Response Guided Therapy Fabien Zoulim Hepatology Department & INSERM Unit 1052, Lyon University Lyon, France

Rationale for response guided therapy (RGT) ? Potent and rapid viral suppression in patients receiving DAA based therapy Can the duration of treatment be shortened in genotype 1-infected patients receiving DAA- based therapy? Is the situation the same for naïve and treatment experienced patients ?

Early viral load decline through Week 12 of telaprevir-based regimens Non-responders to prior PR treatment who received T12/PR24 or T24/PR48 in PROVE3 (n=130) Relapsers after prior PR treatment who received T12/PR24 or T24/PR48 in PROVE3 (n=83) Null responders and partial responders to prior PR treatment who received T12/PR24 or T24/PR48 in roll-over Study 107 (n=79) Relapsers after prior PR treatment who received T12/PR24 or T24/PR48 in roll-over Study 107 (n=28) Treatment-naïve patients who received T12/PR in PROVE1 or PROVE2 (n=338) –1 –2 –4 –3 –5 –6 –7 Median change from baseline (log 10 HCV RNA) Time (weeks) Poordad F, et al. J Hepatol 2010; 52(Suppl. 1):S121–S122

Kinetics of response to Boceprevir based therapy (Sprint-2 & Respond 2) Respond-2Sprint-2 RGT (PR4/BOC-PR32/PR12) RVS n/N (%) PR4/BOC-PR44 RVS n/N (%) Respond-2 Late Responder27/34 (79)29/40 (73) Meeting FDA avril 2011

Can the duration of treatment be shortened in treatment-naïve, genotype 1-infected patients receiving DAA-based therapy?

ADVANCE (telaprevir): study design (N=1088) Weeks T12PR (n=363) TVR + PR Follow-up SVR PR eRVR+ Follow-up SVR PR Follow-up SVR TVR + PR T8PR (n=364) PR Pbo + PR Follow-up SVR eRVR+ PR Follow-up eRVR– Follow-up PR48 (control) (n=361) SVR Pbo + PRPR Jacobson IM, et al. N Engl J Med 2011;364:2405–16 Peg-IFN alfa-2a dose: 180 µg/week; RBV dose: 1000 or 1200 mg/day eRVR: undetectable HCV RNA at Week 4 and 12

ILLUMINATE (telaprevir): study design (N=540) Follow-up SVR Follow-up SVR PR Randomized Treatments Follow-up SVR PR Assigned Treatment eRVR– eRVR+ Non-inferiority (NI) Follow-up 72 weeks T12PRPR eRVR+ T12PR24 n=162 eRVR+ T12PR48 n=160 eRVR– T12PR48 n=118 Weeks Sherman KE, et al. N Engl J Med 2011;365:1014–24 Patients discontinued for any reason before Week 20 randomization were categorized as ‘Other’ (N=100) Peg-IFN alfa-2a dose: 180 µg/week; RBV dose: 1000 or 1200 mg/day eRVR: undetectable HCV RNA at Week 4 and 12

SPRINT-2 (boceprevir): study design (N=1097) Follow-up SVR Follow-up SVR Follow-up SVR PR + BOC PR lead-in PR + Pbo PR48 Control n=363 BOC RGT n=368 BOC44/ PR48 n=366 Weeks 8–24 HCV RNA undetectable HCV RNA detectable at any time from Week 8 onwards, but Week 24 undetectable PR lead-in PR + Pbo Weeks Follow-up SVR 24 Peg-IFN alfa-2b dose: 1.5 µg/kg/week RBV dose: 600–1400 mg/day in a divided daily dose Poordad F, et al. N Engl J Med 2011;364:1195–206 PR + BOC

Baseline characteristics in Phase III trials in treatment-naïve patients Telaprevir ADVANCE and ILLUMINATE trials (N=1264) 1 Boceprevir SPRINT-2 trial (N=1097) 2 Male, %58–6057–62 Black race, %8–1114–15 Age, years50*49–50 ‡ Body mass index, kg/m 2 26–27*27–28 ‡ Baseline HCV RNA, log 10 IU/mL6.4–6.5*6.5** HCV genotype subtype, % 1a 1b 58–67 33–42 63–65 32–34 Bridging fibrosis/cirrhosis, %20–257–11 Note that there are inherent limitations of interpreting findings across different trials Data are shown for patients in the T12PR arms from ADVANCE and ILLUMINATE Pooled data from the telaprevir trials includes T12PR and PR arms only 1 *Median; ‡ mean; **geometric mean 1. Sherman KE, et al. CROI Abstract Poordad F, et al. N Engl J Med 2011;364:1195–206

