Treatment of chronic hepatitis C in drug-naïve patients

Treatment of chronic hepatitis C in drug-naïve patients 8th International Workshop on HIV & Hepatitis Co-infection Madrid, 31. May 2012 Christoph Sarrazin J. W. Goethe-University Hospital Medizinische Klinik I Frankfurt am Main, Germany

Hepatitis C: New treatment era with approval of NS3 protease-inhibitors HCV NS3 Protease-Inhibitor Boceprevir Triple-Therapy HCV Genotype 1 HCV NS3 Protease-Inhibitor Telaprevir Triple-Therapy HCV Genotype 1 EMA Market Authorisation European Union 18.7.2011 EMA Market Authorisation European Union 19.9.2011

Triple-Therapies: Improved SVR rates Treatment-naïve Genotype 1 pts. ADVANCE RGT, TVR 12 vs. 8 wks SPRINT-2 Lead-in(LI), RGT vs. non-rgt Sustained virologic response 80 70 60 50 40 30 20 10 75% 69% 0 Response guided TVR 12 wks + PEG2a + Riba Response guided TVR 8 wks + PEG2a + Riba 44% PEG2a + Riba (48 wks) 80 70 60 50 40 30 20 10 0 63% 66% Response guided LI BOC + PEG2b + Riba 38% TVR TVR SOC BOC BOC SOC LI BOC + PEG2b + Riba (48 wks) PEG2b + Riba (48 wks) Jacobson et al. NEJM 2011 Poordad et al. NEJM 2011

Sustained virologic response 100 80 60 40 20 0 Triple-Therapies: Improved SVR rates Treatment-experienced Genotype 1 pts. REALIZE (+/- Lead-in) TVR 12 wks + PEG2a + Riba 48 weeks 86% 24% TVR SOC REL 57% 15% TVR SOC P-NR 31% NULL 5% TVR SOC 100 80 60 40 20 RESPOND-2/PROVIDE* Lead-in (+/-RGT) BOC + PEG2b + Riba 36 / 48 weeks 0 75% 29% BOC SOC REL 52% P-NR 7% BOC SOC 36%* NULL Relapser (REL): negative at end-of-treatment but relapse thereafter Partial Non-Responder (P-NR): 2log wk12 but pos HCV RNA wk 24 Null-Responder (NULL): <2log wk 12 Zeuzem et al., NEJM 2011 Bacon et al., NEJM 2011 *PROVIDE study, Vierling et al., AASLD 2011

Antiviral activities of Telaprevir / Boceprevir in other HCV genotypes Mean maximum log10 HCV RNA decline during mono-therapies 7-14 days HCV RNA log10 decline 6 5 4 3 2 1 0 4,4 2,1 3,9 1,4 1,7 0,5 0,9 GT 1 GT 2 GT 3 GT 4 GT 5 GT 6 Telaprevr 750mg TID; Reesink et al., Gastro 2006, Foster et al., Gastro 2011, Benhamou et al., EASL 2009 Boceprevir 400mg TID (current dose 800mg TID); Sarrazin et al., Gastroenterology 2007; Silva et al., APASL 2011 no data

Triple-Therapies: HIV co-infection Limited efficacy and long duration of PEG/R Characteristic APRICOT 1 ACTG 5071 2 RIBAVIC 3 Barcelona 4 Number enrolled 868 133 412 95 PEG-IFN 2a 2a 2b 2b RBV 800mg 600mg up to 1g 800mg 800mg up to 1.2g HIV and CD4 status >200/mm 3 or 100 200/mm 3 if HIV-RNA <5,000 copies/ml >100/mm 3 + HIV-RNA <10,000 copies/ml or >300/mm 3, tx naïve + not starting ART during trial >200/mm 3 >250/mm 3 and HIV-RNA <10,000 copies/ml ALT elevated NA NA >1.5 ULN Genotype 1, % 60 61 77 78 48 49 Bridging fibrosis or cirrhosis, % 15 16 9 11 (cirrhosis) 39 30 SVR, n/n (%) Genotype 1 51/176 (29) 7/51 (14) 21/123 (17)* 22/59 (38)* *Genotype 1 or 4 IFN: interferon; RBV: ribavirin; ALT: alanine aminotransferase ULN: upper limit of normal; SVR: sustained virologic response 1.Torriani FJ, et al. N Engl J Med 2004;351:438 450 2. Chung RT, et al. N Engl J Med 2004;351:451 459 3. Carrat F, et al. JAMA 2004;292:2839 2484 4. Laguno M, et al. AIDS 2004;18:F27 36

