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Douglas T. Dieterich, Juergen K. Rockstroh, Kenneth E. Sherman, Nathalie Adda, Lisa Mahnke, Varun Garg, Shahin Gharakhanian, Scott McCallister, Vincente.

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Presentation on theme: "Douglas T. Dieterich, Juergen K. Rockstroh, Kenneth E. Sherman, Nathalie Adda, Lisa Mahnke, Varun Garg, Shahin Gharakhanian, Scott McCallister, Vincente."— Presentation transcript:

1 Douglas T. Dieterich, Juergen K. Rockstroh, Kenneth E. Sherman, Nathalie Adda, Lisa Mahnke, Varun Garg, Shahin Gharakhanian, Scott McCallister, Vincente Soriano, and Mark S. Sulkowski On behalf of the Study 110 Team Interim Analysis of a Phase 2a Double-Blind Study of Telaprevir in Combination with Peginterferon Alfa-2a and Ribavirin in HIV/HCV Coinfected Patients

2 Telaprevir: An Orally-Available HCV Protease Inhibitor Telaprevir (TVR) is a selective inhibitor of NS3/4A HCV serine protease In genotype 1 mono-infected patients, telaprevir with peginterferon alfa- 2a/ribavirin (T/PR) led to substantial improvements in SVR in phase 3 studies 1-4 : o Treatment-naïve patients (ADVANCE trial, N=1088) 1, 69-75% vs 44% in control o Treatment-experienced patients (REALIZE trial, N=662) 3 : 31% vs 5% in control (prior null responders) 57% vs 15% in control (prior partial responders) 86% vs 24% in control (prior relapsers) Modest DDI between TVR and ART (EFV, ATV/r and TDF), no ART dose adjustment was deemed necessary 5 Higher TVR dose (1125 mg q8h) mostly offsets reduced exposures to TVR with EFV 5 1 Jacobson et al 2010, Hepatology 52(Suppl 4)427A; 2 Sherman et al 2010, Hepatology 52(Suppl 4)401A-402A; 3 Foster et al 2011 Hepatology Int 52(Suppl.1):14; 4 Sherman et al. CROI 2011; Poster 957; 5 van Heeswijk et al. CROI 2011; Abstract 146LB

3 Study Design Part A: no ART Weeks1236 Follow-up PR48 (control) PR SVR Pbo + PR T/PR TVR + PR Follow-up SVR PR Follow-up PR48 (control) PR SVR Pbo + PR T/PR TVR + PR Follow-up SVR PR Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC) (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) Roche COBAS® TaqMan® HCV test v2.0, LLOQ of 25 IU/mL (pts with values below 25IU/mL were reported as <25 detectable or undetectable)

4 Principal Eligibility Criteria Male and female patients, 18 to 65 years of age with chronic HCV genotype 1/HIV 1 co infection, and treatment naïve for HCV Liver biopsy within 1 year; compensated cirrhosis permitted Part A: up to 20 patients not receiving ART, with CD4 count 500 cells/mm 3, and HIV RNA 100,000 copies/mL Part B: up to 48 patients receiving a stable ART regimen o TDF/EFV/FTC, or o ATV/r with TDF and FTC or 3TC, with CD4 count 300 cells/mm 3, and HIV RNA 50 copies/mL

5 Study Objectives Primary Objectives: o Safety and tolerability of telaprevir, peginterferon, and ribavirin o Proportion of patients with HCV RNA undetectable after 12 weeks of telaprevir, peginterferon, and ribavirin Secondary Objectives: o Efficacy of telaprevir 24 weeks after last dose (SVR) o Pharmacokinetics of telaprevir, peginterferon and ribavirin o Selection of HCV resistant variants o Part B only: pharmacokinetics of pre-specified ART medications

6 Methods Interim analysis based on 59 of 60 patients who received at least 1 dose of study drugs; 41/59 patients had reached week 12 at time of analysis o 13 patients from Part A o 46 patients from Part B 24 patients received TDF/EFV/FTC and, 22 patients received ATV/r + TDF + FTC or 3TC HIV RNA and CD4: Week 4, 8, 12 during TVR/Pbo HCV RNA: Day 1, 2,4, and week 1, 2, 3, 4, 8 and 12 during TVR/Pbo during TVR/Pbo dosing Proportion of patients with undetectable HCV RNA at weeks 4 and 12

7 Predefined Stopping Rules Viral breakthrough (in all patients), defined as HCV RNA >100 IU/mL after HCV RNA undetectable or a 1 log 10 increase from nadir at Week 4, 8, and 12, discontinue all study drugs TimepointPatients Criteria for Stopping Action Week 4 Week 8 Telaprevir patients HCV RNA >1000 IU/mL Discontinue TVR, continue PR Week 12 TVR patients with 1000 IU/mL at Week 4 and 8 HCV RNA >1000 IU/mL Discontinue all study drugs All other patients HCV RNA <2 log 10 decline Discontinue all study drugs Week 24 Week 36 All patients HCV RNA detectable Discontinue all study drugs

