Sofosbuvir clinical studies

# Clinical Studies

## Description of Clinical Trials
The safety and efficacy of SOVALDI was evaluated in five Phase 3 trials in a total of 1724 HCV mono-infected subjects with genotypes 1 to 6 chronic hepatitis C (CHC) and one Phase 3 trial in 223 HCV/HIV-1 co-infected subjects with genotype 1, 2 or 3 CHC. Among the five trials in HCV mono-infected subjects, one was conducted in treatment-naive subjects with genotype 1, 4, 5 or 6 CHC in combination with peginterferon alfa 2a and ribavirin and the other four were conducted in subjects with genotype 2 or 3 CHC in combination with ribavirin, including one in treatment-naive subjects, one in interferon intolerant, ineligible or unwilling subjects, one in subjects previously treated with an interferon-based regimen, and one in all subjects irrespective of prior treatment history or ability to take interferon. The trial in HCV/HIV-1 co-infected subjects was conducted in combination with ribavirin in treatment-naive subjects with genotype 1 CHC and all subjects with genotype 2 or 3 CHC irrespective of prior treatment history or ability to take interferon. Subjects in these trials had compensated liver disease including cirrhosis. SOVALDI was administered at a dose of 400 mg once daily. The ribavirin (RBV) dose was weight-based at 10001200 mg daily administered in two divided doses when used in combination with SOVALDI, and the peginterferon alfa 2a dose, where applicable, was 180 micrograms per week. Treatment duration was fixed in each trial and was not guided by subjects' HCV RNA levels (no response guided algorithm). 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 quantification (LLOQ) of 25 IU per mL. Sustained virologic response (SVR) was the primary endpoint which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment.

## Clinical Trials in Subjects with Genotype 1 or 4 CHC
Treatment-Naive Adults  NEUTRINO (Study 110)
NEUTRINO was an open-label, single-arm trial that evaluated 12 weeks of treatment with SOVALDI in combination with peginterferon alfa 2a and ribavirin in treatment-naive subjects with genotype 1, 4, 5 or 6 HCV infection compared to pre-specified historical control.
Treated subjects (N=327) had a median age of 54 years (range: 19 to 70); 64% of the subjects were male; 79% were White, 17% were Black; 14% were Hispanic or Latino; mean body mass index was 29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV RNA greater than 6 log10 IU per mL; 17% had cirrhosis; 89% had HCV genotype 1; 9% had HCV genotype 4 and 2% had HCV genotype 5 or 6. Table 8 presents the response rates for the treatment group of SOVALDI + peginterferon alfa + ribavirin.
SVR rates were 98% (93/95) in subjects with baseline IL28B C/C allele and 87% (202/232) in subjects with baseline IL28B non-C/C alleles.
It is estimated that the response rate in patients who previously failed pegylated interferon and ribavirin therapy will approximate the observed response rate in NEUTRINO subjects with multiple baseline factors traditionally associated with a lower response to interferon-based treatment (Table 9). The SVR rate in the NEUTRINO trial in genotype 1 subjects with IL28B non-C/C alleles, HCV RNA >800,000 IU/mL and Metavir F3/F4 fibrosis was 71% (37/52).

## Clinical Trials in Subjects with Genotype 2 or 3 CHC

### Treatment-Naive Adults  FISSION (Study 1231)
FISSION was a randomized, open-label, active-controlled trial that evaluated 12 weeks of treatment with SOVALDI and ribavirin compared to 24 weeks of treatment with peginterferon alfa 2a and ribavirin in treatment-naive subjects with genotype 2 and 3 HCV. The ribavirin doses used in the SOVALDI + ribavirin and peginterferon alfa 2a + ribavirin arms were weight-based 10001200 mg per day and 800 mg per day regardless of weight, respectively. Subjects were randomized in a 1:1 ratio and stratified by cirrhosis (presence vs. absence), HCV genotype (2 vs. 3) and baseline HCV RNA level (<6 log10IU/mL vs. 6 log10IU/mL). Subjects with genotype 2 or 3 HCV were enrolled in an approximately 1:3 ratio.
Treated subjects (N=499) had a median age of 50 years (range: 19 to 77); 66% of the subjects were male; 87% were White, 3% were Black; 14% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 17 to 52 kg/m2); 57% had baseline HCV RNA levels greater than 6 log10 IU per mL; 20% had cirrhosis; 72% had HCV genotype 3. Table 10 presents the response rates for the treatment groups of SOVALDI + ribavirin and peginterferon alfa + ribavirin.
Response rates for subjects with cirrhosis at baseline are presented in Table 11 by genotype.

