Effect of Hepatic Impairment on Sorafenib Pharmacokinetics: Results of a Multicenter, Open-Label, Single-Dose, Phase I Trial J Lettieri, A Mazzu, L Huang, and C Lathia Bayer HealthCare Pharmaceuticals, Montville, NJ 1

Healthy volunteers (control) Study Design Multicenter, open-label, nonrandomized, Phase I study to evaluate the PK profile and safety of oral sorafenib in noncancer participants with hepatic impairment and in healthy volunteers as a control group. All participants were treated with a single 400-mg dose of sorafenib There were 3 cohorts of participants in the study, each with 15 members: Cohort Participants 1 Child-Pugh Class A 2 Child-Pugh Class B 3 Healthy volunteers (control) PK=pharmacokinetic. Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. 2 2 2

Study Design (cont’d) Blood samples for the determination of plasma concentrations of sorafenib and metabolites were collected following study drug administration on Day 1 Blood samples were collected at 0 hour (pre-dose), and at 1, 2, 3, 5, 7, 9, 12, 16, 24, 48, 72, 96, and 120 hours post‑dose. The following PK parameters were derived: AUC, Cmax, tmax, and t½ Safety evaluations included results of physical examination, electrocardiographic evaluation, vital sign assessment, adverse events monitoring, laboratory tests, and use of concomitant medications AUC=area under curve; Cmax=peak concentration; tmax=time to peak concentration; t½=half-life. Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Inclusion Criteria All participants Aged 50 to 75 years Body mass index (BMI) >20 and ≤35 Patients with liver disease* Child-Pugh Class A or B Control participants Healthy volunteers with normal liver function were matched to participants with liver disease with regard to age, weight, gender, and ethnicity * Liver disease was primarily due to hepatitis C (93% of Child-Pugh A patients and 100% of Child-Pugh B patients). Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Exclusion Criteria All Participants Malignancy other than squamous- or basal-cell carcinoma in situ or other malignancies not considered cured according to the criteria of the American Cancer Society Uncontrolled blood pressure (defined as systolic BP ≥160 mm Hg and diastolic BP ≥90 mm Hg) Creatine kinase levels >3 times the upper limit of normal at screening Hematocrit <32% at screening Serum creatinine level >2.0 mg/dL at screening Other abnormal laboratory parameters determined to be clinically significant (in the opinion of the investigator and the sponsor); laboratory values that were slightly outside the normal ranges may have been allowed Major surgery, open biopsy, or significant trauma within 4 weeks of Day 1 BP=blood pressure. Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Exclusion Criteria (cont’d) Patients With Liver Disease Failure of a major organ system other than the liver Elevation of AST, ALT, LDH, bilirubin, and/or all other laboratory parameters related to liver function to levels beyond what would be considered consistent with the diagnosis of liver disease at screening Inability to completely abstain from alcohol consumption for 24 hours before the start of the study (Day 1) and during the study ALT=alanine aminotransferase; AST=aspartate aminotransferase; LDH=lactate dehydrogenase. Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Exclusion Criteria (cont’d) Control Participants Failure of a major organ system or presence of a medical disorder that would impair the participant’s ability to complete the study AST, ALT, and/or LDH >1.2 times the upper limit of normal at screening History of drug or alcohol abuse Positive test for human immunodeficiency virus, hepatitis B virus, or hepatitis C virus Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Patient Demographics Characteristic Child-Pugh Class A (n=15) Child-Pugh Class B (n=15) Healthy Volunteers (n=15) Total (N=45) Male, n (%) 10 (66.7) 13 (86.7) 11 (73.3) 34 (75.6) Female, n (%) 5 (33.3) 2 (13.3) 4 (26.7) 11 (24.4) White, n (%) 14 (93.3) 12 (80.0) 40 (88.9) Black, n (%) 1 (6.7) 4 (8.9) Asian, n (%) 0 (0.0) 1 (2.2) Mean age, years (range) 54.4 (50-58) 57.8 (50-67) 55.8 (51-61) 56.0 (50-67) Weight, kg, (mean+SD) 84.1 (16.9) 78.5 (14.1) 82.8 (6.56) 81.8 (13.2) Height, cm (mean+SD) 171 (7.6) 172 (9.7) 172 (6.0) 172 (7.8) SD=standard deviation. Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Pharmacokinetics PK Assessment of Sorafenib Following a Single 400-mg Dose (geometric mean, % CV) PK Parameter Child-Pugh Class A (n=15) Child-Pugh Class B (n=15) Healthy Volunteers (n=15) AUC, mg-h/L 124 (57%) 107 (75%)* 102 (67%) Cmax, mg/L 4.01 (67%) 3.31 (50%) 3.03 (59%) t½, hours 27.5 (38%) 27.9 (37%) 27.0 (33%) * n=14. CV=coefficient of variation. Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Pharmacokinetics (cont’d) PK Assessment of Metabolite M2 Following a Single 400-mg Dose (geometric mean, % CV) PK Parameter Child-Pugh Class A (n=15) Child-Pugh Class B (n=15) Healthy Volunteers (n=15) AUC, mg-h/L 23.5 (88%)* 30.0 (121%)* 21.1 (72%) Cmax, mg/L 0.89 (84%) 0.97 (87%) 0.78 (59%) t½, hours 27.0 (31%) 25.6 (38%) 27.3 (33%) tmax, hours† 3 (3-12) 5 (2-24) 3 (2-5 ) * n=14; †median (range). Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Pharmacokinetics (cont’d) PK Assessment of Metabolite M4 (demethylated sorafenib) Following a Single 400-mg Dose of Sorafenib (geometric mean, % CV) PK Parameter Child-Pugh Class A (n=15) Child-Pugh Class B (n=15) Healthy Volunteers (n=15) AUC0-tn, mg-h/L 2.29 (217%) 1.68 (1081%) 1.33 (239%) Cmax, mg/L 0.076 (129%) 0.079 (184%) 0.053 (77%) t½, hours 33.9 (78%) 26.9 (38%) 25.8 (53%) tmax, hours* 12 (3-24) 16 (3-24) 9 (3-24) * Median (range). Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Pharmacokinetics (cont’d) Plasma Concentrations of Sorafenib (geometric means) Following a Single 400-mg Dose 10 Child-Pugh A Child-Pugh B Healthy Plasma Concentration (mg/L) 1 0.1 20 40 60 80 100 120 140 Time (hours) Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Pharmacokinetics (cont’d) Results of Statistical Analysis of AUC and Cmax Ratios Between Different Participant Groups Participant Groups Estimated Ratio 90% Confidence Interval A/C AUC 1.22 (0.84-1.77) Cmax 1.32 (0.95-1.85) B/C 1.06 (0.73-1.54) 1.09 (0.78-1.53) B/A 0.86 (0.59-1.26) 0.83 (0.59-1.16) A=Child Pugh A; B=Child Pugh B; C=Healthy. Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Conclusions No evidence for any clinically relevant or statistically significant differences in PK between the 3 participant cohorts (CPA and CPB, and a matched healthy control group) was found in this study, with respect to either sorafenib or its most significant metabolites For unchanged sorafenib, which is the principal drug-related moiety in plasma, slight increases in AUC and Cmax were seen in CPA patients but were not seen in CPB patients, suggesting that these effects are not related directly to hepatic function The 400-mg dose of sorafenib given to the CPA and CPB liver disease patients and to the matched control group of healthy volunteers appeared to be safe and well tolerated based on the review of typically standard protocol- specified safety variables collected and/or monitored in this study. No new or unexpected adverse events were reported Based on these data, no adjustment of sorafenib dose is required in patients with mild to moderate hepatic impairment CPA=Child-Pugh A; CPB=Child-Pugh B. Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.