Treatment of Genotype 2, 3,and 4 David E. Bernstein, MD, FACG Advisory Committee/Board Member: AbbVie Pharmaceuticals, Gilead, Merck, Janssen Consultant: AbbVie Pharmaceuticals, Bristol-Myers Squibb, Gilead, Janssen Grant/Research Support: AbbVie Pharmaceuticals, Bristol-Myers Squibb,, Gilead, Janssen, Merck Speakers Bureau: AbbVie Pharmaceuticals, Gilead TREATMENT OF GENOTYPE 2 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 1
GT 2 and GT 3 Treatment-Naïve: SOF+RBV vs PEG-IFN+RBV FISSION Study Design HCV GT 2 and GT 3 Treatment-naïve N=499 Stratified by HCV genotype, HCV RNA, and cirrhosis Randomized 1:1 Study Week SOF + RBV*, n=256 SVR12 *RBV dose 12 mg/d PEG-IFN + RBV (SOC), n=243 SVR12 mg/d for PEG-IFN+RBV 12 24 36 No response guided therapy HCV RNA analyzed by COBAS TaqMan HCV Test v2. HPS, with LLOQ of 25 IU/mL Lawitz E, et al. N Engl J Med. 213; 368: 1878-1887 FISSION SVR 12 for Genotype 2: TREATMENT NAIVE SOF/RBV 12 wks 97 98 82 78 PEG/RBV 24 wks 91 62 2 Overall No cirrhosis Cirrhosis Lawitz E, et al. N Engl J Med. 213; 368: 1878-1887 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 2
FUSION STUDY: Genotype 2 and 3 Treatment Experienced HCV GT 2 and GT 3 Treatmentexperienced N=21 Stratified by HCV genotype and cirrhosis Randomized 1:1 Study Week SVR12 SOF + RBV, n=13 Placebo SVR12 SOF + RBV, n=98 SOF dose mg QD; RBV dose 12 mg/d 12 16 24 28 No response guided therapy HCV RNA analyzed by COBAS TaqMan HCV Test v2. HPS, with LLOQ of 25 IU/mL Nelson DR, et al. EASL 213. Amsterdam, The Netherlands. Oral #6 Jacobson IM, et al. N Engl J Med. 213 Apr 23 FUSION SVR 12 for Genotype 2: TREATMENT EXPERIENCED 86 94 SOF/RBV 12 wks 96 SOF/RBV 16 wks 78 2 Overall No cirrhosis Cirrhosis Jacobson et al. NEJM 213,368:1867-77 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 3
LONESTAR-2: Sofosbuvir + P/R for 12 Wks in Treatment-Exp d GT2/3 HCV Pts Single-arm trial of pts with treatment failure on P/R Approximately 5% with compensated cirrhosis Wk 12 Pts with GT2 or GT3 HCV and previous treatment failure with P/R (N = 47) SOF mg QD + PegIFN wkly + RBV mg or 12 mg SVR12 (%) 96 93 Lawitz E, et al. AASLD 213. Abstract LB-4. 2 n/n = 22/23 13/14 9/9 GT2 All GT2 F4 GT2 F-3 Treatment of Naïve Genotype 2 with Sofosbuvir + Daclatasvir (NS5A): 24 weeks 98 96 92 89 SVR (%) 2 126 41 41 18 GT 1 Naive GT 1 Experienced GT 2 GT 3 GT 3: 1 lost to f/u 1 viral failure Sulkowski M et al. N Engl J Med. 214;37:211-21. ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 4
NEW THERAPIES ON THE HORIZON FOR GENOTYPE 2 Sofosbuvir + Velpatasvir for G2 Sofosbuvir (SOF) 1,2 Potent antiviral activity against HCV GT 1 6 Once-daily, oral, -mg tablet SOF Nucleotide polymerase inhibitor Velpatasvir 3-5 Picomolar potency against HCV GT 1 6 PK supports once-daily dosing GS-5816 NS5A inhibitor SOF + Velpatasvir 6 Treatment for resulted in high SVR in treatment-naïve patients with HCV GT 1 6 without cirrhosis SOF + GS-5816 1. Jacobson IM, et al. New Engl J Med 213;368:1867-77; 2. Lawitz E, et al. New Engl J Med 213;368:1878-87; 3. Cheng G, et al. EASL 213, poster 1191; 4. German P, et al. EASL 213, poster 1195; 5. Lawitz E, et al. EASL 213, poster 182. 6. Everson G, et al. EASL 214, oral presentation. 3 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 5
