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:
Group 1: TMC435 + peginterferon + ribavirin for 12 weeks, followed by peginterferon + ribavirin + placebo for 36 weeks
Group 2: TMC435 + peginterfron + ribavirin for 24 weeks, followed by peginterferon + ribavirin + placebo for 24 weeks
Group 3: TMC435 + peginterferon + ribavirin for 48 weeks
Group 4: peginterferon + ribavirin + placebo for 48 weeks
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:
68% male, 32% women
age -- 50 years
weight -- 80 kg
41% had HCV genotype 1a
more than 80% had an HCV viral load of 800,000 IU/ml or greater
Treatment History
The effect of previous HCV therapy (peginteferon + ribavirin) on participants in this study was as follows:
40% relapsed
35% had a partial response
25% had no significant decrease in their HCV viral load
Results
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:
Group 1: 67%
Group 2: 72%
Group 3: 80%
Group 4: 23%
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%.
Focus on Virology
Rates of virologic failure were generally low but increased among participants who had unfavourable treatment histories.
Viral breakthrough was more common among participants in the simeprevir 100 mg group (13%) than in the 150 mg group (9%).
After achieving an undetectable viral load, viral relapse was more common among participants taking the simepevir 100 mg dose (11%) than among those taking the 150 mg dose (9%).
At the time of viral breakthrough, 98% of participants with this problem had detectable HCV resistance. Emerging mutations were as follows:
genotype 1a -- usually R155K alone or in combination
genotype 1b -- usually D168V
These mutations conferred significantly reduced susceptibility to simeprevir.
Common side effects seen in all groups included the following:
headache
fatigue
flu-like illness
rash
Rash was more common among participants who received simeprevir as follows:
simeprevir 100 mg once daily -- 23% developed rash
simeprevir 150 mg once daily -- 30% developed rash
placebo -- 18% developed rash
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.
References
Zeuzem S, Berg T, Gane E, et al. TMC435 with peginterferon and ribavirin in treatment-experienced HCV genotype 1 patients: the ASPIRE study, a randomized phase IIb trial. In: Program and abstracts of the 47th annual meeting of the European Association for the Study of the Liver, 18-22 April 2012, Barcelona, Spain.
Lenz O, Fevery B, Vigen L, et al. TMC435 in patients infected with HCV genotype 1 who have failed previous pegylated interferon/ribavirin treatment: virologic analyses of the ASPIRE trial. In: Program and abstracts of the 47th annual meeting of the European Association for the Study of the Liver, 18-22 April 2012, Barcelona, Spain.