Hepatitis C Treatment 2014

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1 Hepatitis C Treatment 214 Brendan M. McGuire, MD UAB Liver Center Outline Epidemiology/National History Terminology for Treatment Treatment Considerations Current Treatment Options Genotype 1 (GT 1) Genotype 2 (GT 2) Genotype 3 (GT 3) Future Therapies 1

2 Outline Epidemiology/National History Terminology for Treatment Treatment Considerations Current Treatment Options Genotype 1 (GT 1) Genotype 2 (GT 2) Genotype 3 (GT 3) Future Therapies Epidemiology of HCV 17 M persons infected worldwide M Americans infected High prevalence rates in USA 2.5% of males 3.2% of African Americans 2.1% of Hispanic Americans Peak age of persons born between World Health Organization (WHO). Wkly Epid Rec.1999;74: WHO. Hepatitis C: Global Prevalence: Update. 23. Semin Liver Dis. 2;2: Semin Liver Dis. 2;2:1-16. Hepatology 28;47:

3 Individuals (n) Two-Thirds of Those With Chronic HCV in the U.S. Were Born ,6, 1,4, 1,2, 1,, 8, 6, 4, 2, Estimated Prevalence by Age Group < Birth Year Group Pyenson B, et al. Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease. New York, NY: Milliman, Inc; Natural History of HCV Infection Acute HCV Infection () Recovery & Clearance of HCV (2) Chronic Infection (8) Mild (24) Moderate (32) Chronic Hepatitis Severe (24) Cirrhosis End-Stage Liver Disease Hepatocellular CA Clin Liver Dis 25;9: Eur J Gastroenterol Hepatol 1996;8: Hepatology 22;36(suppl):S1-S2. Hepatology 22;36(suppl):S35-S46. Ann Intern Med 2;132: Gastroenterology 1997;112:

4 Number of cases Aging of HCV-Infected Persons in the US: Disease Progression Gastroenterology 21;138: Projected Cases of Hepatocellular Carcinoma & Decompensated Cirrhosis Due to HCV 16, 14, 12,, 8, 6, 4, 2, Decompensated cirrhosis Hepatocellular cancer Year Gastroenterology 21;138:

5 Patient Survival Rates with HCV (+) & HCV ( ) After Liver Transplantation HCV (+) HCV (-) Gastroenterology 22;122:889. Outline Epidemiology/National History Terminology for Treatment Treatment Considerations Current Treatment Options Genotype 1 (GT 1) Genotype 2 (GT 2) Genotype 3 (GT 3) Future Therapies 5

6 HCV RNA (log 1 IU/mL) Prevalence of HCV Genotypes (GT) in the USA 2a 1a & 1b 1 & 2 2b 3 4 1a (36%) 1b (39%) J Clin Microbiol. July 211. Patterns of Virologic Response PegIFN & RBV Null Response* Partial Response* 3 2 Relapse 1 Undetectable RVR EVR ETR SVR *Subset of Nonresponse Wks After Start of Therapy 4 weeks - RVR: rapid virological response 12 weeks - ervr: extended RVR & EVR: early virological response weeks - ETR: end of treatment response 24 weeks after treatment - SVR: sustained virological response Hepatology 29;49:

7 Outline Epidemiology/National History Terminology for Treatment Treatment Considerations Current Treatment Options Genotype 1 (GT 1) Genotype 2 (GT 2) Genotype 3 (GT 3) Future Therapies 8 Treatment Evolution of HCV Sustained Viral Response (SVR) % 214 > 9% % 4 34% 42% 39% 2 6% IFN 6m 16% IFN 12m IFN/RBV 6m IFN/RBV 12m Peg-IFN 12m Peg-IFN/ RBV 12m Peg-IFN/ RBV + PI 6-12m DAA + RBV + Peg-IFN/ 3-6m IFN: Interferon; m: months; RBV: Ribavirin; Peg: Pegylated; PI: Protease inhibitor; DAA: Direct Acting Antiviral 7

