C-EDGE CO-STAR: EFFICACY OF GRAZOPREVIR / ELBASVIR FIXED

C-EDGE CO-STAR: EFFICACY OF GRAZOPREVIR / ELBASVIR FIXED

C-EDGE CO-STAR: EFFICACY OF GRAZOPREVIR / ELBASVIR FIXED DOSE COMBINATION FOR 12 WEEKS IN HCV-INFECTED PERSONS WHO INJECT DRUGS ON OPIOID AGONIST THERAPY Dore GJ1, Altice F2, Litwin AH3, Dalgard O4, Gane E5, Shibolet O6, Luetkemeyer A7, Nahass R8, Peng CY9, Conway B10, Grebely J1, Howe A11, Nguyen BY11, Wahl J11, Barr E11, Robertson M11, Platt HL11 The Kirby Institute, UNSW Australia, 2Yale School of Medicine, 3Montefiore Medical Center and Albert Einstein College of Medicine, 4Institute of Clinical Medicine, 5Auckland Clinical Studies, 6Tel-Aviv Medical Center, 7University of California, San Francisco, 8ID Care, 9China Medical University Hospital, 10 Vancouver Infectious Diseases Centre, 11Merck & Co., Inc. 1 ACKNOWLEDGEMENTS AASLD 2015 San Francisco We extend our gratitude to the patients, their families, investigators and site personnel who participated in this study. Australia: Greg Dore, David Iser, Joseph Sasadeusz, Martin Weltman; Canada: Brian Conway, Roger P. LeBlanc, Daniele Longpre; France: Jean-Pierre Bronowicki, Joseph Moussalli, Fabien Zoulim; Germany: Andreas Trein, Albrecht Stoehr; Israel: Oren Shibolet; Netherlands: H. W. Reesink; New Zealand: Edward Gane; Norway: Olav Dalgard, Hege Kileng; Romania: Adrian Octavian Abagiu, Emanoil Ceausu, Adrian Streinu-Cercel; Spain: Juan Ignacio Arenas RuizTapiador, Jose Luis Calleja Panero, Conrado Fernandez Rodriguez, Juan Turnes Vazquez; Taiwan: Wan-Long Chuang, Cheng-Yuan Peng, Sheng-Shun Yang; United Kingdom: Kosh Agarwal, David Bell, Ashley Brown, John Dillon, Daniel M.H. Forton, Andrew Ustianowski; United States: Frederick L. Altice, David Michael Asmuth, Kathleen K. Casey, James N. Cooper, Stuart C. Gordon, Paul Y. Kwo, Jacob Paul Lalezari, William M. Lee, Alain H. Litwin, Annie Luetkemeyer, Andrew J. Muir, Ronald G. Nahass, Grisell Ortiz-Lasanta, K. Rajender Reddy, Kenneth E. Sherman, Jihad Slim, Mark S. Sulkowski, Andrew H. Talal, Joesph Leo Yozviak This study and medical writing support were funded by Merck & Co., Inc. 2 BACKGROUND AND AIM AASLD 2015 San Francisco Injection drug use is the major risk factor for HCV epidemic in most high income countries, with people who inject drugs (PWID) accounting for 50-80% of HCV infections1 HCV treatment uptake in the IFN-containing era has been low, particularly among PWID2, 3 Despite similar HCV treatment outcomes with IFN-containing therapy4,5, PWID with current drug use have been excluded from IFN-free DAA development programs 1. Hajarizadeh B, Grebely J, and Dore GJ. Nat Rev Gastro Hepatol 2013;10:553-62. 2. Iversen J, et al. J Viral Hepatitis 2013; 21:198-207. 3. Alavi M, et al. Liver International 2014; 34:1198-206. 4. Aspinall A, et al. Clin Infect Dis 2013; 57:S80-S89. 5. Grebely J, et al. Int J Drug Policy 2015; 26:1028-38. 3 AASLD 2015 San Francisco

