HCV New Drugs: AASLD:BMS-790052 plus BMS-650032/comb Peg/RBV See Results Nov 2010

Combination Therapy With BMS-790052 and BMS-650032 Alone or With Pegylated Interferon and Ribavirin (pegIFN/RBV) Results in Undetectable HCV RNA Through 12 Weeks of Therapy in HCV Genotype 1 Null Responders

Reported by Jules Levin

AASLD

Oct 29-Nov 3 2010,

Boston Lok A,1 Gardiner D,2 Lawitz E,3 Martorell C,4 Everson G,5 Ghalib R,6 Reindollar R,7 Rustgi V,8 Wendelburg P,2 Zhu K,2 Shah V,2 Sherman D,2 McPhee F,9 Wind-Rotolo M,10 Bifano M,2 Eley T,2 Guo T,9 Persson A,10 Hindes R,9 Grasela D,2 and Pasquinelli C2 1University of Michigan, Ann Arbor, MI; 2Bristol-Myers Squibb, Research and Development, Hopewell, NJ; 3Alamo Medical Research, San Antonio, TX; 4The Research Institute, Springfield, MA; 5University of Colorado-Denver, Aurora, CO; 6The Liver Institute at Methodist, Dallas, TX; 7Carolinas Center for Liver Disease, Statesville, NC; 8Metropolitan Research, Fairfax, VA; 9Bristol-Myers Squibb, Research and Development, Wallingford, CT; 10Bristol-Myers Squibb, Research and Development, Princeton, NJ.

AUTHOR CONCLUSIONS
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BMS-790052 plus BMS-650032 is generally well-tolerated when coadministered for 12 weeks in HCV-infected patients who were null responders to pegIFN/RBV

BMS-790052 plus BMS-650032 provided potent early antiviral activity; however, 6/11 cases of viral breakthrough were observed with the 2 drugs when given alone

BMS-790052 plus BMS-650032 in combination with pegIFN/RBV resulted in undetectable HCV RNA in 9/10 patients by week 12

Should the antiviral activity demonstrated by 4-drug therapy predict SVR, the results would have significant implications for future therapy

Study expansion with additional arms is planned based on future data

ABSTRACT
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Background: BMS-790052 is a potent NS5A inhibitor with broad genotypic coverage while BMS-650032 is a potent hepatitis C virus (HCV) NS3 protease inhibitor with coverage of HCV genotypes (GT) 1a and 1b. Clinical studies combining these compounds alone and with pegylated interferon/ribavirin (pegIFN/RBV) are under way in HCV-infected null responders to determine their safety and efficacy.

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Methods:

AI447011 is a randomized, open-label, phase 2a study comparing the antiviral activity and safety of BMS-790052 (60 mg QD) and BMS-650032 (600 mg BID) alone (Group A) or with pegIFN/RBV (group B) for 24 weeks in HCV GT 1 null responders.

The primary aim was to determine the proportion of subjects achieving undetectable HCV RNA levels (less then 10 IU/mL) at weeks 2 and 4 of therapy and 24 weeks posttreatment.

A week 12 interim analysis was performed.

Results:

Twenty-one patients (11 Group A, 10 Group B) were randomized in a sentinel cohort. Median age was 55 years, 13 patients were male, and 16 were white. Virologic responses are presented below:

Virologic responses are presented below:

. aIntent-to-treat analysis, breakthrough = failure.

bOne subject with HCV RNA less then 25 IU/mL at week 12 was undetectable (UD, less then 10 IU/mL) on retesting.

Rapid virologic response (RVR) = UD by week 4.

Extended rapid virologic response (eRVR) = UD at weeks 4 and 12.Complete early virologic response (cEVR) = UD by week 12.

Six (54.5%) group A subjects experienced viral breakthrough, while all subjects in group B maintained viral suppression.

Viral breakthrough occurred exclusively in individuals infected with GT 1a, occurring as early as week 3 and as late as week 12.

The 2 GT 1b subjects in group A remained HCV RNA undetectable.

The 6 subjects with viral breakthrough had pegIFN/RBV added to their regimen.

HCV RNA levels fell to UD in 2 subjects and to less then 25 IU/mL in another 2 subjects, while the other 2 subjects had more then 1.5 log10 decreases in HCV RNA levels.

No deaths, serious adverse events, or discontinuations due to adverse events were recorded during the analysis period. Diarrhea was the most common adverse event and was mainly mild to moderate in severity.

Conclusions:

Treatment with BMS-790052 and BMS-650032 with or without pegIFN/RBV demonstrated similar RVR rates in HCV-infected GT 1 null responders. Six of 11 subjects receiving 2 direct-acting antiviral agents alone experienced viral breakthrough by week 12 while a 4-drug combination maintained viral suppression in all subjects.

Should this activity predict SVR, these results will have significant implications for future combination HCV antiviral therapy.

