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Post-Congress Activity Expert Review on the EACS, HIV & Aging and the AASLD Meetings With Dr. Mark Wainberg (moderator) and Dr. Fred Crouzat, Dr. Alice.

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Presentation on theme: "Post-Congress Activity Expert Review on the EACS, HIV & Aging and the AASLD Meetings With Dr. Mark Wainberg (moderator) and Dr. Fred Crouzat, Dr. Alice."— Presentation transcript:

1 Post-Congress Activity Expert Review on the EACS, HIV & Aging and the AASLD Meetings With Dr. Mark Wainberg (moderator) and Dr. Fred Crouzat, Dr. Alice Tseng, and Dr. Stephen Shafran

2 AASLD 2011 (The Liver Meeting) November 4-8, 2011 San Francisco, California

3 Direct-Acting Antivirals (DAAs) with Human Virological Data Presented at AASLD 2011 NS3 Protease Inhibitors Boceprevir Telaprevir Danoprevir Simeprevir Asunaprevir Vaniprevir Narlaprevir/r BI MK-5172 GS-9256 ACH-1625 NS5A Inhibitors Daclatasvir GS-5885 GSK PPI-461 NS5B Non Nucleoside Inhibitors Tegobuvir VX-222 BI TMC NS5B Nucleoside/tide Inhibitors Mericitabine PSI-7977 INX 189

4 Telaprevir for HCV in the HIV Co-Infected

5 PR (n = 16) Part B: Stable ART HIV/HCV-1-co-infected patients on stable ART, TDF/FTC/EFV or TDF + (FTC or 3TC) + ATZ/r; CD cells/mm³; HIV-1 RNA 50 c/mL (n = 46) Follow-up Part A: No current ART HIV/HCV-1-co-infected patients; CD cells/mm³; HIV-1 RNA 100,000 c/mL (n = 13) Follow-up Placebo + PR (n = 16) PR (n = 6) Placebo + PR (n = 6) PR (n = 7) Telaprevir 750 mg q8h + PR (n = 7) PR (n = 30) Telaprevir* 750 mg q8h + PR (n = 30) Wk 12Wk 48Wk 72 *Telaprevir dose increased to 1125 mg q8h with efavirenz. PEGinterferon alfa-2a 180 μg/wk; ribavirin 800 mg/day or 1000/1200 France and Germany Study 110: Interim Data on Telaprevir + PR in HIV-HCV Genotype 1-Co-Infected Patients Sherman K, et al. Follow-up of SVR Durability and Viral Resistance in Patients with Chronic Hepatitis C Treated with Telaprevir-Based Regimens: Interim Analysis of the EXTEND Study. [Abstract LB-8]. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

6 Telaprevir 110 Phase 2a HIV-HCV Co-Infection Study: Undetectable HCV RNA at Week 4 (RVR) 5/712/169/150/8 0/ % of patients with Undetectable HCV RNA T/PR n/N = PR No ARTEFV/TDF/FTCATZ/r+TDF+FTC/3TC Total 68 26/380/ Sherman K, et al. Follow-up of SVR Durability and Viral Resistance in Patients with Chronic Hepatitis C Treated with Telaprevir-Based Regimens: Interim Analysis of the EXTEND Study. [Abstract LB-8]. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

7 Telaprevir 110 Phase 2a HIV-HCV Co-Infection Study: Undetectable HCV RNA at Week 12 (cEVR) 6/714/1610/152/8 2/ % of patients with Undetectable HCV RNA T/PR n/N = PR No ARTEFV/TDF/FTCATZ/r+TDF+FTC/3TC Total 79 30/386/ Sherman K, et al. Follow-up of SVR Durability and Viral Resistance in Patients with Chronic Hepatitis C Treated with Telaprevir-Based Regimens: Interim Analysis of the EXTEND Study. [Abstract LB-8]. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

8 Telaprevir 110 Phase 2a HIV-HCV Co-Infection Study: Undetectable HCV RNA at Week 24 6/711/1610/156/84/82/ % of patients with Undetectable HCV RNA T/PR n/N = PR No ARTEFV/TDF/FTCATZ/r+TDF+FTC/3TC Total 71 27/3812/ Sherman K, et al. Follow-up of SVR Durability and Viral Resistance in Patients with Chronic Hepatitis C Treated with Telaprevir-Based Regimens: Interim Analysis of the EXTEND Study. [Abstract LB-8]. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

9 Daclatasvir (BMS ) (a NS5A Inhibitor)

10 COMMAND-1 Study for HCV GT1 and 4 Treatment Naïve Patients (GT1: n=365; GT4: n=30) Hézode C, et al. BMS , A NS5A Replication Complex Inhibitor, Combined with Peginterferon Alfa-2a and Ribavirin in Treatment-Naïve HCV-Genotype 1 or 4 Patients: Phase 2b AI Study Interim Week 12 Results. [Oral 227]. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

