Frequencies of Resistance-Associated Amino Acid Variants Following Combination Treatment with Boceprevir (BOC) Plus PEGINTRON (PegInterferon Alfa-2b) and Ribavirin (P/R) in Patients With Chronic Hepatitis C (CHC), Genotype 1 (G1) Richard J.O. Barnard, Lisa D. Pedicone, Eirum Chaudhri, Xiao Tong, Ping Qiu, Clifford A. Brass, Janice K. Albrecht, Patricia Mendez, and Robert Ralston

SPRINT-1 Methods Phase 2 study of previously untreated adults with genotype 1 HCV Part patients randomized to receive Peg-interferon (P)/Ribavirin (R) for 48 weeks (control) or one of four boceprevir regimens – Arms 3 and 5 of Part 1 received a 4 week lead-in with P/R prior to the addition of boceprevir to: o Achieve steady state of P/R prior to adding 3rd drug o Up-regulate immune response elements o Decrease viral load and quasispecies, thereby decreasing resistance Part patients randomized to receive P/R and low- dose ribavirin

Definitions Sustained Virologic Response (SVR): Plasma HCV-RNA level below the lower limit of detection at follow-up week 12 Incomplete Virologic Response (IVR): A 2 log 10 increase in HCV-RNA viral load compared with the previous two visits and HCV viral load 50,000 IU/mL Viral Breakthrough (BT): Undetectable HCV-RNA and subsequent HCV-RNA 2 log 10 elevation during therapy Relapse (RL): Undetectable HCV-RNA at end of treatment and detectable HCV RNA at follow-up week 24 Nonresponder (NR) (treatment failure): o Subjects in Arm 1 with detectable HCV-RNA at treatment week 24 who crossed over to boceprevir o Subjects in any of the seven treatment arms with detectable HCV-RNA at end of therapy and at follow-up week 24 o Subjects in any of the seven treatment arms with missing HCV-RNA values at follow-up week 24 and do not have an undetectable HCV-RNA at follow-up week 12 Resistance Associated Amino Acid Variant (RAV)

SPRINT-1 Study Design and Sustained Virologic Response

Table 1. Subjects with Baseline RAVs Previously Demonstrated to Confer Reduced Susceptibility to Boceprevir in vitro

Number of RAVs Detected by HCV Genotype 49% 52%

Number of Subjects Having RAVs Detected Post- baseline, Including All Patients Treated with Boceprevir V36A V36G V36I V36L V36M Q41H T54A T54C T54S V55A R155I R155K R155M R155TA156S A156T V158I V158M I170A Patients, n V36A V36G V36I V36L V36M Q41H T54A T54C T54S V55A R155I R155K R155M R155TA156S A156T V158I V158M I170A Patients, n

Frequency of RAVs for Different Treatment Response Categories IVR = Incomplete Virologic Response, BT = Breakthrough RL = Relapse, NR = Non-responder IVRBTRLNR Patients, n Subjects with Variants Detected Subjects with no Variants Detected

RAVs Detected in BOC 28 and 48 Week Treatment Arms Lead-in Arm 2Arm 3Arm 4Arm 5Arm 6Arm 7 Patients, n Subjects Subjects with RAVs Subjects without RAVs

RAVs Detected with No Lead-in (Arm 2) vs. Lead- in (Arm 3) Study Arms (i.e. Arms where Patients Received a Shorter Duration of Treatment with Boceprevir) V36AV36G V36I V36L V36M Q41H T54A T54C T54S V55A R155I R155K R155M R155T A156S A156T V158I V158M I170A I170T V36Apct V36Gpct V36Ipct V36Lpct Patients, n Lead-in No Lead-in

RAVs Detected with No Lead-in (Arms 4) vs. Lead-in (Arm 5) Study Arms (i.e. Arms where Patients Received a Longer Duration of Treatment with Boceprevir) Lead-in No Lead-in V36A V36G V36I V36L V36MQ41H T54AT54CT54S V55A R155I R155K R155M R155TA156S A156T V158I V158M I170A I170T Patients, n V36A V36G V36I V36L V36MQ41H T54AT54CT54S V55A R155I R155K R155M R155TA156S A156T V158I V158M I170A I170T Patients, n

Conclusions In SPRINT-1, combination therapy with boceprevir and peginterferon plus ribavirin increased SVR rates with shorter treatment durations In Non-SVR patients, most frequent RAVs were; o Genotype 1a; V36M, T54S, and R155K o Genotype 1b; T54A, T54S, A156S, and V170A In subjects with detectable RAVs at baseline, the majority achieved SVR The use of lead-in period led to increased SVR rates and reduced the frequency of T54S variant