ADVANCE and ILLUMINATE (telaprevir): undetectable HCV RNA at Weeks 4 and 12 Patients with undetectable HCV RNA (%) Week 4 (RVR) Weeks 4 and 12 (eRVR) Patients eligible to receive 24 weeks of treatment in total PR48 34/361 T12PR 635/903 T12PR 565/903 PR48 29/361 n/N= Adapted from Sherman KE, et al. CROI Abstract 957

ILLUMINATE (telaprevir): SVR rates by treatment duration in patients treated with T12PR (N=540) Treatment duration according to eRVR status 60%* n=322 22% n=118 Sherman KE, et al. N Engl J Med 2011;365:1014–24 <20 weeks 23/100 SVR rate 18% n=100 Eligible for 24 weeks and randomized to 24 or 48 weeks* 48 weeks <20 weeks (due to premature treatment discontinuation) *Patients who achieved eRVR (undetectable HCV RNA at Weeks 4 and 12) and completed the Week 20 visit were randomized to receive an additional 4 or 28 weeks of PR alone 65% of patients achieved an eRVR (352/540); 322/352 were randomized and 30/352 patients discontinued before randomization at Week 20 eRVR+* eRVR– <20 weeks eRVR– T12PR48 76/118 eRVR+ T12PR48 140/160 eRVR+ T12PR24 149/162  4.5% (2-sided 95% CI = –2.1% to +11.1%)

SPRINT-2 (boceprevir): undetectable HCV RNA at Week 8 and Weeks 8 to 24 Patients with undetectable HCV RNA (%) PR48 60/363 BOC44/PR48 204/366 n/N= Week 8Weeks 8 to 24 BOC RGT 208/368 BOC44/PR48 161/366 BOC RGT 162/368 Patients eligible to receive 28 weeks of total treatment Adapted from Poordad F, et al. N Engl J Med 2011;364:1195–206 PR48 43/363

SPRINT-2 (boceprevir): SVR rates and treatment duration in BOC arms <28 wks 18/124 – 48 wks 59/82 SVR rates Treatment duration in RGT arm 28 weeks if undetectable HCV RNA from Weeks 8–24 48 weeks if detectable HCV RNA at least once between Weeks 8–24 but undetectable at Week 24 <28 weeks (discontinued because of detectable HCV RNA at Week 24, adverse events or non-medical reasons) + 28 wks 156/162 44% n=162 34% n=124 22% n=82 <28 weeks28 weeks 48 weeks Poordad F, et al. N Engl J Med 2011;364:1195–206 Bronowicki J-P, et al. Hepatology 2010;52(Suppl.):881A + 48 wks 155/161 – 48 wks 55/73 Undetectable Weeks 8–24 BOC RGT BOC44/PR48

Telaprevir regimen in G1 HCV-infected patients: Treatment-naïve without cirrhosis Weeks Peg-IFN alfa + ribavirin if detectable at Week 4 or 12* Peg-IFN alfa + ribavirin *In Phase III studies, a sensitive real-time PCR assay with a limit of quantification of 25 IU/mL and a limit of detection of 10–15 IU/mL was used to determine whether HCV RNA levels were undetectable. Detectable HCV RNA below the lower limit of assay quantification should not be used as a substitute for ‘undetectable’ for making decisions on treatment duration, as this may lead to an insufficient duration of therapy and higher relapse rates INCIVO (telaprevir) EU SmPC If >1000 IU/mL at Week 4 or 12: discontinue all drugs If detectable at Week 24 or 36: discontinue PR HCV RNA: Telaprevir

Boceprevir regimen in G1 HCV-infected patients: Treatment naïve without cirrhosis PR lead-in BOC + PR* 048 Weeks BOC + PR 36 PR* If detectable at Week 8 but undetectable at Week 24: 12 HCV RNA *This regimen has only been tested in patients who have failed previous therapy who were late responders VICTRELIS (boceprevir) EU SmPC Assess for RGT criterion If ≥100 IU/mL discontinue all drugs If detectable discontinue all drugs Stop treatment at Week 28 if undetectable at Week 8 and 24

Dosing duration in all patients with compensated cirrhosis BOC+ Peg-IFN + RBV Peg-IFN + RBV ≥100 IU/mL: Stop 3 drugs Detectable: Stop 3 drugs TVR + Peg-IFN + RBV Peg-IFN + RBV >1000 IU/mL: Stop 3 drugs >1000 IU/mL: Stop 3 drugs Detectable: Stop PR Detectable: Stop PR INCIVO (telaprevir) EU SmPC; VICTRELIS (boceprevir) EU SmPC

Shorter duration of therapy is possible in naive patients who achieve an eRVR

Can the duration of treatment be shortened in treatment-experienced, genotype 1-infected patients receiving DAA-based therapy?

