HCV Update from AASLD 2016

Transcription

1 HCV Update from AASLD 2016 Ahmed Elsharkawy Consultant Hepatologist QE Birmingham Secretary and Chair-Elect of BVHG BHIVA/BVHG Feedback Meeting November 2016

2 Speaker Name Ahmed Elsharkawy Statement Speaking fees from BMS, Gilead, Abbvie, MSD, Astellas. Advisor to Gilead, BMS and Abbvie. Research funding from Gilead and Abbvie. Date November 2016

3 Disclaimer

4 Outline of Talk Is 8 weeks of Harvoni effective in HIV co-infected patients? Can we use existing drugs in different ways? How long do resistance associated substitutions last for? What regimens are coming in 2017 and 2018? How do we salvage DAA experienced patients? Is there any hope for our G3 renal failure patients? Summary and some probably wrong future gazing

5 Is 8 weeks of Harvoni enough in HIV/HCV Coinfected G1 patients?

6 SVR12 (%) Real-World Analyses of LDV/SOF for 8 Weeks in >6,500 HCV GT1 Treatment-Naive, Non-cirrhotic Patients Primary Analysis: Per-protocol SVR12 outcomes among patients eligible to receive 8 weeks of LDV/SOF from HCV-TRIO, IFI, Temple University/Burman s Pharmacy, and Kaiser / / / / / 202 Overall >65 yrs HIV/HCV White Black F0 F1 F2 F3 GT1a GT1b co-infection Secondary analysis: Meta-analysis of 6 additional real world cohorts (n=5,637) Per protocol SVR12 was 96% (2196/2293) with 8 weeks LDV/SOF and 97% (3251/3344) with 12 weeks LDV/SOF 167/ / / 250 Similar risk for relapse between 8 and 12 weeks LDV/SOF (P=0.508) 138/ / / 237 Sundaram V, AASLD 2016, Poster LB-16

7 SVR12, % German Hepatitis C-Registry (DHC-R) LDV/SOF for 8 or 12 Weeks in HCV-Monoinfected and HIV/HCV-Coinfected Patients Analysis of 2,485 HCV GT 1 patients treated with LDV/SOF for 8 weeks or 12 weeks under real world conditions Patients Baseline Demographics LDV/SOF 8 weeks n=976 LDV/SOF 12 weeks n=1,509 Male, n (%) 466 (48) 874 (58) Mean age, years Age >70 years, % Treatment-naïve, % Fibroscan, mean (kpa) Cirrhosis, % HCV VL >6 million, % HIV/HCV coinfection, n (%) 91 (9.3) 187 (12.4) Overall HIV coinfection LDV/SOF 8 wk SVR12 (PP) Age >70 Patients on OST LDV/SOF 12 wk Under real world conditions, LDV/SOF for 8 weeks achieves comparable SVR rates to 12 week treatment, including HIV co-infected patients, older individuals and patients on OST OST, Opioid Substitution Therapy Buggisch P, AASLD 2016, Poster 883

8 Isakov V, AASLD 2016, Poster 2030 Russia and Estonia Phase 3b Study LDV/SOF for 8 Weeks in Treatment-Naïve, Non-cirrhotic HCV GT 1 Monoinfected and HIV/HCV-Coinfected Patients Week TN HCV Monoinfection n=67 TN HIV/HCV Coinfection n=59 LDV/SOF LDV/SOF 100% (67/67) SVR12 97% (57/59*) SVR12 * 2 patients experienced relapse Baseline Demographics HCV n=67 HIV/HCV n=59 Mean age, y (range) 42 (19-76) 34 (23-58) Male, n (%) 34 (51) 34 (58) Mean BMI, kg/m 2 (range) 25 (18-36) 24 (19-34) GT 1b 64 (96) 44 (75) Mean HCV RNA, log 10 IU/mL (range) 5.9 ( ) 6.1 ( ) HCV RNA>6M IU/mL, n (%) 2 (3) 7 (12) Median CD4 count, IU/L (range) No ARV N/A 565 ( ) HCV n=67 HIV/HCV n=59 Any AE, n (%) 19 (28) 18 (31) Grade 3/4 AE*, n (%) 1 (1) 0 Grade 3-4 lab abnormality, n (%) Safety Summary 5 (7) 4 (7) *1 grade 3 AE of asymptomatic neutropenia based on grade 3 neutrophil count; considered unrelated to study treatment. LDV/SOF for 8 weeks is a beneficial treatment option for treatment-naive, noncirrhotic patients with chronic HCV, including those with HIV/HCV coinfection