Triple-Therapies: HIV co-infection Potential of DDIs with Telaprevir/Boceprevir Telaprevir Boceprevir RTV 1,2 TVR RTV BOC Peg-IFN 2 n/a BOC EFV 2,3 TVR EFV BOC EFV TDF 2,3 TVR TDF BOC TDF ATV/r 3 TVR ATV n/a DRV/r 3 TVR DRV n/a FPV/r 3 TVR FPV n/a LPV/r 3 TVR LPV n/a Methadone 4 TVR R-methadone ( free fraction) n/a Cyclosporine 5 TVR cyclosporine n/a Tacrolimus 5 TVR tacrolimus n/a Midazolam 2 n/a MDZ Diflunisal 2 n/a BOC Clarithromycin 2 n/a BOC Ketoconazole 2,6 TVR KET BOC Oral contraceptives 2,6 EE NOR DRSP EE Renal impairment 7 TVR n/a 1. Garg V, et al. CROI 2011. Abstract 629; 2. Kassera C, et al. CROI 2011. Abstract 118; 3. van Heeswijk R, et al. CROI 2011. Abstract 119 4. van Heeswijk R, et al. J Hepatol 2011;54(Suppl. 1): S491; 5. Garg V, et al. ATC 2011. Abstract 65; 6. Telaprevir French cohort ATU Protocol. Available at http://www.afssaps.fr; 7. van Heeswijk R, et al. J Hepatol 2011;54(Suppl. 1): S492

Triple-Therapies: HIV co-infection Telaprevir Triple-Therapy Study Part A: no ART SVR12 T/PR TVR + PR PR Follow-up 1:1 PR48 (control) Pbo + PR PR SVR12 Follow-up SVR SVR Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC) SVR12 T/PR TVR + PR PR Follow-up 2:1 PR48 (control) Pbo + PR PR SVR12 Follow-up SVR SVR Weeks 0 12 24 36 48 60 72 (EFV)=efavirenz; (TDF)=tenofovir; (FTC)=emtricitabine; (ATV/r)=ritonavir-boosted atazanavir; (3TC)=lamivudine; (T) TVR=telaprevir 750 mg q8h or 1125 mg q8h (with EFV); Pbo=Placebo; (P) Peg-IFN=pegylated interferon alfa-2a (40 kd) 180 µg/wk; (R) RBV=ribavirin 800 mg/day or weight-based (1000 mg/day if weight <75 kg, 1200 mg/day for if weight 75 kg; France, Germany, n=5 patients) Roche COBAS TaqMan HCV test v2.0, LLOQ of 25 IU/mL, LOD of <10 IU/mL Dieterich et al., CROI 2012

Triple-Therapies: HIV co-infection Telaprevir Triple-Therapy Study 100 Patients with SVR (%) 90 80 70 60 50 40 30 71 69 80 74 33 50 50 45 20 10 0 n/n = 5/7 11/16 12/15 28/38 T/PR 2/6 4/8 4/8 10/22 PR No ART EFV/TDF/FTC ATV/r/TDF/FTC Total *Patient was defined as SVR12 if HCV RNA was < LLOQ in the visit window Dieterich et al., CROI 2012

Triple-Therapies: HIV co-infection Boceprevir Triple-Therapy Mallolas et al., EASL 2012

Telaprevir / Boceprevir Triple-Therapies Adverse events % of patients (Phase II / III-studies) Telaprevir/PR N = 1.346 Placebo/PR N = 764 Discont. Telaprevir / Placebo due to AEs 14 4 Pruritus 51 26 Rash 55 33 Nausea 39 29 Diarrhea 26 19 Anorectal symptoms 26 6 Anemia 29 12 % of patients (Phase III-studies) Boceprevir/PR N = 1.057 Placebo/PR N = 443 Discont. entire treatment due to AEs 8-16 2-16 Anemia 43-49 20-29 Dysgeusia 37-45 11-18 Neutropenia (500 to < 750/mm 3 ) 19-25 9-14 Dry skin 21 8 Bacon et al. NEJM 2011, Poordad et al. NEJM 2011, Jacobson et al. NEJM 2011, Zeuzem et al. NEJM 2011, Sherman et al. NEJM 2011

Triple-Therapy Predictors of response Predictors for lower SVR Non-Response PEG-IFN / Ribavirin pre-treatment Non-CC IL28B-Genotype (rs12979860) High HCV-RNA baseline level (> 8 x 10 5 IU/ml) Advanced Fibrosis (F3 / F4) Low LDL HCV-Subtype 1a (approx. 10% lower SVR rate) Importance for treatment algorithm in mono-infected pts. Poordad et al. NEJM 2011 Zeuzem et al. NEJM 2011 Bacon et al. NEJM 2011 Berg et al., AASLD 2011 Jacobson et al. NEJM 2011

