New & Emerging Interferon‐Free, Direct‐Acting Antiviral Regimens for the Treatment of Hepatitis C: An Expert Review of Recent Clinical Data Sponsored for.

New & Emerging Interferon‐Free, Direct‐Acting Antiviral Regimens for the Treatment of Hepatitis C: An Expert Review of Recent Clinical Data Sponsored for CME credit by Rush University Medical Center Supported by independent educational grants from AbbVie, Boehringer Ingelheim and Janssen Therapeutics

Content Development Faculty
Paul Kwo, MD Professor of Medicine Medical Director, Liver Transplantation Indiana University Indianapolis, IN

Introduction

Chronic HCV in the US: Underdiagnosed and Untreated
4.1 M Unaware of Infection Number (in ‘000s) 38% Diagnosed 1.6 M Slide: Chronic HCV in the US: Underdiagnosed and Untreated Prior to and immediately after the approval of boceprevir and telaprevir, only 38% of patients with HCV infection were diagnosed, and HCV treaters managed only 5.5% of chronic HCV patients. These data underscore the fact that HCV in the United States has historically been underdiagnosed and undertreated. 5.5% Treated 89,000 Prevalence Diagnosed Treated Estimated treatment rate is based on Q2 and Q chart audits. Hepatitis C Monitor. Ipsos Healthcare.

Chronic HCV Undetected by Risk-Based Screening in Primary Care
Cross-sectional study ( ) of adult ( ≥18 years) patients in 4 large primary health care systems Among 209,076 patients who attended at least 1 medical appointment: 8.4% (17,464) had been tested for HCV, and 1115 cases were detected Risk factors for HCV positivity among identified cases Applying these risk factors to the entire cohort predicted that 6005 patients had HCV infection Undetected cases (4890) accounted for 81% of HCV infections Predictors of HCV positivity Adjusted odds ratio* Born Male gender Black Hispanic Elevated ALT Intravenous drug use 4.4 1.4 1.9 1.5 4.8 6.3 Slide: Primary Care Setting: HCV Persons Unidentified by Risk-Based Screening Yartel and colleagues estimated the proportion of anti-HCV-positive persons who may have been unidentified using risk-based screening by using electronic medical record data from a four-site retrospective study. In this cross-sectional study, data were collected from 209,076 persons who were >18 years of age. Of these persons, 8.4% were tested for HCV infection.1 The median follow-up was 5 months. A multiple imputation model was used to predict HCV results for patients not tested for HCV. The predicted HCV prevalence was 2.9% and based on identifying 1115 cases from HCV testing and an additional 4890 estimated HCV positive results from those not tested. These data suggest that 81% of the total HCV cases (identified and estimated) in this primary care setting were not identified using risk-based screening.1 Reference Yartel AK, Rein DB, Krauskopf K, et al. Hepatitis C Virus (HCV) antibody positivity and predictors among adult primary care patients: cross-sectional analysis of a multi-site retrospective cohort study. Hepatology. 2013;58(suppl 1):219A. Abstract 24. Yartel AK, et al. Hepatology. 2013;58(suppl 1):219A. Abstract 24.

HCV Screening Recommendations
Testing recommended at least once for persons born between 1945 and 1965 Others: Screen for risk factors and perform one-time testing if risk factors present Annual HCV testing recommended for persons who inject drugs and for HIV-seropositive men who have unprotected sex with men Periodic testing should be offered to other persons with ongoing risk factors for exposure to HCV AASLD and IDSA. Available at: Version March 21, 2014

Risk Factors That Should Prompt One-Time or Periodic Testing
Risk behaviors Injection drug use (current or ever, including only once) Intranasal illicit drug use Risk exposures Long-term hemodialysis (ever) Getting a tattoo in an unregulated setting Healthcare, emergency medical, and public safety workers after needle sticks, sharps, or mucosal exposures to HCV-infected blood Children born to HCV-infected women Prior recipients of transfusions or organ transplants, including persons who: Were notified that they received blood from a donor who later tested positive for HCV infection Received a transfusion of blood or blood components, or underwent an organ transplant before July 1992 Received clotting factor concentrates produced before 1987 Were ever incarcerated Other medical conditions associated with risk HIV infection Unexplained chronic liver disease and chronic hepatitis including elevated alanine aminotransferase levels AASLD and IDSA. Available at: Version March 21, 2014

Preferred Treatment Recommendations: Initial Therapy or Relapsed after Prior PR AASLD-IDSA
Genotype 1 IFN eligible IFN ineligible† Sofosbuvir + PR 12 weeks Sofosbuvir + simeprevir* ± RBV 12 weeks Genotype 2 Sofosbuvir + RBV 12 weeks Genotype 3 Sofosbuvir + RBV 24 weeks Genotype 4 IFN ineligible Genotype 5 or 6 PR: Pegylated interferon + Ribavirin. † Currently recommended only for patients who require immediate treatment. *For genotype 1a, baseline resistance testing for the Q80K polymorphism should be performed and alternative treatments considered if this mutation is present. Do not treat decompensated cirrhosis with PegIFN or simeprevir AASLD and IDSA. Available at: Version March 21, 2014

