Triple Therapy Today Phase III Results in G1 Relapsers and Non Responders – Telaprevir 5 th Paris Hepatitis Conference Paris, 30. January 2012 Stefan Zeuzem.

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Presentation transcript:

Triple Therapy Today Phase III Results in G1 Relapsers and Non Responders – Telaprevir 5 th Paris Hepatitis Conference Paris, 30. January 2012 Stefan Zeuzem Goethe University Hospital Frankfurt a.M., Germany

How should we define failure to prior Peg-IFN/RBV therapy? Detection limit Relapse Null response Breakthrough Partial response Treatment HCV RNA level Weeks 2 log 10 drop Non-response Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:46–52 Neumann A, et al. Science 1998;282:103–7; De Bruijne J, et al. Neth J Med 2008;66:311–22 Peg-IFN: P: peginterferon; RBV: R: ribavirin HCV: hepatitis C virus

SVR 90% (26/29)

SVR 55% (16/29)

SVR 57% (16/28)

REALIZE: 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 Pbo/PR48 ( control ) Pbo + Peg-IFN + RBV Peg-IFN + RBV N=132 Follow-up Randomization was stratified by viral load and prior response. Stopping rules applied for TVR (Weeks 4, 6, and 8 for T12/PR48; Weeks 8, 10 and 12 for LI T12/PR48) and Peg-IFN/RBV (Weeks 12, 24, and 36 for T12/PR48; Weeks 16, 24 and 36 for LI T12/PR48) Peg-IFN: Peg-IFN alfa-2a = 180μg/week; RBV = 1000–1200mg/day; TVR = 750mg every 8 hours ClinicalTrials.gov identifier: NCT LI = lead-in; Pbo = placebo; TVR = telaprevir

T12/PR48 (N=266) LI T12/PR48 (N=264) Pbo/PR48 (N=132) Male, n (%)183 (69)189 (72)88 (67) Caucasian race, n (%)246 (92)252 (95)117 (89) Black race, n (%)11 (4)8 (3)11 (8) Years of age, median (range)51 (23–69)51 (24–70)50 (21–69) HCV RNA ≥800,000 IU/mL, n (%)*238 (89)234 (89)114 (86) Body mass index, mean (SD)28 (5.0)27 (4.8)27 (4.6) HCV genotype, n (%) ‡ 1a 1b 136/262 (52) 126/262 (48) 149/262 (57) 113/262 (43) 67/128 (52) 61/128 (48) Prior response, n (%) Null responder Partial responder Relapser 72 (27) 49 (18) 145 (55) 75 (28) 48 (18) 141 (54) 37 (28) 27 (20) 68 (52) Bridging fibrosis, n (%) § 60 (23)58 (22)29 (22) Cirrhosis, n (%) § 72 (27)67 (25)30 (23) REALIZE: Baseline Characteristics *Determined using the HCV COBAS TaqMan ® assay version 2.0; ‡ Determined by NS3 sequencing; § Defined by local pathologists

REALIZE: Undetectable Viral Load over Time in Prior Relapsers T12/PR48 prior relapsers (n=145) LI T12/PR48 prior relapsers (n=141) Pbo/PR48 prior relapsers (n=68) Undetectable HCV RNA defined as <25 IU/mL

REALIZE: Undetectable Viral Load over Time in Prior Partial and Prior Null Responders Treatment phaseFollow-up phase Time (weeks) T12/PR48 prior partial responders (n=49) LI T12/PR48 prior partial responders (n=48) Pbo/PR48 prior partial responders (n=27) T12/PR48 prior null responders (n=72) LI T12/PR48 prior null responders (n=75) Pbo/PR48 prior null responders (n=37) Patients with undetectable HCV RNA (% ±SE) Undetectable HCV RNA defined as <25 IU/mL

REALIZE: Phase 3 Trial in Tx- Experienced HCV-1 Infected Patients Zeuzem et al., NEJM 2011 Sustained virologic response rates (%) Peginterferon alfa-2a 180 µg qw Ribavirin mg/day Telaprevir 750 mg q8h (n=354)(n=124) (n=184)

Role of PEG/RBV lead-in phase Virologic value of LI phase is questionable –SPRINT-1: higher SVR rates with lead-in (but small number of patients) –REALIZE: Lead-in phase did not affect breakthrough, relapse and SVR rates Lead-in may be clinically useful if physician is willing to take decisions at week 4 –only PEG/RBV, no PI in excellent initial virologic responders (RVR) –stop therapy in patients with poor initial virologic response (< 1 log) to avoid treatment failure and selection of resistant variants Improve adherence

REALIZE: SVR by Baseline Fibrosis Stage and Prior Response Prior relapsers Prior partial responders Prior null responders 2/15 n/N= 53/62144/16712/380/510/1834/473/170/915/3811/321/5 No, minimal or portal fibrosis Cirrhosis Stage Pooled T12/PR48 Pbo/PR48 SVR (%) 2/1548/5724/591/187/501/10 Bridging fibrosis No, minimal or portal fibrosis CirrhosisBridging fibrosis No, minimal or portal fibrosis CirrhosisBridging fibrosis

REALIZE: SVR by HCV Subtype and Prior Response Prior relapsers Prior partial responders Prior null responders 6/31n/N=123/140119/14210/341/1027/4026/553/161/2022/5924/881/17 1a1b HCV subtype 1a Pooled T12/PR48 Pbo/PR48 SVR (%)

