Treatments of Genotype 2, 3,and 4: Now and in the future

Transcription

1 Treatments of Genotype 2, 3,and 4: Now and in the future THERAPY FOR THE TREATMENT OF GENOTYPE 2 Copyright 215 American College of Gastroenterology 1

2 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 8 mg/d for PEG-IFN+RBV 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: FISSION SVR 12 for Genotype 2: TREATMENT NAIVE SOF/RBV 12 wks PEG/RBV 24 wks Overall No cirrhosis Cirrhosis Lawitz E, et al. N Engl J Med. 213; 368: Copyright 215 American College of Gastroenterology 2

3 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 4 mg QD; RBV dose 12 mg/d 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 SOF/RBV 12 wks 96 SOF/RBV 16 wks Overall No cirrhosis Cirrhosis Nelson et al. EASL 213 Amsterdam Copyright 215 American College of Gastroenterology 3

4 SOF + RBV for 12 Weeks: SVR12 in Interferon- Intolerant, Ineligible or Unwilling Patients (POSITRON) 94.5 Genotype SVR12 (%) /92 16/17 91 No Cirrhosis Cirrhosis Lawitz et al., N Engl J Med 213, 368: 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 Pts with GT2 or GT3 HCV and previous treatment failure with P/R (N = 47) SOF 4 mg QD + PegIFN wkly + RBV mg or 12 mg Lawitz E, et al. AASLD 213. Abstract LB-4. Wk 12 (%) SVR n/n = 96 GT2 All 93 GT2 F4 22/23 13/14 9/9 GT2 F-3 Copyright 215 American College of Gastroenterology 4

5 FUTURE THERAPY FOR GENOTYPE 2 Treatment of Naïve Genotype 2 with Sofosbuvir + Daclatasvir (NS5A): 24 weeks Not FDA approved SVR (%) 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: Copyright 215 American College of Gastroenterology 5

6 SOF + GS-5816 for 12 weeks in Treatment- Naive Non-cirrhotic Patients With GT2 Open-label phase II study N = 154 patients t randomized d to 12 wks of SOF + GS mg or mg/day GS-5816: investigational NS5A inhibitor 8 91 SOF + GS mg SOF + GS-5816 mg SVR12 (%) n/n = 1/11 1/1 Genotype 2 Everson GT, et al. EASL 214. Abstract O111. RETREATMENT OF GENOTYPE 2 SOFOSBUVIR FAILURES Copyright 215 American College of Gastroenterology 6

7 Retreatment of Genotype 2 SOF/RBV Failures G G 2 2 PEG/SOF/R 12 SOF/R 24 wks wks N= 4 n=2 Esteban et al. EASL 214 Abstract 8 Treatment of HIV/HCV: The Photon Study: Genotype 2 SOF/RBV for 12 weeks Patients wit th HCV RNA <LLOQ (%) /26 25/26 22/23 22/23 23/26 23/26 23/26 23/26 24/24 24/24 23/23 23/23 22/24 22/24 22/24 22/24 Week 4 EOT SVR12 SVR24 Week 4 EOT SVR12 SVR24 Treatment Naïve 12 Weeks SOF + RBV Treatment Experienced Sulkowski MS, et 24 al. Weeks AASLD 213. SOF + Washington, RBV DC. Oral #212 Copyright 215 American College of Gastroenterology 7

8 Treatment of HIV/HCV: The Photon Study: Genotype 2 SOF/RBV for 12 weeks Patients wit th HCV RNA <LLOQ (%) /26 25/26 22/23 22/23 23/26 23/26 23/26 23/26 24/24 24/24 23/23 23/23 22/24 22/24 22/24 22/24 Week 4 EOT SVR12 SVR24 Week 4 EOT SVR12 SVR24 Treatment Naïve 12 Weeks SOF + RBV Treatment Experienced Sulkowski MS, et 24 al. Weeks AASLD 213. SOF + Washington, RBV DC. Oral #212 AASLD/IDSA Guidance Recommendations: Treatment Naïve and Relapse: Genotype 2 Daily sofosbuvir 4 mg and weight based RBV for 12 weeks [Class 1, level l A] Extending sofosbuvir 4 mg and weight based RBV is recommended in patients with cirrhosis [Class 2b, level C] AASLD/IDSA Guidance Document December 21, 214 Copyright 215 American College of Gastroenterology 8