Astral 1: Velpatasvir (NS5A) + SOF for - Genotype 2, 4, 5 and 6 97 SVR 2 14/14 116/116 41/41 34/35 GT 2 GT 4 GT 5 GT 6 Feld et al. AASLD 215 Abstract LB-2 SVR Astral 2: Velpatasvir (NS5A) + SOF for in Genotype 2 14% cirrhosis 2 99 94 133/134 SOF/VEL 14% PEG/RBV treatment experienced 1 patient in the SOF/VEL took 1 dose and stopped due to 124/132 dizzyness SOF/RBV Sulkowski et al. AASLD 215 Abstract 25 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 6
HCV NS3/4A inhibitor mg once daily, oral HCV NS5A inhibitor 5 mg once daily, oral Grazoprevir (MK-5172) Elbasvir (MK-8742) Broad in vitro activity against most HCV genotypes 1-3 Retains in vitro activity against many clinically relevant RAVs 1-3 All-oral, once-daily regimen 1. Summa V, et al. Antimicrobial Agent Chemother. 212:56; 4161-67. 2. Coburn CA, et al. ChemMedChem. 213:8; 193. 3. Harper S, et al. ACS Med Chem Lett. 212:Mar 2; 3(4):332-6. C-Crest: Grazoprevir/MK-3682 (NS5B) + either elbasvir or MK-88 (NS5A) for 9 86 69 71 95 91 94 91 SVR 2 GZR/EBR/3682 3 mg GZR/EBR/3682 45 mg GZR/88/3682 3 mg GZR/88/3682 45 mg GT 1 GT 2 GT 3 Gane et al. AASLD 215 Abstract LB-15 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 7
Recommendations for Genotype 2 Treatment Population Recommended Regimen Duration Treatment naïve noncirrhosis RBV -12 mg/day Sofosbuvir mg + Sofosbuvir mg + Treatment naïve cirrhosis Ribavirin -12 mg/day 16 weeks Treatment naïve (noncirrhosis and cirrhosis Treatment experienced (PEG-IFN/RBV) Treatment experienced (PEG-IFN/RBV) Treatment experienced (Sofosbuvir + RBV) Daclatasvir mg + sofosbuvir mg Sofosbuvir mg + Ribavirin -12 mg/day Sofosbuvir mg + Ribavirin -12 mg/day + PEG-IFN Dacalatasvir mg + sofosbuvir + RBV http://www.hcvguidelines.org/full-report/initial-treatment-hcv-infection-patients-starting-treatment accessed 11/25/215. 16-24 weeks 24 weeks THERAPY FOR GENOTYPE 3 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 8
GT 3 Is Associated With a Significantly Higher Risk of Cirrhosis and HCC vs GT 1 VA HCV Clinical Case Registry (2-29) 88,348 patients with genotype 1 (%) 13,77 genotype 2 (12%) 8,337 genotype 3 (7.5%) Mean follow-up 5.4 years After adjustment for demographic, clinical and antiviral treatment factors, comparison between genotypes 3 and 1 Hazard Ratio Confidence Interval Cirrhosis 1.31 1.22-1.39 HCC 1. 1.61-2.3 Conclusion: GT 3 is associated with a significantly higher risk of cirrhosis and HCC vs GT 1, independent of age, diabetes, BMI or antiviral treatment Kanwal F et al, Hepatology 214;:98-15 Treatment of Genotype 3 Fission Naive SOF/RBV 12 wks PEG/RBV 24 wks Fusion Treatment Experienced SOF/RBV 12 wks SOF/RBV 16 wks 63 56 71 61 62 63 61 2 34 3 2 3 37 19 Overall No Cirrhosis cirrhosis Overall No Cirrhosis cirrhosis Lawitz E, et al. N Engl J Med. 213; 368: 1878-1887 Jacobson et al. NEJM 213,368: 1867-77 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 9