Alternative Treatment Recommendations: Initial Therapy or Relapsed after Prior PR AASLD-IDSA
Genotype 1 IFN eligible IFN ineligible† Simeprevir* 12 weeks + PR 24 weeks Sofosbuvir + RBV 24 weeks Genotype 2 None Genotype 3 Sofosbuvir + PR 12 weeks Genotype 4 IFN ineligible Simeprevir 12 weeks + PR weeks Genotype 5 or 6 PR 48 weeks PR: Pegylated interferon + Ribavirin. †Currently recommended only for patients who require immediate treatment. *Acceptable alternative for genotype 1b patients, or genotype 1a patients in whom the Q80K polymorphism is not detected before treatment. Do not treat decompensated cirrhosis with PegIFN or simeprevir AASLD and IDSA. Available at: Version March 21, 2014

Not Recommended as Therapy for Treatment-Naïve Patients AASLD-IDSA
Genotype 1 PR ± telaprevir or boceprevir for 24 or 48 weeks Monotherapy with PegIFN, RBV, or a DAA Genotype 2 PR for 24 weeks Telaprevir-, boceprevir-, or simeprevir-based regimens Genotype 3 PR for 24 or 48 weeks Genotype 4 Genotype 5 or 6 Telaprevir- or boceprevir-based regimens PR: Pegylated interferon + Ribavirin. Do not treat decompensated cirrhosis with PegIFN or simeprevir AASLD and IDSA. Available at: Version March 21, 2014

Preferred Treatment Recommendations: Partial or Null Response to Prior PR† AASLD-IDSA
Genotype 1 Prior PR Sofosbuvir + simeprevir ± RBV 12 weeks Prior PR-based triple therapy Sofosbuvir 12 weeks + PR weeks Genotype 2 Sofosbuvir + RBV 12 weeks Genotype 3 Sofosbuvir + RBV 24 weeks Genotype 4 Sofosbuvir + PR 12 weeks Genotype 5 or 6 PR: Pegylated interferon + Ribavirin. †Consideration should be given to postponing treatment, pending release of new drugs for patients with limited hepatic fibrosis (F 0-2) Do not treat decompensated cirrhosis with PegIFN or simeprevir AASLD and IDSA. Available at: Version March 21, 2014

Alternative Treatment Recommendations: Partial or Null Response to Prior PR† AASLD-IDSA
Genotype 1 Prior PR Sofosbuvir 12 weeks + PR weeks Sofosbuvir + RBV 24 weeks Simeprevir 12 weeks + PR 48 weeks* Prior PR-based triple therapy Sofosbuvir + RBV 24 weeks (IFN ineligible) Sofosbuvir + PR 24 weeks (IFN eligible) Genotype 2 None Genotype 3 Sofosbuvir + PR 12 weeks Genotype 4 IFN eligible IFN ineligible Simeprevir 12 weeks + PR weeks Genotype 5 or 6 PR 48 weeks PR: Pegylated interferon + Ribavirin. †Consideration should be given to postponing treatment, pending release of new drugs for patients with limited hepatic fibrosis (F 0-2). *For genotype 1a, baseline resistance testing for Q80K should be performed and alternative treatments considered if this mutation is present. Do not treat decompensated cirrhosis with PegIFN or simeprevir AASLD and IDSA. Available at: Version March 21, 2014

Not Recommended as Therapy for Patients with Partial or Null Response to Prior PR† AASLD-IDSA
Genotype 1 PR ± telaprevir or boceprevir Monotherapy with PegIFN, RBV, or a DAA Genotype 2 Genotype 3 PR ± any current protease inhibitor Genotype 4 PR ± any current HCV protease inhibitor Genotype 5 or 6 PR: Pegylated interferon + Ribavirin. Do not treat decompensated cirrhosis with PegIFN or simeprevir AASLD and IDSA. Available at: Version March 21, 2014

IFN-Free Regimens for Chronic HCV Infection

Rationale for IFN-Free Direct-Acting Antiviral Therapy for HCV
Drawbacks of IFN-based Therapy Challenging tolerability High percentage of patients are ineligible for IFN Long duration of therapy Low SVR rates compared to modern all-oral regimens PR: ~40-50% in treatment-naïve patients Triple therapy PR + boceprevir or telaprevir: ~70% Many patient-specific and virus-specific factors affecting eligibility or treatment response (Race, IL28B, cirrhosis, prior treatment, etc) Development of resistance Requires injection

Overview of DAAs NS3/4A NS5A NS5B Function Serine Protease
Core Envelope Glycoproteins Protease Serine Protease Helicase Serine Protease Cofactor Component of HCV Replicase RNA-dependent RNA polymerase NS3/4A NS5A NS5B Function Serine Protease Component of HCV Replication Complex RNA-dependent RNA polymerase Drugs Covalent Boceprevir Telaprevir Non-covalent Faldaprevir Simeprevir ABT-450 Asunaprevir MK-5172 Ledipasvir Daclatasvir Ombitasvir MK-8742 PPI-668 Nucleoside analogs Sofosbuvir Non-nucleoside BMS Dasabuvir Deleobuvir

Guide to Trials of Sofosbuvir ± Simeprevir
Patient characteristic Recommended (AASLD-IDSA) Supporting Trial Evidence Genotype Sofosbuvir + simeprevir ± RBV 12 weeks COSMOS (phase II) 1 IFN ineligible FISSION POSITRON (IFN ineligible) VALENCE Sofosbuvir + RBV 12 weeks/24 weeks 2/3 Sofosbuvir + RBV 12 weeks/24 weeks Failed prior PR FUSION