9 Can we use existing drugs in different ways?

10 SVR12 (%) The Issue with G3 Cirrhotics ASTRAL-3 Data SVR12 rate numerically lower with vs without BL NS5A RAVs (88% vs 97%) Safety profile similar to ASTRAL P <.001 (superiority) SOF/VEL 12 wks SOF + RBV 24 wks n/n = 0 264/ / / / / 80 55/ / / 204 All Pts No Yes Naive Experienced Cirrhosis 64/ 71 Treatment History 45/ 71 Slide credit: clinicaloptions.com Mangia A, et al. AASLD Abstract 249. Reproduced with permission. Foster GR, et al. N Engl J Med. 2015;[Epub ahead of print].

11 Treatment- Treatmentnaive C-ISLE: A randomized, open-label, UK-based clinical trial in GT3 cirrhotics Target enrollment was 25 patients per arm EBR/GZR + SOF + RBV SVR12 Dosing EBR/GZR FDC (50 mg/100 mg/d) SOF (400 mg/d as per PI) RBV ( mg/d) EBR/GZR + SOF SVR12 experienced EBR/GZR + SOF EBR/GZR + SOF + RBV EBR/GZR + SOF SVR12 SVR12 SVR12 TW0 TW4 TW8 TW12 TW16 FW12 FDC, fixed-dose combination; FW, follow-up week; TW, treatment week. Randomization of treatment-experienced patients was stratified based on prior relapse vs nonrelapse (partial, null, interferon-intolerant). Primary endpoint: HCV RNA <15 IU/mL. Foster GR, et al. AASLD, oral presentation

12 SVR, % SVR12 (mfas) Treatment-naive Treatment-experienced EBR/GZR + SOF + RBV (8 weeks) EBR/GZR + SOF (12 weeks) EBR/GZR + SOF (12 weeks) EBR/GZR + SOF + RBV (12 weeks) EBR/GZR + SOF (16 weeks) Relapse mfas excluded patients who discontinued treatment for reasons unrelated to study medication. Foster GR, et al. AASLD, oral presentation

13 SVR12, % SVR12, % SVR12, % % GT3 NS5A RASs: Prevalence and impact on SVR12 Prevalence of NS5A RAS 100% 75 75% 50 50% 25 25% 0% % NS5A RAVs Absent NS5A RAS present RAS 51% (n = 49) No RAS 49% (n = 47) 100% % % 25 25% 0 0% 98.0% NS5A RAVs Present NS5A RAS absent *Resistance assessed by next generation sequencing with 15% sensitivity threshold; only includes subjects with a virologic outcome. NS5A polymorphisms at positions: 24, 28, 30, 31, 32, 38, 58, 62, 92, or 93 Foster GR, et al. AASLD, oral presentation

14 Non-SVR Patients Three patients discontinued for administrative reasons Treatment history Treatment regimen Reason for discontinuation 1 Naive EBR/GZR + SOF (12 weeks) Lost to follow-up after TW2 2 Experienced EBR/GZR + SOF + RBV (12 weeks) Withdrew consent after day 7 3 Experienced EBR/GZR + SOF (16 weeks) Discontinued after day 7 due to cellulitis Two patients relapsed Treatment history Treatment regimen Time of relapse Baseline NS5A RAVs Failure 1 Naive EBR/GZR + SOF + RBV (8 weeks) FW4 Y93H, P58, S62T P58, S62T 2 Naive EBR/GZR + SOF + RBV (8 weeks) FW8 WT WT WT, wild type. Foster GR, et al. AASLD, oral presentation

15 Author s Conclusions High efficacy was demonstrated in treatment-naive and treatment-experienced cirrhotic HCV GT3-infected patients There were no virologic failures among patients receiving EBR/GZR + SOF ± RBV for 12 or 16 weeks Treatment duration longer than 12 weeks is not needed High efficacy regardless of presence of baseline NS5A RAVs or patient characteristics Generally safe and well tolerated Foster GR, et al. AASLD, oral presentation

16 Is this an economically viable regimen?

17 Sof and Dac for 8 weeks in Noncirrhotic G3 Patients Hezode C, et al. AASLD, poster presentation

18 How long do resistance associated substitutions persist for?

19 Grazoprevir treatment failures 58 patients with HCV GT1 infection with virologic failure following treatment with a grazoprevir-containing regimen in a phase 2/3 clinical trial GT1a (n = 44) EBR/GZR for 12/16 weeks (n = 23) EBR/GZR+RBV for 8/12 weeks (n = 5) GZR+PR for 12 weeks + PR for 12 weeks (n =16) GT1b (n = 14) EBR/GZR for 12 weeks (n = 6) EBR/GZR+RBV for 12 weeks (n = 3) GZR+PR for 12 weeks + PR for 12 weeks (n=3) GZR+RBV for 24 weeks (n = 2) EBR, elbasvir; GT, genotype; GZR, genotype; PR, peginterferon + ribavirin; RBV, ribavirin Assante-Appiah E, et al. AASLD, oral presentation

