Hepatitis C The next generation of Treatment for Hepatitis C

Treatment of CHC: Outcomes  Goal of therapy is to render the patient PCR negative for HCV RNA  Need to remain PCR negative 6 months after end of therapy  Response rates for combination therapy  Genotype 1 up to 40%  Genotypes 2 or 3 up to 80%

Evolution of HCV genotype 1 treatment 1. McHutchison JG, et al. N Engl J Med 1998;339:1485–92; 2. Fried M, et al. N Engl J Med 2002;347:975–82 3. Manns MP, et al. Lancet 2001;358:958–65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346–55 5. Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A 7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14 IFN: interferon; RBV: ribavirin Peg-IFN: peginterferon DAA: direct-acting antiviral SVR: sustained virologic response SVR rate (%) 2–7% IFN 1 16–28% IFN + RBV 1 42–54% Peg-IFN + RBV 2–

Treatment Issues Genotypes 2/3 – nothing new on horizon Genotype 1 – failure rate 50-60% No good options for treatment failures

New treatment for Genotype 1 HCV (Rx naïve patients)

Direct Acting Anivirals (DAAs) DAA-based triple combination therapy led to improved SVR rates over current therapy in Phase II trials –61–85% SVR with telaprevir-based therapy 4–6 –54–75% SVR with boceprevir-based therapy 7 Telaprevir and boceprevir have recently completed Phase III trials in treatment-naïve patients –Telaprevir: ADVANCE 8 and ILLUMINATE 9 –Boceprevir: SPRINT-2 10

ADVANCE (telaprevir): study design (N=1088) Weeks T12PR (N=363) TVR + PR Follow-up SVR PR eRVR+ Follow-up SVR PR Follow-up SVR TVR + PR T8PR (N=364) PR Pbo + PR Follow-up SVR eRVR+ PR Follow-up eRVR– Follow-up PR48 (control) (N=361) SVR Pbo + PRPR Peg-IFN alfa-2a dose: 180 µg/week; RBV dose: 1000 or 1200 mg/day eRVR: extended rapid virologic response (undetectable HCV RNA at Weeks 4 and 12); Pbo: placebo; PR: peginterferon/ribavirin; TVR: telaprevir Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A

SPRINT-2 (boceprevir): study design (N=1097) Follow-up SVR Follow-up SVR Follow-up SVR PR + Boceprevir PR lead-in PR + Placebo PR48 Control N=363 BOC RGT N=368 BOC44/ PR48 N=366 Weeks 8–24 HCV RNA undetectable Weeks 8–24 HCV RNA detectable* PR lead-in PR + Placebo Weeks Follow-up SVR 24 *But with undetectable HCV RNA at Week 24 Peg-IFN alfa-2b dose: 1.5 µg/kg/week RBV dose: 600–1400 mg/day in a divided daily dose RGT: response-guided therapy *But with undetectable HCV RNA at Week 24 Peg-IFN alfa-2b dose: 1.5 µg/kg/week RBV dose: 600–1400 mg/day in a divided daily dose RGT: response-guided therapy Poordad F, et al. Hepatology 2010;52(Suppl.):402A

ILLUMINATE (telaprevir): study design (N=540) Follow-up SVR Follow-up SVR PR Randomized Treatments Follow-up SVR PR Assigned Treatment eRVR– eRVR+ Non-inferiority (NI) Follow-up 72 weeks T12PRPR eRVR+ T12PR24 N=162 eRVR+ T12PR48 N=160 eRVR– T12PR48 N=118 Weeks Sherman KE, et al. Hepatology 2010;52(Suppl.):401A Patients discontinued for any reason before Week 20 randomization were categorized as ‘Other’ (N=100) Stopping rules were similar to ADVANCE

ADVANCE and ILLUMINATE: SVR rates with telaprevir- based therapy versus PR alone T12PR 659/903 T12PR 659/903 PR48 158/361 PR48 158/361 72–75* Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A; Sherman KE, et al. CROI Abstract 957 *p< vs PR48 in ADVANCE (75% versus 44%)

