Post-Congress Activity Expert Review on the EACS, HIV & Aging and the AASLD Meetings, 2011

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

AASLD 2011 (The Liver Mee+ng) November 4-‐8, 2011 San Francisco, California

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

Telaprevir for HCV in the HIV Co-‐Infected

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


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


79

30/38 6/22

25 27


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


71

27/38 12/22

50 55


Daclatasvir (BMS-‐790052) (a NS5A Inhibitor)

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)


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


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

PSI-‐7977 (a nucleo.de analogue NS5B

polymerase inhibitor)

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


PSI-‐7977 ELECTRON


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


Direct-‐Ac.ng An.virals (DAA) Combina.on Therapy

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)


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


Health & Medicine

Post-Congress Activity Expert Review on the EACS, HIV & Aging and the AASLD Meetings, 2011