BACKGROUND

BMS-790052 is a first-in-class, potent, and highly selective inhibitor of hepatitis C virus (HCV) NS5A with in vitro picomolar potency BMS-650032 is a highly active HCV NS3 protease inhibitor Both BMS-790052 and BMS-650032 have been shown to be generally well-tolerated and to produce robust declines in HCV RNA levels following multiple dosing in subjects chronically infected with HCV genotype 1

The coadministration of BMS-790052 and BMS-650032 did not result in a clinically meaningful pharmacokinetic interaction in healthy volunteers (AASLD poster 827) HCV patients who are null responders to pegylated interferon and ribavirin (pegIFN/RBV) may benefit from combination therapy including 2 direct-acting antiviral agents with or without pegIFN/RBV

OBJECTIVES

Primary Objective- To determine the proportion of subjects with undetectable HCV RNA or a decrease in plasma HCV RNA ≥2 log10 IU/mL at week 2 and the proportion of subjects with undetectable HCV RNA at week 4 (rapid virologic response, RVR)

Secondary Objectives-

To assess the safety of coadministration of BMS-790052 and BMS-650032 with and without pegIFN/RBV-

To assess the pharmacokinetic profiles of subjects treated with BMS-790052 and BMS-650032 with and without pegIFN/RBV-

To assess the decrease in HCV RNA levels from baseline to days 4, 7, and 14-

To evaluate the proportion of subjects with RVR-

To evaluate the proportion of subjects with extended RVR (eRVR), defined as undetectable HCV RNA at both weeks 4 and 12-

To describe drug-resistant variants associated with virologic failure

a Intent-to-treat analysis, breakthrough = failure.

b Complete early virologic response (cEVR): undetectable HCV RNA by week 12.

c One subject in group B (1/10) did not meet cEVR (week 12 HCV RNA less then 25 IU/mL); however, on retesting his HCV RNA was undetectable (less then 10 IU/mL).

d Viral breakthrough: a) any increase in HCV RNA ≥1 log10 from nadir, or b) any detectable HCV RNA more then 25 IU/mL on or after week 4, or c) any detectable HCV RNA less then 25 IU/mL on or after week 4 confirmed by retesting.

Viral breakthroughs occurred only in group A subjects with genotype 1a and were observed as early as week 3 and as late as week 12 on therapy

Viral breakthrough occurred with higher baseline HCV RNA levels

Subjects with viral breakthrough had pegIFN/RBV added to their treatment

Preliminary genotypic resistance analysis of subjects demonstrating viral breakthrough indicates detection of drug-resistant variants in both the NS3 protease and NS5A

LOQ = lower limit of quantitation; LOD = limit of detection.

No viral breakthrough occurred in group B

100% of subjects were undetectable by week 6 on therapy

Virologic control was maintained through week 12 in all subjects

One subject with HCV RNA less then 25 IU/mL at week 12 (shown above [*]) was undetectable with immediate retesting

HCV RNA decreased in all 6 patients after the addition of pegIFN/RBV to the 2 direct-acting antiviral agents; 4 patients had HCV RNA less then 25 IU/mL as of the week 12 analysis

Preliminary pharmacokinetic (PK) analysis.

Cmax = maximum observed concentration; Tmax = time to maximum concentration; AUC = area under the concentration vs time curve;

Cmin = minimum observed concentration; GM = geometric mean; CV = coefficient of variation. Exposures largely similar between treatments, suggesting no clinically meaningful effect of pegIFN on either BMS compound

Exposures also largely consistent with those reported in healthy volunteers (Bifano et al, AASLD poster 827)

-100% of subjects completed 12 weeks of therapy
-No serious adverse events or discontinuations of BMS drugs due to adverse events (AEs)
-20/21 (95%) subjects experienced an AE
-AEs were mainly mild to moderate in severity
-3 AEs of neutropenia observed in group B only resulted in dose reduction of interferon
-Only 2 "severe" AEs
- Fatigue in 1 subject in group A
-- Neutropenia in 1 subject in group B

Transient Transaminitis
6/21 subjects experienced ALT >3x ULN
- 2 from group A, 2 from group B, and 2 from group A receiving pegIFN/RBV following viral breakthrough

Onset was between weeks 6 and 20, and all patients but one were asymptomatic

Peak ALT elevation was 7.9 x ULN

Maximum total bilirubin, 1.6 mg/dL (ULN = 1.1 mg/dL)

Maximum direct bilirubin, 0.6 mg/dL (ULN = 0.2 mg/dL)

No apparent association with response to therapy or viral breakthrough

Several subjects were on concomitant medications (acetaminophen [1], pegIFN/RBV [4], both [1])

Therapy was continued without dose interruption or discontinuation, and all subjects experienced improvement or resolution of condition

Circles indicate the 2 subjects in Group A who were also receiving pegIFN/RBV due to viral breakthrough. Both subjects had begun receiving pegIFN/RBV at week 10