C-EDGE Co-Infected: Phase 3 Study of - PowerPoint Presentation

C-EDGE Co-Infected: Phase 3 Study of Grazoprevir / Elbasvir in Patients with HCV/HIV Jürgen K. Rockstroh, Mark Nelson, Christine Katlama, Jay Lalezari, Josep Mallolas, Mark Bloch, Gail Matthews, Michael S. Saag, Philippe Zamor, Chloe Orkin, Jacqueline Gress, Melissa Shaughnessy, Stephanie Klopfer, Janice Wahl, Bach-Yen Nguyen, Eliav Barr, Heather L. Platt, Michael Robertson, Mark Sulkowski

Background HCV NS3/4A inhibitor, 100 mg Grazoprevir (MK-5172) Elbasvir (MK-8742) HCV NS5A inhibitor, 50 mg Broad genotypic activity 1-3 Retains activity against many clinically relevant RAVs 1-3 All-oral, once-daily regimen Summa V, et al. Antimicrobial Agent Chemother 2012:56;4161-67 Coburn CA , et al. ChemMedChem 2013; 8: 1930–40 Harper S, et al. ACS Med Chem Lett. 2012 Mar 2;3(4):332-6.

Background and AimHCV infection is a leading cause of morbidity and mortality among patients with HIV-11-3 rapid progression of liver diseaseincreased risk of cirrhosis, end-stage liver disease, and HCC4,5The aim of the phase 3 C-EDGE Co-infection study was to evaluate the efficacy, safety and tolerability of the HCV regimen, grazoprevir / elbasvir fixed-dose combination in patients with HIV/HCV coinfection 1. Monga HK, et al. Clin Infect Dis 2001;33(2):240-247. 2. Konerman MA, et al. Hepatology 2014;59(3): 767-7753. Pinchoff J, et al. Clin Infect Dis 2014;58(8): 1047-1054. 4. Lo Re V, III, et al. Ann Intern Med 2014;160(6):369-379.5. Rockstroh JK, et al. J Hepatol 2013;59(2):213-220.

STUDY DESIGN An open-label, single-arm, multicenter study across Europe, The US and AustraliaPrimary endpoint: SVR12 (HCV RNA <15 IU/mL*)Treatment-naive patients with HCV GT1, 4 or 6 infection with or without cirrhosis Co-infected with HIV-1: Naive to ART with CD4 + >500 cells/mm 3 and HIV RNA <50,000 copies/mL On stable on ART† for ≥8 weeks and CD4+ > 200 cells/mm3 and undetectable HIV RNA GZR 100 mg / EBR 50 mg D1 TW4 TW8 TW12 FUW4 FUW8 FUW12 n=218 * COBAS TaqMan v2.0 [ LLoQ <15 IU/ mL ] † Stable antiretroviral therapy (ART) included tenofovir or abacavir , and either emtricitabine or lamivudine plus raltegravir , dolutegravir , or rilpivirine Follow-up

Demographics: HCV Disease  All PatientsN = 218 Age, years mean (SD) 48.7 (8.9) Sex, n (%)   Male , 183 (83.9) Female 35 (16.1) Race, n (%)   White 167 (76.6) Black or African-American 38 (17.4) Asian 6 (2.8) Other 7 (3.2) Ethnicity, n (%)   Hispanic / Latino 14 (6.4) Not Hispanic / Latino 194 (89.0) Not reported 10 (4.6) HCV genotype, n (%)   1a 144 ( 66.1) 1b 44 (20.2) 4 28 (12.8) 6 2 (1.0) Baseline HCV RNA >800,000 IU/mL, n (%) 130 (59.6) Cirrhotic*, n (%)35 (16.1)IL28B CC (%) , n (%)77 (35.3) * Of the 35 patients ( 16.1 %) with cirrhosis, 27 were diagnosed by Fibroscan, 6 by biopsy, and 2 by Fibrotest and APRI.