8 Cumulative Mortality SVR & Reduced Risk of All-Cause Mortality US VA Study: Treatment with PegIFN/RBV Clin Gastroenterol Hepatol 211;9: HCV GT 1 P (log-rank) <.1 No SVR SVR Years Genotype N SVR Hazard Ratio for Death with SVR P-value 1 12,166 35%.7 < % %.51.2 HCV Life Cycle 8

9 HCV Life Cycle & DAA Targets NS5A inhibitors Block replication complex formation, assembly Receptor binding and endocytosis Fusion and uncoating Transport and release Translation and polyprotein processing (+) RNA LD ER lumen LD Virion assembly NS3/4 protease inhibitors ER lumen Membranous web LD RNA replication NS5B polymerase inhibitors RNA replication Nucleoside/nucleotide Nonnucleoside Adapted from Manns MP, et al. Nat Rev Drug Discov. 27;6:991-. Outline Epidemiology/National History Terminology for Treatment Treatment Considerations Current Treatment Options Genotype 1 (GT 1) Genotype 2 (GT 2) Genotype 3 (GT 3) Future Therapies 9

10 Boceprevir G1 Telaprevir G1 First Generation Protease Inhibitors (PI) Telaprevir (TEL) & Boceprevir (BOC) Hepat Med. 21;2: Protease Inhibitors HCV Therapies Interferon Free Therapies Interferon & Ribavirin Based Therapies Protease Inhibitor NS5B Polymerase Inhibitor NS5A Inhibitor Non-nuclease Inhibitor 1

11 SVR (%) SVR (%) BOC & TEL + PegIFN/RBV (P/R) GT1 Treatment-Naive Patients PegIFN/RBV BOC or TEL + PegIFN/RBV Poordad F, et al. NEJM 211;364: Jacobson IM, et al. NEJM 211;364: BOC & TEL + PegIFN/RBV (P/R) GT1 Treatment Failures PegIFN/RBV BOC or TEL + PegIFN/RBV Relapsers [1,2] Partial Responders [1,2] Null Responders [2,3] 1. Bacon BR, et al. NEJM 211;364: Zeuzem S, et al. NEJM 211;364: Bronowicki JP, et al. EASL 212. Abstract

12 Side Effects from BOC & TEL Treatment is more effective but much more difficult Other Issues With BOC & TEL Pill burden Food requirement Resistance BOC 12/day RBV 4-7/day PI TEL 6/day RBV 4-7/day Drug-drug interactions CYP3A4 metabolites 12

13 HCV-TARGET: Safety Assessment of P/R + BOC/TEL in Patients Event, % Fried MW, et al. EASL 213. Abstract 818. Cirrhotic (n = 55) Noncirrhotic (n = 787) SAE 8 8 Death, n 2 1 Early discontinuation Due to adverse event Due to lack of efficacy Decompensation 11 1 Infection Severe rash (grade 3/SCAR) 2 1 Hemoglobin < 8.5 g/dl 2 14 RBV dose reduction EPO 1 1 Transfusion Second Generation Protease Inhibitors (PI) Simeprevir (SIM) & Faldaprevir (FAL) Hepat Med. 21;2: Protease Inhibitors 13

14 Boceprevir G1 Telaprevir G1 HCV Therapies Interferon Free Therapies Simeprevir G1 Interferon & Ribavirin Based Therapies Faldaprevir Protease Inhibitor NS5B Polymerase Inhibitor NS5A Inhibitor Non-nuclease Inhibitor QUEST-1/2: Simeprevir (SIM) + P/R RGT in Treatment-Naive GT1 HCV Stratified by GT1 subtype, IL28B genotype Wk 12: RGT Wk 24 Wk 48 Treatment-naive patients with GT1 HCV SIM 15 mg QD + P/R* (n = 264) P/R P/R (N = 394) Placebo + P/R (n = 13) P/R *Response-guided therapy: Patients with HCV RNA < 25 IU/mL at Week 4 & undetectable at wk 12 received a 24 wks of therapy. Patients not achieving this ontreatment response received 48 wks of therapy. Jacobson I, et al. EASL 213. Abstract