20 Detectable RAVs, % Pre-existing NS3 and NS5A RAS Persist >2 years post-treatment NS3 Pre-existing RAS (n = 25) NS5A Pre-existing RAS (n = 28) Time post-virologic failure (weeks) Each data point represents the last time point an individual RAS was detected (scored as 1). A RAS that was detected at the last available time point was scored as 0. GT1a and GT1b patients treated with EBR/GZR ± RBV Any NS3 polymorphism at positions 36, 54, 55,56, 80, 107, 122, 132, 155, 156, 158, 168, 170, 175 Any NS5A polymorphism at positions 28, 30, 31, and 93 Assante-Appiah E, et al. AASLD, oral presentation

21 Detectable RAVs, % Persistence of Treatment-emergent RAS varies by target Region In patients with GT1 infection Treatment-emergent NS5A RAS show persistence >2 years post-treatment Treatment-emergent NS3 RAS show rapid return to wild type NS3 treatment-emergent RAS (n = 35) NS5A treatment-emergent RAS (n = 35) Time post-virologic failure (weeks) GT1a and GT1b patients treated with EBR/GZR ± RBV Any NS3 polymorphism at positions 36, 54, 55,56, 80, 107, 122, 132, 155, 156, 158, 168, 170, 175 Any NS5A polymorphism at positions 28, 30, 31, and 93 Assante-Appiah E, et al. AASLD, oral presentation

22 What is coming in 2017 and 2018? Three regimens had data presented Doublet from Abbvie PI and NS5A Gleceprevir and Pibrenatasvir respectively Triplet from Gilead PI, NS5A inhibitor and NS5B nucleotide inhibitor Voxalaprevir, Valpatasvir and Sofosbuvir respectively Triplet from Merck PI, NS5A inhibitor and NS5B nucleotide inhibitor Grazoprevir, Ruzasvir and MK-3682 respectively

23 Glecaprevir/Pibrentasvir (G/P)

24 ENDURANCE-1: 8 vs 12 week treatment with Glecaprevir/Pibrentasvir (G/P) in GT1 Infection SVR12 (%) GT1 non-cirrhotic TN or TE IFN / peg-ifn ± RBV SOF + RBV ± peg-ifn ± HIV-1 coinfection 1:1 G/P 300 mg/120 mg OD (n=351) G/P 300 mg/120 mg OD (n=352) Time (weeks) Phase 3 Randomised Open-label 125 sites ITT analysis Demographics Treatment-experienced IFN-based, n (%) SOF-based, n (%) Fibrosis stage, n (%) F0 1 F2 F3 G/P 8 wk n= (99) 1 (<1) 297 (85) 22 (6) 30 (9) G/P 12 wk n= (99) 2 (1) 298 (85) 24 (7) 29 (8) GT1a, n (%) 152 (43) 148 (42) HIV coinfection, n (%) 15 (4) 18 (5) * One patient experienced on-treatment virologic failure; one patient d/c on day 2 due to non-compliance; one patient missing SVR12 data. One patient missing SVR12 data. Zeuzem et al., AASLD 2016, Abstract #253

25 ENDURANCE-2: Glecaprevir/Pibrentasvir (G/P) in HCV GT2 Patients without Cirrhosis GT2 Non-cirrhotic TN or TE (peg-ifn + RBV / SOF + RBV) 2:1 G/P 300 mg/120 mg OD Placebo G/P 300 mg/120 mg OD Time 4 (weeks) Phase 3 Randomised Double-blind Placebo-controlled Characteristic HCV RNA, median (range), log 10 IU/mL G/P N= ( ) Placebo N= ( ) Non-CC IL28B genotype, n (%) 111 (55) 50 (50) Fibrosis Stage, n (%) F0-F1 154 (76) 85 (85) F2 18 (9) 9 (9) F3 30 (15) 6 (6) Treatment experienced, n (%) 61 (30) 29 (29) PPI use, n (%) 22 (11) 11 (11) HCV quantified by Roche Cobas Ampliprep / Cobas Taqman 2.0 or higher ITT population: excludes 6 SOF-experienced patients, all of whom achieved SVR12 mitt population: ITT population excluding 1 non-virologic failure who achieved SVR4 Kowdley et al., AASLD 2016, Abstract #73