### Interferon Intolerant, Ineligible or Unwilling Adults  POSITRON (Study 107)
POSITRON was a randomized, double-blinded, placebo-controlled trial that evaluated 12 weeks of treatment with SOVALDI and ribavirin (N=207) compared to placebo (N=71) in subjects who are interferon intolerant, ineligible or unwilling. Subjects were randomized in 3:1 ratio and stratified by cirrhosis (presence vs. absence).
Treated subjects (N=278) had a median age of 54 years (range: 21 to 75); 54% of the subjects were male; 91% were White, 5% were Black; 11% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 18 to 53 kg/m2); 70% had baseline HCV RNA levels greater than 6 log10 IU per mL; 16% had cirrhosis; 49% had HCV genotype 3. The proportions of subjects who were interferon intolerant, ineligible, or unwilling were 9%, 44%, and 47%, respectively. Most subjects had no prior HCV treatment (81%). Table 12 presents the response rates for the treatment groups of SOVALDI + ribavirin and placebo.
Table 13 presents the subgroup analysis by genotype for cirrhosis and interferon classification.

### Previously Treated Adults  FUSION (Study 108)
FUSION was a randomized, double-blinded trial that evaluated 12 or 16 weeks of treatment with SOVALDI and ribavirin in subjects who did not achieve SVR with prior interferon-based treatment (relapsers and nonresponders). Subjects were randomized in a 1:1 ratio and stratified by cirrhosis (presence vs. absence) and HCV genotype (2 vs. 3).
Treated subjects (N=201) had a median age of 56 years (range: 24 to 70); 70% of the subjects were male; 87% were White; 3% were Black; 9% were Hispanic or Latino; mean body mass index was 29 kg/m2 (range: 19 to 44 kg/m2); 73% had baseline HCV RNA levels greater than 6log10 IU per mL; 34% had cirrhosis; 63% had HCV genotype 3; 75% were prior relapsers. Table 14 presents the response rates for the treatment groups of SOVALDI + ribavirin for 12 weeks and 16 weeks.
Table 15 presents the subgroup analysis by genotype for cirrhosis and response to prior HCV treatment.

### Treatment-Naive and Previously Treated Adults  VALENCE (Study 133)
The VALENCE trial evaluated SOVALDI in combination with weight-based ribavirin for the treatment of genotype 2 or 3 HCV infection in treatment-naive subjects or subjects who did not achieve SVR with prior interferon-based treatment, including subjects with compensated cirrhosis. The original trial design was a 4 to 1 randomization to SOVALDI + ribavirin for 12 weeks or placebo. Based on emerging data, this trial was unblinded and all genotype 2 HCV-infected subjects continued the original planned treatment and received SOVALDI + ribavirin for 12 weeks, and duration of treatment with SOVALDI + ribavirin in genotype 3 HCV-infected subjects was extended to 24 weeks. Eleven genotype 3 subjects had already completed SOVALDI + ribavirin for 12 weeks at the time of the amendment.
Treated subjects (N=419) had a median age of 51 years (range: 19 to 74); 60% of the subjects were male; mean body mass index was 26 kg/m2 (range: 17 to 44 kg/m2); the mean baseline HCV RNA level was 6.4 log10 IU per mL; 78% had HCV genotype 3; 58% of the subjects were treatment-experienced and 65% of those subjects experienced relapse/breakthrough to prior HCV treatment.
Table 16 presents the response rates for the treatment groups of SOVALDI + ribavirin for 12 weeks and 24 weeks.
Table 17 presents the subgroup analysis by genotype for cirrhosis and prior HCV treatment experience.

## Clinical Trials in Subjects Co-infected with HCV and HIV-1
SOVALDI was studied in an open-label clinical trial (Study PHOTON-1) evaluating the safety and efficacy of 12 or 24 weeks of treatment with SOVALDI and ribavirin in subjects with genotype 1, 2 or 3 chronic hepatitis C co-infected with HIV-1. Genotype 2 and 3 subjects were either HCV treatment-naive or experienced, whereas genotype 1 subjects were all treatment-naive. Subjects received 400 mg SOVALDI and weight-based ribavirin (1000 mg for subjects weighing 500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+ cell count >200 cells/mm3. Efficacy data 12 weeks post treatment are available for 210 subjects (seeTable 18).
In subjects with HCV genotype 1 infection, the SVR rate was 82% (74/90) in subjects with genotype 1a infection and 54% (13/24) in subjects with genotype 1b infection, with relapse accounting for the majority of treatment failures. SVR rates in subjects with HCV genotype 1 infection were 80% (24/30) in subjects with baseline IL28B C/C allele and 75% (62/83) in subjects with baseline IL28B non-C/C alleles.
In the 223 CHC subjects with HIV-1 co-infection, the percentage of CD4+ cells did not change during treatment. Median CD4+ cell count decreases of 85 cells/mm3 and 84 cells/mm3 were observed at the end of treatment with SOVALDI + ribavirin for 12 or 24 weeks, respectively. HIV-1 rebound during SOVALDI + ribavirin treatment occurred in 2 subjects (0.9%) on antiretroviral therapy.