enetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860, a C to T change) is a strong predictor of response to peginterferon alfa and ribavirin (PR). rs12979860 was genotyped in 454 of 1088 subjects in Study 108 (treatment-naïve) and 527 of 662 subjects in Study C216 (previously treated) [see Clinical Studies (14.2 and 14.3) for trial descriptions]. SVR rates tended to be lower in subjects with the CT and TT genotypes compared to those with the CC genotype, particularly among treatment-naïve subjects receiving PR48 (Table 9). Among both treatment-naïve and previous treatment failures, subjects of all IL28B genotypes appeared to have higher SVR rates with INCIVEK-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: SVR Rates by rs12979860 Genotype Trial rs12979860 Genotype SVR, n/N (%)
T12/PR Pbo/PR48
108 (treatment-naïve) C/C 45/50 (90%) 35/55 (64%)
C/T 48/68 (71%) 20/80 (25%)
T/T 16/22 (73%) 6/26 (23%)
T12 /PR48* Pbo/PR48
C216 (previously treated) C/C 60/76 (79%) 5/17 (29%)
C/T 160/266 (60%) 9/58 (16%)
T/T 49/80 (61%) 4/30 (13%)
*Lead-in and immediate start T12/PR regimens pooled.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
INCIVEK /Peginterferon Alfa/Ribavirin Combination Treatment
Ribavirin was shown to be genotoxic in several in vitro and in vivo assays. Ribavirin was not oncogenic in a 6-month p53+/- transgenic mouse study or a 2-year carcinogenicity study in rat. See the prescribing information for ribavirin.
INCIVEK (telaprevir) Tablets
Evidence of genotoxicity was not observed in a bacterial mutagenicity assay, in vitro mammalian chromosomal aberration assay, or in vivo micronucleus study in mouse. Telaprevir has not been tested for its carcinogenic potential.
Impairment of Fertility
INCIVEK /Peginterferon Alfa/Ribavirin Combination Treatment
Animal studies have shown that ribavirin induced reversible toxicity in males while peginterferon alfa may impair female fertility. See the prescribing information for ribavirin and peginterferon alfa.
INCIVEK (telaprevir) Tablets
Telaprevir treatment alone had effects on fertility parameters in rats. The no observed adverse effect level (NOAEL) for degenerative testicular toxicity was established at exposures 0.17-fold the human exposures at the recommended clinical dose. Potential effects on sperm (e.g., decreased % motile sperm and increased non-motile sperm count) were observed in a rat fertility study at exposures 0.30-fold the human exposures at the recommended clinical dose. Additional effects on fertility include minor increases in percent preimplantation loss, the percent of dams with nonviable embryos and percent of nonviable conceptuses per litter. These effects are likely associated with testicular toxicity in male rats but contributions of the female cannot be ruled out. Degenerative testicular toxicity was not observed in chronic toxicity studies in the dog. Furthermore, mean changes in proposed hormonal biomarkers of testicular toxicity among subjects who received telaprevir we |
