Telaprevir microbiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
Microbiology
Antiviral Activity in Cell Culture
In an HCV subtype 1b replicon assay, the telaprevir EC50 value against wild-type HCV was 354 nM in a 2-day cell culture assay, and in a subtype 1a infectious virus assay, the EC50 value was 280 nM in a 5-day cell culture assay. In biochemical enzymatic assays, the median IC50 values of telaprevir against genotype 2, 3a, and 4a were 16 nM (range 6-32 nM; n=5), 40 nM (range 39-88 nM; n=5), and 130 nM (n=1), respectively, compared to a median IC50 value of 20 nM (range 16-23; n=2) for genotype 1a and 20 nM for genotype 1b (range 13-33; n=4). The presence of 40% human serum reduced the anti-HCV activity of telaprevir by approximately 10-fold. Evaluation of telaprevir in combination with interferon alfa or ribavirin showed no evidence of antagonism in reducing HCV RNA levels in HCV replicon cells.
Resistance
In Cell Culture
HCV genotype 1b replicons with reduced susceptibility to telaprevir have been selected in cell culture and characterized for telaprevir genotypic and phenotypic resistance. Additionally, resistance to telaprevir was evaluated in both biochemical and HCV genotype 1b replicon assays using site-directed mutants and recombinant NS3/4A from telaprevir Phase 2 clinical trials isolates. Variants V36A/M, T54A/S, R155K/T, A156S, R155T+D168N, and V36A+T54A conferred 3- to 25-fold reduced susceptibility to telaprevir; and A156V/T variants and the V36M/A+R155K/T and T54S/A+A156S/T double variants conferred greater than 62-fold reduced susceptibility to telaprevir. No amino acid substitutions were observed at the proteolytic cleavage sites.
In Clinical Trials
In a pooled analysis of subjects who did not achieve SVR (on-treatment virologic failure or relapse) from the controlled Phase 3 clinical trials, NS3 amino acid substitutions V36M/A/L, T54A/S, R155K/T, and A156S/T were determined to emerge frequently on INCIVEK treatment (Table 8). Nearly all of these substitutions have been shown to reduce telaprevir anti-HCV activity in cell culture or biochemical assays. No clear evidence of treatment-emergent substitutions in the NS3 helicase domain or NS4A coding regions of the HCV genome was observed among subjects treated with INCIVEK who did not achieve SVR.
Telaprevir treatment-emergent resistance substitutions emerged in the majority of isolates from subjects who did not achieve SVR (Table 8): in almost 100% of subjects who failed during 12 weeks of T/PR and in the majority of subjects who failed on PR after Week 12 or who relapsed.
HCV genotype 1 subtype-associated patterns of INCIVEK treatment-emergent amino acid substitutions were observed. Subjects with HCV genotype 1a predominately had V36M and R155K or the combination of these variants, while subjects with HCV genotype 1b predominately had V36A, T54A/S, and A156S/T variants (Table 8). Among subjects treated with telaprevir, on-treatment virologic failure was more frequent in subjects with genotype 1a than with genotype 1b and more frequent in prior null responders [see Clinical Studies (14)]. In the C211 Phase 3 clinical trial, there were no differences in the types of emerging variants between subjects receiving telaprevir 1125 mg twice daily and subjects receiving telaprevir 750 mg every 8 hours. Similar proportions of subjects in both treatment groups had telaprevir-resistant variants at the time of failure.[1]
References
- ↑ "INCIVEK (TELAPREVIR) TABLET, FILM COATED [VERTEX PHARMACEUTICALS INCORPORATED]". Retrieved 8 January 2014.
Adapted from the FDA Package Insert.