Sofosbuvir and Velpatasvir (Page 7 of 11)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Sofosbuvir: Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo mouse micronucleus assays.

Sofosbuvir was not carcinogenic in a 2-year mouse study (up to 200 mg/kg/day in males and 600 mg/kg/day in females) and in a 2-year rat study (up to 750 mg/kg/day), resulting in exposures of the predominant circulating metabolite GS-331007 of approximately 3 and 15 times (in mice) and 7 and 9 times (in rats), in males and females, respectively, the exposure in humans at the recommended human dose (RHD).

Velpatasvir: Velpatasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays.

Velpatasvir was not carcinogenic in a 6-month rasH2 transgenic mouse study (up to 1000 mg/kg/day) and a 2-year rat carcinogenicity study (up to 200 mg/kg/day). The exposure of VEL in the 2-year rat study was approximately 6 times the exposure in humans at the RHD.

Impairment of Fertility

Sofosbuvir: Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, AUC exposure to the predominant circulating metabolite GS-331007 was approximately 4 times the exposure in humans at the RHD.

Velpatasvir: Velpatasvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, velpatasvir exposure was approximately 6 times the exposure in humans at the RHD.

14 CLINICAL STUDIES

14.1 Description of Clinical Trials

Table 12 presents the clinical trial design including different treatment groups that were conducted with sofosbuvir and velpatasvir with and without ribavirin in subjects with chronic hepatitis C (HCV) genotype 1, 2, 3, 4, 5, and 6 infection. For detailed description of trial design and recommended regimen and duration [see Dosage and Administration (2.2, 2.3, and 2.4) and Clinical Studies (14.2, 14.3, 14.4, 14.5, 14.6, 14.7, and 14.8)].

Table 12 Trials Conducted with Sofosbuvir and Velpatasvir in Subjects with Genotype 1, 2, 3, 4, 5, or 6 HCV Infection
Trial Population Sofosbuvir and Velpatasvir and Comparator Groups(Number of Subjects Treated)
TN = treatment-naïve subjects; SOF = sofosbuvir; RBV = ribavirin; CP = Child-Pugh; ESRD = End Stage Renal Disease; PWID = People Who Inject Drugs; MAT = Medication-Assisted Treatment.
*
Double-blind, placebo-controlled.
TE = treatment-experienced subjects are those who have failed a peginterferon alfa/ribavirin based regimen with or without an HCV protease inhibitor (boceprevir, simeprevir, or telaprevir).
Open-label.
§
TE = treatment-experienced subjects are those who have failed a peginterferon alfa/ribavirin based regimen or an HCV-specific DAA-based regimen that does not include an NS5A inhibitor.
TE = treatment-experienced subjects are those who have failed a peginterferon alfa/ribavirin or interferon/ribavirin based regimen.
#
TE = treatment-experienced subjects are those who have failed an interferon-based regimen with or without ribavirin and with or without an HCV protease inhibitor (boceprevir, simeprevir, or telaprevir).
ASTRAL-1* (NCT02201940) Genotype 1, 2, 4, 5, and 6 TN and TE , without cirrhosis or with compensated cirrhosis Sofosbuvir and velpatasvir 12 weeks (624)Placebo 12 weeks (116)
ASTRAL-2 (NCT02220998) Genotype 2 TN and TE , without cirrhosis or with compensated cirrhosis Sofosbuvir and velpatasvir 12 weeks (134)SOF + RBV 12 weeks (132)
ASTRAL-3 (NCT02201953) Genotype 3 TN and TE , without cirrhosis or with compensated cirrhosis Sofosbuvir and velpatasvir 12 weeks (277)SOF + RBV 24 weeks (275)
ASTRAL-5 (NCT02480712) Genotype 1, 2, 3, 4, 5, and 6 HCV/HIV-1 coinfected TN and TE , without cirrhosis or with compensated cirrhosis Sofosbuvir and velpatasvir 12 weeks (106)
ASTRAL-4 (NCT02201901) Genotype 1, 2, 3, 4, 5, and 6 TN and TE , with CP class B decompensated cirrhosis Sofosbuvir and velpatasvir 12 weeks (90)Sofosbuvir and velpatasvir + RBV 12 weeks (87)Sofosbuvir and velpatasvir 24 weeks (90)
2104 (NCT02781571) Genotype 1, 2, 3, and 4 TN and TE § liver transplant recipients, without cirrhosis or with compensated cirrhosis Sofosbuvir and velpatasvir 12 weeks (79)
4062 (NCT03036852) Genotype 1, 2, 3, 4, and 6 TN and TE without cirrhosis or with compensated cirrhosis, with ESRD requiring dialysis Sofosbuvir and velpatasvir 12 weeks (59)
SIMPLIFY (NCT02336139) Genotype 1, 2, 3, and 4 PWID, including those on MAT for opioid use disorder, without cirrhosis or with compensated cirrhosis Sofosbuvir and velpatasvir 12 weeks (103)
1143 (NCT03022981) Genotype 1, 2, 3, 4, and 6 TN and TE # pediatric subjects 3 years of age and older Sofosbuvir and velpatasvir 12 weeks (214)

The ribavirin dosage was weight-based (1000 mg daily administered in two divided doses for subjects less than 75 kg and 1200 mg for those greater than or equal to 75 kg) and administered in two divided doses when used in combination with sofosbuvir in the ASTRAL-2 and ASTRAL-3 trials or in combination with sofosbuvir and velpatasvir in the ASTRAL-4 trial. Ribavirin dosage adjustments were performed according to the ribavirin prescribing information. Serum HCV RNA values were measured during the clinical trials using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL. SVR12, defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in all the trials. Relapse is defined as HCV RNA greater than or equal to LLOQ during the post-treatment period after having achieved HCV RNA less than LLOQ at the end of treatment. On-treatment virologic failure is defined as breakthrough, rebound, or non-response.

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