ELIS, or who previously failed treatment with a VICTRELIS-containing regimen.
Effect of Baseline HCV Polymorphisms on Treatment Response
A pooled analysis was conducted to explore the association between the detection of baseline NS3/4A amino acid polymorphisms and treatment outcome in the two Phase 3 studies, SPRINT-2 and RESPOND-2.
Baseline resistance associated polymorphisms were detected in 7% of subjects by a population-based sequencing method. Overall, the presence of these polymorphisms alone did not impact SVR rates in subjects treated with VICTRELIS. However, among subjects with a relatively poor response to PegIntron/REBETOL during the 4-week lead-in period, the efficacy of VICTRELIS appeared to be reduced for those who had V36M, T54A, T54S, V55A or R155K detected at baseline. Subjects with these baseline polymorphisms and reduced response to PegIntron/REBETOL represented approximately 1% of the total number of subjects treated with VICTRELIS.
Cross-Resistance
Many of the treatment-emergent NS3 amino acid substitutions detected in VICTRELIS-treated subjects who did not achieve SVR in the Phase 3 clinical trials have been demonstrated to reduce the anti-HCV activity of other HCV NS3/4A protease inhibitors. The impact of prior exposure to VICTRELIS or treatment failure on the efficacy of other HCV NS3/4A protease inhibitors has not been studied. The efficacy of VICTRELIS has not been established for patients with a history of exposure to other NS3/4A protease inhibitors. Cross-resistance is not expected between VICTRELIS and interferons, or VICTRELIS and ribavirin.
12.5 Pharmacogenomics
A genetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860, a C to T change) is a strong predictor of response to PegIntron/REBETOL. IL28B rs12979860 was genotyped in 653 of 1048 (62%) subjects in SPRINT-2 (previously untreated) and 259 of 394 (66%) subjects in RESPOND-2 (previous treatment failure) [see Clinical Studies (14) for trial descriptions]. Among subjects that received at least one dose of placebo or VICTRELIS (Modified-Intent-to-Treat population), SVR rates tended to be lower in subjects with the C/T and T/T genotypes compared to those with the C/C genotype, particularly among previously untreated subjects receiving 48 weeks of PegIntron and REBETOL (see Table 9). Among previous treatment failures, subjects of all genotypes appeared to have higher SVR rates with VICTRELIS-containing regimens. The results of this retrospective subgroup analysis should be viewed with caution because of the small sample size and potential differences in demographic or clinical characteristics of the substudy population relative to the overall trial population.
Table 9 Sustained Virologic Response (SVR) Rates by IL28B rs12979860 Genotype SVR, % (n/N)
Clinical Study IL28B rs12979860 Genotype PR48* VICTRELIS-RGT* VICTRELIS-PR48*
SPRINT-2 (Previously Untreated Subjects)
C/C 78 (50/64) 82 (63/77) 80 (44/55)
C/T 28 (33/116) 65 (67/103) 71 (82/115)
T/T 27 (10/37) 55 (23/42) 59 (26/44)
RESPOND-2 (Subjects Who Have Failed Previous Therapy)
C/C 46 (6/13) 79 (22/28) 77 (17/22)
C/T 17 (5/29) 61 (38/62) 73 (48/66)
T/T 50 (5/10) 55 (6/11) 72 (13/18)
*For description of each treatment arm, see Clinical Studies (14) .
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
|