VALENCE: Sofosbuvir and Ribavirin Week 12 24 36 GT 3 Sofosbuvir + RBV (n = 25) SVR12 Original Study Protocol: Placebo versus treatment for GT 2 and 3. Amended Protocol: GT3 treatment extended from 12 to 24 weeks; Placebo arm offered alternative treatment Drug Dosing Sofosbuvir mg once daily Ribavirin (weight-based and divided bid): mg/day if < 75 kg or 12 mg/day if 75 kg Zeuzem S, et al. NEJM 214;37:1993-21 VALENCE: 24 Wks SOF + RBV in GT 3 Patients 85 94 92 87 SVR12 (%) 2 212/25 86/92 12/13 87/ 27/45 Overall Naive, Naive, Experienced, Experienced, Non-cirrhotic Cirrhotic Non-cirrhotic Cirrhotic Extending treatment duration to 24 weeks did not significantly increase the incidence of AEs Zeuzem S, et al. NEJM 214;37:1993-21 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 1
Impact of Duration on Efficacy of SOF in Treatment-Experienced GT3 Pts 87 FUSION: 12 wks of SOF/RBV FUSION: 16 wks of SOF/RBV VALENCE: 24 wks of SOF/RBV SVR12 (%) 37 63 61 2 n/n = 14/ 38 25/ No Cirrhosis 87/ 19 5/ 26 14/ 23 Cirrhosis 27/ 45 Genotype 3 Jacobson IM, et al. N Engl J Med. 213;368:1867-1877. Zeuzem S, et al. N Engl J Med. 214 Genotype 3: ALLY-3 Study Design Treatment-naive N = 11 Treatment-experienced N = 51 DCV mg + SOF mg QD DCV mg + SOF mg QD Follow-up Day 1 Week 12 Week 24 Week 36 Primary endpoint: SVR12 SVR12 Eligible patients Age 18 years with chronic GT 3 infection and HCV RNA 1, IU/mL Treatment-naive or -experienced (prior treatment failures), including patients with cirrhosis Those who received prior treatment with NS5A inhibitors were excluded Nelson et al. Hepatology 215; 61:1127-35 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 11
DCV/SOF for GT 3: SVR12 in Treatment-naïve and Treatmentexperienced patients Treated for 12 Weeks (ALLY-3) 9 86 SVR12 (%) 2 91/11 44/51 Treatment-naive Treatment-experienced Nelson DR, Hepatology 215; 61: 1127-1135 SVR12 in Patients With and Without Cirrhosis Treated for 12 Weeks (ALLY-3) Overall Tx-naive Tx-experienced SVR12 (%) 96 97 94 63 58 69 2 No Yes No Yes No Yes Cirrhosis Nelson DR, Hepatology 215; 61: 1127-1135 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 12
Sofosbuvir plus Daclatasvir with and without ribavirin in genotype 3: European Experience SVR Interim analysis of 82 patients in cohort of 12 2 86 88 88 86 SOF/DCV SOF/DCV/RBV Overall Cirrhosis Treatment duration: 24 weeks Includes: Cirrhotics Post-OLT Welzel et al. AASLD 215 Abstract 37 SVR Daclatasvir/Sofosbuvir + RBV for genotype 3 F3 and F4 patients: The French Compassionate Study 96 F3 Results 81 2 DCV/SOF DCV/SOF/RBV 12 week 24 week Hezode et al. AASLD 215. Abstract 26 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 13