COSMOS: Simeprevir + Sofosbuvir ± RBV: Genotype1
No Cirrhosis (F0-F2) Prior PR Null-Responders F3-F4 Treatment-naive and Prior PR Null Responders Simeprevir + sofosbuvir No RBV With RBV Simeprevir + sofosbuvir 2 non-virological failures 2 relapses 1 relapse 96% 93% 93% 79% SVR12, % Patients SVR12, % Patients Slide: COSMOS Study: Interim Results With Simeprevir + Sofosbuvir + RBV In cohort 1, SVR rates ranged from 93% to 96% and from 79% to 93% with 12 and 24 weeks of therapy, respectively.1 In cohort 2, the SVR rates ranged from 93% to 100% regardless of prior exposure to pegIFN + RBV.1 In both cohorts, the addition of RBV did not appear to improve SVR response rates.1 Reference Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non -cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: The COSMOS study. Hepatology. 2013;58(suppl 1):73A. Abstract LB-3. ±RBV +RBV -RBV +RBV -RBV n=27 n=14 n=24 n=15 n=87 27 14 30 16 12 Weeks 24 Weeks Overall 12 weeks 24 Weeks Sulkowski M, et al. EASL International Liver Congress, Abstract O7. Jacobson IM, et al. Hepatology. 2013;58(suppl 1):73A. Abstract LB-3.

FISSION Trial: Sofosbuvir + RBV: GT2 &3
Genotype 2 Genotype 3 Sofosbuvir + RBV PR Sofosbuvir + RBV PR 98% 91% 82% 71% 62% 61% SVR12, % Patients SVR12, % Patients 34% Slide: FISSION Trial: SVR12 Rates by Genotype and Cirrhosis Among patients receiving sofosbuvir + ribavirin, genotype 2 infection and an absence of cirrhosis were strongly associated with high SVR rates compared with genotype 3 patients and patients receiving peginterferon + ribavirin.1,2 References Gane E, Lawitz E, Rodriquez-Torres M, et al. Phase 3 randomized controlled trial of all-oral treatment with sofosbuvir+ribavirin for 12 weeks compared to 24 weeks of peg+ribavirin in treatment-naïve Gt2/3 HCV-infected patients (FISSION). J. Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368: 30% n=59 n=54 n=11 n=13 n=145 n=139 n=38 n=37 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:

POSITRON: Sofosbuvir + RBV for 12 Weeks
Genotype 2 Genotype 3 94% 92% 68% SVR12 (%) Patients (%) Slide: POSITRON Trial: SVR12 Rates With Sofosbuvir + RBV by Genotype and Cirrhosis Among patients without cirrhosis, 92% with HCV genotype 2 infection and 68% with HCV genotype 3 infection had a SVR compared with 94% of HCV genotype 2 and 21% of HCV genotype 3 with cirrhosis.1,2 References Jacobson IM, Yoshida EM, Sulkowski MS, et al. Treatment with sofosbuvir+ribavirin for 12 weeks achieves SVR12 of 78% in GT2/3 interferon-ineligible, -intolerant, or -unwilling patients: results of the phase 3 POSITRON trial. J. Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368: 21% No Cirrhosis (n=92) Cirrhosis (n=17) No Cirrhosis (n=84) Cirrhosis (n=14) SVR12 rate was 0% in the placebo arm. Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:

VALENCE Trial: Sofosbuvir + RBV
Genotype 2 (12 weeks) Genotype 3 (24 weeks) Treatment-naïve or experienced Approximately 20% with cirrhosis 100 97 93 94 92 91 87 88 85 60 SVR12 (%) Slide: VALENCE Trial: SVR12 Rates in HCV Genotype 2 or 3 As shown in this slide, the overall SVR12 rate was 93% and 85% in patients with HCV genotype 2 and 3, respectively. The presence of cirrhosis did not appear to impact the SVR12 rates among treatment-naïve patients. In contrast, HCV genotype 3, treatment-experienced patients with cirrhosis at baseline had lower SVR12 rates compared with those who were non-cirrhotic.1 Reference Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. Hepatology. 2013;58(suppl 1):733A-734A. Abstract 1085. n=73 n=250 n=30 n=92 n=2 n=13 n=33 n=100 n=8 n=45 Overall Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Treatment-Naive Treatment-Experienced No resistance detected in patients with relapse. Zeuzem S, et al. Hepatology. 2013;58(suppl 1):733A-734A. Abstract 1085.

