rials 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.
12.5Pharmacogenomics
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) |
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Use with Ribavirin and Peginterferon alfa: Ribavirin is genotoxic in in vitro and in vivo assays. Ribavirin was not oncogenic in mouse and rat carcinogenicity studies at doses less than the maximum recommended daily human dose. Please refer to ribavirin Package Inserts for additional information.
Two-year carcinogenicity studies in mice and rats were conducted with boceprevir. Mice were administered doses of up to 500 mg/kg in