Daclatasvir/Sofosbuvir + RBV for genotype 3 F3 and F4 patients: The French Compassionate Study F4 Results 69 85 81 SVR 2 DCV/SOF 4/4 DCV/SOF/RBV 12 week 24 week Hezode et al. AASLD 215. Abstract 26 Daclatasvir/Sofosbuvir + RBV for genotype 3 F3 and F4 patients: The French Compassionate Study Results by Childs Class 9 84.8 7 7 SVR 2 33 DCV/SOF DCV/SOF/RBV Childs A Childs B Hezode et al. AASLD 215. Abstract 26 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 14
ALLY 3+ :DCV + SOF + RBV in GT 3 and advanced fibrosis and cirrhosis 9 92 88 83 89 88 86 SVR 2 2 N=24 N=26 Overall 12 week 16 week F 3 F 4 TE cirrhosis 12 wk 16 wk Leroy et al. AASLD 215 Abstract LB-3 SOF/LDV with or without RBV for G3 16 patients, open label 82 Naïve: 2% cirrhosis i 64 2 TE: 44% cirrhosis 12 week treatment Gane et al. Gastro 215;149:1454-61 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 15
SOF+PEG/RBV x 12 Wks vs SOF+RBV x 24 Weeks: SVR12 in GT 3 Patients By Subgroup (BOSON Study) SOF + RBV 16 weeks SOF + RBV 24 weeks SOF + PEG/RBV 83 96 9 82 91 94 82 76 57 77 86 SVR12 (%) 47 2 58 7 Foster et al., Gastro 215; 149: 1462-7 65 72 68 71 12 18 21 41 44 94/112 83/ 1/11 21 22 23 54 54 TN No no Cirrhosis cirrhosis TN Cirrhosis cirrhosis TE No no Cirrhosis cirrhosis TE Cirrhosis cirrhosis Treatment Naïve 49 52 17 36 26 34 Treatment Experienced 3 35 NEW THERAPIES ON THE HORIZON FOR GENOTYPE 3 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 16
Study Design ASTRAL-3 Week 12 24 36 n=25 SOF/VEL SVR12 n=25 SOF + RBV SVR12 Open-label, active-comparator trial Broad inclusion criteria 1:1 randomization to SOF/VEL or SOF + RBV Stratified by prior treatment (TN/TE) and cirrhosis (presence/absence) Conducted at 76 sites in US, Canada, UK, Germany, France, Italy, Australia, and New Zealand Mangia et al AASLD 215 33 Results: SVR12 ASTRAL-3 p <.1* 95 SVR12 (%) 2 264/277 221/275 SOF/VEL 12 Weeks SOF + RBV 24 Weeks *p-value for superiority of SOF/VEL compared with SOF+ RBV. Error bars represent 95% confidence intervals. 34 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 17
Results: SVR12 by Cirrhosis and Treatment History ASTRAL-3 SOF/VEL SOF + RBV 98 93 91 9 89 73 71 58 SVR12 (%) 2 1 163 No 141 156 43 Yes 33 45 31 34 No 22 31 33 37 Yes 22 38 Cirrhosis Treatment Naïve Treatment Experienced Error bars represent 95% confidence intervals. 35 C-Crest: Grazoprevir/MK-3682 (NS5B) + either elbasvir or MK-88 (NS5A) for 8 weeks 95 95 91 94 91 71 SVR 45 2 GZR/EBR+RBV for 12 wks GZR/88/3682 3 mg for 8 GZR/88/3682 45 mg for 8 wks GT 1 GT 2 GT 3 wks Gane et al. AASLD 215 Abstract LB-15 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 18
