13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, 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 were comparable to placebo.

14 CLINICAL STUDIES
14.1 Description of Adult Clinical Studies
The efficacy and safety of INCIVEK in subjects with genotype 1 chronic hepatitis C were eva luated in three adequate and well-controlled clinical trials: two in treatment-naïve subjects and one in previously treated subjects (relapsers, partial responders, and null responders). Subjects in these studies had compensated liver disease, detectable HCV-RNA, and liver histopathology consistent with chronic hepatitis C. In all three studies, INCIVEK was administered at a dosage of 750 mg every 8 hours; the peginterferon alfa-2a (Peg-IFN-alfa-2a) dose was 180 µg/week, and the ribavirin (RBV) dose was 1000 mg/day (subjects weighing less than 75 kg) or 1200 mg/day (subjects weighing greater than or equal to 75 kg). Plasma HCV-RNA values were measured during the clinical trials using the COBAS® TaqMan® HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantitation of 25 IU/mL. SVR in all studies was defined as HCV-RNA less than 25 IU/mL at 24 weeks after the planned end of treatment.

14.2 Treatment-Naïve Adults
Study 108 (ADVANCE)

Study 108 was a randomized, double-blind, parallel-group, placebo-controlled, trial conducted in treatment-naïve subjects (had received no pri