post-congress activity expert review on the eacs, hiv & aging and the aasld meetings, 2011
DESCRIPTION
Focus on AASLD 2011TRANSCRIPT
Post-‐Congress Ac.vity Expert Review on the EACS, HIV & Aging
and the AASLD Mee.ngs
With Dr. Mark Wainberg (moderator) and Dr. Fred Crouzat, Dr. Alice Tseng, and
Dr. Stephen Shafran
Direct-‐Ac.ng An.virals (DAAs) with Human Virological Data Presented at AASLD 2011
NS3 Protease Inhibitors
• Boceprevir
• Telaprevir
• Danoprevir • Simeprevir
• Asunaprevir
• Vaniprevir
• Narlaprevir/r
• BI 201335 • MK-‐5172
• GS-‐9256
• ACH-‐1625
NS5A Inhibitors • Daclatasvir • GS-‐5885 • GSK 2336805 • PPI-‐461
NS5B Non Nucleoside Inhibitors • Tegobuvir • VX-‐222 • BI 201127 • TMC 647055
NS5B Nucleoside/.de Inhibitors • Mericitabine • PSI-‐7977 • INX 189
PR†
(n = 16)
Part B: Stable ART HIV/HCV-‐1-‐co-‐infected paQents on stable ART, TDF/FTC/EFV or TDF + (FTC or 3TC) + ATZ/r; CD4+ ≥ 300 cells/mm³; HIV-‐1 RNA ≤ 50 c/mL
(n = 46)
Follow-up
Part A: No current ART HIV/HCV-‐1-‐co-‐infected paQents;
CD4+ ≥ 500 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 12 Wk 48 Wk 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 Pa.ents
Sherman K, et al. Follow-‐up of SVR Durability and Viral Resistance in PaQents with Chronic HepaQQs C Treated with Telaprevir-‐Based Regimens: Interim Analysis of the EXTEND Study. [Abstract LB-‐8]. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
Telaprevir 110 Phase 2a HIV-‐HCV Co-‐Infec.on Study: Undetectable HCV RNA at Week 4 (RVR)
5/7 12/16 9/15 0/8 0/8 0/6
71 75
0
60
0
% of p
a.en
ts w
ith Und
etectable HCV
RNA
T/PR
n/N =
PR
0 10 20 30 40 50 60 70 80 90
100 No ART EFV/TDF/FTC ATZ/r+TDF+FTC/3TC Total
68
26/38 0/22
0 0
Sherman K, et al. Follow-‐up of SVR Durability and Viral Resistance in PaQents with Chronic HepaQQs C Treated with Telaprevir-‐Based Regimens: Interim Analysis of the EXTEND Study. [Abstract LB-‐8]. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
Telaprevir 110 Phase 2a HIV-‐HCV Co-‐Infec.on Study: Undetectable HCV RNA at Week 12 (cEVR)
6/7 14/16 10/15 2/8 2/8 2/6
86 88
33
67
25
% of p
a.en
ts w
ith Und
etectable HCV
RNA
T/PR n/N =
PR
0 10 20 30 40 50 60 70 80 90
100 No ART EFV/TDF/FTC ATZ/r+TDF+FTC/3TC Total
79
30/38 6/22
25 27
Sherman K, et al. Follow-‐up of SVR Durability and Viral Resistance in PaQents with Chronic HepaQQs C Treated with Telaprevir-‐Based Regimens: Interim Analysis of the EXTEND Study. [Abstract LB-‐8]. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
Telaprevir 110 Phase 2a HIV-‐HCV Co-‐Infec.on Study: Undetectable HCV RNA at Week 24
6/7 11/16 10/15 6/8 4/8 2/6
86 75
33
67 75
% of p
a.en
ts w
ith Und
etectable HCV
RNA
T/PR n/N =
PR
0 10 20 30 40 50 60 70 80 90
100 No ART EFV/TDF/FTC ATZ/r+TDF+FTC/3TC Total
71
27/38 12/22
50 55
Sherman K, et al. Follow-‐up of SVR Durability and Viral Resistance in PaQents with Chronic HepaQQs C Treated with Telaprevir-‐Based Regimens: Interim Analysis of the EXTEND Study. [Abstract LB-‐8]. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
COMMAND-‐1 Study for HCV GT1 and 4 Treatment Naïve Pa.ents (GT1: n=365; GT4: n=30)
Hézode C, et al. BMS-‐790052, A NS5A ReplicaQon Complex Inhibitor, Combined with Peginterferon Alfa-‐2a and Ribavirin in Treatment-‐Naïve HCV-‐Genotype 1 or 4 PaQents: Phase 2b AI444010 Study Interim Week 12 Results. [Oral 227]. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
