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Paul Y Kwo, MD Professor of Medicine Medical Director, Liver Transplantation

Predictors of response with boceprevir and telaprevir combined with pegylated interferon and ribavirin. Paul Y Kwo, MD Professor of Medicine Medical Director, Liver Transplantation Gastroenterology/Hepatology Division Indiana University School of Medicine 975 W. Walnut, IB 327

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Paul Y Kwo, MD Professor of Medicine Medical Director, Liver Transplantation

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  1. Predictors of response with boceprevir and telaprevir combined with pegylated interferon and ribavirin Paul Y Kwo, MD Professor of Medicine Medical Director, Liver Transplantation Gastroenterology/Hepatology Division Indiana University School of Medicine 975 W. Walnut, IB 327 Indianapolis, IN 46202-5121 phone 317-274-3090 fax 317-274-3106 pkwo@iupui.edu

  2. Factors Predictive of Response to IFN/RBV based therapy 1995-2000 • Genotype 2/3 • No advanced fibrosis • Low viral load • Younger age • <40 years • Female • Weight 2007-2011 • Lack of steatosis/insulin resistance • Adherence • Rapid viral response (RVR) • Ribavirin dosage • Race/ethnicity • IL-28B • Anemia 2011-present • Race/ethnicity • low viral load • absence of cirrhosis • statin use • IIL-28B • Genotype 1a/1b • On treatment viral response • Lead-in • eRVR McHutchison JG, et al. N Engl J Med. 2009;361(6):580-593. Manns MP, et al. Lancet. 2001;358(9286):958-965. Patton HM, et al. J Hepatol. 2004;40(3):484-490. Poynard T, et al. Lancet. 1998;352(9138):1426-1432.

  3. Pre-treatment predictors of responseTelaprevir based therapy

  4. T12PR PR Significantly Higher SVR rates in Telaprevir-Treated Patients Compared to Peg IFN/Ribavirin Alone P<0.0001 100 90 75 80 70 60 Percent of patients with SVR 44 50 40 30 20 10 0 n/N = 271/363 158/361 SVR Jacobson IM, et al. NEJM 2011

  5. ADVANCE Study: Influence of race on SVR with PegIFN/RBV ±Telaprevir 100% PR+TVR PR 75 75% 62 (16/26) 46 50% Patients Achieving SVR (%) 25 (7/28) 25% 0 % Race White Black Race White Black Jacobson NEJM 2011

  6. ADVANCE Study: Role of Age on SVR with PegIFN/RBV ±Telaprevir 100% PR+TVR PR 83 70 75% 52 50% Patients Achieving SVR (%) 38 25% 0 % Age Age < 45 ≥ 45<65 < 45 ≥ 45<65 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;

  7. ADVANCE Study: Role of viral level on SVR with PegIFN/RBV ±Telaprevir 100% PR+TVR PR 78 70 74 75% 50% Patients Achieving SVR (%) 36 25% 0 % HCV RNA < 800,000 ≥ 800,000 HCV RNA < 800,000 ≥ 800,000 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;

  8. Role of HCV Genotype Journal of Medical Virology 81:2029–2035 (2009) Journal of Medical Virology 83:437–444 (2011) Science, 2000 • Evidence that 1a more difficult to treat than 1b with PR • Genotype 1a associated with lower SVR than genotypes 1b, 4a, and 4d when treated with PR for 48 weeks in 537 patients • Genotype 1a associated with lower SVR in 115 patients receiving PR for 48 weeks than 1b • Initial HCV subgenomic replicons derived from genotype 1b virus

  9. ADVANCE Study: Influence HCV Genotype on SVR with PegIFN/RBV ±Telaprevir 100% PR+TVR 79 71 75% PR 48 41 50% Patients Achieving SVR (%) 25% 0 % Genotype Genotype 1b 1a 1b 1a Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;

  10. ADVANCE Study: Influence of hepatic fibrosis on SVR with PegIFN/RBV ±Telaprevir 100% PR+TVR PR 81 75 75% 62 62 (13/21) 48 46 50% Patients Achieving SVR (%) 33 (7/21) 33 25% 0 % Fibrosis F0-F1 F2 F3 F4 Fibrosis F0-F1 F2 F3 F4 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;

  11. ADVANCE Study: Role of IL28B on SVR with PegIFN/RBV ±Telaprevir 42% (454 of 1088) of patients available for IL28B analysis; all patients were white TVR increased SVR rates across IL28B genotypes, but CC still did better 100% 90 PR+TVR 73 71 PR 75% 64 50% Patients Achieving SVR (%) 25% 25 23 0 % IL-28B CC CT TT IL-28B CC CT TT Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;

  12. On treatment response predicts SVR with Telaprevir based therapy

  13. ADVANCE/ILLUMINATE: Anemia and Ribavirin dose reduction did not predict SVR in Telaprevir arms Anemia :Hgb < 10 g /dl n/N = n/N =

  14. SVR Rates According to Maximum Hemoglobin Decrease from Baseline ≤ 1 > 1-2 > 2-3 > 3-4 > 4-5 > 5 g/dL 77 76 76 62 46 47 42 43 42 Patients with SVR (%) 29 25 0 0/6 8/19 53/86 211/ 275 244/ 321 1/4 4/14 27/65 45/ 105 42/ 92 35/ 74 135/ 178 n/N = T12PR PR

  15. T12PR PR Achieving extended RVR Associated with SVR 97 100 89 90 80 70 54 60 Percent of patients with SVR 50 39 40 30 20 10 0 n/N = 189/212 28/29 82/151 130/332 eRVR- eRVR+ (TVR patients received a 24 weeks regimen) (All patients received 48 weeks regimen)

  16. SPRINT 2: SVR* and Relapse Rates SVR Relapse Rate p <0.0001 p =0.004 p < 0.0001 p = 0.044 211 316 213 311 29 55 125 311 22 52 37 162 12 52 6 35 21 232 18 230 2 14 3 25 Non-Black Patients Black Patients *SVR was defined as undetectable HCV RNA at the end of the follow-up period. The 12-week post-treatment HCV RNA level was used if the 24-week post-treatment level was missing (as specified in the protocol). A sensitivity analysis was performed counting only patients with undetectable HCV RNA documented at 24 weeks post-treatment and the SVR rates for Arms 1, 2 and 3 in Cohort 1 were 39%, 66% and 68%, respectively and in Cohort 2 were 21%, 42% and 51%, respectively.