Demographics: HIV Disease  All PatientsN = 218 Antiretroviral therapy, n (%)   Receiving ART with undetectable HIV RNA 211 ( 96.8) Naïve to ART 7 (3.2) Baseline CD4 count (cells/µL) Mean (SD) Median (1 st quartile – 3 rd quartile)  613 (0.57)568 (424-766) Antiretroviral therapy, n (%)   Abacavir containing regimen 47 ( 21.6) Tenofovir containing regimen 164 ( 75.2) Raltegravir 113 ( 51.8) Dolutegravir 59 ( 27.1) Rilpivirine 38 ( 17.4)

SVR12 Discontinued unrelated to VF1 0 1 0 Relapse 5 4 0 1 Reinfection 2 1 1 0 *2 patients with GT6 infection were also included; both patients achieved SVR12 . GT = genotype 210 /217* 139 /144 42 /44 210 /218* 27 /28

SVR12 Variable n/m % (95% CI) ALL 210/218 96.3 (92.9, 98.4) Gender Male 175/183 95.6 (91.6, 98.1) Female 35/35 100.0 (90.0, 100.0) Age <65 years 204/212 96.2 (92.7, 98.4) ≥65 years 6/6 100.0 (54.1, 100.0) Race White 161/167 96.4 (92.3, 98.7 ) African American 36/38 94.7 (82.3, 99.4) Asian 6/6 100 (54.1, 100.0) IL28B genotype CC 76/77 98.7 (93.0, 100.0) Non-CC 134/141 95.0 (90.0, 98.0) Cirrhosis No 175/183 95.6 (91.6, 98.1) Yes 35/35 100 (90.0, 100.0) Baseline viral load ≤800,000 IU/mL 89/91 97.8 (92.3, 99.7) >800,000 IU/mL 121/127 95.3 (90.0, 98.2) Svr12 – Subgroup analyses Full analysis set 80 9 0 100 SVR12 (95% CI)

SVR12 Variable n/m % (95% CI) ALL 210/218 96.3 (92.9, 98.4) ART regimen Abacavir -containing 44/47 93.6 (82.5, 98.7) Tenofovir -containing 160/164 97.6 (93.9, 99.3) ART third agent Raltegravir 109/113 96.5 (91.2, 99.0) Dolutegravir 59/59 100.0 (93.9, 100.0) Rilpivirine 36/38 94.7 (82.3, 99.4) Svr12 according to art regimen full analysis set 80 9 0 100 SVR12 (95% CI)

Relapse and reinfection 5 patients relapsedAll noncirrhoticGT1a n=4; GT4 n=1Four patients were receiving ARTTenofovir-based ART n=3Abacavir-based ART n=12 patients were reinfectedOne patient with GT1a at enrolment; GT3 at FW12One patient with GT1b at enrolment; GT3 at FW12Per protocol, these patients was classified as a failure for analysis, but sequencing and phylogenetic data are consistent with post-treatment reinfection

Resistance Associated Variants in patients with relapse or reinfection      Baseline HCV GT ARV regimen Resistance Associated Variants At baseline At failure NS3 NS5A NS3 NS5A RELAPSES 56 yr black/AA male 1a tenofovir, emtricitabine, rilpivirine V36M/L L31M/L Q80K, D168A Q30K , L31M 63 yr black/AA male 1a None Q80K Y93S Q80K , D168A Q30R , Y93S 37 yr white male 1a tenofovir, emtricitabine, raltegravir WT WT WT Q30R/Q 43 yr white male 1a abacavir, lamivudine, raltegravir WT WT WT WT 53 yr white male 4 tenofovir, emtricitabine, raltegravir WT WT WT L28S REINFECTIONS 35 yr white male 1b abacavir, lamivudine, raltegravir WT WT (GT3) (GT3)43 yr white male1atenofovir, emtricitabine, rilpivirineV55A/VWT(GT3)(GT3) Bold indicates RAV detected at virologic failure not previously detected at baseline.