FUSION Trial: SVR12 Rates by Genotype and Cirrhosis
Sofosbuvir + RBV 12 weeks 16 weeks Sofosbuvir + RBV 12 weeks 16 weeks 100% 96% 78% 63% 60% 61% Patients (%) Patients (%) 37% Slide: FUSION Trial: SVR12 Rates by Genotype and Cirrhosis SVR rates were decreased among those with cirrhosis at baseline relative the absence of cirrhosis. The SVR rate among patients with cirrhosis in the 12-week arm was 31% (60% with HCV genotype 2 infection and 19% with HCV genotype 3 infection), as compared with 61% among patients without cirrhosis (96% with HCV genotype 2 infection and 37% with HCV genotype 3 infection).1,2 Among patients with cirrhosis in the 16-week arm, the SVR rate was 66% (78% with HCV genotype 2 infection and 61% with HCV genotype 3 infection) as compared with 76% among patients without cirrhosis (100% with HCV genotype 2 infection and 63% with HCV genotype 3 infectionn.1,2 References Nelson DR, Feld J, Kowdley KV, et al. All oral therapy with sofosbuvir+ribavirin for 12 or 16 weeks in treatment experienced Gt2/3 HCV-infected patients: results of the phase 3 FUSION trial. J. Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368: 19% n=26 n=23 n=10 n=9 n=38 n=40 n=26 n=23 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368: Failed prior IFN-based therapy Targeted 30% with cirrhosis

Kris Kowdley, MD Director, Liver Center of Excellence Digestive Disease Institute Virginia Mason Medical Center Clinical Professor of Medicine University of Washington Seattle, WA

Investigational, IFN-Free, DAA Combination Regimens
Part A: Treatment-Naïve Patients Phase III Trials

SAPPHIRE-I: ABT-450/r + Ombitasvir + Dasabuvir + RBV (3D + RBV)
Double-blind Treatment Period NS3/4A  NS5A NS5B Non-Nuc Open-label Treatment Period 3D + RBV Phase 3 Placebo 3D + RBV 60 72 Weeks Other Key Inclusion Criteria and patient characteristics Plasma HCV RNA > 10,000 IU/ml About 69% IL28B non-CC genotype 67-68% GT1a Genotype 1 Treatment-naïve No cirrhosis Primary analysis: SVR12 3D: Co-formulated ABT-450/ritonavir/ombitasvir, 150 mg/ 100 mg/ 25 mg + dasabuvir, 250 mg RBV: mg daily, weight-based Feld JJ, et al. EASL International Liver Congress, Abstract O60. Feld JJ, et al. NEJM 2014 DOI: /NEJMoa

NS3/4A  NS5A NS5B Non-Nuc Phase 3 SVR12 non-inferior and superior to a historical control of telaprevir + PR (78%) SVR12, % Patients All Patients (N=473) GT1a (n=322) GT1b (n=151) Feld JJ, et al. EASL International Liver Congress, Abstract O60. Feld JJ, et al. NEJM 2014 DOI: /NEJMoa

NS3/4A  NS5A NS5B Non-Nuc Phase 3 SVR12, % Patients Male Female Black Non- Black <30 ≥30 F0-F1 F2 F3 <800K ≥3800K Yes No Gender Race BMI (kg/m2) Fibrosis Stage RBV Modification Baseline HCV RNA (IU/ml) Feld JJ, et al. EASL International Liver Congress, Abstract O60. Feld JJ, et al. NEJM 2014 DOI: /NEJMoa

PEARL-III: ABT-450/r + Ombitasvir + Dasabuvir (3D) ± RBV
NS3/4A  NS5A NS5B Non-Nuc Phase 3 Genotype 1b Treatment-naïve No cirrhosis 3D + RBV versus 3D alone SVR12, % Patients Other Key Inclusion Criteria and patient characteristics Plasma HCV RNA > 10,000 IU/ml About 79% IL28B non-CC genotype 3D +RBV (n=210) 3D (n=209) 3D: Co-formulated ABT-450/ritonavir/ombitasvir, 150 mg/ 100 mg/ 25 mg + dasabuvir, 250 mg RBV: mg daily, weight-based Ferenci P, et al. EASL International Liver Congress, Abstract P1299.

ION-1: Ledipasvir + Sofosbuvir 12 Weeks Versus 24 Weeks and ± RBV
NS3/4A NS5A  NS5B Nuc LDP/SOF SVR12 LDP/SOF + RBV SVR12 Phase 3 LDP/SOF SVR12 LDP/SOF + RBV SVR12 Weeks Other Key Inclusion Criteria and patient characteristics 24-35% IL28B CC genotype 66-68% GT1a Genotype 1 Treatment-naïve Targeted 20% with cirrhosis (actual 15-17%) Platelet count ≥50,000, no neutrophil minimum LDP/SOF: Ledipasvir/Sofosbuvir fixed-dose combination tablet (90 mg/400 mg daily) Mangia A, et al. EASL International Liver Congress, Abstract O164. Afdhal N, et al. NEJM 2014 DOI: /NEJMoa

NS3/4A NS5A  NS5B Nuc Phase 3 SVR12, % Patients LDV/SOF (n=214) LDV/SOF + RBV (n=217) LDV/SOF (n=217) LDV/SOF + RBV (n=217) 12 Weeks 24 Weeks Treatment duration Mangia A, et al. EASL International Liver Congress, Abstract O164. Afdhal N, et al. NEJM 2014 DOI: /NEJMoa

NS3/4A NS5A  NS5B Nuc Phase 3 SVR12, % Patients n=180 n=34 n=184 n=33 n=180 n=33 n=181 n=36 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Treatment duration Mangia A, et al. EASL International Liver Congress, Abstract O164. Afdhal N, et al. NEJM 2014 DOI: /NEJMoa