9 Regimens NOT Recommended for Treatment Naïve and Relapse Genotype 2 Patients PEG-IFN/RBV for 24 weeks Telaprevir, boceprevir or ledipasvir containing regimens Monotherapy with PEG-IFN, RBV or DAA AASLD/IDSA Guidance Document December 21, 214 THERAPY FOR GENOTYPE 3 Copyright 215 American College of Gastroenterology 9

10 FISSION SVR 12 for Genotype 3: TREATMENT NAIVE SOF/RBV 12 wks PEG/RBV 24 wks Overall No cirrhosis Cirrhosis Lawitz E, et al. N Engl J Med. 213; 368: FUSION SVR 12 for Genotype 3: TREATMENT EXPERIENCED SOF/RBV 12 wks SOF/RBV 16 wks Overall No cirrhosis Cirrhosis Nelson et al. EASL 213 Amsterdam Copyright 215 American College of Gastroenterology 1

11 SOF + RBV for 12 Weeks: SVR12 in Interferon- Intolerant, Ineligible or Unwilling Patients (POSITRON) SVR12 (%) 8 Genotype / 84 3/14 No Cirrhosis Cirrhosis Lawitz et al., N Engl J Med 213, 368: VALENCE: Sofosbuvir and Ribavirin for HCV GT 3 Week GT 3 Sofosbuvir + RBV (n = 25) SVR12 Original Study Protocol: Placebo versus 12 weeks treatment for GT 2 and 3. Amended Protocol: GT3 treatment extended from 12 to 24 weeks; Placebo arm offered alternative treatment Drug Dosing Sofosbuvir 4 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. N Engl J Med. 214 May 4. [Epub ahead of print] Copyright 215 American College of Gastroenterology 11

12 VALENCE: 24 Wks SOF + RBV in GT 3 Patients SVR12 (%) /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. N Engl J Med. 214 May 4. [Epub ahead of print] 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 8 SVR12 (%) n/n = 14/ 38 25/ 4 No Cirrhosis 87/ Genotype / 26 14/ 23 Cirrhosis 27/ 45 Jacobson IM, et al. N Engl J Med. 213;368: Zeuzem S, et al. N Engl J Med. 214 Copyright 215 American College of Gastroenterology 12

13 SOF + RBV for 12 vs 24 Weeks: SVR12 in HCV/HIV Coinfected Patients Based on Genotype SVR12 (%) GT 1 GT 2 GT /114 23/26 22/24 Treatment Naive, 24 Weeks Treatment Naive, 12 Weeks Treatment Experienced, 24 Weeks 28/42 Treatment Naïve, 12 Weeks 16/17 Treatment Experienced, 24 Weeks Sulkowski MS, et al. JAMA. 214;312: New DAA Regimens For Genotype 3 Copyright 215 American College of Gastroenterology 13

14 Variable EC5 s for NS5A Inhibitors Against Genotype 3 EC5 (nm) in replicons Drug 1a 1b 3a 4a Daclatasvir Ledipasvir GS MK ACH <.2 <.2 IDX Gao M, Current Opinion in Virology 213;3:514-2 ALLY-3: Study Design GT 3 Treatment-naive N = 11 Treatment-experienced N = 51 DCV 6 mg + SOF 4 mg QD DCV 6 mg + SOF 4 mg QD Follow-up Day 1 Week 12 Week 24 Week 36 SVR12 Primary endpoint: 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 a Nelson et al. AASLD Copyright 215 American College of Gastroenterology 14

15 SVR12: Primary Endpoint Treatment-naive Treatment-experienced SVR12, % a,b a HCV RNA < LLOQ (25 IU/mL); error bars reflect 95% confidence intervals. b Patients with missing HCV RNA measurements at posttreatment Week 12 counted as treatment failures. 29 SVR12 in Patients With Cirrhosis or FibroTest F SVR12, % a Absent Present F-F3 F4 Cirrhosis b FibroTest c a HCV RNA < LLOQ (25 IU/mL); error bars reflect 95% confidence intervals. b Cirrhosis determined by liver biopsy (METAVIR > F3), FibroScan (> 14.6 kpa), or FibroTest score.75 and aspartate aminotransferase to platelet ratio index > 2. c FibroTest assessments could have been performed up to Day 1 (baseline). Nelson et al AASLD Copyright 215 American College of Gastroenterology 15