ns5A Phylogenetic analysis of reinfection:AN191535 Day 1 At failure

NS5a Phylogenetic analysis of Reinfection:AN191554 Day 1 At failure

Adverse events  Patients with:All Patients N = 218 Serious AE, n (%) 8* (2.8) Serious drug-related AE, n (%) 0 (0) Discontinuation due to AE, n (%) 0 (0) Deaths, n (%) 0 (0) Any adverse event † , n (%) 167 ( 76.6) Fatigue 29 ( 13.3) Headache 27 (12.4) Nausea 20 (9.2) Late ALT or AST >5.0 x ULN ‡ , n (%) 2 (0.9)   Lowest hemoglobin on treatment, n (%)   ≥8.5 to <10 g/ dL 1 (0.5) Elevation of total bilirubin ¶ , n (%)   >2.5 – 5.0 × baseline 8 (3.7) >5.0 × baseline 1 (0.5) Creatinine >2.5 x baseline, n (%) 0 (0) *2 SAEs were reported during the treatment period (convulsion and pneumonia) and 6 SAEs were reported during follow-up (erysipelas ; acute psychosis and urinary retention; ulnar fracture; spontaneous bacterial peritonitis, cellulitis, and urinary retention) †All AEs, regardless of relationship to study drug reported in > 5% of patients. ‡ALT/AST >5× ULN after TW4 with an ALT/AST ≤ ULN between TW2 and TW4 ¶ Bilirubin elevations were not associated with simultaneous ALT increases

HIV ParametersTwo patients receiving ART experienced transient HIV viremia during treatment Both patients subsequently achieved undetectable HIV RNA with additional compliance education, and without a change in ARV regimen.No notable change in CD4+ cells from baseline compared to TW12Mean change of 52.9 cells/µL (SD 156.14, n=207)

Conclusions High rates of SVR were achieved in patients with HCV GT1, 4 and 6 and HIV co-infection receiving the all-oral, fixed-dose combination of GZR / EBR Comparable response rates to other studies in HCV mono-infected patientsComparable response rates across all patient subgroups, including black/African AmericanComparable response rates in cirrhotic and non-cirrhotic patientsGenerally well tolerated with few SAEs, and no discontinuationLow rates of adverse events, once-daily administration, and suitability for use in patients also receiving antiretroviral therapy suggest GZR / EBR may represent a highly effective treatment option for patients with HCV/HIV co-infection .

Published 09-July-15

Acknowledgements We extend our gratitude to the patients, their families, investigators and site personnel who participated in this study.Australia: Gail Matthews, Mark Theo BlochCanada: Jason Brunetta, Brian ConwayDenmark: Jan Gerstoft, Nina Weis, Alex Lund Laursen France : Marc Bourliere , Christine Katlama , Stanislas PolGermany: Stefan Mauss, Jürgen K. Rockstroh, Michael SabranskiIsrael : Yaacov Baruch, Oren Shibolet, Ziv Ben Ari Spain: Juan Gonzalez Garcia, Josep Mallolas, Christina TuralUnited Kingdom: Mark Nelson, Chloe Orkin United States: David Michael Asmuth , Michael David, Laveeza Bhatti, Edwin DeJesus, Princy N. Kumar, Jacob Paul Lalezari, Kristen Marks, Frederick Nunes, Ponni Perumalswami, Peter Jerome Ruane, Alyssa So Young Shon, Mark S. Sulkowski, David Wyles, Philippe J. Zamor , David J Prelutsky , Michael S Saag , Anthony Mills. This study and medical writing support by ApotheCom were funded by Merck & Co., Inc

Conclusions High rates of SVR were achieved in patients with HCV GT1, 4 and 6 and HIV co-infection receiving the all-oral, fixed-dose combination of GZR / EBR Comparable response rates to other studies in HCV mono-infected patientsComparable response rates across all patient subgroups, including black/African AmericanComparable response rates in cirrhotic and non-cirrhotic patientsGenerally well tolerated with few SAEs, and no discontinuationLow rates of adverse events, once-daily administration, and suitability for use in patients also receiving antiretroviral therapy suggest GZR / EBR may represent a highly effective treatment option for patients with HCV/HIV co-infection .