11 HCV RNA Reductions Through Week 12 in Patients with Genotype 1 Week On-treatment analysis (missing data = missing) Hézode C, et al. BMS , A NS5A Replication Complex Inhibitor, Combined with Peginterferon Alfa-2a and Ribavirin in Treatment-Naïve HCV-Genotype 1 or 4 Patients: Phase 2b AI Study Interim Week 12 Results. [Oral 227]. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

12 Virologic Responses at Weeks 4 and 12 in Patients with Genotype 1 LLOQ, lower limit of quantitation =25 IU/mL Undetectable < 10 IU/mL Hézode C, et al. BMS , A NS5A Replication Complex Inhibitor, Combined with Peginterferon Alfa-2a and Ribavirin in Treatment-Naïve HCV-Genotype 1 or 4 Patients: Phase 2b AI Study Interim Week 12 Results. [Oral 227]. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

13 PROTON: PSI-7977 & PEG/RBV in Treatment-Naïve Patients with HCV GT1: Sustained Virologic Response E Lawitz, JP Lalezari, T Hassanein, KV Kowdley, FF Poordad, AM Sheikh, NH Afdhal, DE Bernstein, E DeJesus, B Freilich, DR Nelson, DT Dieterich, IM Jacobson, D Jensen, GA Abrams, JM Darling, M Rodriguez-Torres, KR Reddy, MS Sulkowski, NH Bzowej, MP DeMicco, JS Strohecker, RH Hyland, M Mader, R Hindes, E Albanis, WT Symonds, MM Berrey

14 PSI-7977 (a nucleotide analogue NS5B polymerase inhibitor)

15 Wk PEG/RBV N=48 N=47 N=26 HCV GT1 Stop SVR24 Stop SVR24 PEG/RBV NON-eRVR PEG/RBV PEG/RBV PSI mg QD PEG/RBV NON-eRVR PEG/RBV PEG/RBV PSI mg QD PEG/RBV PEG/RBV Study Design: Dose Ranging in GT1 Double-blind, randomized, placebo-controlled 121 treatment-naïve patients with HCV GT1 Wk HCV GT2 or GT3, open-label N=25 PSI mg QD PEG/RBV SVR12SVR24 25 treatment-naïve patients with HCV GT2 or GT3; one pt lost to F/U after Day 1 24/25 RVR, SVR12 and SVR24 (EASL 2011, Lelazari et al.) Lawitz E, et al. Once-Daily PSI-7977 Plus Peg/RBV in Treatment-naïve Patients with HCV GT1: Robust End of Treatment Response Rates are Sustained Post-treatment. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

16 Rapid HCV RNA Suppression in all 95 Subjects with HCV GT1 on PSI or 400 mg QC + PEG/RBV Lawitz E, et al. Once-Daily PSI-7977 Plus Peg/RBV in Treatment-naïve Patients with HCV GT1: Robust End of Treatment Response Rates are Sustained Post-treatment. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

17 PROTON Study: Virologic Responses* in Genotype 1 (SVR results still pending in PR control population) *ITT Analysis SVR12 was 98% in patients who received 8 weeks of PSI mg QD + PR Lawitz E, et al. Once-Daily PSI-7977 Plus Peg/RBV in Treatment-naïve Patients with HCV GT1: Robust End of Treatment Response Rates are Sustained Post-treatment. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

18 PSI-7977 ELECTRON Study Aim: To determine the shortest duration of interferon, if any, required to achieve SVR when PSI ribavirin are administered for 12 weeks Why HCV GT 2/3? HCV GT2/3 population was selected due to higher response to rescue with PEG/RBV in the event of breakthrough Gane E, et al. Once Daily PSI-7977 plus RBV: Pegylated Interferon-ALFA not Required for Complete Rapid Viral Response in Treatment-Naïve Patients with HCV GT2 or GT3. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

19 PSI-7977 ELECTRON Study Design for HCV GT2/3 Treatment-naïve, non-cirrhotic, age 18 years HCV RNA >50,000 IU/mL Allowed concurrent methadone use Stratified by HCV genotype and IL28B genotype Randomized 1:1:1:1 into IFN-sparing or IFN-free Wk n=10 PSI RBV + PEG-IFN PSI RBV PSI RBV + PEG-IFN PSI RBV 24 SVR12 Gane E, et al. Once Daily PSI-7977 plus RBV: Pegylated Interferon-ALFA not Required for Complete Rapid Viral Response in Treatment-Naïve Patients with HCV GT2 or GT3. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

20 PSI-7977 ELECTRON Gane E, et al. Once Daily PSI-7977 plus RBV: Pegylated Interferon-ALFA not Required for Complete Rapid Viral Response in Treatment-Naïve Patients with HCV GT2 or GT3. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

