- Category: Experimental HCV Drugs
- Published on Thursday, 10 April 2014 00:00
- Written by Keith Alcorn
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/ribavirin, according to a presentation Thursday at the 49th EASL International Liver Congress (EASL 2014) in London.
Simeprevir is a second-generation HCV protease inhibitor that is better tolerated than the first-generation protease inhibitors telaprevir (Incivek or Incivo) and boceprevir (Victrelis). Simeprevir received US marketing approval in November 2013 and a positive scientific opinion from the European Medicines Agency in March 2013. The EMA is expected to grant European Union marketing approval in May 2014.
The data presented on the responses of European patients are derived from the PROMISE study, a randomized comparison of simeprevir versus placebo, combined with pegylated interferon and ribavirin. The international study evaluated simeprevir-based triple therapy in treatment-experienced patients with hepatitis C genotype 1 infection. 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 patients was carried out in order to determine the efficacy of simeprevir in a patient population with a very low prevalence of HCV 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 U.S. patients with genotype 1a infection who participated in Phase 2 studies of simeprevir. In contrast, only 5.5% of European participants in the PROMISE study who had genotype 1a had the Q80K polymorphism. The U.S. Food and Drug Administration has recommended that all patients with genotype 1a should be tested for Q80K to determine whether simeprevir treatment will be suitable.
A total of 393 patients were recruited to this randomized, double-blind, placebo-controlled Phase 3 study. All were infected with HCV genotype 1 and had relapsed after dual therapy with pegylated interferon/ribavirin. Participants were 65% male, 98% white, and 70.4% had HCV genotype 1b infection.
Therapy in the treatment arm consisted of the protease inhibitor simeprevir (150 mg once-daily) for 12 weeks plus pegylated interferon/ribavirin for 24 or 48 weeks, according to treatment response. Individuals in the control arm received placebo for 12 weeks plus pegylated interferon and ribavirin for 48 weeks. The primary outcome was sustained virological response 12 weeks after the completion of treatment (SVR12).
Overall, 79% of participants in the PROMISE study receiving simeprevir achieved a 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 simeprevir-treated patients. Most (94%) were eligible for 24-weeks of treatment with pegylated interferon/ribavirin, and 91% of these achieved SVR12. Impressive outcomes were observed among patients with stage F3 and F4 fibrosis or cirrhosis, who comprised 29% of participants: 87% and 85%, respectively, achieved SVR12, compared with 88% of those with stage F0-F2 fibrosis.
Treatment outcomes did not differ greatly between patients with HCV genotype 1a and 1b (88% vs 87%). As expected, SVR rates were higher among patients with the IL28B CC polymorphism compared to patients 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 simeprevir-treated patients and the placebo group in the proportion 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 (21% vs 16%) and photosensitivity (4% vs 0%) occurred more frequently in the simeprevir- treated patients, as did influenza-like illness (30% vs 20%).
X Forns, E Lawitz, S Zeuzem, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in European patients who relapsed after previous interferon-based therapy: the Promise Trial. 49th Annual Meeting of the European Association for the Study of the Liver (EASL 2014). London, April 9-13, 2014. Abstract 013