15 Patients (%) SVR12 (%) SVR12 (%) QUEST-1, QUEST-2, PROMISE: SIM + P/R in GT1 Treatment-Naive Patients/Relapsers Treatment-Naive Patients Prior Relapsers SIM + P/R P/R / / 13 29/ / 134 QUEST-1 [1] QUEST-2 [2] 2 26/ 26 49/ 133 PROMISE [3] 1. Jacobson I, et al. EASL 213. Abstract Manns M, et al. EASL 213. Abstract Lawitz E, et al. DDW 213. Abstract 869b. QUEST: 88% Qualified for Shortened Therapy in SIM Phase III Studies n/n = 459/ 521 Met RGT Criteria 45/ 459 Achieved SVR Pts who did not meet RGT SVR 25%; therefore, RGT not recommended in US label Jacobson I, et al. AASLD 213. Abstract

16 SVR12 (%) SVR12 (%) QUEST Studies: GT 1a 1b Simeprevir + P/R (RGT ) Placebo + P/R / 254 Likely relates to presence of Q8K polymorphism in GT1a Jacobson I, et al. AASLD 213. Abstract / 131 GT1a 228/ 267 7/ 133 GT1b QUEST: No Benefit of SIM if Q8K SIM + P/R 84 P/R n/n = 228/ 267 GT1b 7/ / / 83 GT1a no Q8K 49/ 84 23/ 44 GT1a + Q8K Q8K present in 34% of GT1a patients No benefit of SIM if Q8K positive Jacobson I, et al. AASLD 213. Abstract

17 Mean (µmol/l) Mean (µmol/l) SVR24 (%) SIM in Treatment-Experienced Patients P/R + SIM (12 wks)+ P/R (36 wks) P/R x 48 wks / / 27 Relapsers Zeuzem S et al. Gastroenterology 214;146: / /23 Partial Responders FDA extended indication to partial & null responders 45 15/ / 16 Null Responders SIM Is Well Tolerated 3 Bilirubin 2 Hemoglobin 2 1 SIM + P/R P/R SIM + P/R P/R Wks Wks Mild unconjugated hyperbilirubinemia transporter No anemia signal beyond P/R Rash up to 25% (mild) Manns M, et al. EASL 213. Abstract

18 SIM + P/R for GT1 HCV: Approved Indications Simeprevir 15 mg/day with food, administered with P/R Fixed duration Treatment-naive patients & relapsers (including cirrhotic patients) 12 weeks 12 weeks Simeprevir + P/R P/R $86, Previous partial or null responders (including cirrhotic patients) 12 weeks 36 weeks Simeprevir + P/R P/R Stopping rules Treatment Wk HCV RNA (IU/mL) Action 4 25 Discontinue simeprevir, pegifn, & RBV $ 15, Discontinue pegifn & RBV (SIM stops at 12 wks) Discontinue pegifn & RBV Simeprevir [package insert]. November 213. NS5B (Nucleotide) Polymerase Inhibitor Sofosbuvir (SOF) Hepat Med. 21;2: NS5B polymerase Inhibitors 18

19 HCV RNA < LLOQ (%) Boceprevir G1 Telaprevir G1 HCV Therapies Interferon Free Therapies SOF + Riba G2, SOF G1, 4-6, Naive Simeprevir G1 Interferon & Ribavirin Based Therapies Faldaprevir Protease Inhibitor NS5B Polymerase Inhibitor NS5A Inhibitor Non-nuclease Inhibitor NEUTRINO: 12 Wks Sofosbuvir (SOF) + P/R in Treatment-Naive GT 1/4/5/6 HCV Pts Open-label, single-arm study of sofosbuvir 4 mg QD + P/R for 12 wks in treatment-naive patients with GT 1/4/5/6 HCV 17% had cirrhosis; 89% had GT 1, 9% had GT 4, < 1% had GT 5, 2% had GT 6 HCV P/R: pegifn alfa-2a 18 µg/wk + RBV -12 mg/day Lawitz E, et al. NEJM 213;368: n/n = / / /327 Wk 4 EOT SVR12 19