21 PSI-7977 ELECTRON What is the Role of Ribavirin? PSI-7977 monotherapy arm (n=10) was added No on-treatment viral breakthroughs or resistance 6/10 subjects achieved SVR4 Further studies of PSI-7977 monotherapy in progress PSI-7977/RBV for 12 weeks being advanced in IFN-free Phase 3 program Gane E, et al. Once Daily PSI-7977 plus RBV: Pegylated Interferon-ALFA not Required for Complete Rapid Viral Response in Treatment-Naïve Patients with HCV GT2 or GT3. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

22 Direct-Acting Antivirals (DAA) Combination Therapy

23 Ongoing, Open-Label Phase 2a Study Sentinel Cohort, Study AI Non-cirrhotic Japanese adults with HCV genotoype 1 infection, HCV RNA > 10 5 IU/mL, and prior null response to PEG-IFN/RBV Primary efficacy endpoint: undetectable HCV RNA 12 weeks post-treatment (SVR12) – Secondary: Undetectable HCV RNA at week 4 (RVR), week 12 (cEVR), weeks (eRVR), end of treatment (week 24;EOTR) and at 24 weeks post-treatment (SVR24) Dual oral treatment with daclatasvir and asunaprevir for 24 weeks – Daclatasvir 60 mg once-daily – Asunaprevir initially 600 mg twice-daily, subsequently reduced to 200 mg twice daily due to elevated transaminases at 600 mg in a concurrent dose-ranging study 1 ClinicalTrials.gov identifier NCT cEVR, complete early virologic response; EOTR, end of treatment response; eRVR, extended rapid virologic response; IFN, interferon; RVR, rapid virologic response. 1 Bronowicki JP, et al. J Hepatol 2011;54(suppl 1):S472. Daclastavir + Asunaprevir (n=10)Follow-up x 24 weeks Wk 4 (RVR) Wk 12 (cEVR) Wk 24 (EOTR) Post-trx Wk 12 (SVR12) Post-trx Wk 24 (SVR24) Chayama, K et al. Dual Oral Combination Therapy with the NS5A Inhibitor BMS and the NS3 Protease Inhibitor BMS Achieved 90% Sustained Virologic Response (SVR12) in HCV Genotype 1b-Infected Null Responders. [Oral LB-4]. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

24 HCV RNA: Individual Patients (n=10) HCV RNA determined by Roche COBAS ® TaqMan ® HCV Auto assay (Roche Diagnostics KK, Tokyo, Japan), lower limit of quantitation (LLOQ) = 15 IU/mL Chayama, K et al. Dual Oral Combination Therapy with the NS5A Inhibitor BMS and the NS3 Protease Inhibitor BMS Achieved 90% Sustained Virologic Response (SVR12) in HCV Genotype 1b-Infected Null Responders. [Oral LB-4]. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

25 ZENITH Study: PR + Two DAAs for HCV GT1 Treatment Naïve (non-cirrhotics) Study Weeks Arm C Arm D PR Stop if week 2 & 8 HCV RNA undetectable VX mg + TVR 1125 mg BID + PEG- IFNα-2a + RBV VX mg + TVR 1125 mg BID + PEG- IFNα-2a + RBV Nelson D, et al. New Treatment Paradigms. [Abstract 32]. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

26 ZENITH Arms C and D: Patient Disposition and Reasons for Discontinuation Prior to Week 12 a. AEs include: fatigue, pneumonia, rash, and facial bones fracture. b. Other reasons include: protocol deviation, use of prohibited medication, and HCV RNA detectable. n (%) C 100 mg VX-222 (n=29) D 400 mg VX-222 (n=30) Patients who completed 12 weeks25 (86)27 (90) Patients who discontinued all study drugs prior to week 12 4 (14)3 (10) - Due to viral breakthrough00 - Due to AE a 2 (7) - Due to other reasons b 2 (7)1 (3) Nelson D, et al. New Treatment Paradigms. [Abstract 32]. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

27 ZENITH Arms C & D: Key Virologic Endpoints a. Criteria for 12 weeks therapy. b. 2 patients in arm C and 1 patient in arm D have missing value 12 weeks after EOT. c. 1 patient with relapse received only 1 week of treatment. n (%) C 100 mg VX-222 (n=29) D 400 mg VX-222 (n=30) Week 2 HCV RNA-11 (38)17 (57) Week 4 (RVR)25 (86)26 (87) Weeks 2 & 8 neg a 11 (38)15 (50) Week 12 (cEVR)24 (83)27 (90) SVR1224 (83)27 (90) Relapse2/28 (7)2/30 (7) c Nelson D, et al. New Treatment Paradigms. [Abstract 32]. Presented at the 62 nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.


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