8 Demographics and Baseline Characteristics Part APart B No ARTEFV/TDF/FTCATV/r + TDF + FTC/3TC T/PR N=7 PR N=6 T/PR N=16 PR N=8 T/PR N=14 PR N=8 Gender, n (%): Male 6 (86)4 (67)16 (100)7 (88)12 (86)7 (88) Caucasian, n(%) Black/African American, n(%) 2 (29) 4 (57) 3 (50) 12 (75) 3 (19) 5 (62) 3 (38) 12 (86) 2 (14) 7 (88) 1 (12) Ethnicity : Hispanic, n (%) 3 (43)2 (33)5 (31)1 (12)3 (21)3 (38) Age, median years (range) 39 (34-51)48 (43-65)48 (31-57)47 (31-53)54 (37-60)39 (26-53) BMI, median kg/m 2 (range) 29 (22-37)31 (26-37)24 (21-32)23 (19-29)24 (23-33)25 (22-30) HCV RNA 800,000 IU/mL**, n (%) 7 (100)5 (83)13 (81)7 (88)10 (71)7 (88) HCV Genotype Subtype*, n (%) 1a 1b 3 (43) 4 (57) 3 (50) 2 (33) 12 (75) 4 (25) 6 (75) 1 (12) 11 (79) 3 (21) 5 (62) 3 (38) Bridging Fibrosis, n(%) Cirrhosis, n (%) 1 (14) 0 (0) 2 (12) 1 (12) 0 (0) 1 (12) 0 (0) HIV RNA median copies/mL (range) 1495 (155-53,450) 267 (50-21,950) <50 CD4+ median cells/mm 3 (range) 604 ( ) 672 ( ) 533 ( ) 514 ( ) 492 ( ) 535 ( ) Race and ethnicity were self-reported *5NC InnoLipa line probe assay **Roche COBAS® TaqMan® HCV test v2.0, LLOQ of 25 IU/mL (pts with values below 25IU/mL were reported as <25 detectable or undetectable)

9 Undetectable HCV RNA at Week 4 (ITT) 5/712/169/140/81/80/ Percent of patients with HCV RNA Undetectable Telaprevir + PR n/N = PR No ARTEFV/TDF/FTCATV/r+TDF+FTC/3TC PR 70 26/371/22 5 Total

10 Undetectable HCV RNA at Week 12 (ITT) 5/712/168/141/8 1/ Percent of patients with HCV RNA Undetectable Telaprevir + PR n/N = PR No ARTEFV/TDF/FTCATV/r+TDF+FTC/3TC PR /2225/37 Total

11 Median (IQR) Telaprevir Trough Plasma Concentrations were Similar with and without ART EFV/TDF/FTC (n=6-11) ATV/r + TDF + FTC/3TC (n=6-8) No ART (n=5-6) Weeks 0 Telaprevir Trough Plasma Concentrations (ng/mL) IQR: Interquartile range = Q3-Q1

12 HCV Virological Failure 2 telaprevir patients experienced viral breakthrough*: o 1 patient at week 4 (receiving ATV/r + TDF + FTC) o 1 patient at week 8 (receiving EFV/TDF/FTC) 4 patients discontinued treatment due to stopping rules: o 1 telaprevir patient (receiving EFV/TDF/FTC) at week 8 o 3 placebo patients HCV sequencing has not been performed yet *defined as HCV RNA >100 IU/mL after HCV RNA undetectable or a 1 log 10 increase from nadir

13 Change from Baseline in Median (IQR) ART Trough Plasma Concentrations after T/PR Initiation Time (Weeks) Tenofovir (n=14-19) Efavirenz (n=9-12) Atazanavir (n=5-6) Change from Baseline (%) < 20% median change from baseline concentration IQR: Interquartile range = Q3-Q1

14 Weeks Mean (SD) Log 10 HIV RNA Change Mean (SD) HIV RNA Changes from Baseline No ART (T/PR)EFV/TDF/FTC (T/PR) ATV/r+TDF+FTC/3TC (T/PR) No ART (PR)EFV/TDF/FTC (PR)ATV/r+TDF+FTC/3TC (PR)

15 Most Common Adverse Events* *Reported in > 15% of patients regardless of severity in any treatment arm, in bold event occurring at > 10% points in any T group vs PR Mild and moderate rash events occurred in 16% and 11% of T/PR patients, respectively and in 14% and <1% of PR patients

16 Serious Events and Treatment Discontinuation Part APart B No ARTEFV/TDF/FTCATV/r + TDF + FTC/3TC T/PR N=7 PR N=6 T/PR N=16 PR N=8 T/PR N=14 PR N=8 Any AE, n(%)7 (100)5 (83)15 (94)7 (88)14 (100)8 (100) Serious AE*, n (%)1 (14)0002 (14)0 Discontinuation of all study drugs due to AE, n (%) (14)0 Due to jaundice00001 (7)0 Due to anemia00001 (7)0 Due to rash *Bacterial infection (n=2), anemia (n=1)

17 Interim Analysis Summary In this interim analysis, the most common adverse events in telaprevir patients with or without concurrent ART were fatigue, nausea, and headache; no severe rash events were reported Patients in the T/PR arms in both parts exhibited a higher on- treatment HCV RNA response at week 4 o T12/PR: 26 of 37 patients (70%) o PR: 1 of 22 patients (5%) No unexpected trends in HIV viral loads and/or CD4 counts were observed No clinically significant PK interactions were observed

18 Acknowledgements We thank all the Study 110 trial patients and investigators France Vlad Ratziu Pierre-Marie Girard Germany Peter Buggish Juergen Rockstroh Spain Cristina Tural Llacher Vincent Soriano USA Laveesa Bhatti Edwin De Jesus Douglas Dieterich Brad Hare Gregory Huhn Dushyantha Jayaweera Jacob Lalezari Kenneth Sherman Mark Sulkowski David Wyles We also thank study coordinators, and CROs who participated in the Study 110 trial, Elizabeth Zobre (I3) for statistical analysis, Christina Karunaratne and Dawn Vargas (Vertex Pharmaceuticals) for clinical project management, and Valérie Philippon, PhD, (Vertex Pharmaceuticals) for medical writing


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