20 SVR12 (%) NEUTRINO: SOF + P/R for 12 Weeks in Treatment-Naive GT 1/4/5/6 HCV n/n = 295/327 Overall 261/292 27/28 7/7 GT1 GT4 GT5, /273 43/54 No Cirrhosis Cirrhosis Lawitz E, et al. NEJM 213;368: NEUTRINO Study: SVR12 by Pre-specified Subgroups Overall HCV GT Cirrhosis Race HCV RNA level IL28B 1 (1a, 1b, 1a/b) 1a 1b 4, 5, 6 No Yes Black Non-black < 6 log 1 IU/mL 6 log 1 IU/mL CC Non-CC SVR12 Rate, % (95% CI) SOF + PegIFN + RBV Lawitz E, et al. NEJM 213;368:

21 SVR (%) SOF + RBV for 24 Weeks in 6 GT 1 Pts Intolerable to PegIFN SOF+ RBV 6 mg/d SOF + RBV - 12 mg/d No one discontinued treatment due to adverse events. Most frequent adverse events were headache, anemia, fatigue & nausea Osinusi A, et al. JAMA 213;31: SOF + P/R for GT1 HCV: Approved Indications SOF 4 mg/day with or without food, administered with P/R All GT1 patients receive same regimen, regardless of previous treatment history or fibrosis level Same regimen approved for GT4 HCV 12 weeks Sofosbuvir + P/R $ 91,5 Additional option for GT1 patients ineligible for IFN therapy Sofosbuvir + ribavirin for 24 weeks $ 168, If drugs combined with sofosbuvir must be permanently discontinued, sofosbuvir should also be discontinued Sofosbuvir [package insert]. December

22 Boceprevir G1 Telaprevir G1 HCV Therapies Interferon Free Therapies SOF + Riba G2, SOF G1, 4-6, Naive Simeprevir G1 Interferon & Ribavirin Based Therapies Faldaprevir Protease Inhibitor NS5B Polymerase Inhibitor NS5A Inhibitor Non-nuclease Inhibitor COSMOS: SIM + SOF ± RBV in GT 1 HCV Patients Planned interim analysis of randomized phase IIa study 2 cohorts with same study design evaluating impact of duration & RBV Primary endpoint: SVR12 Randomized 2:1:2:1 Patients With GT1 HCV Cohort 1: Previous null responders, F-F2 (N = 8) Cohort 2: Naives & previous null responders, F3-F4 (N = 87) SIM + SOF + RBV SIM + SOF Wk 12 Wk 24 SIM + SOF + RBV SIM + SOF SIM 15 mg QD; SOF 4 mg QD; weight-based RBV -12 mg/day. Jacobson I, et al. AASLD 213. Abstract LB-3. 22

23 SVR12 (%) SVR4 (%) COSMOS: SVR12 in F-F2 Pts (All Arms) & SVR4 in F3-F4 Pts (12-Wk Arms Only) 78% GT1a 5% Q8K 94% non-cc All nulls SMV + SOF + RBV 12 wks / 27 13/ 14 F-F2 Fibrosis SMV + SOF 12 wks 96 26/ 27 14/ 14 F3/F4 Fibrosis 78% GT1a 4% Q8K 79% non-cc 47% F4 54% Null Major caveats: small n, no plan for phase III trial Jacobson I, et al. AASLD 213. Abstract LB-3. Outline Epidemiology/National History Terminology for Treatment Treatment Considerations Current Treatment Options Genotype 1 (GT 1) Genotype 2 (GT 2) Genotype 3 (GT 3) Future Therapies 23