Back up slides

Backup slides Treatment N n (%) 95% Confidence Interval † p-Value ‡ GZR/EBR for 12 Weeks 218 210 (96.3) (92.9, 98.4) <.001 † Based on Clopper -Pearson method. ‡ Based on a one-sided exact test for a binomial proportion. A one-sided p-value<0.025 supports a conclusion that the true SVR 12 is >70%. N = Number of subjects included in the analysis. n (%) = Number of subjects who achieved SVR 12 and the percentage calculated as (n/N)*100. LLoQ is 15 IU/ mL. Analysis of Sustained Virologic Response (HCV RNA < LLoQ ) at Follow-up Week 12 Visit (SVR 12 ) in Treatment-Naïve Subjects Full Analysis Set Full Analysis Set: 210/218 5 relapses 2 reinfections 1 discontinuation

Backup slides Treatment N n (%) 95% Confidence Interval † GZR/EBR for 12 Weeks 217 210 (96.8) (93.5, 98.7) † Based on Clopper-Pearson method. N = Number of subjects included in the analysis. n (%) = Number of subjects who achieved SVR 12 and the percentage calculated as (n/N)*100. LLoQ is 15 IU/mL. Data Source: [16.4] Analysis of Sustained Virologic Response (HCV RNA < LLoQ ) at Follow-up Week 12 Visit (SVR 12 ) in Treatment-Naïve Subjects Per Protocol Per Protocol Analysis: 210/217 5 relapses 2 reinfections

Backup slides: subgroup analysis  GZR/EBR for 12 Weeks   N n (%) 95% Confidence Interval † Gender Male 183 175 (95.6) (91.6, 98.1) Female 35 35 (100.0) (90.0, 100.0) Age <65 212 204 (96.2) (92.7, 98.4) >=65 6 6 (100.0) (54.1, 100.0) Race White 167 161 (96.4) (92.3, 98.7) African American 38 36 (94.7) (82.3, 99.4) Asian 6 6 (100.0) (54.1, 100.0) Other 7 7 (100.0) (59.0, 100.0) Ethnicity Hispanic or Latino 14 14 (100.0) (76.8, 100.0) Not Hispanic or Latino 194 186 (95.9) (92.0, 98.2) Other 10 10 (100.0) (69.2, 100.0) Genotype 1a 144 139 (96.5) (92.1, 98.9) 1b 44 42 (95.5) (84.5, 99.4) 1-other 0 0 (0.0) NA 4 28 27 (96.4) (81.7, 99.9) 6 2 2 (100.0) (15.8, 100.0) IL28B CC genotype CC genotype 77 76 (98.7) (93.0, 100.0) Non-CC genotype 141 134 (95.0) (90.0, 98.0) Fibrosis Stage Non-Cirrhotic 183 175 (95.6) (91.6, 98.1) Cirrhotic 35 35 (100.0) (90.0, 100.0) Baseline HCV RNA <=800,000 IU/mL 91 89 (97.8) (92.3, 99.7) >800,000 IU/mL 127 121 (95.3) (90.0, 98.2) <=2,000,000 IU/mL 135 131 (97.0) (92.6, 99.2) >2,000,000 IU/mL 83 79 (95.2) (88.1, 98.7) <=10,000,000 IU/mL 214 206 (96.3) (92.8, 98.4) >10,000,000 IU/mL 4 4 (100.0) (39.8, 100.0) Prior Treatment Summary of Sustained Virologic Response (HCV RNA < LLoQ ) at Follow-up Week 12 Visit (SVR 12 ) by Subgroup Full Analysis Set

Backup slides: subgroup analysis continued  GZR/EBR for 12 Weeks   N n (%) 95% Confidence Interval † Naïve 194 186 (95.9) (92.0, 98.2) Naïve – Interferon Ineligible 11 11 (100.0) (71.5, 100.0) Naïve – Interferon Unwilling 13 13 (100.0) (75.3, 100.0) Antiretroviral therapy with NRTI backbone Abacavir containing regimen ‡ 47 44 (93.6) (82.5, 98.7) Tenofovir containing regimen 164 160 (97.6) (93.9, 99.3) Antiretroviral therapy with 3rd agent in ARV Regimen Raltegravir 113 109 (96.5) (91.2, 99.0) Dolutegravir 59 59 (100.0) (93.9, 100.0) Rilpivirine 38 36 (94.7) (82.3, 99.4) † Based on the Clopper-Pearson method. ‡ Includes one subject who was on abacavir, lamivudine, and tenofovir. N = Number of subjects included in the analysis. n (%) = Number of subjects who achieved SVR 12 and the percentage calculated as (n/N)*100. LLoQ is 15 IU/mL. Data Source: [16.4]

Phylogenetic data

ns5A Phylogenetic tree

NS3 Phylogenetic tree