  17. Pre-treatment predictors of responseBoceprevir based therapy

  18. SPRINT 2 : Influence of Race on SVR with PegIFN/RBV ±Boceprevir 100% PR+ BOC RGT PR+BOC PR 68 67 75% 53 (29/55) 42 (22/52) 50% Patients Achieving SVR (%) 40 23 (12/52) 25% 0 % Race Race Race White Black White Black White Black Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;

  19. SPRINT 2 : Influence of Age on SVR with PegIFN/RBV ±Boceprevir 100% PR+ BOC RGT PR+BOC PR 73 65 69 64 75% 52 34 50% Patients Achieving SVR (%) 25% 0 % Age Age Age < 40 >40 < 40 >40 < 40 >40 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;

  20. SPRINT 2 : Influence of Viral Level on SVR with PegIFN/RBV ±Boceprevir 100% PR+BOC PR+ BOC RGT PR 85 76 63 75% 61 64 50% Patients Achieving SVR (%) 33 25% 0 % HCV RNA HCV RNA HCV RNA < 800,000 < 800,000 < 800,000 ≥ 800,000 ≥ 800,000 ≥ 800,000 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;

  21. SPRINT 2 : Influence of HCV Genotype on SVR with PegIFN/RBV ±Boceprevir 100% PR+ BOC RGT PR+BOC PR 70 66 63 75% 59 50% Patients Achieving SVR (%) 40 35 25% 0 % Genotype Genotype 1b 1a Genotype 1b 1a 1b 1a Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;

  22. SPRINT 2 : Influence of Fibrosis on SVR with PegIFN/RBV ±Boceprevir 100% PR+ BOC RGT PR+BOC PR 67 67 75% 52 (22/42) 41 14/34) 50% Patients Achieving SVR (%) 38 (9/34) 38 25% 0 % Fibrosis Fibrosis Fibrosis F0-F2 F3-F4 F0-F2 F3-F4 F0-F2 F3-F4 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;

  23. SPRINT 2 : Influence of Cirrhosis SVR with PegIFN/RBV ±Boceprevir 100% PR+ BOC RGT PR+BOC PR 67 75% 66 42 (10/24) 46 (6/13) 50% Patients Achieving SVR (%) 37 31 (5/16) 25% 0 % No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;

  24. SPRINT 2 : Influence of Statin use on SVR with PegIFN/RBV ±Boceprevir PR PR+BOC PR+ BOC RGT 86 (6/7) 100 (3/3) 100% 67 (6/9) 66 75% 63 50% Patients Achieving SVR (%) 37 25% 0 % Statin user non-statin user Statin user non-statin user Statin user non-statin user Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;

  25. Why would statin use be associated with SVR? • HCV forms lipoviral particles which represent the primary form of HCV within the circulation • LDL receptor is thought to play a role in the receptor binding and endocytosis of the virus • Antiviral effects of statins have been shown with HIV-1 respiratory syncytial virus, and HCV • Higher SVR rates with PR reported for those taking statins • Statins reduce/delay resistance in combination with HCV protease inhibitors • Significant Drug-Drug interactions occur with TVR/BOC w and certain statins Pandya Gastro 2011 Hepatology. 2009 Jul;50(1):6-16.

  26. SPRINT-2: SVR by IL28B Polymorphism 62% of individuals (653/1048) had consented to IL28 pharmacogenomic studies % SVR 50 64 63 77 44 55 33 116 67 103 82 115 10 37 23 42 26 44 * *~90% eligible for short duration therapy

  27. On treatment response predicts SVR with Boceprevir based therapy

  28. SVR by Week 4 PR Lead-In Response ≥1 log 10 HCV RNA decline from baseline <1 log 10 HCV RNA decline from baseline 178 218 187 228 16 24 22 36 SVR (%) SVR (%) 121 234 12 26 31 79 5 16 21 73 6 24 3 62 0 21 Non-Black Patients Black Patients

  29. IL28B is no longer an important predictor of SVR when Lead-in Response is considered Only covariates remaining significant at α=0.05 after adjustment for the other variables were retained in the model as shown in the table.

  30. SVR by Absence/Presence of Anemia Anemia on treatment was identified as a significant factor for attaining SVR (P<0.001) SPRINT-2 PR48 BOC/PR SVR (%) 80 109 263 362 77 246 212 363 Hb ≥10g/dL Hb <10g/dL Hb ≥10g/dL Hb <10g/dL Sulkowski M, et al. EASL 2011, Abst. 476.

  31. Summary: Addition of TVR or BOC to Peg IFN/RBV improves SVR rates across all treatment groups • Black race, high baseline HCV RNA, genotype 1a, age, cirrhosis all with lower SVR rates • Anemia, statin use predicts SVR with BOC • IL-28B • CC: High likelihood of 24-28 weeks of therapy • CT/TT : marked improvement with TVR/BOC addition • On treatment response remains strongest predictor of SVR • Response to 4 week lead –in • Achieving eRVR

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