NS5A and polymerase inhibitors

Mark Sulkowski, MD

Professor of Medicine

Johns Hopkins University

Baltimore Maryland 21212

Case

57 yo woman with genotype 1a and bridging fibrosis– PROVE-1 study – treated with TVR x 12

wks and 48 weeks PR– Viral relapse

Treatment options?

The Goal of Combination Regimens

B

C

Prevention of emergent resistance (pre-existing or de novo)

+

+

AProfound suppression of broad range of viral variants, including pre-existing variants

Polymerase Inhibitors

Non-nucleoside– VX-222– ANA-598– ABT-072; ABT-033– GS-9190

Nucleos(t)ide analogue – PSI (GS)-7977– Mericitabine (RG7128)

ZENITH Study: VX-222 + Telaprevir +PegIFN Alfa-2a + RBV in Chronic HCV

Phase 2b Treatment-naive

Genotype 1HCV RNA

>5 log10 IU/mLNo cirrhosis

(nonblack: 89%)

Nelson DR, et al. Hepatology. 2011;54(supp):1435A. Abstract LB-14.

Week 0 12 24* 36*

(n=18)

Weight-based ribavirin dosing (1000-1200 mg).*Patients undetectable HCV RNA at weeks 2 and 8 discontinue treatment at week 12; patients with detectable HCV RNA at week 2 or 8 started PegIFN + RBV at week 12 (until 24 weeks of PegIFN + RBV are received).

(n=29)

(n=30) PegIFN + RBV*

PegIFN + RBV*

(n=29)

VX-222 (100 mg bid) +Telaprevir (1125 mg bid)

PegIFN + RBV*

VX-222 (400 mg bid) +Telaprevir (1125 mg bid)

PegIFN + RBV*VX-222 (100 mg bid) +

Telaprevir (1125 mg bid)

+ PegIFN + RBV

VX-222 (400 mg bid) +Telaprevir (1125 mg bid)

+ PegIFN + RBV

Dual RegimensTerminated

Quad Regimens(stratified by genotype 1a/1b)

ZENITH Study: Virologic Response

0

20

40

60

80

100

HCV RNAUndetectable Week 24

(n=29/30)

SVR24(12 total weeks of treatment)

(n=11/15)

Pat

ien

ts (

%)

83%90%

VX-222 100 mg + telaprevir + PegIFN + RBVVX-222 400 mg + telaprevir + PegIFN + RBV

93%

82% 83%87%

Nelson DR, et al. Hepatology. 2011;54(supp):1435A. Abstract LB-14.

SVR12(24 total weeks of treatment)

(n=18/15)

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

PSI-7977 + RBVPSI-7977 + RBV

PSI-7977+RBV+Peg-IFNPSI-7977+RBV+Peg-IFN PSI-7977 + RBVPSI-7977 + RBV

PSI-7977 +RBV + Peg-IFNPSI-7977 +RBV + Peg-IFN PSI-7977 + RBVPSI-7977 + RBV

PSI-7977 + RBV + Peg-IFNPSI-7977 + RBV + Peg-IFN

n=10

SVR12

SVR12

SVR12

SVR12

n=10

n=10

n=10

4 8Wk 0 12 24

PSI-7977 ELECTRON: Study Design for HCV GT2/3

Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 34.

Time Wk

PSI-7977RBV

12 weeks PEG

PSI-7977RBV

8 weeks PEG

PSI-7977RBV

4 weeks PEG

PSI-7977RBV

NO PEG

n %<LOD n %<LOD n %<LOD n %<LOD

2 9/11 82 7/8 88 8/9 89 8/10 80

4 11/11 100 10/10 100 9/9 100 10/10 100

8 11/11 100 10/10 100 9/9 100 10/10 100

12 11/11 100 10/10 100 9/9 100 10/10 100

SVR4 11/11 100 10/10 100 9/9 100 10/10 100

SVR8 11/11 100 10/10 100 9/9 100 10/10 100

SVR12 11/11 100 10/10 100 9/9 100 10/10 100

SVR24 6/6 100 5/5 100 5/5 100 4/4 100

PSI-7977 ELECTRON100% concordance of SVR12 with SVR24

Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 34.

Assay LLOD 15 IU/mL

PSI-7977 ELECTRONRibavirin may decrease relapse

PSI-7977 monotherapy arm (n=10)• No on-treatment viral

breakthroughsor resistance

• 6/10 subjects achieved SVR4

• 4/10 subjects had viral relapse w/o ribavirin

PSI-7977/RBVPSI-7977 Monotherapy

Combined IFN Arms

Time (Days)0 2 7 14 21 28

Mea

n H

CV

RN

A (

Log 1

0 IU

/mL)

0

1

2

3

4

5

6

7

Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 34.

NS5A: Replication Complex Inhibitors

Daclatasvir – phase 3 Others in phase 2

– Abbott, ABT-267– Gilead, GS-5885

BMS NS5A + PEG / RBV

PDR (protocol-defined response): HCV RNA <LLQ (25 IU/mL) at week 4 and undetectable (<10 IU/mL) at week 10.