BACKGROUND HCV NS5A inhibitor, 50 mg Elbasvir (MK-8742) HCV NS3/4A inhibitor, 100 mg Grazoprevir (MK-5172) Broad activity versus most HCV genotypes in vitro1-3 Efficacious in treatment-naive & treatment-experienced cirrhotic and noncirrhotic patients with HCV, and in HIV/HCV co-infected patients4-6 All-oral, once-daily regimen 1. Summa V, et al. Antimicrobial Agent Chemother 2012:56;4161; 2. Coburn CA,, et al. ChemMedChem 2013; 8: 1930; 3. Harper S, et al. ACS Med Chem Lett. 2012 Mar 2;3(4):332; 4. Zeuzem et al., Ann Int Med 2015; 163:1; 5. Lawitz et al., Lancet 2015; 385:1075; 6. Rockstroh et al., Lancet HIV 2015; 2:e319 4 AASLD 2015 San Francisco TRIAL DESIGN Phase 3, randomized, parallel-group, placebo-controlled, double-blind trial Treatment nave, GT1, 4, 6; mixed genotypes of 1, 4, and 6 allowed On opiate agonist therapy (OAT) for at least 3 months, and consistently kept at least 80% of scheduled appointments while on OAT Goal of 20% with cirrhosis and may be co-infected with HIV Immediate Treatment Arm EBR / GZR, n = 201 Unblinding Deferred Treatment Arm Placebo, n = 100 Unblinding D1 W4 W8 W12 5 W16 Follow-up for 24 weeks

Follow-up for 24 weeks EBR / GZR W22 W28 W36 W52 EFFICACY ANALYSES AASLD 2015 San Francisco Endpoints Primary endpoint: SVR12 (HCV RNA <15 IU/mL*) Secondary endpoint: SVR24 (HCV RNA <15 IU/mL*) Analysis Populations Full Analysis Set (FAS) Includes all patients Reinfections are counted as failures Modified Full Analysis Set (mFAS): Primary efficacy endpoint Excludes patients who discontinued the trial for non-treatment related reasons (e.g., lost-to-follow-up and or discontinued due to reasons other than virologic failure) Patients with data consistent with clearance of baseline infection and HCV RNA >15 IU/mL consistent with reinfection are counted as successes *HCV RNA determined with COBAS AmpliPrep/COBAS Taqman HCV Test, v2.0 6 AASLD 2015 San Francisco DEMOGRAPHICS Male Age [median yrs; (range)] Race White Immediate treatment arm (n=201) n (%) 153 (76.1) Deferred treatment arm (n=100) n (%) 77 (77.0) 48 (23-66)

47 (24-64) Total (N=301) n (%) 230 (76.4) 48 (23-66) 158 (78.6) 84 (84.0) 242 (80.4) African American 31 (15.4) 7 (7.0) 38 (12.6) Asian/Other 12 (6.0) 9 (9.0) 21 (7.0) 165 (54.8) Baseline HCV RNA (IU/mL) >2,000,000 IU/mL 114 (56.7) 51 (51.0) HCV Genotype 1a 154 (76.6) 75 (75.0) 229 (76.1) 1b 30 (14.9) 15 (15.0) 45 (15.0) 4 12 (6.0) 6 (6.0)

18 (6.0) 6 5 (2.5) 4 (4.0) 9 (3.0) Cirrhosis Yes (F4) 7 HCV/HIV Co-infected 40 (19.9) 16 (8.0) 22 (22.0) 62 (20.6) 5 (5.0) 21 (7.0) AASLD 2015 San Francisco SVR12 IN THE IMMEDIATE TREATMENT GROUP: FULL ANALYSIS SET (FAS) % SVR12 (95% CI) Full Analysis Set 100 90 80 70 60 50 40 30 20 10 0 91.5 93.5 93.3 mFAS 95.5 91.7 20.0

All GT GT1a* GT1b GT4 GT6 mFAS 184/201 144/154 28/30 11/12 1/5 189/198 Reinfection 7 5 4 3 1 0 0 0 2 2 7 -- LTFU or discontinued unrelated to VF 5 3 1 1 0 2 (excluded)