24 Boceprevir G1 Telaprevir G1 HCV Therapies Interferon Free Therapies SOF + Riba G2, SOF G1, 4-6, Naive Simeprevir G1 Interferon & Ribavirin Based Therapies Faldaprevir Protease Inhibitor NS5B Polymerase Inhibitor NS5A Inhibitor Non-nuclease Inhibitor FISSION: SOF/RBV vs P/R in Treatment- Naive GT 2/3 HCV Patients Randomized, controlled, open-label phase III noninferiority trial 21% had cirrhosis; 72% had GT 3 HCV Treatment-naive patients with GT 2/3 HCV (N = 499) Stratified by HCV GT (2 vs 3), HCV RNA (< vs 1 6 IU/mL), cirrhosis (yes vs no) Wk 12 SOF 4 mg QD + RBV -12 mg/day (n = 256) PegIFN alfa-2a 18 µg/wk + RBV 8 mg/day (n = 243) Wk 24 Gane E, et al. NEJM 213;368:

25 SVR12 (%) HCV RNA < LLOQ (%) FISSION: SOF/RBV Noninferior to P/R in Tx-Naive GT 2/3 HCV Patients Sofosbuvir + RBV PegIFN + RBV P < n/n = 249/25 158/ /244 27/224 NA 188/19 Wk 4 Wk 12 Wk 24 On Treatment 17/ /243 SVR12 Gane E, et al. NEJM 213;368: FISSION: SVR12 According to GT & Fibrosis Level Sofosbuvir + RBV PegIFN + RBV n/n = 58/59 44/54 1/11 8/13 89/145 99/139 13/38 11/37 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis Genotype 2 Genotype 3 Gane E, et al. NEJM 213;368:

26 FISSION: Better Tolerability Profile With SOF/RBV vs P/R Grade 3 AEs: 7% with SOF/RBV vs 19% for pegifn/rbv Discontinuations due to AEs: 1% for SOF/RBV vs 11% for pegifn/rbv AEs Occurring in 15% in Either Arm, % Gane E, et al. NEJM 213;368: SOF/RBV (n = 256) PegIFN/RBV (n = 243) P Value Fatigue <.1 Headache <.1 Nausea Insomnia <.1 Rash Diarrhea Irritability Decreased appetite Myalgia Pruritus Influenzalike symptoms 3 18 <.1 Chills 3 18 <.1 FUSION: SOF + RBV for 12 or 16 Wks in Tx-Experienced GT 2/3 HCV Pts Randomized, double-blind, placebo-controlled phase III trial 62% to 64% had GT 3 HCV, 33% to 35% had cirrhosis, 75% to 76% were previous relapsers Treatmentexperienced pts with GT 2/3 HCV (N = 21) Stratified by HCV GT (2 vs 3), cirrhosis (yes vs no) SOF 4 mg QD + RBV -12 mg/day (n = 13) Wk 12 SOF 4 mg QD + RBV -12 mg/day (n = 98) Placebo Wk 16 Jacobson IM, et al. NEJM 213;368:

27 SVR12 (%) SVR12 (%) HCV RNA < LLOQ (%) FUSION: Overall Efficacy Outcomes of SOF + RBV in GT 2/3 SOF + RBV 12 wks SOF + RBV 16 wks n/n = 97/ 93/95 / 95/95 Wk 4 End of Treatment 5/ 69/95 SVR12 Jacobson IM, et al. NEJM 213;368: FUSION: SVR by GT & Cirrhosis in Treatment-Experienced Patients 96 SOF + RBV 12 wks 6 Jacobson IM, et al. NEJM 213;368: SOF + RBV 16 wks / 23/ 14/ 25/ 14/ n/n = /1 7/ /26 23 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis GT2 GT3 12 weeks sufficient for GT2 16 weeks better than 12 weeks for GT3 so what about 24 weeks?