ION-3: Sofosbuvir + Ledipasvir 8 Weeks Vs 12 Weeks
NS3/4A NS5A  NS5B Nuc LDP/SOF SVR12 Phase 3 LDP/SOF + RBV SVR12 LDP/SOF 8 20 SVR12 Weeks Other Key Inclusion Criteria and patient characteristics 26-28% IL28B CC genotype 80% GT1a Genotype 1 Treatment-naïve Non-cirrhotic LDP/SOF: Ledipasvir/Sofosbuvir fixed-dose combination tablet (90 mg/400 mg daily) Kowdley KV, et al. EASL International Liver Congress, Abstract O56. Kowdley KV, eta l. NEJM 2014;370:

ION-3: Sofosbuvir + Ledipasvir 8 Weeks Vs 12 Weeks
NS3/4A NS5A  NS5B Nuc P=0.70 P=0.30 Non-inferiority analysis SVR12, % Patients LDV/SOF (n=215) LDV/SOF + RBV (n=216) LDV/SOF (n=216) 8 Weeks 12 Weeks Treatment duration Kowdley KV, et al. EASL International Liver Congress, Abstract O56. Kowdley KV, eta l. NEJM 2014;370:

HALLMARK DUAL: Daclatasvir + Asunaprevir: GT1b
NS3/4A  NS5A NS5B DCV + ASV Treatment- naive 12-week arm discontinued and participants invited to enroll in separate 24-week trial DCV + ASV STOP Enter another study DCV + ASV 24 weeks Phase 3 DCV + ASV Nonresponder Ineligible/ Intolerant DCV + ASV Weeks Genotype 1b Treatment-naïve, prior null or partial response to PR, IFN intolerant or ineligible Other Key Inclusion Criteria and patient characteristics Causes for interferon ineligibility/intoleranceincluded depression, anemia/neutropenia, compensated advanced fibrosis/cirrhosis (F3-F4) with thrombocytopenia 14-35% IL28B CC genotype DCV: Daclatasvir, 60 mg daily ASV: Asunaprevir, 100 mg twice daily Manns M, et al. EASL International Liver Congress, Abstract O166.

NS3/4A  NS5A NS5B Phase 3 SVR12, % Patients Treatment-naive (n=203) 16% cirrhosis Nonresponders (n=205) 31% cirrhosis Ineligible/Intolerant (n=235) 47% cirrhosis Manns M, et al. EASL International Liver Congress, Abstract O166.

Part A: Treatment-Naïve Patients Phase II Trials

Study 014: Daclatasvir + Asunaprevir + BMS-791325
NS3/4A  NS5A NS5B Non-nuc DCV + ASV + BMS (75 mg twice daily) SVR12 Phase 2 SVR12 DCV + ASV + BMS (150 mg twice daily) Weeks Genotype 1 Treatment-naïve Cirrhosis allowed (9% enrolled) Other Key Inclusion Criteria and patient characteristics 82% GT1a DCV: Daclatasvir, 30 mg twice daily ASV: Asunaprevir, 200 mg twice daily Everson GT, et al. Hepatology. 2013;58(suppl 1):73A. Abstract LB-1.

Study 014: Daclatasvir + Asunaprevir + BMS-791325
Daclatasvir (30 mg twice daily) + Asunaprevir (200 mg twice daily) + BMS NS3/4A  NS5A NS5B Non-nuc 75 mg twice daily 150 mg twice daily Phase 2 SVR12, % Patients N=77 84 65 68 12 16 24 28 53 56 8 7 69 77 Overall 1a 1b CC Non-CC Cirrhotic Non- cirrhotic Everson GT, et al. Hepatology. 2013;58(suppl 1):73A. Abstract LB-1. Genotype IL28B

C-WORTHY: MK-5172 + MK-8742 ± RBV
NS3/4A  NS5A NS5B MK-5172 (100 mg) MK-8742 (20 mg) + RBV SVR24 GT1a/b MK-5172 (100 mg) MK-8742 (50 mg) + RBV Phase 2 Part A GT1a/b MK-5172 (100 mg) MK-8742 (50 mg) GT1b MK-5172 (100 mg) MK-8742 (50 mg) +RBV (8 weeks) GT1a Ongoing MK-5172 (100 mg) MK-8742 (50 mg) +RBV Genotype 1 Treatment-naïve Non-cirrhotic Part B GT1a/b Other Key Inclusion Criteria and patient characteristics Minimum baseline hemoglobin 12 g/dL (females) or 13 g/dL (males) ALT and AST levels <350 IU/ml 18-30% IL28B CC genotype MK-5172 (100 mg) MK-8742 (50 mg) GT1a Weeks Hezode C, et al. EASL International Liver Congress, Abstract O10.

C-WORTHY: MK-5172 + MK-8742 ± RBV
Interim results (SVR4-24) NS3/4A  NS5A NS5B Phase 2 SVR 4-24, % Patients n=30 n=35 n=44 8 Weeks +RBV (GT1a) 12 Weeks +RBV (GT1a 61% GT1b 39%) 12 Weeks no RBV (GT1a 68% GT1b 32%) Hezode C, et al. EASL International Liver Congress, Abstract O10.

Faldaprevir + Deleobuvir + PPI-668 ± RBV
NS3/4A  NS5A NS5B Non-nuc DBV (600 mg twice daily FDV (120 mg daily) PPI-668 (200 mg daily) +RBV SVR12 Phase 2 DBV (400 mg twice daily FDV (120 mg daily) PPI-668 (200 mg daily) +RBV DBV (600 mg twice daily FDV (120 mg daily) PPI-668 (200 mg daily) (no RBV) Other Key Inclusion Criteria and patient characteristics Plasma HCV RNA > 10,000 IU/ml IL28B CC genotype Weeks Genotype 1a Treatment-naïve IL28BB restricted to no more than 1/3 of patients Non-cirrhotic DBV: Deleobuvir FDV: Faldaprevir Lalezari J, et al. EASL International Liver Congress, Abstract O65.

