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. Study 110: Interim Data on Telaprevir + PR in HIV-HCV Genotype 1-Co-Infected Patients
Wk 12
Wk 48
Wk 72
Telaprevir 750 mg q8h + PR†
(n = 7)
PR†
(n = 7)
Part A: No current ART
HIV/HCV-1-co-infected patients;
CD4+ ≥ 500 cells/mm³;
HIV-1 RNA ≤ 100,000 c/mL
(n = 13)
Follow-up
Placebo + PR
(n = 6)
PR†
(n = 6)
Part B: Stable ART
HIV/HCV-1-co-infected patients
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)
Telaprevir*
750 mg q8h + PR
(n = 30)
PR†
(n = 30)
Follow-up
Placebo + PR
(n = 16)
PR†
(n = 16)
*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
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 62nd 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)
No ART
EFV/TDF/FTC
ATZ/r+TDF+FTC/3TC
Total
100 90 80 75 71 68 70 60 60 50
% of patients with Undetectable HCV RNA 40 30 20 10
n/N =
5/7
12/16
9/15
26/38
0/6
0/8
0/8
0/22 PR
T/PR
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 62nd 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)
No ART
EFV/TDF/FTC
ATZ/r+TDF+FTC/3TC
Total
100 88 90 86 79 80 67 70 60 50
% of patients with Undetectable HCV RNA 33 40 27 25 25 30 20 10
n/N =
6/7
14/16
10/15
30/38
2/6
2/8
2/8
6/22 PR
T/PR
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 62nd 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
No ART
EFV/TDF/FTC
ATZ/r+TDF+FTC/3TC
Total
100 86 90 75 75 80 71 67 70 55 60 50 50
% of patients with Undetectable HCV RNA 33 40 30 20 10
n/N =
6/7
11/16
10/15
27/38
2/6
4/8
6/8
12/22
T/PR PR
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 62nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

9. Daclatasvir (BMS-790052) (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 62nd 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
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 62nd 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 62nd 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. Study Design: Dose Ranging in GT1
HCV GT1 Wk
SVR24
Stop
N=48
PSI mg QD PEG/RBV
PEG/RBV
NON-eRVR PEG/RBV
SVR24
Stop
N=47
PSI mg QD PEG/RBV
PEG/RBV
PEG/RBV
PEG/RBV
NON-eRVR PEG/RBV
N=26
PEG/RBV
SVR24
Double-blind, randomized, placebo-controlled
121 treatment-naïve patients with HCV GT1
HCV GT2 or GT3, open-label Wk
N=25
PSI mg QD PEG/RBV
SVR12
SVR24
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 62nd 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-7977 200 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 62nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

17. PROTON Study: Virologic Responses
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 62nd 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 62nd 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 0 4 8 12 24
PSI RBV + PEG-IFN
SVR12
PSI RBV + PEG-IFN
PSI RBV
SVR12
n=10
PSI RBV + PEG-IFN
PSI RBV
SVR12
PSI RBV
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 62nd 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 62nd 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 62nd 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 AI447-017
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)
Non-cirrhotic Japanese adults with HCV genotoype 1 infection, 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 (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 study1
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. 1Bronowicki JP, et al. J Hepatol 2011;54(suppl 1):S472.
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 62nd 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 62nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

25. VX-222 400 mg + TVR 1125 mg BID + PEG-IFNα-2a + RBV
ZENITH Study: PR + Two DAAs for HCV GT1 Treatment Naïve (non-cirrhotics)
VX mg + TVR 1125 mg BID + PEG- IFNα-2a + RBV
Stop if week 2 & 8 HCV RNA undetectable
Arm C PR
VX mg + TVR 1125 mg BID + PEG-IFNα-2a + RBV
Stop if week 2 & 8 HCV RNA undetectable
Arm D PR 24 12
Study Weeks
Nelson D, et al. New Treatment Paradigms. [Abstract 32]. Presented at the 62nd 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
C 100 mg VX-222
(n=29)
D 400 mg VX-222 (n=30)
Patients who completed 12 weeks
25 (86)
27 (90)
Patients who discontinued all study drugs prior to week 12
4 (14)
3 (10)
- Due to viral breakthrough
- Due to AEa
2 (7)
- Due to other reasonsb
1 (3)
a. AEs include: fatigue, pneumonia, rash, and facial bones fracture.
b. Other reasons include: protocol deviation, use of prohibited medication, and HCV RNA detectable.
Nelson D, et al. New Treatment Paradigms. [Abstract 32]. Presented at the 62nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.

27. ZENITH Arms C & D: Key Virologic Endpoints
Strategic Communications
ZENITH Arms C & D: Key Virologic Endpoints
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
15 (50)
Week 12 (cEVR)
24 (83)
27 (90)
SVR12
Relapse
2/28 (7)
2/30 (7)c
The median time to undetectable HCV RNA was 4 and 2 weeks in arms C and D, respectively.
• Most patients achieved SVR (83% and 90% in arms C and D, respectively). No patient in either QUAD arm experienced viral breakthrough. However, 2 patients relapsed in arm C and 2 patients (including 1 patient who received only 1 week of treatment) in arm D.
• More patients had undetectable HCV RNA at Weeks 2 and 8 in arm D than in arm C (50% vs. 38%). These patients were eligible for 12-week treatment duration, and 82% (arm C) and 93% (arm D) of these patients achieved SVR.
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.
Nelson D, et al. New Treatment Paradigms. [Abstract 32]. Presented at the 62nd Annual Meeting of the AASLD 2011, November 4-8, 2011, San Francisco, USA.
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