26 ENDURANCE-4: Glecaprevir/Pibrentasvir (G/P) Treatment in GT4, 5, or 6 Infection GT4, 5, 6 Non-cirrhotic TN or TE (IFN / peg-ifn ± RBV / SOF + RBV ± peg-ifn) Demographics GT4/5/6 76/26/19 (63%/21%/16%) Treatment exp ed IFN / SOF Mean HCV RNA at baseline ABT-493/ABT mg/120 mg OD (N=121) 0 4 Time (weeks) 8 12 Patients (N=121) 39 (32%) 39 (100%) / log 10 IU/mL Non-CC IL28B 75% F2 F3 14% Phase 3 Open-label Overall G4 G5 G6 Overall G4 G5 G6 G/P regimen achieved high SVR12 rates in 12 weeks for non-cirrhotic patients with HCV GT4 6 infection Asselah et al., AASLD 2016, Abstract #114

27 SURVEYOR-II, Part 4: Glecaprevir/Pibrentasvir (G/P) in GT2, 4, 5, or 6 Infection without Cirrhosis for 8-Weeks GT2, 4, 5, 6 Non-cirrhotic TN or TE (IFN- or SOF-based regimens) Phase 2, open-label, randomised, multicentre study G/P 300 mg/120 mg OD (N=203) Time (weeks) Baseline demographics (N=203) Male, n (%) 98 (48) White race, n (%) 155 (76) Age, median (range), years 55 (19 83) BMI, median (range), kg/m ( ) Treatment-naïve, n (%) 176 (87) SOF treatment-experienced, n (%) 6 (3) HCV RNA, median (range) log 10 IU/mL 6.45 ( ) GT2/4/5/6, % 71%/23%/1%/5% Baseline fibrosis F0 1/F2/F3, n 170/12/21 Hassanein et al., AASLD 2016, #LB-15

28 SURVEYOR-II Part 3: Glecaprevir/Pibrentasvir (G/P) in GT3 patients with Treatment Experience ± Cirrhosis TN + cirrhosis GT3 Non-cirrhotic TE (IFN ± RBV / SOF + RBV ± peg-ifn) TE + cirrhosis 1:1 G/P 300 mg/120 mg OD G/P 300 mg/120 mg OD Time (weeks) Phase 2/3 Partially randomised Open-label 1:1 Randomised TE w/o Cirrhosis 12 Weeks N = 22 TE w/o Cirrhosis 16 Weeks N = 22 TN w/ Cirrhosis 12 Weeks N = 40 TE w/ Cirrhosis 16 Weeks N = 47 Characteristic IL28B non-cc, n (%) 15 (68) 19 (86) 20 (50) 34 (72) HCV RNA, median log 10 IU/mL (range) 6.6 ( ) 6.1 ( ) 6.2 ( ) 6.5 ( ) Prior treatment history, n (%) Naïve (100) 0 IFN/pegIFN ± RBV 14 (64) 13 (59) 0 22 (47) SOF + RBV ± pegifn 8 (36) 9 (41) 0 25 (53) *Data missing for 1 patient in Arm A (column 1) and 1 patient in Arm B (column 3) Wyles et al., AASLD 2016, Abstract #113

29 SURVEYOR-II Part 3: ITT SVR12 with Glecaprevir/Pibrentasvir (G/P) in GT3 patients with Prior Treatment Experience ± Cirrhosis :1 Randomised Cirrhosis 1:1 Randomised + + Treatmentexperienced % of patients had HCV RNA <LLOQ by treatment week 4 Wyles et al., AASLD 2016, Abstract #113

30 Sofosbuvir/Velpatasvir/Voxaleprevir

31 POLARIS Phase 3 Program POLARIS-1 DAA-Experienced POLARIS-4 POLARIS-2 POLARIS-3 N = 415 N = 333 N = 941 N = 219 ± cirrhosis Cirrhosis NS5Aexperienced ± cirrhosis Non-NS5Aexperienced ± cirrhosis DAA-Naïve GT GT GT GT SOF/VEL/VOX 12 weeks (n=263) SOF/VEL/VOX 12 weeks (n=182) SOF/VEL/VOX 8 weeks (n=501) SOF/VEL/VOX 8 weeks (n=110) Placebo (n=152) SOF/VEL 12 weeks (n=151) SOF/VEL 12 weeks (n=440) SOF/VEL 12 weeks (n=109) Bourliere M, AASLD 2016, Oral 194. Zeuzem S, AASLD 2016, Oral 109. Jacobson IM, AASLD 2016, Oral LB-12. Foster GR, AASLD 2016, Oral 258

