A combination of three direct-acting antivirals developed by
Bristol-Myers Squibb cured chronic hepatitis C infection in over 90% of
previously untreated patients in a mid-stage study, Gregory Everson of the
University of Colorado reported at 'The Liver Meeting 2013', the 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD) in
Washington, DC, on
The combination proved equally effective in people with
genotype 1a and 1b hepatitis C.
Bristol-Myers Squibb is one of several pharmaceutical companies
working to develop a highly effective combination of oral direct-acting
antivirals that can be used without interferon to cure hepatitis C infection with 12 to 24 weeks of treatment. Current hepatitis C treatment consists of pegylated interferon and ribavirin combined with a protease inhibitor, and lasts 24 to 48 weeks.
Interferon-free combinations contain drugs which attack different steps in the hepatitis C viral life-cycle, so that viral replication can be interrupted and quickly reduced, allowing rapid elimination of hepatitis C from the liver and the blood.
AbbVie, Boehringer Ingelheim, Gilead Sciences and Merck have also presented
data on the progress of their own interferon-free combinations at this year’s
The first interferon-free combination is likely to receive
marketing approval for treatment of genotype 2 and 3 hepatitis C in December 2013
(sofosbuvir and ribavirin, manufactured by Gilead Sciences). AbbVie is likely
to file for approval of its own interferon-free combination for treatment of
genotype 1 infection in the United States and European Union in the second
quarter of 2014.
Bristol-Myers Squibb is developing a fixed-dose combination
containing drugs from three classes. Daclatasvir, an NS5A inhibitor active
against all genotypes, is being combined with asunaprevir, a protease inhibitor
active against genotypes 1, 4, 5 and 6, and BMS-791325, a non-nucleoside
polymerase inhibitor active against genotypes 1, 3, 4, 5 and 6. The fixed-dose
combination is designed to be dosed twice a day.
Gregory Everson presented interim results of a phase IIb
dose-comparison study designed to compare two doses of BMS-791325 (75mg and
150mg) for the purpose of selecting a dose for phase III studies.
The study recruited previously untreated patients with
genotype 1 infection. Nine per cent of patients had cirrhosis, and patients with cirrhosis were evenly distributed between the two study arms. Patients were also
stratified by genotype 1a and 1b. Eighty patients were recruited to the 75mg arm
and 86 to the 150mg arm.
Eight-two per cent of patients had genotype 1a hepatitis C
infection and 38% had advanced liver disease (stage F3 or F4 fibrosis as
measured by Fibroscan).
Twelve weeks after the completion of treatment 71 of 77
(92.2%) participants in the 75mg arm and 77 of 84 (91.7%) participants in the 150mg arm
had a sustained virologic response (SVR12). Three people were lost to follow-up after completion of treatment. Six cases of virological failure occurred in
the 75mg arm (2 viral breakthroughs and 4 post-treatment relapses) and five in
the 150mg arm (3 viral breakthroughs and 2 viral relapses). All viral relapses
occurred within four weeks of completing treatment.
The two doses showed equivalent efficacy across all
sub-groups (sub-groups, genotype 1a and 1b, IL28B CC and non-CC genotype) with
the exception of people with cirrhosis, where the 75mg dose was associated with a higher
rate of SVR (100 vs 71%) due to one treatment discontinuation and one viral
The combination was well tolerated. One person in each arm
discontinued treatment due to an adverse event (one cancer and one episode of
severe throat tightness). One person experienced a grade 3 liver enzyme
elevation (AST) which normalised during treatment.
The most frequent side-effects were headache (24.7%),
diarrhoea (15.1%), fatigue (11.4%) and nausea (10.2%), none of them severe.
The 75mg dose of BMS-791352 will now be used as part of the three-drug
combination in phase III studies.