HCV RNA Reduc.ons Through Week 12 in Pa.ents with Genotype 1
Week On-treatment analysis (missing data = missing)
Hézode C, et al. BMS-‐790052, A NS5A ReplicaQon Complex Inhibitor, Combined with Peginterferon Alfa-‐2a and Ribavirin in Treatment-‐Naïve HCV-‐Genotype 1 or 4 PaQents: Phase 2b AI444010 Study Interim Week 12 Results. [Oral 227]. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
Virologic Responses at Weeks 4 and 12 in Pa.ents with Genotype 1
LLOQ, lower limit of quan.ta.on =25 IU/mL Undetectable < 10 IU/mL
Hézode C, et al. BMS-‐790052, A NS5A ReplicaQon Complex Inhibitor, Combined with Peginterferon Alfa-‐2a and Ribavirin in Treatment-‐Naïve HCV-‐Genotype 1 or 4 PaQents: Phase 2b AI444010 Study Interim Week 12 Results. [Oral 227]. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
PROTON: PSI-‐7977 & PEG/RBV in Treatment-‐Naïve Pa.ents 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
Wk 0 12 24 48 72
PEG/RBV
N=48
N=47
N=26
HCV GT1
Stop SVR24
Stop SVR24
SVR24
PEG/RBV NON-eRVR PEG/RBV PEG/RBV PSI-‐7977 400mg QD PEG/RBV
NON-eRVR PEG/RBV PEG/RBV PSI-‐7977 200mg QD PEG/RBV
PEG/RBV
Study Design: Dose Ranging in GT1
• Double-‐blind, randomized, placebo-‐controlled
• 121 treatment-‐naïve paQents with HCV GT1
Wk 0 12 24 36 HCV GT2 or GT3, open-label
N=25 PSI-‐7977 400mg QD PEG/RBV
SVR12 SVR24
• 25 treatment-‐naïve paQents with HCV GT2 or GT3; one pt lost to F/U ater 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 PaQents with HCV GT1: Robust End of Treatment Response Rates are Sustained Post-‐treatment. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
Rapid HCV RNA Suppression in all 95 Subjects with HCV GT1 on PSI-‐7977 200 or 400 mg QC + PEG/RBV
Lawitz E, et al. Once-‐Daily PSI-‐7977 Plus Peg/RBV in Treatment-‐naïve PaQents with HCV GT1: Robust End of Treatment Response Rates are Sustained Post-‐treatment. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
PROTON Study: Virologic Responses* in Genotype 1 (SVR results s.ll pending in PR control popula.on)
*ITT Analysis SVR12 was 98% in paQents who received ≥ 8 weeks of PSI-‐7977 400 mg QD + PR
Lawitz E, et al. Once-‐Daily PSI-‐7977 Plus Peg/RBV in Treatment-‐naïve PaQents with HCV GT1: Robust End of Treatment Response Rates are Sustained Post-‐treatment. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
PSI-‐7977 ELECTRON
Study Aim: To determine the shortest duraQon of interferon, if
any, required to achieve SVR when PSI-‐7977 + ribavirin are administered for 12 weeks
Why HCV GT 2/3? HCV GT2/3 populaQon 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 PaQents with HCV GT2 or GT3. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
PSI-‐7977 ELECTRON Study Design for HCV GT2/3
• Treatment-‐naïve, non-‐cirrho.c, age ≥ 18 years
• HCV RNA >50,000 IU/mL
• Allowed concurrent methadone use • Stra.fied by HCV genotype and IL28B genotype
• Randomized 1:1:1:1 into IFN-‐sparing or IFN-‐free
Wk 0 4 8 12
n=10
PSI-7977 + RBV + PEG-IFN
PSI-7977 + RBV + PEG-IFN PSI-7977 + RBV
PSI-7977 + RBV + PEG-IFN PSI-7977 + RBV
PSI-7977 + RBV
24
SVR12
SVR12
SVR12
SVR12
Gane E, et al. Once Daily PSI-‐7977 plus RBV: Pegylated Interferon-‐ALFA not Required for Complete Rapid Viral Response in Treatment-‐Naïve PaQents with HCV GT2 or GT3. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
