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 phone fax

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

Pre-treatment predictors of response Telaprevir based therapy 3

Significantly Higher SVR rates in Telaprevir- Treated Patients Compared to Peg IFN/Ribavirin Alone SVR P< /363158/361n/N = Percent of patients with SVR T12PRPR Jacobson IM, et al. NEJM 2011

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

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

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

Role of HCV Genotype  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 8 Journal of Medical Virology 81:2029–2035 (2009) Journal of Medical Virology 83:437–444 (2011) Science, 2000

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

Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% Fibrosis F0-F1 F2 F3 F (7/21) 48 Patients Achieving SVR (%) 75% 25% ADVANCE Study: Influence of hepatic fibrosis on SVR with PegIFN/RBV ±Telaprevir 62 (13/21) 33 PR+TVR PR 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; 100% 0 % 50% IL-28B CC CT TT 73 Patients Achieving SVR (%) 75% 25% ADVANCE Study: Role of IL28B on SVR with PegIFN/RBV ±Telaprevir PR+TVR PR % (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 IL-28B CC CT TT

On treatment response predicts SVR with Telaprevir based therapy 12

ADVANCE/ILLUMINATE: Anemia and Ribavirin dose reduction did not predict SVR in Telaprevir arms AnemiaNo Anemia RBV Dose Reduction No RBV Dose Reduction 145/ / / / / / / / / / / / / / / / 245 n/N = Anemia :Hgb < 10 g /dl

SVR Rates According to Maximum Hemoglobin Decrease from Baseline 0/6244/ Patients with SVR (%) T12PR n/N = /19211/ PR 53/86 135/ 178 1/435/ 74 4/1442/ 92 27/6545/ 105 ≤ 1> 1-2> 2-3> 3-4> 4-5> 5 g/dL

Achieving extended RVR Associated with SVR 189/21228/29130/33282/ eRVR+ eRVR- n/N = Percent of patients with SVR (All patients received 48 weeks regimen) (TVR patients received a 24 weeks regimen) T12PRPR

SPRINT 2: SVR* and Relapse Rates p < Non-Black Patients p = p =0.004 Black Patients SVR Relapse Rate *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

Pre-treatment predictors of response Boceprevir based therapy 17

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

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

Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% Patients Achieving SVR (%) 75% 25% SPRINT 2 : Influence of Viral Level on SVR with PegIFN/RBV ±Boceprevir PR+BOCPR+ BOC RGT PR HCV RNA < 800,000 ≥ 800,000 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; 100% 0 % 50% Genotype Patients Achieving SVR (%) 75% 25% 1b 1a SPRINT 2 : Influence of HCV Genotype on SVR with PegIFN/RBV ±Boceprevir Genotype 1b 1a PR+BOC PR+ BOC RGT Genotype 1b 1a PR 40 35

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

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

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

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 25 Pandya Gastro 2011 Hepatology Jul;50(1):6-16.

SPRINT-2: SVR by IL28B Polymorphism % SVR *~90% eligible for short duration therapy * 62% of individuals (653/1048) had consented to IL28 pharmacogenomic studies

On treatment response predicts SVR with Boceprevir based therapy 27

SVR by Week 4 PR Lead-In Response Non-Black PatientsBlack Patients ≥1 log 10 HCV RNA decline from baseline <1 log 10 HCV RNA decline from baseline SVR (%)

IL28B is no longer an important predictor of SVR when Lead-in Response is considered SPRINT-2 (effect)Odds Ratio (95% CI)p-value BOC/PR48 vs PR487.0 (4.1, 12.0)< BOC/RGT vs PR486.0 (3.5, 10.2)< Baseline HCV-RNA: ≤400,000 vs. >400,000 IU/mL5.8 (1.9, 17.5)0.002 Log decline in HCV-RNA at TW 4 (continuous variable) 2.6 (2.1, 3.0)< Genotype: 1b/others vs 1a2.3 (1.5, 3.6)< BMI: kg/m 2 vs. >30 kg/m (1.4, 3.9)0.002 BMI: ≤25 kg/m 2 vs. >30 kg/m (1.1, 3.3)0.02 Only covariates remaining significant at α=0.05 after adjustment for the other variables were retained in the model as shown in the table.

Anemia on treatment was identified as a significant factor for attaining SVR (P<0.001) SVR by Absence/Presence of Anemia Sulkowski M, et al. EASL 2011, Abst SVR (%) Hb ≥10g/dL Hb <10g/dL Hb ≥10g/dL Hb <10g/dL PR48 BOC/PR SPRINT

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 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 31