Relapse 8 *Includes one subject with mixed infection (GT1a and GT1b) who achieved SVR12 Includes one subject with HCV RNA>LLoQ consistent with reinfection; this subject was lost to follow-up and did not return for confirmation of HCV RNA; this subject was discontinued for administrative reason and counted as a failure in the FAS GT = genotype; LTFU = lost-to-follow-up; VF=virologic failure AASLD 2015 San Francisco % S V R 1 2 ( 9 5 % C I) SVR12 IN THE IMMEDIATE TREATMENT GROUP: MODIFIED FULL ANALYSIS SET (mFAS) Modified Full Analysis Set (mFAS) 100 90 80 70 60 50 40 30 20 10 0 95.5 96.1 96.6 100.0 60.0 All GT GT1a* GT1b GT4 GT6 189/198 147/153 28/29 11/11 3/5

7 2 4 2 1 0 0 0 2 0 5 3 0 0 2 1 0 Failures Relapse Discontinuation Reinfection counted as success LTFU or discontinued unrelated to Virologic Failure excluded from mFAS analysis 3 9 1 1 *Includes one subject with mixed infection (GT1a and GT1b) who achieved SVR12 AASLD 2015 SVR12 IN THE IMMEDIATE TREATMENT GROUP: San Francisco SUBGROUP ANALYSIS OF MODIFIED FULL ANALYSIS SET (mFAS) Overall SVR12=95.5% n/m SVR12 % (95% CI) 144/151 95.4 (90.7, 98.1)

Female 45/47 95.7 (85.5, 99.5) 50 years 85/91 93.4 (86.2, 97.5) < 50 years 104/107 97.2 (92.0, 99.4) White 152/155 98.1 (94.4, 99.6) 29/31 6/9 93.5 (78.6, 99.2) 66.7 (29.9, 92.5) GT1a 146/152 96.1 (91.6, 98.5) GT1b GT4 28/29 11/11 96.6 (82.2, 99.9) 100 (71.5, 100) GT6 3/5 60.0 (14.7, 94.7) Non-cirrhotic Cirrhotic 151/158 38/40 95.6 (91.1, 98.2) 95.0 (83.1, 99.4)

HCV RNA 2 million HCV RNA >2 million 83/85 106/113 97.6 (91.8, 99.7) 93.8 (87.7, 97.5) Positive drug screen 127/133 95.5 (90.4, 98.3) Negative drug screen 62/65 95.4 (87.1, 99.0) Subgroup Male African-American Asian 10 10 20 30 40 50 60 70 80 % SVR12 (Mean; 95% CI) 90 100 PROBABLE REINFECTIONS IN THE IMMEDIATE TREATMENT GROUP AASLD 2015 San Francisco 5 patients were successfully treated for their baseline virus, but at the time of virologic failure had a different genotype, subtype, or viral strain detected In all 5 cases, population sequencing and phylogenetic analysis of the nucleotide sequences support phylogenetically distinct viral strains at followup compared to baseline Demographics Fibrosis Stage

GT at Baseline UDS at Baseline* UDS at TW12* Time point of detectable HCV RNA GT at Follow-up 48 yo Asian male NC 1a BZP, OPA BZP FW8 6a 33 yo white female NC 1a -- AMP, OPA FW8 1a 55 yo white female C 1a BZP, OPA BZP, OPA FW8 3a

45 yo Asian male NC 6a -- OPA FW8 1b 37 yo Asian female NC 6a AMP, BZP, OPA AMP, BZP, OPA FW8 6a *excludes opiate agonist therapy; AMP=amphetamines; BZP=benzodiazepines; OPA=opiates 11 Immediate Treatment Arm; EBR/GZR Treatment Phase Deferred Treatment Arm; Placebo Phase 70 70 Any drug use of 8 classes* 60 Any drug use of 7 classes (excl. cannabinoids) 50 40 Cannabinoids 30 Benzodiazepines 20