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 PaQents with HCV GT2 or GT3. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
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 PaQents with HCV GT2 or GT3. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
Ongoing, Open-‐Label Phase 2a Study Sen.nel Cohort, Study AI447-‐017
• Non-‐cirrhoQc Japanese adults with HCV genotoype 1 infecQon, HCV RNA > 105 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 4 + 12 (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 iniQally 600 mg twice-‐daily, subsequently reduced to 200 mg twice daily due to elevated transaminases at 600 mg in a concurrent dose-‐ranging study1
ClinicalTrials.gov idenQfier NCT01051414. cEVR, complete early virologic response; EOTR, end of treatment response; eRVR, extended rapid virologic response; IFN, interferon; RVR, rapid virologic response. 1Bronowicki 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 CombinaQon Therapy with the NS5A Inhibitor BMS-‐790052 and the NS3 Protease Inhibitor BMS-‐650032 Achieved 90% Sustained Virologic Response (SVR12) in HCV Genotype 1b-‐Infected Null Responders. [Oral LB-‐4]. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
HCV RNA: Individual Pa.ents (n=10)
HCV RNA determined by Roche COBAS® TaqMan® HCV Auto assay (Roche DiagnosQcs KK, Tokyo, Japan), lower limit of quanQtaQon (LLOQ) = 15 IU/mL
Chayama, K et al. Dual Oral CombinaQon Therapy with the NS5A Inhibitor BMS-‐790052 and the NS3 Protease Inhibitor BMS-‐650032 Achieved 90% Sustained Virologic Response (SVR12) in HCV Genotype 1b-‐Infected Null Responders. [Oral LB-‐4]. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
ZENITH Study: PR + Two DAAs for HCV GT1 Treatment Naïve (non-cirrhotics)
Study Weeks
24 0 12
Arm C
Arm D PR
PR
Stop if week 2 & 8 HCV RNA undetectable
Stop if week 2 & 8 HCV RNA undetectable
VX-222 100 mg + TVR 1125 mg BID + PEG- IFNα-2a + RBV
VX-222 400 mg + TVR 1125 mg BID + PEG-
IFNα-2a + RBV
Nelson D, et al. New Treatment Paradigms. [Abstract 32]. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
ZENITH Arms C and D: Pa.ent Disposi.on and Reasons for Discon.nua.on Prior to Week 12
a. AEs include: faQgue, pneumonia, rash, and facial bones fracture. b. Other reasons include: protocol deviaQon, use of prohibited medicaQon, and HCV RNA detectable.
n (%)
C 100 mg VX-‐222
(n=29)
D 400 mg VX-‐222
(n=30)
PaQents who completed 12 weeks 25 (86) 27 (90)
PaQents who disconQnued all study drugs prior to week 12
4 (14) 3 (10)
-‐ Due to viral breakthrough 0 0
-‐ Due to AEa 2 (7) 2 (7)
-‐ Due to other reasonsb 2 (7) 1 (3)
Nelson D, et al. New Treatment Paradigms. [Abstract 32]. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.
ZENITH Arms C & D: Key Virologic Endpoints
a. Criteria for 12 weeks therapy. b. 2 paQents in arm C and 1 paQent in arm D have missing value 12 weeks ater EOT. c. 1 paQent 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 nega 11 (38) 15 (50)
Week 12 (cEVR) 24 (83) 27 (90)
SVR12 24 (83) 27 (90)
Relapse 2/28 (7) 2/30 (7)c
Nelson D, et al. New Treatment Paradigms. [Abstract 32]. Presented at the 62nd Annual MeeQng of the AASLD 2011, November 4-‐8, 2011, San Francisco, USA.