (-. log IU/ml) 75 mg QD (-.9 log IU/ml) 5 mg QD (-.5 log IU/ml) 75 mg BID (-2. log IU/ml) 5 mg BID (-2.7 log IU/ml) Period Study Day Hezode C, et al. New Engl J Med. 29;36(8): McHuthcison et al NEJM 29. Kwo P, et al. Lancet 2. No Evidence of Viral Rebound During 4 Days of Monotherapy Source: Reddy. Abstract #LB-9. AASLD 27. 4

5 Phase Combination Data with R728 Nucleoside Polymerase Inhibitor % PCR neg % P+R 28 Day Data 3% P+R+R728 5 mg bid 85% P+R+R728 5 mg bid Mean log decline McHutchison. EASL 28 INFORM-: 4-Day Response Rates in Tx-Naive and Tx-Experienced G HCV Pts New data at higher dose AASLD R728/R7227 Doses, mg n Pt Population Median Change From Baseline, Log IU/mL HCV RNA < LLOQ, % < 4 IU/mL < 5 IU/mL 5/ TID 8 Naive /2 TID 8 Naive / TID 7 Naive /2 TID 8 Naive /9 BID 8 Naive /6 BID 8 Exp, nonnull /9 BID 8 Exp, null No serious adverse events, treatment-related discontinuations, or grade 3/4 laboratory abnormalities observed in any treatment arm Gane EJ, No et evidence al. AASLD of 29. emergent Abstract drug 93. resistance during treatment Mean Decline in HCV RNA 24 Hours After Single Dose of NS5a inhibitor BMS mg mg mg -.8 (Range.8-3. log ) (Range log ) (Range log ) mg dose: mean in HCV RNA of 3.6 log IU/mL (range log IU/mL) at 48 hours after maintained at 44 hours All active drug recipients had.5 log from baseline HCV RNA 8/6 (5%) active drug recipients had 3 log IU/mL in HCV RNA One active drug recipient achieved HCV RNA < LLQ Nettles et al. AASLD. October 3-November 4, 28; San Francisco, CA. Poster LB2. Conclusions Addition of telaprevir and boceprevir to Peg interferon/ ribavirin will improve SVR rates significantly Treatment durations weeks Phase 3 results to be reported AASLD 2 Non-responders will also derive benefit with risk of resistance, relapsers can be treated with low risk Greater side effects Combinations of DAA/STAT-C C agents with/without PEG IFN/RBV will explored Trials to achieve SVR without interferon/ribavirin The future is bright INFORM-: Dual Polymerase and Protease Inhibitors R728 and R7227 For HCV Genotype Day 4 Day 7 Day 4 Wk 48 RG728 5 mg BID + RG7227 mg TID RG728 5 mg BID + RG mg TID (n = 8 active, placebo) Treatment naive RG728 mg BID + RG7227 mg TID (n = 8 active, placebo) RG728 mg BID + RG mg TID Pts infected (n = 8 active, 4 placebo) with G HCV RG728 mg BID + RG mg BID (N = 86)* Previous nonresponders RG728 mg BID + RG mg BID to IFN (excluding null responders) Previous null RG728 mg BID + RG mg BID responders to IFN *2 additional arms not included in current analysis. PegIFN, peginterferon alfa-2a 8 μg/wk; RBV, ribavirin -2 mg/day. Gane EJ, et al. AASLD 29. Abstract 93. 5