Opiates 10 0 Day 1 TW1 Cocaine Amphetamines TW2 TW4 TW6 TW8 TW10 TW12 % of Patients with Positive Urine Drug Screen % o f P a ti e n t s w it h P o s iti v e U r in e D r u g S c r e e n URINE DRUG SCREEN RESULTS: DAY 1 TO TREATMENT WEEK 12 AASLD 2015 San Francisco 60 50 40 30 20 10 0 Day 1 TW1 TW2 TW4 TW6 TW8 TW10 TW12 Time Point Time Point * 8 drug classes: amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, phencyclidine, propoxyphene 12 AASLD 2015 San Francisco ADHERENCE % Adherence >80% (>67 doses) 100 90 80 70 60 50 40 30 20 10

0 >90% (>76 doses) 100.0 99.0 96.5 199 199 197 199 192 199 Immediate treatment arm (Active study medication) 13 >95% (>79 doses) 100.0 100.0 100.0 97 97 97 97 97 97 Deferred treatment arm (Placebo) PERCENTAGE OF PATIENTS WHO MISSED DOSES OF STUDY MEDICATION Number (%) of Patients with Number of Missed Doses Number of missed doses 0 1 2 3 4 5 6 7 8 9 10 11 12 14 Immediate treatment arm

(n=199) 153 (76.9) 23 (11.6) 8 (4.0) 8 (4.0) 1 (0.5) 0 2 (1.0) 1 (0.5) 1 (0.5) 0 0 2 (1.0) 0 Deferred treatment arm (n=97) 80 (82.5) 8 (8.2) 6 (6.2) 0 3 (3.1) 0 0 0 0 0 0 0 0 AASLD 2015 San Francisco PERCENTAGE OF PATIENTS WHO MISSED DOSES OF STUDY MEDICATION AASLD 2015 San Francisco Number (%) of Patients with Number of Missed Doses Number of missed doses 0 1 2 3 4 5 6 7 8 9 10 11 12 15 Immediate treatment arm (n=199)

153 (76.9) 23 (11.6) 8 (4.0) 96.5% 8 (4.0) 1 (0.5) 0 2 (1.0) 1 (0.5) 1 (0.5) 0 0 2 (1.0) 0 Deferred treatment arm (n=97) 80 (82.5) 8 (8.2) 6 (6.2) 96.9% 0 3 (3.1) 0 0 0 0 0 0 0 0 SAFETY DURING INITIAL TREATMENT PERIOD AND FIRST 14 DAYS OF FOLLOW-UP Serious AEs, n (%) Serious Drug Related AEs, n (%) Discontinuations, n (%) Deaths, n (%) Any adverse event, n (%) Fatigue Headache Nausea Diarrhea Late ALT/AST > 5 x ULN, n (%) Bilirubin >2.6 x ULN, n (%) Hemoglobin <8.5 gm/dL, n (%) Creatinine >2.5x baseline, n (%) 16 Immediate Treatment Arm (Active), n=201 7 (3.5) 1 (0.5) 2 (1.0) 0 166 (82.6) 32 (15.9) 26 (12.9) 23 (11.4)

20 (10.0) 0 0 0 0 Deferred Treatment Arm (Placebo), n=100 4 (4.0) 1 (1.0) 2 (2.0) 1 (1.0) 83 (83.0) 20 (20.0) 14 (14.0) 9 (9.0) 9 (9.0) 0 0 1 (1.0) 0 AASLD 2015 San Francisco Total (n =301) 11 (3.7) 2 (0.7) 4 (1.3) 1 (0.3) 249 (82.7) 52 (17.3) 40 (13.3) 32 (10.6) 29 (9.6) 0 0 1 (0.3) 0 CONCLUSIONS AASLD 2015 San Francisco EBR/GZR demonstrated high efficacy in GT1 and 4-infected patients receiving Opiate Agonist Therapy Limited by small number of GT6-infected patients Acceptable safety profile with comparable adverse event rates between the immediate and deferred treatment arms High study medication adherence Stable ongoing drug use throughout the initial treatment phase in both groups Data demonstrate support for treating HCV among subjects receiving Opiate Agonist Therapy 17

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