IL28B (rs12979860) Correlation with SVR / Importance for treatment algorithm? Therapy Tx naive (RGT-arms) Tx experienced (48 weeks) Boceprevir (SVR) Telaprevir (SVR) PEG/R (SVR) CC 82% 90% 64 78% CT/TT 62% 72% 25 27% CC 77% 79% 29 46% CT/TT 73% 61% 15 26% Treatment-naive pts. without cirrhosis: Shortening of Triple-Therapy in patients with IL28B CC-genotype? Poordad et al. EASL 2011, Pol et al. EASL 2011

Telaprevir Phase 2 Study (PROVE2) SVR Rates SVR rate PR48 (n=82) Placebo + Peg-IFN + RBV Peg-IFN + RBV 46% T12PR24 (n=81) TVR + Peg-IFN + RBV Peg-IFN + RBV 69% T12PR12 (n=82) TVR + Peg-IFN + RBV 60% T12P12 (n=78) (no RBV) TVR + Peg-IFN 36% 0 12 24 36 48 Weeks Hézode C, et al. N Engl J Med 2009;360:1839 50

Short treatment in IL28B CC patients SVR rate PR48 (n=82) Placebo + Peg-IFN + RBV Peg-IFN + RBV 46% T12PR24 (n=81) TVR + Peg-IFN + RBV Peg-IFN + RBV 69% T12PR12 (n=82) TVR + Peg-IFN + RBV SVR: 100% for 12/12 patients with IL28B CC 2 T12P12 (n=78) (no RBV) TVR + Peg-IFN 36% 0 12 24 36 48 Weeks Prospective ongoing study (CONCISE) for 12 weeks triple therapy with TVR BID in treatment naïve genotype 1, CC patients Bronowicki et al, EASL 2012, poster (1094)

Triple Therapy New response definitions Abbreviation Meaning Comment SVR Sustained virologic response HCV-RNA undetectable 24 weeks after end of treatment Relapse Partial Non- Response Relapse after end of treatment Week 12 2 log-decline of HCV-RNA but HCV RNA detectable at week 24 Null-Response < 2 log-decline of HCV-RNA at week 12 RVR rapid virologic response HCV-RNA negative at week 4 ervr (TVR) extended RVR Telaprevir HCV-RNA negative at week 4 and 12 ervr (BOC) extended RVR Boceprevir HCV-RNA negative at week 8 and 24 Breakthrough Virologic breakthorough HCV-RNA positive after undetectability or increase of > 1 log step

Treatment algorithms for HCV mono-infected patients: Lead-in Boceprevir Telaprevir TW0 TW4 TW8 TW24 TW28 TW36 TW48 TW0 TW4 TW12 TW24 TW48 Naive 4W LI 4W LI 24W BOC 32W BOC 12W PR Naive Relapser 12W TVR 12W TVR +/- 12W PR 36W PR Part.Resp. Relapser 4W LI 32W BOC 12W PR Part.Resp. Null Resp. 12W TVR 36W PR Null Resp. F4 Fibrosis 4W LI 44W BOC F4 Fibrosis 12W TVR 36W PR = undetectable HCV RNA

Lead-in versus no Lead-in Individual decision Tolerability of PEG-IFN / Ribavirin alone during Lead-in Adherence on PEG-IFN / Ribavirin alone during Lead-in Individual decision on further treatment Treatment-naive patient with RVR during Lead-in and possibility of 24 weeks PEG/Riba Treatment experienced patient with Null- Response, F4 and < 1 log-decline during Lead-in

TVR/BOC sparing treatment RVR during lead-in with PEG/Riba Rates of RVR (HCV RNA undetectable / <12-50 IU/ml at week 4) in treatment-naive patients with chronic hepatitis genotype 1 infection and treatment with PEG-IFN / Ribavirin alone range from 12-65% in different studies from the U.S., Europe and Asia Fried et al., J Hepatol 2011, McHutchison et al., NEJM 2009, Ferenci et al., Gastroenterology 2008, Mangia et al., Hepatology 2008, Berg et al., Gastroenterology 2006, Sarrazin et al., Gastroenterology 2011, Sanchez-Tapias et al., Gastroenterology 2006, Bronowicki et al., Gastroenterology 2006, Buti et al., Hepatology 2010, Yu et al., Hepatology 2008, Liu et al., Clin Infect Dis 2008 Response group HCV RNA Baseline negative* at viral load week 4 <800.000 IU/ml week 4 800.000 IU/ml * HCV RNA undetectable by TMA Assay (<5-10 IU/ml) INDIV-2 Study (genotype 1, treatment-naïve) PEG-Interferon alfa 2b plus Ribavirin ITT population (n=398) PP population Treatment (n=346) duration n (%) SVR (%) n SVR (%) (weeks) 24 41 (10) 36 (88) 36 36 (100) 30 7 (2) 6 (86) 6 6 (100) Sarrazin et al. Gastroenterology 2011