SVR Rates in LI T12/PR48 Arm by HCV RNA Reduction at Week 4 and Prior Response Patients (%) SVR rate SVR rate Proportion of patients ≥1 log 10 HCV RNA reduction at Week Prior relapsers Prior partial responders Prior null responders Proportion of patients <1 log 10 HCV RNA reduction at Week Overall SVR rate Overall

Overall Baseline IL28B Genotype Distribution CC Patients (%) n/N= Pooled T12/PR48 76/422 Pbo/ PR48 17/105 CTTT Pooled T12/PR48 266/422 Pbo/ PR48 58/105 Pooled T12/PR48 80/422 Pbo/ PR48 30/105

SVR Rates by IL28B Genotype and Prior Response Prior relapsers Patients achieving SVR (%) Prior partial responders Prior null responders CCCT TT CCCT TT CCCT TT Pooled T12/PR48 (n=209) Pbo/PR48 (n=52) Pooled T12/PR48 (n=79) Pbo/PR48 (n=20) Pooled T12/PR48 (n=134) Pbo/PR48 (n=33) 51/58 4/12100/117 6/3029/34 3/105/81/5 33/57 2/1010/14 0/5 4/1027/92 1/1810/32 1/15 n/N= n/a

REALIZE: AEs Occurring in ≥25% of Patients During any Treatment Phase Patients, n (%) T12/PR48 (N=266) LI T12/PR48 (N=264) Pbo/PR48 (N=132) Fatigue145 (55)131 (50)53 (40) Pruritus138 (52)132 (50)36 (27) Headache112 (42)109 (41)49 (37) Rash99 (37)95 (36)25 (19) Nausea94 (35)87 (33)31 (23) Influenza-like illness85 (32)94 (36)33 (25) Anemia79 (30)94 (36)20 (15) Anorectal symptoms75 (28)59 (22)10 (8) Insomnia68 (26)84 (32)34 (26) Diarrhea66 (25)69 (26)18 (14) Pyrexia60 (23)71 (27)36 (27) Cough62 (23)66 (25)26 (20) Asthenia51 (19)60 (23)38 (29) AE = adverse event

T12/PR48 (N=266) LI T12/PR48 (N=264) Pbo/PR48 (N=132) Discontinuation of all study drugs during TVR treatment phase, n (%) Any AE Rash events Anemia events Pruritus Anorectal signs and symptoms 17 (6) 2 (1) 0 2 (1) 11 (4) 2 (1) 1 (<1) 0 4 (3) 0 Discontinuation of TVR or Pbo during TVR treatment phase, n (%) Any AE Rash events Anemia events Pruritus Anorectal signs and symptoms 39 (15) 12 (5) 6 (2) 1 (<1) 2 (1) 29 (11) 10 (4) 9 (3) 3 (1) 1 (<1) 4 (3) 0 REALIZE: AEs Leading to Study Drug Discontinuation

Telaprevir and Boceprevir - Resistance Sarrazin & Zeuzem; Gastroenterology 2010; 138: V36M + R155K HCV-1a:2 steps required (clinically observed) HCV-1b:4 steps required (not yet clinically observed) TVRBOC V36A/M++ T54S/A++ V55A in vitro + R155K/T/Q++ A156S++ A156T/V+ in vitro D168A/V/T V170A/T in vitro + AGG  AAG (R155) (R155K) CGG  AGG  AAG (R155) (R155) (R155K) HCV-1a HCV-1b

0.6 Probability Time after failure (months) Probability of Resistant Variant by Subtype Time (months) 1a1b 016%46% 322%66% 632%87% 1260%98% 1694%100% Significant difference (p<0.0001) between subtypes for the time to become WT by population sequencing (median, 95% CI) HCV-1a: 10 months (9,11) HCV-1b: 0.8 months (0,2) Based on Kaplan-Meier estimation using population sequencing; hash marks in plot indicate censored observations Probability of a patient being WT 1 median Sherman et al., AASLD 2011

750 mg (two 375-mg tablets) q8hr with food (not low fat; standard fat meal is >20 g, eg, 1/2-cup nuts or 2-oz cheddar cheese) Treatment-naive patients with compensated cirrhosis and eRVR may benefit from additional 36 wks of pegIFN + RBV (ie, to Wk 48) No eRVR; PR Telaprevir in Genotype 1 Patients TVR + PR eRVR; stop at Wk 24 PR Telaprevir [package insert]. May EMA. Telaprevir [package insert] Time PointCriterionStopping Rule Wk 4 or 12HCV RNA > 1000 IU/mLDiscontinue all therapy Wk 24Detectable HCV RNADiscontinue PR AnyDiscontinuation of PR for any reasonDiscontinue TVR Treatment Naive and Previous Relapsers Previous Partial or Null Responders TVR + PR PR wks

Conclusions Substantial increases in SVR in tx-experienced patients with Telaprevir + P/R Strict stopping/futility rules Additive side effects of PIs to PEG-IFN/RBV Both, previous response and on-treatment PEG- IFN/RBV response (lead-in) are strong predictors of SVR IL28B less important with potent DAAs Lead-in phase does not affect virologic response rates, but may be applied as a decision tool Further improvements in particular required for previous null responders Insufficient data for patients with high unmet need (e.g. cirrhosis, post-Ltx, HIV/HCV coinfected patients) DAA combinations and Quad therapies in development