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The next generation of Treatment for 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%.

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The next generation of Treatment for Hepatitis C

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  1. The next generation of Treatment for Hepatitis C

  2. 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%

  3. Evolution of HCV genotype 1 treatment 100 80 • 42–54% Peg-IFN + RBV2–4 • 16–28% 60 IFN + RBV1 SVR rate (%) • 2–7% IFN1 40 20 1990 2000 2020 2010 • IFN: interferon; RBV: ribavirin Peg-IFN: peginterferonDAA: direct-acting antiviralSVR: sustained virologic response 1. McHutchison JG, et al. N Engl J Med 1998;339:1485–92; 2. Fried M, et al. N Engl J Med 2002;347:975–823. Manns MP, et al. Lancet 2001;358:958–65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346–555. Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14

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

  5. New treatment for Genotype 1 HCV(Rx naïve patients)

  6. 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 therapy4–6 • 54–75% SVR with boceprevir-based therapy7 • Telaprevir and boceprevir have recently completed Phase III trials in treatment-naïve patients • Telaprevir: ADVANCE8 and ILLUMINATE9 • Boceprevir: SPRINT-210

  7. Pbo + PR TVR + PR PR PR PR PR Pbo + PR TVR + PR PR ADVANCE (telaprevir): study design (N=1088) PR48 (control)(N=361) SVR Follow-up SVR eRVR+ Follow-up Follow-up T12PR(N=363) eRVR– SVR Follow-up SVR eRVR+ Follow-up Follow-up T8PR(N=364) SVR eRVR– Follow-up 0 8 12 24 36 48 72 Weeks Peg-IFN alfa-2a dose: 180 µg/week; RBV dose: 1000 or 1200 mg/dayeRVR: 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

  8. SVR SVR SVR SVR PRlead-in PRlead-in PRlead-in Follow-up PR + Placebo Follow-up Follow-up Follow-up PR + Boceprevir PR + Boceprevir PR + Placebo SPRINT-2 (boceprevir): study design (N=1097) PR48 ControlN=363 Weeks 8–24 HCV RNA undetectable BOC RGT N=368 Weeks 8–24 HCV RNA detectable* BOC44/ PR48 N=366 24 28 0 4 8 48 72 Weeks *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 doseRGT: response-guided therapy Poordad F, et al. Hepatology 2010;52(Suppl.):402A

  9. eRVR+ T12PR48N=160 eRVR+ T12PR24 N=162 eRVR– T12PR48 N=118 PR PR PR T12PR PR ILLUMINATE (telaprevir): study design (N=540) SVR 72 weeks Follow-up Follow-up Non-inferiority (NI) Randomized Treatments eRVR+ SVR Follow-up Assigned Treatment SVR eRVR– Follow-up 0 12 20 20 24 36 48 60 72 Weeks Patients discontinued for any reason before Week 20 randomization were categorized as ‘Other’ (N=100)Stopping rules were similar to ADVANCE Sherman KE, et al. Hepatology 2010;52(Suppl.):401A

  10. ADVANCE and ILLUMINATE: SVR rates with telaprevir-based therapy versus PR alone 72–75* T12PR 659/903 PR48 158/361 Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A; Sherman KE, et al. CROI 2011. Abstract 957 *p<0.0001 vs PR48 in ADVANCE (75% versus 44%)

  11. SPRINT-2: SVR rates with boceprevir-based therapy versus PR alone BOC44/PR48 242/366 PR48 137/363 BOC RGT 233/368 For non-Black patients, p<0.0001 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 Adapted from Poordad F, et al. Hepatology 2010;52(Suppl.):402A

  12. Tripple therapy works in advanced fibrosisADVANCE (telaprevir): SVR rates by fibrosis stage ADVANCE1 No, minimal or portal fibrosis Bridging fibrosis or cirrhosis SVR (%) PR48134/288 T12PR226/290 PR4824/73 T12PR45/73 n/N= 1. Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A;

  13. Tripple therapy works in all IL28B genotypesADVANCE (telaprevir): SVR rates by IL28B genotype CC CT TT SVR (%) PR4820/80 T12PR48/68 PR4835/55 T12PR45/50 PR486/26 T12PR16/22 n/N= Samples were available for 454/1088 (42%) patients enrolled in ADVANCE Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542

  14. 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 Characteristics3. 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):147. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Bacon BR, et al. Hepatology 2010;52(Suppl.):430A AE: adverse event

  15. Evolution of HCV genotype 1 treatment 100 • 59–75% DAA+Peg-IFN + RBV5–8 80 • 42–54% Peg-IFN + RBV2–4 • 16–28% 60 IFN + RBV1 SVR rate (%) • 2–7% IFN1 40 20 1990 2000 2020 2010 • IFN: interferon; RBV: ribavirin Peg-IFN: peginterferonDAA: direct-acting antiviralSVR: sustained virologic response 1. McHutchison JG, et al. N Engl J Med 1998;339:1485–92; 2. Fried M, et al. N Engl J Med 2002;347:975–823. Manns MP, et al. Lancet 2001;358:958–65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346–555. Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14

  16. What about Genotype 1 patients with previous treatment failure?

  17. Definitions of failure on prior Peg-IFN/RBV therapy Null response Relapse Non-response 2 log10 drop HCV RNA level Partial response Detection limit Treatment Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:46–52Neumann A, et al. Science 1998;282:103–7; De Bruijne J, et al. Neth J Med 2008;66:311–22

  18. REALIZE (telaprevir): SVR in prior relapsers, partial responders and null responders Prior relapsers Prior partialresponders Prior null responders * * * * SVR (%) * * LI T12/PR4826/48 T12/PR4829/49 PR48 4/27 PR48 2/37 LI T12/PR4825/75 T12/PR4821/72 PR48 16/68 LI T12/PR48124/141 T12/PR48121/145 n/N= *p<0.001 vs PR48; post-hoc analysis Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):14

  19. RESPOND-2 (boceprevir): SVR in prior relapsers and partial responders Prior relapsers Prior partialresponders Prior null responders were excluded from RESPOND-2 SVR (%) BOCRGT 23/57 BOC44/PR4830/58 PR48 2/29 PR48 15/51 BOC RGT 72/105 BOC44/PR4877/103 n/N= Bacon BR, et al. Hepatology 2010;52(Suppl.):430A

  20. 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

  21. 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 - 8000 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

  22. Who will get the new drugs?

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