Faldaprevir + Deleobuvir + PPI-668 ± RBV
NS3/4A  NS5A NS5B Non-nuc Phase 2 SVR 12, % Patients Development of deleobuvir discontinued in Jan 2014 because of adverse events. *Confounding factors; The no RBV arm had one patients self-discontinue treatment (considered a treatment failure) but achieve SVR8, 1 patient had rebound at week 12 associated with very low plasma levels of study drugs. Two patients relapsed 4 weeks after treatment completion. n=12 n=12 n=12 (Confounding factors) DBV 600 mg twice daily +RBV DBV 400 mg twice daily +RBV DBV 600 mg twice daily no RBV Lalezari J, et al. EASL International Liver Congress, Abstract O65.

Part B: Treatment-Experienced Patients

SAPPHIRE-II: ABT-450/r + Ombitasvir + Dasabuvir + RBV (3D + RBV)
Double-blind Treatment Period NS3/4A  NS5A NS5B Non-Nuc Open-label Treatment Period 3D + RBV Phase 3 Placebo 3D + RBV 60 72 Weeks Other Key Inclusion Criteria and patient characteristics Plasma HCV RNA > 10,000 IU/ml 87-93% IL28B non-CC genotype 58% GT1a Genotype 1 Prior PR (Relapse, Partial response, or Null response) No cirrhosis Primary analysis: SVR12 3D: Co-formulated ABT-450/ritonavir/ombitasvir, 150 mg/ 100 mg/ 25 mg + dasabuvir, 250 mg RBV: mg daily, weight-based Zeuzem S, et al. EASL International Liver Congress, Abstract O1. Zeuzem S, et al. NEJM 2014 DOI: /NEJMoa

SAPPHIRE-II: ABT-450/r + Ombitasvir + Dasabuvir + RBV (3D + RBV)
NS3/4A  NS5A NS5B Non-Nuc Phase 3 SVR12, % Patients Prior Relapse (N=86) Prior Partial Response (n=65) Prior Null Response (n=146) Zeuzem S, et al. EASL International Liver Congress, Abstract O1. Zeuzem S, et al. NEJM 2014 DOI: /NEJMoa

ION-2: Sofosbuvir + Ledipasvir
NS3/4A NS5A  NS5B Nuc LDP/SOF SVR12 LDP/SOF + RBV SVR12 Phase 3 LDP/SOF SVR12 LDP/SOF + RBV SVR12 Weeks Other Key Inclusion Criteria and patient characteristics Plasma HCV RNA > 10,000 IU/ml 9-16% IL28B CC genotype 79% GT1a 41-46% prior non-responders 46-61% prior protease inhibitor failures Genotype 1 Failed prior PR or Triple therapy 20% of patients had cirrhosis Platelet count ≥50,000, no neutrophil minimum LDP/SOF: Ledipasvir/Sofosbuvir fixed-dose combination tablet (90 mg/400 mg daily) Afdahl N, et al. EASL International Liver Congress, Abstract O109. Afdhal N, et al. NEJM 2014 DOI: /NEJMoa

ION-2: Sofosbuvir + Ledipasvir
NS3/4A NS5A  NS5B Nuc Phase 3 SVR12, % Patients LDV/SOF (n=109) LDV/SOF + RBV (n=111) LDV/SOF (n=109) LDV/SOF + RBV (n=111) 12 Weeks 24 Weeks Treatment duration Afdahl N, et al. EASL International Liver Congress, Abstract O109. Afdhal N, et al. NEJM 2014 DOI: /NEJMoa

HALLMARK-DUAL: Daclatasvir + Asunaprevir: GT1b
NS3/4A  NS5A NS5B DCV + ASV Treatment- naive 12-week arm discontinued and participants invited to enroll in separate 24-week trial DCV + ASV STOP Enter another study DCV + ASV 24 weeks Phase 3 DCV + ASV Nonresponder Ineligible/ Intolerant DCV + ASV Weeks Genotype 1b Treatment-naïve, prior null or partial response to PR, IFN intolerant or ineligible Other Key Inclusion Criteria and patient characteristics Causes for interferon ineligibility/intoleranceincluded depression, anemia/neutropenia, compensated advanced fibrosis/cirrhosis (F3-F4) with thrombocytopenia 14-35% IL28B CC genotype DCV: Daclatasvir, 60 mg daily ASV: Asunaprevir, 100 mg twice daily Manns M, et al. EASL International Liver Congress, Abstract O166.

HALLMARK-DUAL: Daclatasvir + Asunaprevir: GT1b
NS3/4A  NS5A NS5B Phase 3 SVR12, % Patients The Study design for HALLMARK-DUAL was presented earlier. N=119 N=84 N=71 N=87 N=77 Null Partial Depression Anemia/ neutropenia Advanced fibrosis/ cirrhosis with thrombocytopenia Prior Non-responders Ineligible/Intolerant Manns M, et al. EASL International Liver Congress, Abstract O166.