28 SVR12 (%) SVR12 (%) VALENCE: SOF + RBV for 12 or 24 Weeks in Naive & Exp d GT2/3 HCV Pts Phase III study in Europe Original protocol amended to lengthen treatment for all GT3 pts when emerging data suggested benefit of additional treatment for this group* Primary endpoint: SVR12 Wk 12 Wk 24 HCV-infected GT2 tx-naive or exp d pts (N = 323) GT3 SOF 4 mg QD + RBV mg or 12 mg/day (n = 73) SOF 4 mg QD + RBV mg or 12 mg/day (n = 25) *Small number of GT3 patients (n = 11) who had already completed 12 wks at time of protocol amendment were included in safety analysis with GT2 but analyzed separately for efficacy. Patients randomized to placebo in original protocol offered alternative treatment protocol. Zeuzem S, et al. AASLD 213. Abstract 185. VALENCE: SVR12 With 12 or 24 Wks of SOF + RBV in GT2 & GT3 Pts 8 6 GT2 12-Wk Treatment (n = 73) GT3 24-Wk Treatment (n = 25) n/n = 29/3 2/2 3/33 7/8 n/n = Naive, Naive, Exp d Exp d, Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic No increase in AEs seen with longer duration treatment AEs seen consistent with RBV 2 86/92 12/13 87/ 27/45 Naive, Noncirrhotic Naive, Cirrhotic Exp d Noncirrhotic Exp d, Cirrhotic Zeuzem S, et al. AASLD 213. Abstract

29 SVR12 (%) SVR12 (%) VALENCE: Efficacy With 24-Week SOF + RBV in GT3 Patients 8 6 No Cirrhosis Treatment Naive [1] Treatment Experienced [1] Cirrhosis FUSION [2] n/n = 86/ 92 12/ 13 87/ 24 weeks better for treatment-naive patients 27/ 45 Not ideal for cirrhotic treatment failures 4 2 n/n = 24 Wks 24 Wks 16 Wks 14/ Zeuzem S, et al. AASLD 213. Abstract Jacobson IM, et al. NEJM 213;368: POSITRON: SOF + RBV for 12 Wks in GT 2/3 IFN- Unwilling/Intolerant/Ineligible Randomized, double-blind, placebo-controlled phase III trial IFN unwilling, intolerant, or ineligible pts with GT 2/3 HCV (N = 278) Baseline Factor, n (%) Stratified by cirrhosis (yes vs no) Jacobson I, et al. NEJM 213;368: SOF 4 mg QD + RBV -12 mg/day (n = 27) Placebo (n = 71) Sofosbuvir + RBV (n = 27) Wk 12 Placebo (n = 71) GT 2 19 (53) 34 (48) Cirrhosis 31 (15) 13 (18) Interferon unwilling 12 (49) 3 (42) Interferon ineligible 88 (43) 33 (47) Interferon intolerant 17 (8) 8 (11) 29

30 HCV RNA < LLOQ (%) SVR12 (%) POSITRON: Virologic Response in GT 2/3 IFN-Unwilling/Intolerant/Ineligible Overall Outcomes No cirrhosis Cirrhosis n/n = 22/ 24 Wk 4 22/ 22 EOT 161/ 27 SVR /92 16/17 57/84 3/14 GT 2 GT 3 21 SVR12 % for placebo Jacobson I, et al. NEJM 213;368: Sofosbuvir + RBV for GT 2 & 3 HCV: Approved Indications All GT2 patients receive same regimen, regardless of previous treatment history or fibrosis level 12 weeks SOF + RBV $ 86,3 All GT3 patients receive same regimen, regardless of previous treatment history or fibrosis level 24 weeks SOF + RBV $ 172,6 If drugs combined with sofosbuvir must be permanently discontinued, sofosbuvir should also be discontinued Sofosbuvir [package insert]. December

