TMC435 is a once-daily NS3/4A HCV protease inhibitor that is taken orally. It is effective against HCV genotype 1 and shows preliminary efficacy against other strains or genotypes of HCV.
A phase II study was conducted to assess preliminary safety and efficacy using volunteers who had previously been treated with interferon + ribavirin and who did not respond to this therapy.
Researchers randomly assigned four groups of participants to receive the following drugs in a double-blind manner:
At the end of each treatment period (48 weeks), participants were monitored for an additional 24 weeks.
In groups 1, 2 and 3, half of the participants received TMC435 at a dose of 100 mg daily and the other half received this drug at a dose of 150 mg daily.
The average profile of participants upon entering the study was as follows:
The effect of previous HCV therapy (peginteferon + ribavirin) on participants in this study was as follows:
The final analysis from this study relied on data collected from 462 participants. Proportions of participants in each group who were cured were as follows:
In general, the longer the time on simeprevir, the greater the chances of recovery from HCV infection. Participants who received simeprevir at the higher dose (150 mg once daily) also had better responses to therapy. Response to therapy was good among those who had previously relapsed (85%), prior partial responders (75%) and even prior null responders (51%).
HCV genotype did not significantly affect response to therapy.
Cure rates among participants who had cirrhosis varied between 31% and 81%.
Rates of virologic failure were generally low but increased among participants who had unfavourable treatment histories.
At the time of viral breakthrough, 98% of participants with this problem had detectable HCV resistance. Emerging mutations were as follows:
These mutations conferred significantly reduced susceptibility to simeprevir.
Common side effects seen in all groups included the following:
Rash was more common among participants who received simeprevir as follows:
Changes in red blood cell levels were similar among all groups.
The 150-mg dose of simeprevir has been selected for phase III clinical trials.