Mark Sulkowski, MD Professor of Medicine Medical Director, Viral Hepatitis Center Johns Hopkins University School of Medicine Baltimore, MD

Part C: Cirrhosis

TURQUOISE-II: ABT-450/r + Ombitasvir + Dasabuvir + RBV (3D + RBV)
NS3/4A  NS5A NS5B Non-Nuc 3D + RBV SVR12 Phase 3 3D + RBV SVR12 Other Key Inclusion Criteria and patient characteristics Platelet count ≥60,000/mL Serum albumin ≥2.8 g/dL Total bilirubin< 3 mg/dL INR ≤2.3 AFP ≤100 ng/mL Patients with radiographic ascites or with varices were allowed 57-59% treatment-experienced 67-70% GT1a Genotype 1 Treatment-naïve or prior PR; no prior therapy with DAAs All patients had compensated cirrhosis (Child-Pugh A) at screening 3D: Co-formulated ABT-450/ritonavir/ombitasvir, 150 mg/ 100 mg/ 25 mg + dasabuvir, 250 mg RBV: mg daily, weight-based Poordad F, et al. EASL International Liver Congress, Abstract O163. Poordad F, et al. NEJM 2014 DOI: /NEJMoa

NS3/4A  NS5A NS5B Non-Nuc Phase 3 SVR12, % Patients N=140 N=121 N=68 N=51 12 Weeks 24 Weeks 12 Weeks 24 Weeks GT1a GT1b Poordad F, et al. EASL International Liver Congress, Abstract O163. Poordad F, et al. NEJM 2014 DOI: /NEJMoa

NS3/4A  NS5A NS5B Non-Nuc Phase 3 Treatment Duration SVR12, % Patients 12 Weeks 24 Weeks N=64 56 15 13 11 10 50 42 Naive Prior Relapse Prior Partial Response Prior Null Response Poordad F, et al. EASL International Liver Congress, Abstract O163. Poordad F, et al. NEJM 2014 DOI: /NEJMoa GT1a

NS3/4A  NS5A NS5B Non-Nuc Phase 3 Treatment Duration SVR12, % Patients 12 Weeks 24 Weeks N=45 33 163 139 25 18 183 154 <100 ≥100 <35 ≥35 Baseline Platelet Count (x109/L) Baseline Serum Albumin (g/L) Poordad F, et al. EASL International Liver Congress, Abstract O163. Poordad F, et al. NEJM 2014 DOI: /NEJMoa

NS3/4A NS5A  NS5B Nuc LDP/SOF SVR12 LDP/SOF + RBV SVR12 Phase 3 LDP/SOF SVR12 LDP/SOF + RBV SVR12 Weeks Genotype 1 Treatment-naïve Targeted 20% with cirrhosis (actual 15-17%) Platelet count ≥50,000, no neutrophil minimum LDP/SOF: Ledipasvir/Sofosbuvir fixed-dose combination tablet (90 mg/400 mg daily) Mangia A, et al. EASL International Liver Congress, Abstract O164. Afdhal N, et al. NEJM 2014 DOI: /NEJMoa

ION-1: Ledipasvir + Sofosbuvir Treatment-Naïve, Cirrhotic Patients
NS3/4A NS5A  NS5B Nuc Phase 3 SVR12, % Patients n=180 n=34 n=184 n=33 n=180 n=33 n=181 n=36 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Treatment duration Mangia A, et al. EASL International Liver Congress, Abstract O164. Afdhal N, et al. NEJM 2014 DOI: /NEJMoa

ION-2: Sofosbuvir + Ledipasvir Treatment-Experienced, Cirrhotic Patients
NS3/4A NS5A  NS5B Nuc Phase 3 SVR12, % Patients n=87 n=22 n=89 n=22 n=87 n=22 n=89 n=22 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Treatment duration Afdahl N, et al. NEJM DOI10/1056/NEJMoa Afdhal N, et al. NEJM 2014 DOI: /NEJMoa

NS3/4A  NS5A NS5B Phase 3 Treatment Duration SVR12, % Patients Cirrhotic Non-Cirrhotic N=206 437 32 171 63 142 111 124 Overall Treatment-Naive Non-Responder Ineligible/ Intolerant Kao J-H, et al. EASL International Liver Congress, Abstract P1300.

C-WORTHY: MK-5172 + MK-8742 ± RBV Cirrhosis
NS3/4A  NS5A NS5B MK-5172 MK-8742 + RBV MK-5172 MK-8742 No RBV Phase 2 MK-5172 (100 mg) MK-8742 (50 mg) +RBV MK-5172 (100 mg) MK-8742 (50 mg) No RBV 18 Weeks Genotype 1 Treatment-Naïve with Cirrhosis Prior Null-Responders ± Cirrhosis MK mg daily MK mg daily Lawitz E, et al. EASL International Liver Congress, Abstract O61.