QUARTZ-II/III: Paritaprevir/r/Ombitasvir and sofosbuvir with and without RBV in genotype 3 for 91 2 9/9 1/11 No RBV RBV Shafran et al. AASLD 215. Abstract LB-16 SURVEYOR-II Part 1 (GT3): Study Design SURVEYOR-II is an open-label, multicenter phase 2 trial evaluating the safety and efficacy of co-administered ABT-493 and ABT-53, at varying doses, ± ribavirin (RBV), in patients with HCV GT2 or GT3 infection Day 1 Week 12 PT Week 24 Treatment period Post-treatment (PT) period n=3 n=3 a n=31 n=3 ABT-493 3 mg + ABT-53 12 mg ABT-493 2 mg + ABT-53 12 mg ABT-493 2 mg + ABT-53 12 mg + RBV b ABT-493 2 mg + ABT-53 mg ClinicalTrials.gov: NCT2243293. N=121. a Includes one patient who was incorrectly assigned to treatment in the GT2 cohort. b Daily dose of mg or 12 mg RBV dosed BID based on patient body weight being <75 kg or 75 kg. Kwo et al AASLD 215 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 19
SURVEYOR-II Part 1 (GT3): Per Protocol SVR12 Rates by Treatment* ABT-493 + ABT-53 3 mg + 12 mg *Excluding non-virologic failures. 2 mg + 12 mg 2 mg + 12 mg + RBV 2 mg + mg Kwo et al AASLD 215 Treatment Recommendations for Genotype 3 Population Recommended Regimen Duration Treatment naive Treatment naïve cirrhosis Treatment naïve Treatment naïve, IFN eligible Treatment experienced Treatment experienced non-cirrhosis Treatment ** not FDA experienced approved cirrhosis or SOF/RBV failure Sofosbuvir mg + Daclatasvir mg Sofosbuvir + daclatasvir mg with or without ribavirin Sofosbuvir mg + RBV -12 mg/day Sofosbuvir mg + pegifn + RBV -12 mg/day ** Sofosbuvir mg + pegifn + RBV -12 mg/day Sofosbuvir mg + Daclatasvir mg Sofosbuvir mg + daclatsavir mg plus RBV 24 weeks 24 weeks 24 weeks ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 2
TREATMENT OF GENOTYPE 4 Pearl-I GT4-Infected Treatment- Experienced Patients: ITT Efficacy Analysis Abbvie Technivie Package Insert July 29, 215 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 21
NEW THERAPIES ON THE HORIZON FOR GENOTYPE 4 44 C-Edge Naïve Study: SVR12 % 95% 92% 99% % % Patients, % 75% 5% 25% % 299/316 All Patients 144/157 129/131 18/18 GT1a GT1b GT4 8/1 GT6 Non-virologic failure 4 3 1 Breakthrough 1 1 Relapse 12 9 1 2 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 22
Grazeprevir + Elbasvir for for treatment naïve and TE cirrhotic patients Treatment n/n SVR Duration Genotype 4 6/6 % n/n SVR SVR Genotype 4 TE 16/18 wks 4/4 % Pooled data from 6 studies Jacobson et al. AASLD 215 Abstract 42 Astral 1: Velpatasvir (NS5A) + SOF for 12 weeks- Genotype 2, 4, 5 and 6 97 SVR 2 14/14 116/116 41/41 34/35 GT 2 GT 4 GT 5 GT 6 Feld et al. AASLD 215 Abstract LB-2 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 23
Treatment Recommendations for Genotype 4 Population Recommended Regimen Duration Treatment naive Paritaprevir/ritonavir/ombitasvir + RBV -12 mg/day Ledipasvir/sofosbuvir Sofosbuvir mg + RBV -12 mg/day Sofosbuvir mg + pegifn + RBV -12 mg/day 24 weeks AASLD/IDSA treatment recommendation acessed 11/25/215s. Treatment Recommendations for Genotype 4 Population Recommended Regimen Duration IFN/RBV treatment experienced Paritaprevir/ritonavir/ombitasvir + RBV -12 mg/day Ledipasvir/sofosbuvir Sofosbuvir mg + RBV -12 mg/day Sofosbuvir mg + pegifn + RBV -12 mg/day ** 24 weeks AASLD/IDSA treatment recommendations accessed 11/25/215 ACG 215 Nashville Hepatitis School Copyright 215 American College of Gastroenterology 24