HCV NS5A Inhibitor BMS-790052 Suppresses Viral Replication in Combination with Pegylated Interferon/ribavirin

BMS-790052, Bristol-Myers Squibb's investigational hepatitis C virus (HCV) NS5A inhibitor, demonstrated potent early antiviral activity at 4 and 12 weeks when combined with the standard regimen of pegylated interferon plus ribavirin in previously untreated patients with HCV genotype 1, investigators reported at the at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) this month in Vienna.

The function of HCV's non-structural NS5A protein has not been determined, but it appears to play a crucial role in HIV replication -- likely in conjunction with the NS5B polymerase -- and possibly in changing the physiology of the host cell to better accommodate the virus.

S. Pol and colleagues conducted a Phase 2a clinical trial to compare BMS-790052, the first-in-class once-daily HCV NS5A inhibitor, versus placebo in combination with pegylated interferon and ribavirin. Previous Phase 1 studies showed that the drug was well-tolerated and exhibited potent antiviral activity.

The study included 48 treatment-naive genotype 1 chronic hepatitis C patients. About two-thirds were men and the median age was about 50 years; approximately 20% were black.

Participants were randomly assigned (12 per arm) to receive either placebo or 3 mg, 10 mg, or 60 mg BMS-790052 once-daily plus pegylated interferon alfa-2a (Pegasys) and ribavirin for 48 weeks.

The researchers assessed rates of rapid virological response (RVR), or undetectable HCV RNA at week 4, and complete early virological response (cEVR), or undetectable viral load at week 12. The primary endpoint was the proportion of participants with "extended rapid virological response (eRVR)," defined as HCV RNA < 10 IU/mL at both week 4 and week 12. Treatment will continue for 48 weeks, with follow-up 12 and 24 weeks after completion of therapy to determine sustained virological response.

Results

• Participants in all 3 arms receiving BMS-790052 had a significantly higher response rate than placebo recipients.

• The 2 higher BMS-790052 doses, however, were more effective than the 3 mg dose.

• RVR rates at week 4 were 42% in the 3 mg BMS-790052 arm, 92% in the 10 mg arm, and 83% in the 60 mg arm, compared with 8% in the placebo arm.

• Complete EVR rates at week 12 were 58%, 83%, 83%, and 42%, respectively.

• Extended RVR rates (undetectable at both week 4 and 12) were 42%, 83%, 75%, and 8%, respectively.

• Confirmed viral breakthrough did not occur in the 10 mg or 60 mg BMS-790052 arms through week 12.

• BMS-700952 was generally well-tolerated.

• Adverse events were similar across the study arms and were consistent with those typically seen with pegylated interferon/ribavirin.

• 1 person in each of the 3 BMS-700952 dose arms experienced serious adverse events.

• 1 person in the 2 lower dose BMS-700952 arms and 3 people in the 60 mg arm developed skin rash.

"BMS-790052 is a potent once-daily NS5A inhibitor that yielded higher extended RVR, RVR, and complete EVR rates when combined with [pegylated interferon/ribavirin] than [pegylated interferon/ribavirin] alone," the investigators concluded.

"The addition of BMS-790052 to [pegylated interferon/ribavirin] was well-tolerated with an adverse event profile comparable to [pegylated interferon/ribavirin]," they continued. "These results support further development of BMS-790052 in combination with [pegylated interferon/ribavirin] or other HCV antivirals."

Hôpital Cochin, Paris, France; University of Colorado Denver & Hospital, Denver, CO; The Liver Institute at Methodist Dallas Medical Center, Dallas, TX; Metropolitan Research, Fairfax, VA; The Research Institute, Springfield, MA; Options Health Research, Tulsa, OK; Yale University School of Medicine, New Haven, CT; CHU Henri Mondor, Creteil, France; Bristol-Myers Squibb Company, Wallingford, CT.

4/30/10

Reference

S Pol, G Everson, R Ghalib, and others. Once-daily NS5A inhibitor (BMS-790052) plus peginterferon-alpha-2a and ribavirin produces high rates of extended rapid virologic response in treatment-naive HCV-genotype 1 subjects: phase 2a trial. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).