REALIZE (telaprevir): study design (N=662) Weeks 72 T12/PR48 Peg-IFN + RBV TVR + Peg-IFN + RBV Pbo + Peg-IFN + RBV n=266 Follow-up SVR assessment TVR + Peg-IFN + RBV Peg-IFN + RBV LI T12/ PR48 n=264 Follow-up Pbo + Peg-IFN + RBV PR48 (control) Pbo + Peg-IFN + RBVPeg-IFN + RBV n=132 Follow-up Zeuzem S, et al. N Engl J Med 2011;364:2417–28 Randomization was stratified by viral load and prior response category. Stopping rules applied for telaprevir (Weeks 4, 6, and 8 after telaprevir start) and PR (Weeks 12/16 [depending on treatment arm], 24, and 36) Peg-IFN alfa-2a: 180μg/week subcutaneously; RBV: 1000–1200mg/day; TVR: 750mg every 8 hours

RESPOND-2 (boceprevir): study design (N=403) Weeks 72 SVR assessment Pbo + Peg-IFN + RBV PR48 (control) n=80 Follow-up Peg-IFN + RBV BOC + Peg-IFN + RBV BOC44/ PR48 n=161 Follow-up Peg-IFN + RBV 36 Pbo + Peg-IFN + RBV Follow-up Week 8 detectable HCV RNA + Week 12 undetectable HCV RNA Follow-up Week 8 and 12 undetectable HCV RNA Patients with detectable HCV RNA at Week 12 were considered treatment failures and discontinued treatment Peg-IFN alfa-2b: 1.5μg/kg/week; RBV: 600–1400mg/day; BOC: 800mg q7–9h Bacon BR, et al. N Engl J Med 2011;364:1207–17 BOC + Peg-IFN + RBV BOC RGT n=162 Peg-IFN + RBV

21 Telaprevir: SVR in prior relapsers eligible to receive 24 weeks of therapy SVR (%) n/N = Study 106 T12/PR24 25/28 Study 107 T12/PR24 24/24 INCIVO (telaprevir) EU SmPC Patients with undetectable HCV RNA at Weeks 4 and 12 of subsequent telaprevir-based treatment

PR48 7/7 BOC44/PR48 74/84 SVR (%) Undetectable HCV RNA at treatment week 8 Detectable HCV RNA at treatment week 8 BOC RGT 64/74 n/N= PR48 8/65 BOC44/PR48 30/70 BOC RGT 29/72 22 RESPOND-2 (boceprevir): SVR by Week 8 HCV RNA levels* Bacon BR, et al. N Engl J Med 2011;364:1207–17; Bacon BR, et al. Hepatology 2010;52(Suppl.):430A Overall, 46% of patients eligible to receive 36 weeks of total treatment *Some patients had missing values at Week 8

Shorter duration of therapy is possible in relapsers/partial responders who achieve an eRVR during DAA based triple therapy

Telaprevir regimen in genotype 1 HCV-infected patients: patients with prior treatment failure Weeks Telaprevir + PR Peg IFN alfa + Ribavirin if detectable at Week 4 or 12 Telaprevir +PR Peg IFN alfa + Ribavirin Prior relapsers without cirrhosis Prior partial and null responders INCIVO (telaprevir) EU SmPC *In Phase III studies, a sensitive real-time PCR assay with a limit of quantification of 25 IU/mL and a limit of detection of 10–15 IU/mL was used to determine whether HCV RNA levels were undetectable. Detectable HCV RNA below the lower limit of assay quantification should not be used as a substitute for ‘undetectable’ for making decisions on treatment duration, as this may lead to an insufficient duration of therapy and higher relapse rates. In prior null responders, consideration should be given to conducting an HCV RNA test between Weeks 4 and 12 and if HCV RNA >1000 IU/mL all drugs should be stopped HCV RNA Stop treatment at Week 24 if undetectable at Week 4 and 12* If >1000 IU/mL at Week 4 or 12: discontinue all drugs If detectable at Week 24 or 36: discontinue PR

Boceprevir regimen in genotype 1 HCV-infected patients: patients with prior treatment failure PR lead-in 048 Weeks BOC + PR 36 PR 12 HCV RNA PR lead-in BOC + PR VICTRELIS (boceprevir) EU SmPC Prior partial responders and prior relapsers without cirrhosis Prior null responders If ≥100 IU/mL discontinue all drugs If detectable discontinue all drugs

Dosing duration in all patients with compensated cirrhosis BOC+ Peg-IFN + RBV Peg-IFN + RBV ≥100 IU/mL: Stop 3 drugs Detectable: Stop 3 drugs TVR + Peg-IFN + RBV Peg-IFN + RBV >1000 IU/mL: Stop 3 drugs >1000 IU/mL: Stop 3 drugs Detectable: Stop PR Detectable: Stop PR INCIVO (telaprevir) EU SmPC; VICTRELIS (boceprevir) EU SmPC

Response Guided Therapy Can be applied to: Naive patients without cirrhosis Relapsers Partial responders Cannot be applied to: Cirrhotics Null responders Blacks IL28