SPRINT-2: SVR rates with boceprevir-based therapy versus PR alone BOC RGT 233/368 BOC RGT 233/368 BOC44/PR48 242/366 BOC44/PR48 242/366 PR48 137/363 PR48 137/363 Adapted from Poordad F, et al. Hepatology 2010;52(Suppl.):402A For non-Black patients, p< for both boceprevir arms versus PR48; for Black patients, p=0.044 and p=0.004 for BOC RGT and BOC44/PR48, respectively, versus PR48

Tripple therapy works in advanced fibrosis ADVANCE (telaprevir): SVR rates by fibrosis stage SVR (%) PR48 134/288 n/N= ADVANCE 1 1. Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A; T12PR 226/290 PR48 24/73 T12PR 45/73 No, minimal or portal fibrosis Bridging fibrosis or cirrhosis

Tripple therapy works in all IL28B genotypes ADVANCE (telaprevir): SVR rates by IL28B genotype Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542 SVR (%) PR48 35/55 n/N= CCTT T12PR 45/50 PR48 6/26 T12PR 16/22 PR48 20/80 T12PR 48/68 CT Samples were available for 454/1088 (42%) patients enrolled in ADVANCE

Safety and tolerability with DAAs Common AEs with PR include: 1–3 –Fatigue, headache, nausea, pyrexia and myalgia –Anemia and neutropenia –Depression, irritability and insomnia –Rash Additional management considerations with DAAs –Telaprevir: 4–6 rash, anemia –Boceprevir: 7,8 anemia and dysgeusia 1. Pegintron EMA Summary of Product Characteristics; 2. Pegasys EMA Summary of Product Characteristics 3. Rebetol EMA Summary of Product Characteristics; 4. Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A 5. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A; 6. Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):14 7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Bacon BR, et al. Hepatology 2010;52(Suppl.):430A AE: adverse event

Evolution of HCV genotype 1 treatment 1. McHutchison JG, et al. N Engl J Med 1998;339:1485–92; 2. Fried M, et al. N Engl J Med 2002;347:975–82 3. Manns MP, et al. Lancet 2001;358:958–65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346–55 5. Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A 7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14 IFN: interferon; RBV: ribavirin Peg-IFN: peginterferon DAA: direct-acting antiviral SVR: sustained virologic response SVR rate (%) 2–7% IFN 1 16–28% IFN + RBV 1 42–54% Peg-IFN + RBV 2–4 59–75% DAA + Peg-IFN + RBV 5–

What about Genotype 1 patients with previous treatment failure?

Definitions of failure on prior Peg-IFN/RBV therapy Detection limit Relapse Null response Partial response Treatment HCV RNA level 2 log 10 drop Non-response Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:46–52 Neumann A, et al. Science 1998;282:103–7; De Bruijne J, et al. Neth J Med 2008;66:311–22

REALIZE (telaprevir): SVR in prior relapsers, partial responders and null responders PR48 4/27 T12/ PR48 29/49 SVR (%) Prior relapsersPrior partial responders LI T12/ PR48 26/48 n/N= PR48 2/37 T12/ PR48 21/72 LI T12/ PR48 25/75 PR48 16/68 T12/ PR48 121/145 LI T12/ PR48 124/141 Prior null responders * * * * * * Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):14 *p<0.001 vs PR48; post-hoc analysis

RESPOND-2 (boceprevir): SVR in prior relapsers and partial responders PR48 2/29 BOC44/ PR48 30/58 SVR (%) Prior relapsersPrior partial responders BOC RGT 23/57 n/N= PR48 15/51 BOC44/ PR48 77/103 BOC RGT 72/105 Prior null responders were excluded from RESPOND-2 Bacon BR, et al. Hepatology 2010;52(Suppl.):430A

Summary of Tripple therapy with DAAs Only for Genotype 1 Hepatitis C Uses Peg Inf + Ribavirin + DDA Improved response in naïve patients (65-75%) Improved response in prior non-responders Improved response in difficult to treat groups

COST  Cost of treatment  genotype 1 £12,782 for 48 weeks treatment  genotype 2 or 3 £5,233 for 24 weeks  Supportive therapy with:  Epoetin units twice weekly = £3,216 for 6 months  G-CSF - Neupogen 30million units/wk = £1752 for 6 months  Cost of addition of DAA £14,000 - £24,000  To be confirmed Sept 2011

Who will get the new drugs?