31 SVR12 (%) SVR12 (%) LONESTAR-2: SOF + 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 Primary endpoint: SVR12 Pts with GT2 or GT3 HCV & previous treatment failure with P/R (N = 47) Lawitz E, et al. AASLD 213. Abstract LB-4. SOF 4 mg QD + PegIFN 18 µg once wkly + RBV mg or 12 mg/d Wk n/n = 96 22/23 GT2 83 2/24 GT3 Similar rates of SVR12 in pts with & without cirrhosis Do We Still Need PegIFN for GT3? LONESTAR-2: SOF + PegIFN + RBV x 12 wks / 9 Lawitz E, et al. AASLD 213. Abstract LB / 14 GT 2 GT 3 Small single-center study but looks promising... PegIFN is not dead yet! 83 1/ / 12 No cirrhosis Cirrhosis 85% previous treatment failures 31

32 Outline Epidemiology/National History Terminology for Treatment Treatment Considerations Current Treatment Options Genotype 1 (GT 1) Genotype 2 (GT 2) Genotype 3 (GT 3) Future Therapies Future DAA to Treat HCV Class Drug Dosing NS3/4A protease inhibitor ABT-45/RTV 15/ mg NS3 protease inhibitor Asunaprevir 2 mg BID NS3/4A protease inhibitor Faldaprevir 12 mg or 24 mg QD NS3 protease inhibitor GS mg QD NS3/4A protease inhibitor MK-5172 mg QD NS5B nonnucleoside polymerase inhibitor ABT mg BID NS5B nonnucleoside polymerase inhibitor BMS mg or 15 mg BID NS5B nonnucleoside polymerase inhibitor Deleobuvir 6 mg BID NS5B nonnucleoside polymerase inhibitor GS mg QD NS5A inhibitor ABT mg QD NS5A inhibitor Daclatasvir 3 mg BID or 6 mg QD NS5A inhibitor Ledipasvir 9 mg QD NS5A inhibitor MK or 5 mg QD NS5A inhibitor PI mg QD 32

33 Boceprevir G1 Telaprevir G1 Future of HCV Therapies Interferon Free Therapies Ledipasvir SOF ABT 45/RTV ABT 267 ABT 333 RBV Asunaprevir Daclatasvir BMS 325 Asunaprevir Daclatasvir SOF + Riba G2, SOF G1, 4-6, Naive Simeprevir G1 Interferon & Ribavirin Based Therapies Faldaprevir Daclatasvir Asunaprevir Protease Inhibitor NS5B Polymerase Inhibitor NS5A Inhibitor Non-nuclease Inhibitor Potential Targets for Direct Acting Antiviral (DAA) Agents Against HCV Gene Products Hepat Med. 21;2: NS5A Inhibitors 33

34 SVR12 (%) SVR4 or 12 (%) SOF + Ledipasvir (NS5A) + RBV Treatment-naive pts (noncirrhotic) 95 19/2 SOF/LDV 21/21 SOF/LDV + RBV 8 wks 95 18/19 SOF/LDV 12 wks No breakthrough; 2 relapses, both without RBV 95 18/19 SOF/LDV PI failures (5% cirrhotic) 21/21 12 wks SOF/LDV + RBV 1 case of resistance retreated with SOF/LDV + RBV x 24 weeks SVR Lawitz E, et al. Lancet 214 (in press). ELECTRON: SOF/Ledipasvir + RBV for 6 Wks in Naive GT1 HCV Pts Open-label phase II trial in GT1 HCV pts 68% SVR12 rate with 6 wks of SOF/LDV + RBV lower [1] than SVR rates previously achieved with 8 wks [2] or 12 wks [3] treatment with this regimen Tx-naive pts, GT1 HCV, F-F2 (n = 25) SOF/LDV + RBV (n = 25) SOF 4 mg QD;/ledipasvir 9 mg QD; weight-based RBV -12 mg/day Wk ELECTRON [1] LONESTAR [2] ELECTRON [3] 68 n/n = 17/25 21/21 25/25 6 Wks 8 Wks 12 Wks Duration of SOF/LDV + RBV in Tx-Naive Pts 1. Gane EJ, et al. AASLD 213. Abstract Lawitz E, et al. AASLD 213. Abstract Gane EJ, et al. NEJM 213;368:

