Triple Therapy Today: Phase III Results in G1 Relapsers and Nonresponders Bruce R. Bacon, M.D. James F. King MD Endowed Chair in Gastroenterology Professor of Internal Medicine Division of Gastroenterology and Hepatology Saint Louis University School of Medicine Saint Louis University Liver Center St. Louis, Missouri

Before May 2011 Approach to Pegylated Interferon/Ribavirin Nonresponders Retreat with other pegylated interferon Retreat with Infergen Refer for clinical trial Watch and wait

After May 2011 Approval of telaprevir and boceprevir Added to PEG-Interferon/ribavirin In naïve patients – SVR rates up to 75% In partial responders and relapsers SVR rates up to 60% to 85%

RESPOND-2 Previous Treatment Failure Patients Study Design (N=403) Stopping Rule Weeks Placebo + PR 44 wks PR 4 wks Follow-up 24 wks Arm 1 PR48 Control TW 8 Undetectable BOC + PR 32 wks PR 4 wks Follow-up 36 wks Placebo + PR 12 wks Follow-up 24 wks TW 8 Detectable Arm 2 BOC RGT BOC + PR 44 wks PR 4 wks Follow-up 24 wks Arm 3 BOC/ PR Decision point for long vs. short therapy Lead-in Stopping Rule: Patients with detectable HCV-RNA at week 12 were discontinued from treatment for futility. Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus ribavirin (R) using weight-based dosing of mg/day in a divided daily dose. BOC administered 800 mg TID.

RESPOND-2 SVR and Relapse Rates Intention to treat population p < SVR Relapse Rate week HCV RNA level used if 24-week post-treatment level was missing. A sensitivity analysis where missing data was considered as non-responder, SVR rates for Arms 1, 2 and 3 were 21% (17/80), 58% (94/162) and 66% (106/161), respectively. SVR rates in BOC RGT and BOC/PR48 arm not statistically different (OR, 1.4; 95% CI [0.9, 2.2]) % of Patients PR 48 BOC RGT BOC/PR48

SVR by Week 8 HCV RNA Response Intention to Treat Population Undetectable HCV RNA at Week 8 Detectable HCV RNA at Week 8 SVR (%)  46% of patients in BOC RGT arm were eligible for shorter therapy  ~6 times as many patients on BOC regimens (46-52%) achieved undetectable HCV RNA at week 8 compared to control (9%) PR 48 BOC BOC/PR48 RGT

RESPOND-2: SVR in Prior Relapsers and Prior Non-Responders Prior RelapsersPrior Partial Responders BOC RGT BOC/ PR48 BOC RGT BOC/ PR48 HCV G1 patients with previous treatment failure n/N= 2 29 Bacon B, et al. N Engl J Med. 2011;364(13): © 2011 Massachusetts Medical Society.

PR 4 Week Lead-In As a Predictor of Response Interferon responsiveness may not remain constant over time Viral load decline of <1 log 10 after 4 weeks of PR is significantly correlated to a <2 log 10 decline after 12 weeks of treatment 1 –Phase 3 trial (IDEAL) of PR alone - only 4% (31/750) of patients with <1 log 10 decline after 4 weeks of PR achieved SVR 2 Lead-in allows real time assessment of patient’s interferon responsiveness vs. historic response 26% (102/393) of RESPOND-2 patients had a < 1 log 10 decline in HCV viral load at week 4 1. Poordad F, et al. AASLD, Boston, MA, 2010, abstract # McHutchison JG, et al. NEJM. 2009; 360:

SVR by Week 4 PR Lead-In Response Poorly Responsive to IFN <1 log 10 viral load decline at treatment week 4 Responsive to IFN ≥1 log 10 viral load decline at treatment week SVR (%) PR 48 BOC RGT BOC/PR48

Triple Therapy with Boceprevir: Nearly Half of Previous Treatment Failures in the Boceprevir and PR Arms Were Early Responders Boceprevir RGTBoceprevir PR48 PR48

Boceprevir RGTBoceprevir PR48 PR48 Triple Therapy with Boceprevir: Patients Who Were Not Early Responders Still Achieved Virologic Cure (SVR)

Treatment Algorithm – Previous Treatment Failures Without Cirrhosis Boceprivir + PR for 32 weeks Boceprivir + PR for 32 weeks

Treatment Algorithm – Patients With Compensated Cirrhosis, Historical Null Responders, and Poorly Interferon Responsive Patients Boceprevir +PR for 44 weeks Patients with compensated cirrhosis and historical null responders (patients with <2-log 10 decline in HCV RNA by treatment week 12 of their previous therapy) should receive 4 weeks PR followed by 44 weeks boceprevir + PR Consideration should be given to treating treatment-naïve patients who are poorly interferon responsive (with <1 log 10 decline in HCV RNA at treatment week 4) with 4 weeks PR followed by 44 weeks of boceprevir +PR

