ility to telaprevir have been selected in cell culture and characterized for telaprevir genotypic and phenotypic resistance. Additionally, resistance to telaprevir was eva luated 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 Studies
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 INCIVEK-treated subjects 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 )].
Table 8: Treatment Emergent Substitutions in Pooled Phase 3 Studies: Subjects who did not achieve SVR24 in INCIVEK Combination Treatment Arms Emerging Substitutions* in NS3 Percent of No SVR Subjects (n)
N=525 Percent Subtype 1a
No SVR Subjects (n)
N=356 Percent Subtype 1b
No SVR Subjects (n)
N=169
Any substitution at V36, T54, R155, A156 or D168 62% (323) 69% (247) 45% (76)
R155K/T 38% (201) 56% (200) 0.6% (1)
V36M 33% (178) 49% (173) 3% (5)
V36M + R155K† 27% (142) 40% (142) 0% (0)
T54A/S 13% (68) 9% (31) 22% (37)
V36A/L 12% (65) 10% (37) 17% (28)
A156S/T 9% (48) 8% (28) 12% (20)
V36G/I, I132V, R155G/M, A156V/F/N or D168N Less than 2% Less than 2% Less than 2%
*Alone or in combination with other substitutions (includes mixtures)
†Subjects with this combination are also encompassed in two V36M and R155K rows above.
Persistence of Resistance-Associated Substitutions
Persistence of telaprevir-resistant NS3 amino acid substitutions has been observed following treatment failure. Of a combined 255 treatment-naïve and previously treated subjects from Studies 108, 111, and C216 in whom telaprevir-resistant variants had emerged during treatment, 103 (40%) had detectable resistant variants by population sequencing at end of study (follow-up range 2-70 weeks, median 45 weeks) and results for |