Boceprevir Stopping rules Boceprevir TW0 TW4 TW12 TW24 TW28 TW36 Naive 4W LI 24W BOC 4W LI 32W BOC 12W PR Part.Resp. Relapser 4W LI 32W BOC 12W PR Null Resp. F4 Fibrosis 4W LI 44W BOC Stopping rules for Boceprevir : HCV RNA > 100 IU/ml at TW12 HCV RNA detectable at TW24

Stopping rules Boceprevir Triple Treatment naive: SPRINT-2-Study, n = 734 Entire treatment was discontinued within the study if HCV RNA was detectable at week 24 Retrospective analysis for introduction of early stopping rules Rate of pts. with stop Week 8 Week 12 missed SVR Rate of pts. with stop missed SVR 50 IU/ml 147 (20%) 26 78 (11%) 4 100 IU/ml 120 (16%) 16 65 (9%) 0 < 3 log-decline 34 (5%) 1 34 (5%) 0 Jacobson et al. AASLD 2011

Telaprevir Stopping rules Telaprevir TW0 TW4 TW12 TW24 TW48 Naive Relapser 12W TVR 12W TVR +/- 12W PR 36W PR Part.Resp. Null Resp. 12W TVR 36W PR F4 Fibrosis 12W TVR 36W PR Stopping rules for Telaprevir: HCV RNA > 1000 IU/ml at TW4 or TW12 HCV RNA detectable at TW24

Stopping rules Telaprevir Triple Treatment-naive: ADVANCE-Study, n = 903 Telaprevir was discontinued within study if HCV-RNA > 1.000 IU/ml at week 4 and entire treatment was discontinued if < 2 log decline of HCV RNA at week 12 / HCV-RNA positive at week 24 Retrospective analysis for introduction of early stopping rules Week 4 Week 12 Rate of pts. with stop missed SVR Rate of pts. with stop missed SVR 100 but < 1.000 IU/ml 19 (2%) 5 10 (1%)? 1.000 IU/ml 15 (2%) 0 9 (1%) 0 Adda et al. HepDart 2011

Viral kinetics of triple-therapy 10 8 Treatment naive (n = 15) Treatment experienced (n = 15) 10 8 10 7 10 7 10 6 10 6 HCV-RNA IU/ml 10 5 10 4 10 43 HCV-RNA IU/ml 10 5 10 4 10 43 10 2 10 2 10 1 0 2 4 6 8 10 12 10 1 0 2 4 6 8 10 12 Weeks /therapy Weeks /Therapy Adda et al. HepDart 2011

Telaprevir / Boceprevir Treatment algorithms Determination of extended rapid virologic response Boceprevir Telaprevir TW0 TW4 TW8 TW24 TW28 TW36 TW48 TW0 TW4 TW12 TW24 TW48 Naive 4W LI 4W LI 24W BOC 32W BOC 12W PR Naive Relapser 12W TVR 12W TVR +/- 12W PR 36W PR Part.Resp. Relapser 4W LI 32W BOC 12W PR Part.Resp. Null Resp. 12W TVR 36W PR Null Resp. F4 Fibrosis 4W LI 44W BOC F4 Fibrosis 12W TVR 36W PR = undetectable HCV RNA

Response guided Triple-Therapie Definition of extended RVR Boceprevir & Telaprevir Studies: HPS/Cobas TaqMan Assay Boceprevir ervr HCV RNA undetectable* at week 8 and 24 * Below the limit of detection (approx. 10 IU/ml) Telaprevir ervr HCV RNA undetectable* at week 4 and 12 * Below the limit of detection (approx. 10 IU/ml) Importance of residual viremia? Differences between different HCV RNA assays?

