Genvoya (Page 8 of 11)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Elvitegravir

Long-term carcinogenicity studies of elvitegravir were carried out in mice (104 weeks) and in rats for up to 88 weeks (males) and 90 weeks (females). No drug-related increases in tumor incidence were found in mice at doses up to 2000 mg per kg per day alone or in combination with 25 mg per kg per day RTV at exposures 3- and 14 times, respectively, the human systemic exposure at the recommended daily dose of 150 mg. No drug-related increases in tumor incidence were found in rats at doses up to 2000 mg per kg per day at exposures 12- to 27 times, respectively in male and female, the human systemic exposure.

Elvitegravir was not genotoxic in the reverse mutation bacterial test (Ames test) and the rat micronucleus assay. In an in vitro chromosomal aberration test, elvitegravir was negative with metabolic activation; however, an equivocal response was observed without activation.

Elvitegravir did not affect fertility in male and female rats at approximately 16- and 30 times higher exposures (AUC), respectively, than in humans at the recommended 150 mg daily dose.

Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 18 times higher than human exposures at the recommended 150 mg daily dose.

Cobicistat

In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the recommended daily dose.

Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.

Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 4 times higher than human exposures at the recommended 150 mg daily dose.

Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 1.2 times higher than human exposures at the recommended 150 mg daily dose.

Emtricitabine

In long-term carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (23 times the human systemic exposure at the therapeutic dose of 200 mg per day) or in rats at doses up to 600 mg per kg per day (28 times the human systemic exposure at the recommended dose).

Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.

Emtricitabine did not affect fertility in male rats at approximately 140 times or in male and female mice at approximately 60 times higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended 200 mg daily dose.

Tenofovir Alafenamide (TAF)

Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice is observed after TAF administration compared to TDF administration, carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the 300 mg therapeutic dose of TDF for HIV-1 infection. The tenofovir exposure in these studies was approximately 167 times (mice) and 55 times (rat) those observed in humans after administration of GENVOYA treatment. At the high dose in female mice, liver adenomas were increased at tenofovir exposures 10 times (300 mg TDF) and 167 times (10 mg TAF in GENVOYA) that in humans. In rats, the study was negative for carcinogenic findings.

TAF was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.

There were no effects on fertility, mating performance or early embryonic development when TAF was administered to male rats at a dose equivalent to 155 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 14 days prior to mating through Day 7 of gestation.

13.2 Animal Toxicology and/or Pharmacology

Minimal to slight infiltration of mononuclear cells in the posterior uvea was observed in dogs with similar severity after three and nine month administration of TAF; reversibility was seen after a three month recovery period. At the NOAEL for eye toxicity, the systemic exposure in dogs was 5 (TAF) and 15 (tenofovir) times the exposure seen in humans at the recommended daily GENVOYA dosage.

14 CLINICAL STUDIES

14.1 Description of Clinical Trials

The efficacy and safety of GENVOYA were evaluated in the studies summarized in Table 15.

Table 15 Trials Conducted with GENVOYA in Subjects with HIV-1 Infection
Trial Population Study Arms (N) Timepoint (Week)
*
Randomized, double blind, active controlled trial.
Randomized, open label, active controlled trial.
HIV-1 RNA less than 50 copies per mL.
§
Open label trial.
Estimated creatinine clearance between 30 and 69 mL per minute by Cockcroft-Gault method.
#
End stage renal disease (estimated creatinine clearance of less than 15 mL per minute by Cockcroft-Gault method).
Study 104*Study 111* Treatment-naïve adults GENVOYA (866)STRIBILD (867) 144
Study 109 Virologically-suppressed adults GENVOYA (959)ATRIPLA® or TRUVADA® +atazanavir+cobicistat or ritonavir or STRIBILD (477) 96
Study 112§ Virologically-suppressed adults with renal impairment GENVOYA (242) 144
Study 1825§ Virologically-suppressed adults with ESRD # receiving chronic hemodialysis GENVOYA (55) 48
Study 106 (cohort 1)§ Treatment-naïve adolescents between the ages of 12 to less than 18 years (at least 35 kg) GENVOYA (50) 48
Study 106 (cohort 2)§ Virologically-suppressed children between the ages of 6 to less than 12 years (at least 25 kg) GENVOYA (52) 48

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