Ns5a and polymerase inhibitors
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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?.

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NS5A and polymerase inhibitors

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Ns5a and polymerase inhibitors

NS5A and polymerase inhibitors

Mark Sulkowski, MD

Professor of Medicine

Johns Hopkins University

Baltimore Maryland 21212


Ns5a and polymerase inhibitors

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

The Goal of Combination Regimens

A

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

+

B

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

+

C


Polymerase inhibitors

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

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

VX-222 (100 mg bid) +

Telaprevir (1125 mg bid)

PegIFN + RBV*

(n=18)

Dual Regimens

Terminated

VX-222 (400 mg bid) +

Telaprevir (1125 mg bid)

PegIFN + RBV*

(n=29)

Quad Regimens

(stratified by genotype 1a/1b)

VX-222 (100 mg bid) +

Telaprevir (1125 mg bid)

+ PegIFN + RBV

(n=29)

Phase 2b

Treatment-naive

Genotype 1

HCV RNA

>5 log10 IU/mL

No cirrhosis

(nonblack: 89%)

PegIFN + RBV*

VX-222 (400 mg bid) +

Telaprevir (1125 mg bid)

+ PegIFN + RBV

(n=30)

PegIFN + RBV*

Week 0 12 24* 36*

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).

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


Zenith study virologic response

ZENITH Study: Virologic Response

VX-222 100 mg + telaprevir + PegIFN + RBV

VX-222 400 mg + telaprevir + PegIFN + RBV

93%

90%

87%

83%

83%

82%

Patients (%)

SVR24

(12 total weeks of treatment)

(n=11/15)

SVR12

(24 total weeks of treatment)

(n=18/15)

HCV RNA

Undetectable Week 24

(n=29/30)

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


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

24

8

12

4

Wk 0

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

PSI-7977 + RBV + Peg-IFN

SVR12

n=10

PSI-7977 +RBV + Peg-IFN

PSI-7977 + RBV

SVR12

n=10

PSI-7977+RBV+Peg-IFN

PSI-7977 + RBV

n=10

SVR12

PSI-7977 + RBV

n=10

SVR12

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


Psi 7977 electron 100 concordance of svr12 with svr24

PSI-7977 ELECTRON100% concordance of SVR12 with SVR24

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


Psi 7977 electron ribavirin may decrease relapse

PSI-7977 monotherapy arm (n=10)

7

Combined IFN Arms

6

PSI-7977/RBV

PSI-7977 Monotherapy

5

4

Mean HCV RNA (Log10 IU/mL)

3

2

1

0

0

2

7

14

21

28

Time (Days)

PSI-7977 ELECTRONRibavirin may decrease relapse

  • No on-treatment viral breakthroughsor resistance

  • 6/10 subjects achieved SVR4

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

Assay LLOD 15 IU/mL

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


Ns5a replication complex inhibitors

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.

BMS NS5A + PEG / RBV

Follow-up from Weeks 24 or 48

Weeks 1-12

Weeks 13-24

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

Placebo + peg-alfa/RBV

Peg-alfa/RBV

Follow-Up

20 mg BMS-790052 + peg-alfa/RBV

Follow-up

YES

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

PDR

Follow-up

Placebo + peg-alfa/RBV

Placebo + peg-alfa/RBV

alfa/RBV

NO

60 mg BMS-790052 + peg-alfa/RBV

Follow-up

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

YES

Follow-up

Placebo + peg-alfa/RBV

Placebo + peg-alfa/RBV

Peg-alfa/RBV

NO

Week 4 RNA

Week 10 RNA

Week 12 Interim Efficacy Analysis and Re-randomization

Week 24 Interim SafetyAnalysis

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

Virologic Responses Through Week 12 in Patients With Genotype 1 Infection

100

HCV RNA <LLQ and Detectable

84

85

90

84

HCV RNA Undetectable

76

7

25

80

9

78

19

75

70

60

53

54

54

60

57

Percentage of Patients

50

10

40

43

30

24

20

9

14

15

10

0

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

Week 12

Weeks 4 and 12

n =

146

72

147

146

72

147

146

72

147

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

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

BMS-790052 (60 mg QD) +

BMS-650032 (600 mg BID)

(n=11)

Follow-up x 48 weeks

Group A

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

+ PR (n=10)

Follow-up x 48 weeks

GroupB

24-week treatment

Post treatment: Week 24: SVR24

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

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

Dual Therapy Group: Resistance Variants in Patients with Viral Breakthrough

8

BL

1

6

2

3

HCV RNA

(log10 IU/mL)

4

4

5

1000 IU/mL

6

2

LOQ

LOD

0

0

4

6

8

10

12

2

Week

*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.


Ns5a and polymerase inhibitors

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

  • 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

SVR (%)

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).

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


Combination therapy

Combination therapy

  • 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.


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