32 POLARIS 2 (only G3 cirrhotics excluded) Phase 3, global, multicenter, randomised, open-label Wk 0 Wk 8 Wk 12 Wk 20 Wk 24 n=501 n=440 SOF/VEL/VOX SOF/VEL SOF/VEL/VOX 8 weeks n=501 SOF/VEL 12 weeks n=440 Mean age, y (range) 53 (18 78) 52 (19 82) Male, n (%) 255 (51) 237 (54) White, n (%) 391 (78) 365 (83) Mean BMI, kg/m 2 (range) 27 (17 57) 27 (18 54) Cirrhosis, n (%) 90 (18) 84 (19) Genotype, n (%)* 1a / 1b / Other 169 (34) / 63 (13) / 1 (<1) 172 (39) / 59 (13) / 1 (<1) 2 / 3 / 4 63 (13) / 92 (18) / 63 (13) 53 (12) / 89 (20) / 57 (13) 5 / 6 / Unknown 18 (4) / 30 (6) / 2 (<1) 0 / 9 (2) / 0 IFN experienced, n (%) 118 (24) 100 (23) Mean HCV RNA, log 10 IU/mL (range) 6.1 ( ) 6.2 ( ) *Treatment-naïve or treatment-experienced with an IFN-based regimen and no prior exposure to a DAA Jacobson IM, AASLD 2016, Oral LB-12

33 SVR12, % POLARIS 2 Overall SVR relapses 4 LTFU 476/501 SOF/VEL/VOX 8 weeks 3 relapses 1 DC due to AE 4 LTFU 432/440 SOF/VEL 12 weeks Proportional difference (2-sided 95% CI) -3.4 (-6.2% to -0.6%) noninferiority not met; Jacobson IM, AASLD 2016, Oral LB-12

34 SVR12, % SVR12 in GT SOF/VEL/VOX 8 weeks SOF/VEL 12 weeks relapses 4 LTFU 16 relapses 14 relapses 2 relapses 20 3 relapses 1 AEDC 4 LTFU 2 relapses 2 LTFU 1 relapse 1 LTFU 1 relapse 1 LTFU Overall 1 1a 1b Overall GT 1 GT 1a GT 1b 2 of 2 patients (100%) with GT 1 Other achieved SVR12 (1 each in SOV/VEL/VOX and SOF/VEL arm). AEDC, Discontinuation due to AE Jacobson IM, AASLD 2016, Oral LB-12

35 SVR12, % SVR12 in G2-6 SOF/VEL/VOX 8 weeks, n=501 SOF/VEL 12 weeks, n= relapses 1 LTFU 2 relapses 3 LTFU 2 LTFU 1 DC due to AE 1 relapse 1 relapse GT 2 GT 3 GT 4 GT 5 GT 6 Unknown Jacobson IM, AASLD 2016, Oral LB-12

36 SVR12, % SVR12, % SVR12 by Cirrhosis Status 100 No Cirrhosis n= Cirrhosis n= relapses 3 LTFU 2 relapses 4 LTFU 1 DC due to AE relapses 1 LTFU 1 relapse 0 394/ /356 82/90 0 SOF/VEL/VOX 8 weeks SOF/VEL 12 weeks SOF/VEL/VOX 8 weeks 83/84 SOF/VEL 12 weeks Jacobson IM, AASLD 2016, Oral LB-12

37 POLARIS 3 DAA Naïve G3 Cirrhotics Phase 3, global, multicenter, randomised, open-label study Wk 0 Wk 8 Wk 12 Wk 20 Wk 24 n=110 n=109 SOF/VEL/VOX SOF/VEL SOF/VEL/VOX 8 weeks n=110 SOF/VEL 12 weeks n=109 Mean age, years (range) 54 (25 75) 55 (31 69) Male, n (%) 74 (67) 83 (76) White, n (%) 100 (91) 97 (89) Mean BMI, kg/m 2 (range) 28 (20 50) 27 (18 46) Mean platelets, x10 3 /µl (range) 140 (37-351) 150 (51-292) Platelets<100 x10 3 /µl (range), n (%) 30 (29) 21 (19) Mean Fibroscan, kpa (range) 23 (13-75) 22 (13-75) IFN experienced, n (%) 35 (32) 32 (29) Mean HCV RNA, log 10 IU/mL (range) 6.0 ( ) 6.3 ( ) Foster GR, AASLD 2016, Oral 258