Safety Profile Over Entire Course of Therapy 48 PR N = 80 BOC RGT N = 162 BOC/PR48 N = 161 Median treatment duration, days DeathsN=0N=1N=0 Serious AEs5%10%14% Discontinued due to AE3%8%12% Dose modification due to AE14%29%33% Hematologic parameters Neutrophil count (<750 to 500/mm 3 / <500/mm 3 ) 9% / 4%19% / 6%20% / 7% Hemoglobin (<10 to 8.5 g/dL / <8.5 g/dL) Discontinuation due to anemia Dose reductions due to anemia Erythropoietin use Mean (median) days of use 24% / 1% 0% 8% 21% 65 (55) 43% / 5% 0% 19% 41% 135 (155) 35% / 14% 3% 22% 46% 130 (90) Boceprevir Resistance Assoc Variants % (n/n) < 1 log 10 Decline Wk 4 Lead-In ≥ 1 log 10 Decline Wk 4 Lead-In NA28% (13/46) 8% (9/110) 32% (14/44) 6% (7/112)

Boceprevir: Anemia Summary In clinical trials, patients treated with BOC had: –Average additional decrease of Hgb of approximately 1 g/dL –Higher frequency of Hgb reductions to Grade 3 or higher Mechanism of anemia thought to be result of bone marrow suppressive effect, not due to RBC hemolysis as was observed with RBV Anemia was managed with RBV dose reduction and/or erythropoietin –RBV dose reduction does not appear to impact BOC efficacy SVR rates with BOC higher in anemic vs non-anemic patients US Food and Drug Administration; April 27, MeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf. Accessed April 28, Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.

Boceprevir: SVR According to EPO Use and RBV Dose Reduction N = 1097 treatment-naïve; N = 403 previous-treatment-failure Retrospective analysis of SPRINT-2 and RESPOND-2 Sulkowski MS, et al. Poster presented at: EASL: The International Liver Congress 2011; March 30-April 3, 2011; Berlin, Germany. Poster Previously Untreated (SPRINT-2) BOC arms only Previous Treatment-Failures (RESPOND-2) BOC arms only SVR (%) No anemia EPO alone NeitherBothR dose reduction alone Anemia SVR (%) No anemia EPO alone NeitherBothR dose reduction alone Anemia

Predictors of Sustained Virologic Response Among Poor Interferon Responders When Boceprevir is Added to Peginterferon alfa-2b/Ribavirin B. Bacon 1, S. Bruno 2, E. Schiff 3, P. Kwo 4, M. Buti 5, L. Pedicone 6, W. Deng 6, M. Burroughs 6, C. Brass 6, J. Albrecht 6, S. Flamm 7 1 Saint Louis University School of Medicine, St. Louis, MO, 2 A.O. Fatebenefratelli e Oftalmico, Milan, Italy, 3 University of Miami, Miami, FL, 4 Indiana University School of Medicine, Indianapolis, IN, 5 Vall d'Hebron University Hospital, Barcelona, Spain, 6 Merck, Sharp & Dohme Corp., Whitehouse Station, NJ, 2 Northwestern Feinberg School of Medicine, Chicago, IL

Background Pre-treatment predictors of SVR for IFN-based therapies include IL-28B, baseline VL, virus genotype, age, ethnicity, body weight and fibrosis stage In two phase 3 studies of BOC + PR, response to a 4 week PR lead-in was the strongest predictor of SVR –Poor IFN response (<1 log decline after lead-in) occurred in up to 28% of patients in SPRINT-2 1 and RESPOND-2 2 –Among patients receiving BOC, 28-38% of the poor IFN responders achieved SVR, compared with 0-4% of poor IFN responders in the PR control arm BOC, boceprevir; IFN, interferon; PR, peginterferon alfa-2b plus ribavirin; SVR, sustained virologic response; VL, viral load. 1. Poordad F, et al. N Engl J Med. 2011;364: Bacon BR, et al. N Engl J Med. 2011;364:

Objective To identify predictors of SVR in poor IFN responders (<1 log decline after 4 week PR lead-in) in patients with genotype 1 hepatitis C virus receiving BOC + PR BOC, boceprevir; IFN, interferon; SVR, sustained virologic response.

