function of HCV's non-structural NS4A 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
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
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
in all 3 arms receiving BMS-790052 had a significantly higher
response rate than placebo recipients.
2 higher BMS-790052 doses, however, were more effective
than the 3 mg dose.
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.
EVR rates at week 12 were 58%, 83%, 83%, and 42%, respectively.
RVR rates (undetectable at both week 4 and 12) were 42%,
83%, 75%, and 8%, respectively.
viral breakthrough did not occur in the 10 mg or 60 mg BMS-790052
arms through week 12.
was generally well-tolerated.
events were similar across the study arms and were consistent
with those typically seen with pegylated interferon/ribavirin.
person in each of the 3 BMS-700952 dose arms experienced
serious adverse events.
person in the 2 lower dose BMS-700952 arms and 3 people
in the 60 mg arm developed skin rash.
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.
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).