16 Ledipasvir/Sofosbuvir ± RBV 12 Weeks for Treatment-naïve Noncirrhotic G3 SVR12 (%) /25 26/26 LDV/SOF LDV/SOF/RBV Gane E.J, et al. Presented at: EASL; 214; London. Abstract O6. Efficacy of LDV/SOF Regimens for 12 Weeks for Treatment Experienced Genotype 3 SVR12 rates Patients (%) /5 25/28 16/22 Overall No cirrhosis Cirrhosis Gane EJ et al, AASLD 214, LB-11 Copyright 215 American College of Gastroenterology 16

17 Once-daily SOF With GS-5816 for 8 Weeks ± RBV in Treatmentnaive G3 Non-cirrhotics: ELECTRON-2 Study SVR12% SOF + 27/27 21/24 26/27 26/ mg mg + RBV 5816 mg 5816 mg+rbv Background Sofosbuvir (SOF) 1,2 Potent antiviral activity against HCV GT 1 6 Once-daily, oral, 4-mg tablet SOF Nucleotide polymerase inhibitor GS Picomolar potency against HCV GT 1 6 PK supports once-daily dosing GS-5816 NS5A inhibitor SOF + GS Treatment for 12 weeks resulted in high SVR in treatment-naïve patients with HCV GT 1 6 without cirrhosis SOF + GS Jacobson IM, et al. New Engl J Med 213;368: ; 2. Lawitz E, et al. New Engl J Med 213;368: ; 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 Everson G, et al. EASL 214, oral presentation. 3 Copyright 215 American College of Gastroenterology 17

18 Results: SVR12 after 12 weeks of therapy Treatment-Experienced GT 3 Without Cirrhosis SVR12 (%) GS-5816, mg RBV 22/ /28 27/27 26/ Error bars represent 95% confidence intervals. 35 Results: SVR12 after 12 weeks of therapy Treatment-Experienced GT 3 With Cirrhosis SVR12 (%) GS-5816, mg RBV 15/ /25 23/26 25/ Error bars represent 95% confidence intervals. 36 Copyright 215 American College of Gastroenterology 18

19 Sofosbuvir + Daclatasvir (NS5A): 24 weeks SVR (%) 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: AASLD/IDSA Guidance Recommendations: Treatment Naïve and Relapse: Genotype 3 Daily sofosbuvir 4 mg and weight based RBV for 24 weeks [Class 1, level l A] AASLD/IDSA Guidance Document December 21, 214 Copyright 215 American College of Gastroenterology 19

20 AASLD/IDSA Guidance Alternate Treatment Recommendations: Treatment Naïve and Relapse: Genotype 3 Daily sofosbuvir 4 mg and weight based RBV plus PEG-IFN for 12 weeks [Class 1, level B] AASLD/IDSA Guidance Document December 21, 214 Regimens NOT Recommended for Treatment Naïve and Relapse: Genotype 3 Patients PEG-IFN/RBV for weeks Telaprevir, boceprevir or ledipasvir containing regimens Monotherapy with PEG-IFN, RBV or DAA AASLD/IDSA Guidance Document December 21, 214 Copyright 215 American College of Gastroenterology 2

21 Daclatasvir for Genotype 3: EU Approval 8/27/214 Regimen Treatment Duration Treatment experienced DAC/SOF/RBV 24 weeks Compensated cirrhosis DAC/SOF/RBV 24 weeks THE TREATMENT OF GENOTYPE 4 Copyright 215 American College of Gastroenterology 21

22 Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 4,5,6 NEUTRINO Trial: Results Patie ents with SVR 12 (%) NEUTRINO: SVR 12 by Genotype /292 27/28 7/7 GT 1 GT 4 GT 5,6 GT = genotype Lawitz E, et al. N Engl J Med. 213;368: FUTURE THERAPY FOR GENOTYPE 4 Copyright 215 American College of Gastroenterology 22