HCV G1 Subtype as a Predictor of SVR in Patients with Poor IFN Response (BOC Arms Combined) % SVR a 1b RESPOND-2SPRINT-2Combined Studies p = 0.001p = 0.028p < 0.001

Baseline Fibrosis Score* as a Predictor of SVR in Patients with Poor IFN Response (BOC Arms Combined) % SVR F0/1/2 F3/4 RESPOND-2SPRINT-2Combined Studies p = 0.029p = 0.025p = F0/1/2 F3/4 * Excludes 1 patient with missing data for METAVIR score

Baseline Viral Load as a Predictor of SVR in Patients with Poor IFN Response (BOC Arms Combined) % SVR RESPOND-2SPRINT-2Combined Studies p = 0.014p <0.001P<0.001 ≤ 2,000,000 IU/mL> 2,000,000 IU/mL ≤ 2,000,000 IU/mL > 2,000,000 IU/mL ≤ 2,000,000 IU/mL > 2,000,000 IU/mL

SVR in Poor IFN Responders Based on Hemoglobin Decline (g/dL) During 4 Week PR Lead-In (BOC Arms Combined) % SVR RESPOND-2SPRINT-2Combined Studies ≤ 3> 3≤ 3> 3≤ 3> 3

SVR in Poor IFN Responders Based on TW8 Response (Log Decline in VL Compared to BL VL) (BOC Arms Combined) % SVR RESPOND-2SPRINT-2Combined Studies 5 Undetectable Undetectable 5 Undetectable

Summary of Predictors of SVR in Poor IFN Responders TW8 virological response –No patient with <3 log decline at TW8 achieved SVR –Patients with undetectable HCV RNA at TW8 had best chance to achieve SVR Pre-treatment factors predictive of SVR –Genotype 1b –F0/1/2 –BL viral load <2,000,000 IU/mL

Conclusions In poor IFN responders, HCV subtype, fibrosis score, and baseline viral load remain important pre-treatment predictors of SVR. In addition, virological response at TW8 (4 weeks of PR + 4 weeks of BOC/PR) provides additional information in predicting SVR.

Analysis of Sustained Viral Response and Boceprevir Resistance Following Combination Treatment With Boceprevir Plus Peginterferon Alfa-2a/Ribavirin in HCV Genotype 1 Prior Relapsers And Nonresponders J Howe 1, R Ogert 1, R Barnard 1, D Hazuda 1, LD Pedicone 1, CA Brass 1, JK Albrecht 1, and S Flamm 2 1 Merck, Sharp & Dohme Corp., Whitehouse Station, NJ; 2 Northwestern Feinberg School of Medicine, Chicago, IL

Study Design Stopping Rule Weeks Placebo + PEG2a/R 44 wks PEG2a/R 4 wks Follow-up 24 wks PEG2a/R Control N = 67 BOC + PEG2a/R 44 wks BOC/ PEG2a/R N = Lead-in Stopping rule: patients with detectable HCV-RNA at week 12 were discontinued from treatment for futility. Undetectable defined as <LLD (9.3 IU/mL) Peginterferon alfa-2a administered subcutaneously at 180 μg once weekly plus ribavirin using weight based dosing of mg/day in a divided daily dose. Boceprevir was administered 800 mg TID 4 Follow-up 24 wks PEG2a/R 4 wks

Level observed in RESPOND-2 trial using PEG2b SVR and Relapse Rates Are Consistent With RESPOND 2 PEG2a/R BOC/PEG2a/R p<

Triple Therapy at Saint Louis University Boceprevir, telaprevir approved in the United States in May, 2011 Between June, 2011 and December, 2011, 130 patients started boceprevir 62% males; 12% AA 54% advanced fibrosis/cirrhosis 58% null responders; 30% partial responders

Triple Therapy at Saint Louis University Pretreatment HCV RNA 1,606,111 IU/mL After 4 weeks lead-in 493,197 IU/mL 1 log drop in HCV RNA 50% IL28B 91% TC/TT

Triple Therapy at Saint Louis University 36 patients have completed 8 weeks of treatment –44% were HCV RNA non-detected 22 patients have completed 12 weeks of treatment –46% were HCV RNA non-detected –64% were HCV RNA < 1,000 IU/mL

Summary and Conclusions Triple therapy was generally well-tolerated –Anemia and dysgeusia occurred more often in the boceprevir groups than the control group Boceprevir added to PR significantly increased SVR compared to PR control –Can be used to treat patients with all categories of interferon responsiveness RGT and BOC/PR 48 were equally effective for treatment failure patients PR lead-in allows for real time assessment of patient’s interferon responsiveness –Poorly responsive: 33-34% achieved SVR vs 0% in control –Responsive: 73-79% achieved SVR vs 26% in control