C-WORTHY: MK-5172/ MK-8742 ± RBV Cirrhosis
NS3/4A  NS5A NS5B Phase 2 Pooled 12- and 18-week arms ±RBV 4-8 week follow-up HCV RNA<25 IU/ml, % Patients N=85 N=32 N=33 N=14 Treatment- Naive Null-Response Treatment- Naive Null-Response Lawitz E, et al. EASL International Liver Congress, Abstract O61. GT1a, Cirrhosis GT1b, Cirrhosis

Part D: HIV Co-infection

HIV-ERADICATE: Sofosbuvir + Ledipasvir
SOF + LDV NS3/4A NS5A  NS5B Nuc ARV Untreated CD4 count stable and HIV RNA <500 copies OR CD4 count >500 cells/mm3 SVR12 ARV Treated CD4 count >100 cells/mm3 HIV RNA <40 copies Current ARVs ≥8 weeks Currently SVR4 Other Key Inclusion Criteria and patient characteristics 22-38% had HAI fibrosis stage 3 75-81% GT1a Median CD4 T cell count HIV/HCV Co-infected HCV Genotype 1 Treatment-Naive F0-3 SOF: Sofosbuvir 400 mg daily LDV: Ledipasvir 90 mg daily ARVs: tenofovir, emtricitabine, efavirenz, rilpivirine, and raltegravir Osinusi A, et al. EASL International Liver Congress, Abstract O14.

NS3/4A NS5A  NS5B Nuc ARV regimens in the ARV-treated group (n=37) Regimen N(%) Tenofovir/Emtricitabine plus Efaviranz (EFV) 15 (41) Raltegravir (RAL) 10 (27) Rilpivirine (RPV) 8 (21) RPV/RAL 3 (8) EFV/RAL 1 (3) Osinusi A, et al. EASL International Liver Congress, Abstract O14.

NS3/4A NS5A  NS5B Nuc Interim Results ARV Untreated HCV RNA< LLQ, % patients ARV Treated 13 37 13 30 12 22 10 10 Week 8 End of Treatment SVR4 SVR8 SVR12 Osinusi A, et al. EASL International Liver Congress, Abstract O14.

ARV Untreated (n=13) ARV Treated (n=37) No clinically significant changes in HIV RNA during HCV treatment One patient with transient HIV viral breakthrough Missed ARV for 4 days Re-suppressed on the same regimen HIV RNA tests on treatment days 0, 1, 3, 5, 7 and weeks 2, 4, 8,and 12 Osinusi A, et al. EASL International Liver Congress, Abstract O14.

C-WORTHY: MK-5172/ MK-8742 ± RBV
NS3/4A  NS5A NS5B MK-5172 MK-8742 + RBV SVR12 Phase 2 MK-5172 MK-8742 No RBV SVR12 HIV/HCV Co-infected HCV Genotype 1 Non-cirrhotic Stable on raltegravir + two NRTIs for 8 weeks prior to enrollment ART dose modification not permitted during 8 weeks preceding enrollment unless dose modification due to tolerability failure CD4 >300 cells/mm3 Undetectable HIV RNA for 24 weeks Sulkowski M, et al. EASL International Liver Congress, Abstract O63.

C-WORTHY: MK-5172/ MK-8742 ± RBV
NS3/4A  NS5A NS5B Interim Results Phase 2 MK MK-8742 + RBV HCV RNA< LLQ, % patients No RBV 29 30 29 30 29 30 29 29 Week 4 Week 8 Week 12 SVR4 Sulkowski M, et al. EASL International Liver Congress, Abstract O63.

Summary (1 of 4): Genotype 2/3 Chronic HCV
Sofosbuvir + RBV is approved and recommended for treatment of genotype 2/3 patients with chronic HCV and who are treatment-naïve or relapsed after prior PR Genotype 2 chronic HCV (12 weeks of therapy) Genotype 3 chronic HCV (24 weeks of therapy)

Summary (2 of 4): Genotype 1 Chronic HCV
Two regimens have demonstrated very high SVR12 rates (>90%) in phase III trials of treatment-naïve patients, and patients who failed prior therapy (relapsed, null response, partial response) 3D +RBV (ABT ombitasvir + dasabuvir +RBV) Ledipasvir + Sofosbuvir Both regimens were studied in trials using 12-week duration of therapy The ION-3 trial suggests that 8 weeks of therapy may be sufficient for ledipasvir + sofosbuvir therapy (±RBV) in treatment-naïve patients without cirrhosis

Other regimens showing high SVR12 rates in phase II trials include Daclatasvir + asunaprevir + BMS MK MK8742 ± RBV Faldaprevir + Deleobuvir + PPI-668 ± RBV Cirrhotic Patients The phase III TURQUOISE-II trial enrolled only patients with compensated cirrhosis and showed high SVR12 rates for 12 or 24 weeks of therapy with 3D + RBV (treatment-naïve and prior PR failures) The cirrhotic subgroups of other trials also showed high SVR12 rates for Ledipasvir + sofosbuvir ± RBV (treatment-naïve patients) Daclatasvir + asunaprevir (Gt1b patients)

HIV Co-infected Patients Phase II trials have found high SVR12 rates for treatment of HCV genotype 1 patients, with acceptable HIV-related safety for: Sofosbuvir + ledipasvir MK MK-8742 ± RBV

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New & Emerging Interferon‐Free, Direct‐Acting Antiviral Regimens for the Treatment of Hepatitis C: An Expert Review of Recent Clinical Data Sponsored for.

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Presentation on theme: "New & Emerging Interferon‐Free, Direct‐Acting Antiviral Regimens for the Treatment of Hepatitis C: An Expert Review of Recent Clinical Data Sponsored for."— Presentation transcript:

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