Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 11 Hemoglobin Decline Associated with SVR Among HCV G1-Infected Persons: Analysis from the IDEAL Study Sulkowski MS, Shiffman ML, Afdhal N, Reddy R, McCone J, Lee WM, Herrine SK, Harrison S, Deng W, Brass CA, Koury K, Noviello S, Albrecht JK, McHutchison JG on behalf of the IDEAL Study Team EASL 2009 Copenhagen, Denmark April 25, 2009

Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 22 Background and Study Design   Treatment-Related Anemia (30% of patients)   Hemolysis (RBV) and bone marrow suppression (PegIFN)   RBV dose reductions and treatment discontinuations   Erythropoietin (EPO) supplementation   Maintains RBV dose levels and improves patient quality of life   Study objectives   To test the hypothesis that treatment related hemoglobin decline are associated with virologic response during treatment with peginterferon and ribavirin therapy   To assess the relationship of anemia, epoetin alfa use and virologic response during treatment with peginterferon and ribavirin

Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 33 Study Schema and Treatment Regimens N = 1019 PEG-IFN alfa-2b 1.5 μg/kg/wk + RBV mg/d ×48 weeks N = 1035 PEG-IFN alfa-2a 180 μg/wk + RBV mg/d ×48 weeks N = 1035 PEG-IFN alfa-2a 180 μg/wk + RBV mg/d ×48 weeks N = 1016 PEG-IFN alfa-2b 1.0 μg/kg/wk + RBV mg/d N = 1016 PEG-IFN alfa-2b 1.0 μg/kg/wk + RBV mg/d ×48 weeks N = 1016 PEG-IFN alfa-2b 1.0 μg/kg/wk + RBV mg/d N = 1016 PEG-IFN alfa-2b 1.0 μg/kg/wk + RBV mg/d ×48 weeks ScreeningScreening Follow-up 24 weeks  Stratified by baseline viral load (> or ≤ 600,000 IU/mL) and race (African American)  Standard response stop criteria applied at weeks 12 (no EVR) and 24 (HCV RNA-positive) HCV RNA a LLQ <27 IU/mL (COBAS TaqMan; Roche) a LLQ <27 IU/mL (COBAS TaqMan; Roche)

Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 44 Anemia and EPO Use   Anemia   Protocol defined as Hb level <10 g/dL   RBV dose reductions   PEG-IFN alfa-2b + RBV arms   Full dose mg  decrease by 200 mg (first dose reduction) then by 200 mg (second dose reduction)   Full dose 1400 mg  decrease by 400 mg (first dose reduction) then by 200 mg (second dose reduction)   PEG-IFN alfa-2a + RBV arm   Full dose mg  decrease to 600 mg (product insert)   EPO use criteria   Permitted in patients with Hb level <10 g/dL with simultaneous RBV dose reduction   At the discretion of investigator and patient   Not provided by study

Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 55 Subject Characteristics: Hgb Decline Hb Decline ≤3 g/dL n=771 Hb Decline >3 g/dL n=2252 P values Male47%64%<.001 Race Caucasian63%75%<.001 African American/Black27%15%<.001 Age, y, mean (SD)45.6 (8.6)48.2 (7.7)<.001 Weight, kg, mean (SD)82.0 (16.9)83.9 (16.1).007 Baseline HCV RNA >600,000 IU/mL79%83%.023 Steatosis Absence40%35%.011 Presence56%60%.038 METAVIR fibrosis score F0/1/288%83%.002 F3/48%12%.004 Baseline Hb conc, g/dL, mean (SD)14.3 (1.2)15.2 (1.2)<.001 Baseline Cr, μmol/L, mean (SD)70.6 (14.2)75.4 (14.0)<.001 Baseline estimated Cr clearance, a mL/min, mean (SD)123.3 (34.0)118.0 (30.8)<.001 Initial RBV dose (mg/kg/d), mean (SD)13.4 (1.6)13.4 (1.5).640 Hb <10 g/dL during treatment5%37%<.001 EPO Use3%20%<.001 a Using Cockcroft-Gault equation. Cr = creatinine.

Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 66 SVR and Maximum Hb Decline

Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 7 EOT a and SVR b Responses by Decline in Hb 7 a EOT rates for >3 g/dL = 61.6% (1386/2250) and ≤3 g/dL = 41.8% (323/773); P < b SVR rates for >3 g/dL = 43.7% (984/2250) and ≤3 g/dL = 29.9% (231/773); P < Hemoglobin Decline Patients, %

Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 88 Subject Characteristics: Anemia/EPO No Anemia (A) n = 2158 Anemia/ No EPO (B) n = 416 Anemia/ EPO (C) n = 449 P A vs B P A vs C P B vs C Male67%38%44%< Race Caucasian72%68%72% African American/Black17%21%20% Age, y, mean (SD)46.8 (7.9)48.7 (8.2)50.2 (7.6)< Weight, kg, mean (SD)84.7 (16.1)79.8 (16.9)80.5 (15.9)< Baseline HCV RNA >600,000 IU/mL83%77%84% Steatosis Absence36%38% Presence60%58%55% METAVIR fibrosis score F0/1/285% 80% F3/410%12%13% Baseline Hb conc, g/dL, mean (SD)15.2 (1.2)14.3 (1.1)14.3 (1.2)< Baseline Cr, μmol/L, mean (SD)74.5 (14.1)72.7 (13.5)74.1 (15.1) Baseline estimated Cr clearance, a mL/min, mean (SD) (31.6)110.2 (30.8)108.9 (28.9)< a Using Cockcroft-Gault equation. Cr = creatinine.

Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 9 Median and Mean RBV Exposure (mg/kg/d) Higher in PEG-IFN alfa-2a Arm Than in alfa-2b Arms PEG-IFN alfa-2a + RBV a P <.001 for PEG-IFN alfa-2b RBV vs PEG-IFN alfa-2a + RBV and for PEG-IFN alfa-2b RBV vs PEG-IFN alfa-2a + RBV; P =.012 for PEG-IFN alfa-2b RBV vs PEG-IFN alfa-2b RBV. b P <.001 for PEG-IFN alfa-2b RBV vs PEG-IFN alfa-2a + RBV; P =.002 for PEG-IFN alfa-2b RBV vs PEG-IFN alfa-2a + RBV; P =.270 PEG-IFN alfa-2b RBV vs PEG-IFN alfa-2b RBV. c P <.001 for PEG-IFN alfa-2b RBV vs PEG-IFN alfa-2a + RBV; P =.001 for PEG-IFN alfa-2b RBV vs PEG-IFN alfa-2a + RBV; P =.616 for PEG-IFN alfa-2b RBV vs PEG-IFN alfa-2b RBV. Treatment No Anemia a Anemia/No EPO b Anemia/EPO c PEG-IFN alfa-2b RBV PEG-IFN alfa-2b RBV Mean (SD) 12.6 (1.3)11.5 (1.7)11.7 (2.0) Mean (SD) 12.8 (1.2)11.8 (1.7)11.8 (1.4) Mean (SD) 13.4 (2.0)12.6 (2.7)12.5 (2.3) Median RBV Exposure, mg/kg/d

Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 10 Early Anemia Treated with EPO Resulted in Higher SVR Rate* Onset of Anemia Anemia/No EPO % (n/N) Anemia/EPO % (n/N) P-value ≤4 weeks of treatment23.5% (19/81)43.0% (58/135).004 >4-8 weeks of treatment29.0% (18/62)47.6% (49/103).019 >8-12 weeks of treatment51.6% (32/62)47.4% (27/57).644 >12 weeks of treatment61.6% (130/211)57.8% (89/154).462 *P<0.001 for early anemia (≤8 weeks of treatment).

Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 11 Lower Discontinuation Rates in Early Anemia Treated with EPO Onset of Anemia Anemia/No EPO % (n/N) Anemia/EPO % (n/N) P-value ≤4 weeks of treatment6% (5/81)<1% (1/135).019 >4-8 weeks of treatment29% (18/62)2% (2/103)<.001 >8-12 weeks of treatment6% (4/62)14% (8/57).170 >12 weeks of treatment22% (46/211)27% (42/154).227

Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 12 Odds Ratios for SVR (EPO vs No EPO) 12 Onset of AnemiaModelOdds Ratio (95% CI)P-Value Early (<=8 weeks)Unadjusted a 2.34 (1.49, 3.68)<0.001 Model 1 b 3.52 (2.05, 6.03)<0.001 Model 2 c 3.13 (1.86, 5.28)<0.001 Late (> 8 weeks)Unadjusted a 0.84 (0.58, 1.20)0.336 Model 1 b 0.95 (0.62, 1.45)0.806 Model 2 c 0.92 (0.61, 1.39)0.699 All Anemic SubjectsUnadjusted a 1.08 (0.82, 1.41)0.591 Model 1 b 1.35 (0.99, 1.84)0.059 Model 2 c 1.29 (0.96, 1.75)0.097 a No control for potentially confounding factors. b Odds ratio adjusted for all potentially confounding factors (age, gender, race, BMI, baseline viral load, fibrosis, steatosis, fasting glucose, ALT, hemoglobin, platelet count, ribavirin (mg/kg/day) assigned, genotype (1a, 1b), and body weight). c Odds ratio adjusted for factors related to outcome (stepwise variable selection procedure based on all anemic subjects: race, baseline viral load, fibrosis, steatosis, fasting glucose, and body weight).

Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 13 Safety No AnemiaAnemia a / No EPOAnemia a /EPO Serious adverse events9%12%14% Relevant adverse events, % Fatigue64%67%74% Anaemia b 9%87%97% Dyspnea/exertional dyspnea19%29%33% Cardiac events Hypertension4% Increased blood pressure1%<1%1% Myocardial infarction<1% Coronary artery disease<1% 0 Congestive heart failure0<1% Angina pectoris<1%00 Thromboembolic events Pulmonary embolism<1%0 Deep venous thrombosis<1%01% Cerebrovascular accident00<1% Cerebral hemorrhage<1%00 Cancer1%<1%1% a Anemia based on Hb conc <10 g/dL. b Anemia based on adverse event as reported by the investigator.

Sulkowski MS, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/25/09 14 Conclusions   Higher magnitude of Hb decline is associated with higher likelihood of SVR   EPO use was associated with higher SVR rates if anemia occurred in the first 8 weeks of treatment   No benefit of EPO use in patients who became anemic after 8 weeks of treatment   Magnitude of Hb decline may be a pharmacokinetic marker for efficacy of treatment and EPO may prevent treatment discontinuation in patients with early anemia