38 SVR12, % POLARIS 3 Overall SVR relapses 1 withdrew consent 1 death 106/110 SOF/VEL/VOX 8 weeks p <0.001 for superiority compared with prespecified 83% performance goal 1 breakthrough 1 relapse 1 discontinued due to AE 1 LTFU 105/109 SOF/VEL 12 weeks Foster GR, AASLD 2016, Oral 258

39 MK-3682/Grazoprevir/Ruzasvir

40 GT1 (n = 88) GT2 (n = 32) GT3 (n = 53) C-CREST Design MK3 SVR12 1 Endpoint GT2 (n = 31) GT3 (n = 50) MK3 + RBV GT1 (n = 88) GT2 (n = 46) GT3 (n = 79) MK3 GT2 (n = 16) GT3 (n = 80) MK3 + RBV GT2 (n = 26) GT3 (n = 50) MK3 GT3 (n = 25) MK3 + RBV D1 TW4 TW8 TW12 TW16 FW12 TW=treatment week; FW=follow-up week; RBV=ribavirin Lawitz E, AASLD 2016, Oral

41 SVR12 SVR12, (% <15 % IU/mL) C-CREST SVR12 (Full Analysis Set) Weeks 12 Weeks 16 weeks GT1a GT1b GT2 GT3 Relapse Discontinuation (DR-AE)* Reinfection* Non-virologic failure* *GT1a 8 weeks, No RBV: 1 patient achieved SVR8 but was reinfected with a different HCV strain by phylogenetic analysis at FW12; GT1a 12 weeks, No RBV: 1 patient died due to study-drug unrelated bacterial sepsis; GT2 8 weeks + RBV: 1 patient discontinued at Day 5 due to drug-related AEs of fatigue, malaise; 1 patient lost to follow-up; GT2 12 weeks, No RBV: 2 patients lost to follow-up; GT3 8 weeks, RBV arm: 1 patient lost to follow-up; GT3 12 weeks, No RBV: 1 patient withdrew due to pregnancy, lost to follow-up; GT3 16 weeks arm: 1 patient lost to follow-up Lawitz E, AASLD 2016, Oral

42 SVR12 SVR12, (%<25 % IU/mL) C-CREST SVR12 (Per Protocol) No cirrhosis Cirrhosis Weeks, No RBV 12 Weeks, No RBV 12 Weeks + RBV 16 Weeks, No RBV Genotype GT2 GT3 GT3 GT3 Duration 12 Weeks 12 Weeks, 12 Weeks, 16 Weeks, No RBV No RBV + RBV No RBV Relapse Lawitz E, AASLD 2016, Oral

43 C-CREST Author s Conclusions MK3 (MK-3682/grazoprevir/ruzasvir) for 8 or 12 weeks was highly effective in GT1 patients (SVR12 = 97%) MK3 for 12 or 16 weeks was highly effective in GT2 patients (SVR12 = 98%) The addition of ribavirin did not increase SVR12 MK3 for 8, 12 or 16 weeks was highly effective in GT3 treatmentnaïve or treatment-experienced patients (SVR12 = 96%) The addition of ribavirin did not increase SVR12 Efficacy was maintained in GT3 treatment-experienced patients with cirrhosis (SVR12 = 99%) Treatment with MK3 was generally safe and well-tolerated Lawitz E, AASLD 2016, Oral

44 Salvage Therapy in DAA Experienced Patients

45 POLARIS 1 Trial Design Phase 3, global, multicenter, randomised, double-blind, placebo-controlled Wk 0 Wk 12 Wk 24 n=263 n=152 SOF/VEL/VOX Placebo SOF/VEL/VOX 12 weeks n=263 Placebo 12 weeks n=152 Mean age, years (range) 58 (27 84) 59 (29 80) Male, n (%) 200 (76) 121 (80) White, n (%) 211 (80) 124 (82) Mean BMI, kg/m 2 (range) 29 (18 67) 29 (18 61) Cirrhosis, n (%) 121 (46) 51 (34) Genotype, n (%) 1a / 1b / Other 101 (38) / 45 (17) / 4 (2) 117 (77) / 31 (20) / 2 (1) 2 5 (2) 3 78 (30) 4 22 (8) 5 / 6 / Unknown 1 (<1) / 6 (2) / 1 (<1) 0 / 2 (1) /0 Mean HCV RNA, log 10 IU/mL (range) 6.3 ( ) 6.3 ( ) Bourliere M, AASLD 2016, Oral 194

