Twelve weeks of treatment with a three-drug
combination of new directly acting antivirals that contained neither pegylated
interferon nor ribavirin led to a sustained virologic response 12 weeks after
completion of treatment (SVR12) in up to 94% of previously untreated
patients with hepatitis C genotype 1, in a preliminary phase 2 trial in 16
patients, Dr Greg Everson of the University of Colorado reported at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in
Boston on Tuesday.
The combination of drugs, under development
by Bristol-Myers Squibb, contained agents from three classes of directly acting
antiviral: daclatasvir, an NS5A inhibitor, asunaprevir, a protease inhibitor,
and BMS-791325, a non-nucleoside polymerase inhibitor.
The study was designed to provide preliminary
information on whether adding BMS-791325 to asunaprevir and daclatasvir
improved the efficacy of an interferon-sparing regimen in people with
hepatitis C genotype 1a, and whether a higher dose of this drug had a substantial effect on
efficacy. The study was also designed to test whether it was possible to
shorten the treatment duration to twelve weeks when using this three-drug
combination in all patients, or to shorten treatment according to sub-genotype.
The study compared 12- and 24-week treatment
regimens, and also two doses of BMS-791325 (75mg and 150mg twice daily).
All participants received asunaprevir (200mg
twice daily) and daclatasvir (60mg once daily).
Participants were then randomised to
receive either 75mg or 150mg of BMS-791325, and then further randomised to
either 12 or 14 weeks of treatment.
The results presented at AASLD comprised
SVR12 results from the participants randomised to receive BMS-791325
75mg for twelve weeks and SVR4 results from those randomised to
receive the 75mg dose for 24 weeks.
Sixteen treatment-naive patients were
recruited to each arm of the phase 2a, open-label study. All had genotype 1
Their median age was 48 years, 75% were
African American and mean baseline viral load was 6.26 log10 copies
iu/ml. Only 28% of participants had the IL28B 'CC' mutation predicting favourable
response to interferon-containing therapy, and 75% of participants had genotype 1a
infection, both indicators of a harder-to-treat patient population.
All participants had a successful treatment
response (viral load below the limit of detection (LLOQ)) by week four of
therapy, and all had an end of treatment response.
Ninety-four per cent of participants in each
group had a sustained virological response at four and twelve weeks after the
completion of therapy respectively. In each arm, the non-responders were
individuals who either withdrew from the study for reasons other than adverse
events or viral breakthrough, or were lost to follow up.
By implication, all patients with HCV
genotype 1a and a non-CC IL28 host genotype achieved a sustained virological
response at week 4 or week 12.
Treatment was well tolerated. There were no
discontinuations because of adverse events. The most common side-effects were
headache, diarrhoea and general weakness. Each of these occurred in over 10% of
patients. Only one serious adverse event was reported, but this was not thought
to be due to the study treatment. No serious elevations (grade 3-4) in liver
enzymes or bilirubin were observed.
“Further investigation of this regimen in
the treatment of HCV is warranted,” the researchers concluded. Phase 3
licensing studies will begin shortly. Results of the higher dose 150mg arm are
still awaited, as are longer term data that confirm the lack of viral
breakthrough beyond four weeks after completion of treatment in the 24-week