Almost 90% of European patients who had relapsed after previous
treatment with pegylated interferon and ribavirin were cured of hepatitis C
after 24 weeks of treatment with the protease inhibitor simeprevir (Olysio) combined with pegylated
interferon and ribavirin, the 49th Annual Meeting of the European
Association for the Study of the Liver (EASL) heard on Thursday in London.
Simeprevir is a second-generation HCV protease inhibitor that is better
tolerated than the first-generation protease inhibitors telaprevir (Incivo) and boceprevir (Victrelis). Simeprevir received
marketing approval in the United States in November 2013 and a positive
scientific opinion from the European Medicines Agency in March 2014. The
European Medicines Agency is expected to grant European Union marketing
approval for simeprevir in May 2014.
The data presented on the responses of European patients are derived
from the PROMISE study, a randomised comparison of simeprevir or placebo,
combined with pegylated interferon or ribavirin. The international study
evaluated simeprevir-based triple therapy in treatment-experienced patients
with hepatitis C virus (HCV) genotype 1. Results of the study were
first released in May 2013.
PROMISE recruited patients in both North America (30%) and Europe (70%).
An analysis of European study participants was carried out in order to determine the
efficacy of simeprevir in a patient population with a very low prevalence of
genotype 1a virus that carries the Q80K polymorphism. This naturally occurring
variation in the virus reduces the efficacy of simeprevir, and was present in
48% of US patients with genotype 1a infection who participated in phase II
studies of simeprevir. In contrast, only 5.5% of European participants in the
PROMISE study who had genotype 1a infection had the Q80K polymorphism.
The US Food and Drug Administration has recommended that all patients
with genotype 1a infection should be tested for the Q80K polymorphism to
determine whether simeprevir treatment will be suitable.
A total of 393 people were recruited to this randomised, double-blind,
placebo-controlled phase III study. All the participants had HCV
genotype 1 and had relapsed after dual therapy with pegylated
Therapy in the treatment arm consisted of the protease inhibitor
simeprevir (150mg once daily) for twelve weeks plus pegylated
interferon/ribavirin for 24 or 48 weeks, according to treatment response.
Individuals in the control arm received a placebo for twelve weeks plus
pegylated interferon and ribavirin for
The primary outcome was sustained virological response twelve weeks
after the completion of treatment (SVR12).
The study population was 65% male, 98% white, and 70.4% of participants had HCV genotype 1b infection.
Overall, 79% of participants in the PROMISE study receiving simeprevir
achieved SVR12 compared to 36% of those in the placebo arm. Restricting
analysis to European patients showed that SVR rates were 88% and 43% in the
treatment and control arms, respectively.
Further analysis was restricted to the European participants taking simeprevir. Most (94%) were eligible for 24-weeks treatment with pegylated
interferon/ribavirin and 91% achieved SVR12.
Impressive outcomes were observed among participants with stage F3 and F4
fibrosis who made up 28.7% of participants. Of these participants, 87% and 85% respectively achieved
SVR12, compared with 88% of those with F0-F2 fibrosis.
Treatment outcomes did not differ greatly between people with genotype
1a and 1b infection (88 vs 87%). As expected, SVR rates were higher among
participants with the IL28B CC polymorphism compared to participants without this
polymorphism (CC = 93% vs CT = 88% vs TT = 77%).
Response to simeprevir was reduced among patients with genotype 1
infection and the Q80K polymorphism, although the number of patients was small
(8). 75% of genotype 1a patients with the Q80K polymorphism achieved SVR12,
compared to 90% of genotype 1a patients without the polymorphism. In
comparison, 87% of genotype 1b patients achieved SVR12.
There was no significant difference between the people taking simeprevir and the placebo group in the proportion of patients who experienced
grade 3 or 4 serious adverse events. The majority of side-effects (80%) were
mild to moderate. The most common adverse events were fatigue, headache and
flu-like illness. Rash (20.7 vs 15.6%) and photosensitivity (4.3 vs 0%) occurred
more frequently in people taking simeprevir, as did influenza-like
illness (29.9 vs 20%).