Response guided Triple Therapy Definitions of extended RVR HCV RNA concentrations <25 IU/ml are frequently observed during TVR/BOC tripletherapies (52-67% in Phase 3 studies with TVR/BOC until week 4/8) Overall increased probability of treatment failure in patients with residual viremia (<25 IU/ml but detectable HCV RNA) at week 4/8 during Telaprevir / Boceprevir triple-therapies Harrington et al., Hepatology 2011

Response guided Triple Therapy Definitions of extended RVR Higher Relapse-Rates in patients with residual viremia (<25 IU/ml) at week 4 / 12 in patients with shortened treatment duration (24 weeks). Study Time Duration SVR Relapse Boceprevir SPRINT-1 Telaprevir 104 / PROVE1/2 <25 IU/ml wk. 8 28 wks 5/13 (38%) 5/10 (50%) 48 wks 9/12 (75%) 0/9 (0%) negative wk. 8 28 wks 53/62 (85%) 4/57 (7%) 48 wks 62/66 (94%) 0/62 (9%) <25 IU/ml wk. 4 24 wks 6/15 (40%) 4/9 (44%) 48 wks 4/7 (57%) 2/6 (33%) negative wk. 4 24 wks 89/120 (74%) 6/88 (7%) 48 wks 49/64 (77%) 0/44 (0%) Harrington et al., Hepatology 2011

International commercially available HCV RNA assays 10 8 IU/ml 10 7 10 6 10 5 10 4 10 3 10 2 10 1 10 0 34 5-10 615 10 50 500 10 10 HCV RT artus TM TMA bdna kpcr Versant TM qual. quant. real-time Amplicor TM vs2 TaqMan TM real-time RealTime HCV TM Qiagen (CE) Siemens (CE/FDA für TMA/bDNA) Roche Diagnostics (CE/FDA) Abbott (CE/FDA)

Response guided Triple Therapy Differences between assays Samples obtained from the TMC435 PILLAR study (TMC435-C205) o Treatment-naïve patients received once-daily TMC435 in combination with PegIFNα-2a/RBV o 79-86% of TMC435-treated patients were eligible for shortened treatment of 24 weeks, of whom 85-96% achieved SVR24 In PILLAR, HCV RNA was assessed using Roche High-Pure-System/ COBAS TaqMan assay v2 (HPS) A total of 1411 plasma samples with sufficient volume were selected from 290 of 309 TMC435-treated patients, and re-analysed in a blinded fashion with the Abbott RealTime (ART) assay Visit Number of samples Screening 113 Baseline 16 Day 3 28 Week 1 135 Week 2 186 Week 3 164 Week 4 261 Week 6 108 Week 8 140 Week 12 260 Total 1411 Fevery et al., EASL 2012

Differences between HCV RNA Assays Overall HCV RNA quantification N=326 Abbott RealTime (ART), log 10 IU/mL 7 6 5 4 3 2 1 LLOQ HPS (r 2 =0.978) LLOQ ART 1 2 3 4 5 6 7 Roche TaqMan (HPS), log 10 IU/mL *censored values excluded Fevery et al., EASL 2012

Differences between HCV RNA Assays HCV RNA undetectability 217/766 (28.3%) Abbott RealTime (ART) 35/584 (6.0%) <12 IU/mL not detected <12 IU/mL detected 12 IU/mL but <25 IU/mL 25 IU/mL Roche TaqMan (HPS) <25 IU/mL not detected <25 IU/mL detected 549 181 28 8 35 128 86 65 25 IU/mL 0 5 19 307 217/766 (28.3%) samples from different time points with HCV RNA undetectable by HPS had detectable/quantifiable HCV RNA by ART 35/584 (6.0%) samples undetectable by ART had detectable/quantifiable HCV RNA by RCT For both assays, the majority of these discrepant samples had HCV RNA levels <25 IU/mL Fevery et al., EASL 2012

Differences between HCV RNA Assays Assessment of rapid virologic response Proportion of patients, % 100 80 60 40 20 0 75.5% <25 IU/mL undetectable 75,5 Not detected 16,5 <25 IU/mL detected 8,0 25 IU/mL Proportion of patients, % 100 80 60 40 20 0 49.4% <12 IU/mL undetectable 49,4 Not detected 79.7% <12 IU/mL 30,3 <12 IU/mL detected 7,7 12 and <25 IU/mL 12,6 25 IU/mL Roche TaqMan (HPS) Abbott RealTime (ART) At Week 4, 197/261 (75.5%) samples were undetectable by HPS whereas 129/261 (49.4%) were undetectable and 79/261 (30.3%) <12 IU/mL detectable by ART, leading to a different determination of RVR in 68/261 (26.1%) of cases Fevery et al., EASL 2012

Summary New era with Boceprevir / Telaprevir triple-therapies - significant improvement of SVR rates - genotype 1 only - high efficacy also in HIV co-infected patients - complex management, high pill burden, additional AEs, DDI and limited efficacy in non-responders Response guided therapy according to HCV RNA viral kinetics (stopping rules, ervr) Lead-in may be used for testing tolerability, PI sparing and prediction of non-response to PIs IL28B may be used to tailor treatment in the future Importance of HCV RNA assays