23 Sofosbuvir + Ledipasvir for Genotype 4: NIAID SYNERGY Trial Patients <LLOQ (%) * 9 95 * 95 95** 15/21 19/21 2/21 2/21 19/2 Week 4 Week 8 Week 12 EOT *1 dropout, counted as failure in ITT SVR4 ** 1 pending SVR12 Kapoor R, et al. AASLD 214, Boston. #24 Copyright 215 American College of Gastroenterology 23

24 Treatment Options for GT4 HCV SYNERGY: SOF/LDV x 12 Wks [1] PEARL-I: Paritaprevir/RTV/Ombitasvir ± RBV x 12 Wks [2] 91 8 < LLOQ (%) 6 4 SVR12 (%) /21 19/2 SVR4 SVR12 2 n/n = 4/ 44 2 DAAs Naive Pts 42/ 42 2 DAAs + RBV 49/ 49 2 DAAs + RBV P/R Failure 1. Kapoor R, et al. AASLD 214. Abstract Pol S, et al. AASLD 214. Abstract Copyright 215 American College of Gastroenterology 24

25 DCV/ASV/ for 12 weeks in genotype 4, naïve patients Regimen # of patients On treatment End of treatment SVR 12 week 2 viral viral loss loss DCV 3 11 % % % mg/asv 2mg/BMS mg BID DCV 3 1 % % % mg/asv 2mg/BMS Daclatasvir 15 mg NS5a inhibitor BID Asunaprevir NS3 protease inhibitor BMS non-nucleotide polymerase inhibitor Hassanein et al. EASL 214 AASLD/IDSA Guidance Recommendations: Treatment Naïve and Relapse: Genotype 4 Daily fixed dose combination ledipasvir 9 mg/sofosbuvir 4 mg for 12 weeks [Class 2b, level B] Daily fixed dose combination of paritaprevir 15 mg/ritonavir mg/ ombitasvir 25 mg and weight based RBV for 12 weeks [Class 1, level B] Daily sofosbuvir 4 mg plus and weight based RBV for 24 weeks [Class 2a, level B] AASLD/IDSA Guidance Document December 21, 214 Copyright 215 American College of Gastroenterology 25

26 AASLD/IDSA Guidance Alternate Treatment Recommendations: Treatment Naïve and Relapse: Genotype 4 Daily sofosbuvir 4 mg and weight based RBV plus PEG-IFN for 12 weeks [Class 2, level B] Daily sofosbuvir 4 mg plus simeprevir 15 mg for 12 weeks AASLD/IDSA Guidance Document December 21, 214 Regimens NOT Recommended for Treatment Naïve and Relapse: Genotype 4 Patients PEG-IFN/RBV with or without simeprevir for weeks Telaprevir or boceprevir based regimens Monotherapy with PEG-IFN, RBV or DAA AASLD/IDSA Guidance Document December 21, 214 Copyright 215 American College of Gastroenterology 26

27 Daclatasvir for Genotype 4: EU Approval 8/27/214 Regimen Duration Options No cirrhosis SOF/DAC 12 weeks Consider 24 weeks if previously treated Compensated cirrhosis Compensated cirrhosis/non- cirrhotics SOF/DAC 24 weeks Consider 12 weeks for untreated patients of those with CC and/or low baseline viral load PEG/RBV/DAC 24/48 If HCV-RNA negative at week 4 weeks and 12, 24 weeks of therapy If HCV-RNA positive at either week 4 or 12, additional 24 weeks of PEG/RBV Summary of Treatments for Genotype 2, 3,and 4 Now G2 SOF/RBV G3 SOF/RBV G4 PEG/RBV/SOF Future G2 SOF/DAC SOF/GS5816 SOF/LDV G3 PEG/RBV/SOF SOF/LDV + RBV SOF/DAC ABT-45/R/Ombitasvir + RBV SOF/GS-5816 G4 SOF/LDV DAV/ASV/BMS Copyright 215 American College of Gastroenterology 27