46 Patients, % Prior NS5A Treatment (%) LDV DCV OMB Other 3 patients received both LDV and DCV; DCV, daclatasvir; LDV, ledipasivir; OMB, ombitasvir. Bourliere M, AASLD 2016, Oral 194

47 SVR12, % SVR12 Results Overall and by Cirrhosis Status in POLARIS relapses 1 on-treatment failure** 2 withdrew consent 1 LTFU 1 withdrew consent 1 LTFU 6 relapses 1 on-treatment failure 1 withdrew consent 0 253/ / /121 Overall* No Cirrhosis Cirrhosis * p <0.001 for superiority compared with prespecified 85% performance goal for SOF/VEL/VOX ** Exposure was consistent with non-adherence Bourliere M, AASLD 2016, Oral 194

48 SVR12, % SVR12 Results by Genotype GT GT 1a GT 1b GT 2 GT 3 GT 4 GT 5 GT Bourliere M, AASLD 2016, Oral 194

49 POLARIS 4 Non-NS5A Inhibitor DAA- Experienced G1 4 Phase 3, global, multicenter, randomised, open-label study Wk 0 Wk 12 Wk 24 n=182 n=151 SOF/VEL/VOX SOF/VEL SOF/VEL/VOX 12 weeks n=182 SOF/VEL 12 weeks n=151 Mean age, y (range) 57 (25 85) 57 (24 80) Male, n (%) 143 (79) 114 (75) White, n (%) 160 (88) 131 (87) Mean BMI, kg/m 2 (range) 29 (18 45) 29 (18 53) Cirrhosis, n (%) 84 (46) 69 (46) 1a / 1b 54 (30) / 24 (13) 44 (29) / 22 (14) Genotype, n (%) 2 31 (17) 33 (22) 3 54 (30) 52 (34) 4 19 (10) Mean HCV RNA, log 10 IU/mL (range) 6.3 ( ) 6.3 ( ) Zeuzem S, AASLD 2016, Oral 109.

50 Patients, % POLARIS 4 Prior DAA Treatment SOF Other SOF+SMV Other Other NS5B NS5B + NS3 Other 2 5 Zeuzem S, AASLD 2016, Oral 109.

51 SVR12, % POLARIS 4 Overall SVR12 1 relapse 1 death 3 LTFU 1 breakthrough 14 relapses 177/ /151 SOF/VEL/VOX 12 weeks* SOF/VEL 12 weeks *p <0.001 for superiority compared with prespecified 85% performance goal for SOF/VEL/VOX Zeuzem S, AASLD 2016, Oral 109.

52 SVR12, % SVR12 Results by Cirrhosis Status No Cirrhosis n=180 Cirrhosis n=153 96/98 81/84 77/82 59/69 SOF/VEL/VOX 12 weeks SOF/VEL 12 weeks SOF/VEL/VOX 12 weeks SOF/VEL 12 weeks Zeuzem S, AASLD 2016, Oral 109.

53 SVR12, % POLARIS 4 SVR12 Results by Genotype SOF/VEL/VOX 12 weeks (n=182) SOF/VEL 12 weeks (n=151) X x x x X x x x X x x x X x x x X x x x GT 1a GT 1b GT 2 GT 3 GT 4 Zeuzem S, AASLD 2016, Oral 109.

54 C-SURGE 1 Trial Design This multicenter, open-label trial randomized 94 HCV GT1-infected patients who relapsed after a regimen of LDV/SOF or EBR/GZR (randomized 1:1; stratified by GT1a/1b and cirrhosis) SVR12* 1 Endpoint MK GZR + RZR + RBV (16 weeks), n=45 MK GZR + RZR (24 weeks), n=49 D1 TW8 TW16 TW24 FW12 MK-3682: 450 mg once-daily; GZR: 100 mg once-daily; RZR: 60 mg once-daily *SVR12 = HCV RNA <15 IU/mL at 12 weeks after end of treatment (COBAS AmpliPrep/COBAS Taqman HCV Test, v2.0 ) RBV dose based on body weight (<65 kg=800 mg/d; kg=1000 mg/d; > kg=1200 mg/d; >105 kg=1400 mg/d) Patients could be compensated cirrhotic (platelet cutoff=75,000/μl; excluded Child-Pugh B & C) or non-cirrhotic patients TW= treatment week; FW=follow-up week Wyles D et al, AASLD 2016, Oral.

