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
Monday.
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.
Glossary
- FibroScan
A non-invasive test, used instead of a biopsy, to measure the stiffness
or elasticity of the liver using an ultrasound probe.
- IL28B
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
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
AASLD conference.
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).
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
breakthrough.
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.