20 mg BMS-790052 + peg-alfa/RBV (n=180)

60 mg BMS-790052 + peg-alfa/RBV (n=180)

20 mg BMS-790052 + peg-alfa/RBV

60 mg BMS-790052 + peg-alfa/RBV

Week 12 Interim Efficacy

Analysis and Re-randomization

Placebo + peg-alfa/RBV

Placebo + peg-alfa/RBV

Weeks 1-12 Weeks 13-24

Week 4 RNA Week 10 RNA

NO

YES

NO

YES

Follow-Up

alfa/RBV

Peg-alfa/RBV

Placebo + peg-alfa/RBV

Follow-up

Follow-up

Placebo + peg-alfa/RBV

Follow-up

Follow-up

Placebo + peg-alfa/RBV (n=60) Placebo + peg-alfa/RBV Peg-alfa/

RBV

Week 24 Interim Safety

Analysis

PDR

Follow-up from Weeks 24 or 48

Hezode C, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 277.

Virologic Responses Through Week 12 in Patients With Genotype 1 Infection

LLQ, lower limit of quantitation = 25 IU/mL Undetectable < 10 IU/mL

HCV RNA <LLQ and Detectable

HCV RNA Undetectable

54 54

14

60

25

57

19

15

9

787

75

9

43

10

0

10

20

30

40

50

60

70

80

90

100

20 mg +

peg-alfa/RBV

60 mg +

peg-alfa/RBV

Placebo +

peg-alfa/RBV

20 mg +

peg-alfa/RBV

60 mg +

peg-alfa/RBV

Placebo +

peg-alfa/RBV

20 mg +

peg-alfa/RBV

60 mg +

peg-alfa/RBV

Placebo +

peg-alfa/RBV

Week 4 Weeks 4 and 12Week 12

Perc

enta

ge o

f Pati

ents

8576

24

84 84

53

147 146 72 147 146 72n = 147 146 72

Hezode C, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 277.

Dual Oral vs Quad Therapy: BMS-790052 + BMS-650032 ± PR

Phase 2a study; N=21; 19 with CT/TT IL28B genotype. BMS-790052=NS5A replication complex inhibitor; BMS-650032=NS3 PI

BMS-790052 (60 mg QD) +BMS-650032 (600 mg BID)

(n=11)

BMS-790052 (60 mg QD) + BMS-650032 (600 mg BID)

+ PR (n=10)

Follow-up x 48 weeks

Follow-up x 48 weeks

24-week treatment Post treatment: Week 24: SVR24

Group A

GroupB

Lok As et al. New Engl J Med 2012

Dual Therapy Group: Resistance Variants in Patients with Viral Breakthrough

Viral breakthrough in 6 of 11 pts: All G1a; no resistance variants detected at baseline

NS3 protease and NS5A resistance variants detected after viral breakthrough

Role of emerging variants confirmed by phenotypic analysis– NS3:30- to 525-fold resistance

– NS5A:3400- to >330,000-fold resistance

Patient # 1 2 3 4 5 6*

Week tested 2 4 7 8 10 12

NS3 protease variants (%)

D168Y (87)D168A (13)

R155K (100) D168Y (100) D168E (100) R155K (100) D168V

NS5A variants (%)

Y93N (100) L31V (100) Q30R (100)L31M (100)

Q30R (76)L31V (100)Y93C (17)

Q30R (45)L31V (77)H58P (39)Y93C (16)Y93N (13)

Q30RL31VH54YY93C

0 2 4 6 8 10 12

0

2

4

6

8

1000 IU/mL

LOQLOD

HC

V R

NA

(l

og

10 IU

/mL

)

Week

1

23

45

6

BL

*Clonal analysis not performed on patient 6

McPhee F, et al. Presented at: EASL: The International Liver Congress 2011; March 30 - April 3, 2011; Berlin, Germany. Oral Presentation 63.

Present study: dual therapy in 10 G1b null responders, non-cirrhotic

Treated for 24 weeks

Dose of BMS 650032 reduced from 600mg bid to 200mg bid secondary to ALT elevations

No viral breakthrough and no effect of pre Existing viral mutants

2 SAE’s: 1 hyperbilirubineia, 1 pyrexia

SV

R (

%)

Chayama K, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. LB-4

Dual oral combination therapy with the NS5A inhibitor BMS-790052 and the NS3 PI BMS-650032 achieved 90% SVR24 in

HCV G1b-infected null responders

Confirmation of high SVR in G1b patients with IFN-free regimen despite history of null response to PR. Need for high resistance barrier component of IFN-free regimens may be subtype-dependent (less in G1b than G1a).

Antiviral activity in all HCV genotypes No selection of resistance

All-oral combination regimen Short treatment duration

QD (or BID) dosing Excellent safety and tolerability

Applicable in difficult-to-treat populations: Transplant Coinfection End-stage renal disease, etc.

Combination therapy