55 Percent of Patients with HCV RNA <15 IU/mL C-SURGE 1 Efficacy (Full Analysis Set*) Weeks + RBV 24 Weeks without RBV TW4 SVR4 SVR TW = treatment week; SVR4 = % of patients with HCV RNA <15 IU/mL at 4 weeks after end of treatment; SVR8= % of patients with HCV RNA <15 IU/mL at 8 weeks after end of treatment *Full analysis set = all patients who received at least one dose of study medication. One patient from the 16-week + RBV arm withdrew from the study after taking 3 doses of study medication Wyles D et al, AASLD 2016, Oral.

56 SVR4 No Impact of Baseline NS5A or NS3 RAVs on SVR4 (Resistance Analysis Population) NS5A NS3 16 Weeks + RBV 24 Weeks 16 Weeks + RBV 24 Weeks PREVALENCE No RAVS 12/43 28% RAVs 31/43 72% 3/38 RAVs 35/38 92% No RAVS 19/43 44% RAVs 24/43 56% No RAVS 10/38 26% RAVs 28/38 74% 100% 80% 60% 40% 20% 0% 100% 100% 100% 100% 100% 100% 100% 100% Weeks + RBV 24 Weeks 16 Weeks + RBV 24 Weeks Patients without RAVs Patients with RAVs SVR4=proportion of patients with HCV RNA <15 IU/mL at 4 weeks after end of treatment. *RAVs detected by next-generation sequencing with 15% sensitivity; NS5A RAV: any change from wild-type at 4 positions (28, 30, 31, or 93); NS3 RAVs = any change from wild-type at 14 positions (36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, or 175). Excludes 1 patient from the 16-week group who withdrew after receiving 3 doses of study medication; Includes 38 of 49 patients who have reached follow-up week Wyles D et al, AASLD 2016, Oral.

57 Renal Failure Data finally a regimen for all genotypes!

58 EXPEDITION-IV: Glecaprevir/Pibrentasvir (G/P) in Adults with Renal Impairment and G1 6 Infection SVR12 (%) GT1 6 ± compensated cirrhosis TN or TE (IFN- or SOF-based regimens) egfr <30 ml/min/1.73 m 2 Demographics N=104 Treatment-experienced, IFN/pegINF + RBV / SOF + RBV +/- peginf, n (%) G/P 300/120 mg OD (N=104) 42 (40) / 2 (2) Compensated cirrhosis, n (%) 20 (19) Time (weeks) Phase 3 Single-arm Open-label HCV genotype, n (%) GT1a / GT1b / GT1 other GT2 GT3 GT4 / GT5 / GT6 CKD stage 4 / 5, n (%) egfr <15 ml/min/1.73 m 2, n (%) Dialysis, n (%) 23 (22) / 29 (28) / 2 (2) 17 (16) 11 (11) 20 (19) / 1 (1) / 1 (1) 13 (12) / 91 (88) 86 (83) 85 (82) Gane et al., AASLD 2016, Abstract #LB-11

59 Safety in EXPEDITION 4 G/P Event, n (%) N = 104 Any AE 74 (71) Serious AE 25 (24) Serious AE related to DAA * 0 AEs leading to study drug d/c 4 (4) Death 1 (1) AEs occurring in 10% of patients Pruritus 21 (20) Fatigue 15 (14) Nausea 12 (12) *As assessed by study physician AEs for 4 subjects were: 1)diarrhoea, 2) pruritis, 3) pulmonary oedema, hypertensive cardiomyopathy with congestive failure and 4) hypertensive crisis Patient who died experienced SAE of cerebral haemorrhage, not related to study drug, at post-treatment week 2 Event, n (%) Haemoglobin Grade 3 (< g/dl) AST Grade 2 (>3 20 ULN) ALT Grade 2 (>3 20 ULN) Total bilirubin Grade 3 (>3 10 ULN) G/P N = (5) (1) Gane et al., AASLD 2016, Abstract #LB-11

60 In Summary Harvoni 8 weeks in treatment naïve G1 co-infected patients appears efficacious We can use current drugs in novel ways (cost permitting) Most if not all non-cirrhotics will be treated for 8 weeks with the newer regimens Selected treatment naïve cirrhotics may also be candidates for 8 weeks of treatment Salvage therapy even with NS5A RAS will be possible in the near future, although cirrhotics may still need ribavirin There is now data for the management of renal failure patients regardless of genotype

61 Acknowledgements Abbvie Rashpal Sohal BMS Pandora Jacquemet Gilead Kate Dorrington MSD - Pari Skamnioti

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