35 HCV RNA < LLOQ (%) SYNERGY: SOF/Ledipasvir (LDV) ± GS (NS5Bnns) or GS-9541 (NS3) in GT1 HCV Pts NIAID nonrandomized parallel-arm phase II trial GT 1 Primary endpoint: SVR12 Wk 6 Wk 12 Treatment naive, F-F4 (n = 2) Treatment naive, F-F3 (n = 2) Treatment-experienced, F-F3 (n = 2) SOF/LDV SOF/LDV + GS-9669 SOF/LDV + GS-9451 SOF 4 mg QD/LDV 9 mg QD; GS mg QD; GS mg QD. Kohli A, et al. AASLD 213. Abstract LB-8. SYNERGY: High Response Rates With 6-Wk Triple-Drug Regimens Very high response rates with all-oral therapy without RBV 1 pt in SOF/LDV + GS-9669 arms relapsed & 1 missed SVR4 visit No serious AEs leading to discontinuation 8 9 SOF/LDV 12 wks SOF/LDV + GS-9669, 6 wks SOF/LDV + GS-9451, 6 wks /2 2/2 2/2 2/2 18/2 2/2 2/2 EOT SVR4 SVR12 Kohli A, et al. AASLD 213. Abstract LB-8. 35

36 SVR12 (%) SVR12 (%) ELECTRON: SOF/Ledipasvir ± RBV or GS (NS5Bnns) in Cirrhotic GT1 HCV Pts Open-label phase II trial SVR12 rate enhanced with addition of RBV or GS-9669 Treatment-experienced pts with HCV GT1, F4 (N = 2) Treatment-experienced pts with HCV GT1, F3 or F4 (N = 5) SOF/LDV (n = 1) SOF/LDV + RBV (n = 1) SOF/LDV + RBV (n = 25) SOF/LDV + GS-9669 (n = 25) Wk 12 SVR12, % 7 SOF 4 mg QD/ledipasvir 9 mg QD; GS mg QD; weight-based RBV -12 mg/day Gane EJ, et al. AASLD 213. Abstract 73. Protease, NS5a, & Nonnucleoside Polymerase Inhibitor + RBV for 12 wks GT1 treatment-naive noncirrhotic pts: ABT-45/RTV/ABT-267 FDC + ABT RBV n/n = / / 322 Kowdley KV, et al. NEJM 214;37: / 151 Overall GT1a GT1b GT1 treatment-experienced noncirrhotic pts (49% null responders): ABT-45/RTV/ABT-267 FDC + ABT RBV n/n = / / / 123 Overall GT1a GT1b 5 drugs (3 pills daily) with < 1% discontinuing treatment 36

37 Boceprevir G1 Telaprevir G1 Vertex 135 MK 8742 MK 5172 Future of HCV Therapies Interferon Free Therapies ABT 45/RTV ABT 267 ABT 333 RBV Asunaprevir Daclatasvir BMS 325 Asunaprevir Daclatasvir Ledipasvir SOF SOF + Riba G2, SOF G1, 4-6, Naive Simeprevir G1 Interferon & Ribavirin Based Therapies Faldaprevir Daclatasvir Daclatasvir Vaniprevir Asunaprevir Protease Inhibitor NS5B Polymerase Inhibitor NS5A Inhibitor Non-nuclease Inhibitor Summary GT 1 patients can be treated with SOF + P/R x 12 weeks in GT1 Off label with SOF + SIM x 12 weeks in GT1 GT 2 patients can be treated with SOF + RBV x 12 weeks GT 3 patients can be treated with SOF + RBV x 24 weeks SOF + PegIFN + RBV x 12 weeks Within the next year we should be PegIFN free 37

38 Hepatitis C Treatment 214 Conclusions 38