Date: 2015-09-21
Type of information: Results
phase: 3
Announcement: results
Company: Gilead (USA - CA)
Product: sofosbuvir and velpatasvir
Action
mechanism: direct-acting antiviral agent/nucleotide analog/enzyme inhibitor. Sofosbuvir is an oral nucleotide analog inhibitor of the HCV NS5B polymerase enzyme, which plays an essential role in HCV replication. This direct-acting agent interferes directly with the HCV life cycle by suppressing viral replication. Velpatasvir (GS-5816) is a second-generation investigational NS5A inhibitor.
Disease: genotype 1-6 chronic hepatitis C virus (HCV) infection
Therapeutic area: Infectious diseases
Country: Australia, Belgium, Canada, China, France, Germany, Italy, New Zealand, Puerto Rico, UK, USA
Trial
details: ASTRAL-1 : This study has evaluated the efficacy, safety, and tolerability of sofosbuvir/velpatasvir (SOF/VEL) fixed dose combination (FDC) for 12 weeks in adults with chronic genotype 1, 2, 4, 5, or 6 hepatitis C virus (HCV) infection. (NCT02201940) ASTRAL-2 : This study has evaluated safety, tolerability, and efficacy of treatment with sofosbuvir/velpatasvir (SOF/VEL) fixed dose combination (FDC) for 12 weeks compared to treatment with sofosbuvir (SOF) plus ribavirin (RBV) for 12 weeks in participants with chronic genotype 2 hepatitis C virus (HCV) infection.(NCT02220998) ASTRAL-3 : This study has evaluated the safety, tolerability, and efficacy of treatment with sofosbuvir (SOF)/velpatasvir (VEL; GS-5816) fixed dose combination (FDC) for 12 weeks compared to treatment with SOF plus ribavirin (RBV) for 24 weeks in participants with chronic genotype 3 hepatitis C virus (HCV) infection. (NCT02201953) ASTRAL-4 : This study has evaluated the efficacy, safety, and tolerability of sofosbuvir (SOF)/velpatasvir (VEL; GS-5816) fixed dose combination (FDC) with and without ribavirin (RBV) for 12 weeks and SOF/VEL FDC for 24 weeks in adults with hepatitis C virus (HCV) infection and Child-Pugh (CPT) class B cirrhosis.(NCT02201901)
Latest
news: * On September 21, 2015, Gilead Sciences announced topline results from four international Phase 3 clinical studies (ASTRAL-1, ASTRAL-2, ASTRAL-3 and ASTRAL-4) evaluating a once-daily, fixed-dose combination of the nucleotide analog polymerase inhibitor sofosbuvir (SOF) with velpatasvir (VEL), an investigational pangenotypic NS5A inhibitor, for the treatment of genotype 1-6 chronic hepatitis C virus (HCV) infection. In the ASTRAL-1, ASTRAL-2, and ASTRAL-3 studies, 1,035 patients with genotype 1-6 HCV infection received 12 weeks of SOF/VEL. Among these patients, 21 percent had compensated cirrhosis and 28 percent had failed prior treatments. The ASTRAL-4 study randomized 267 patients with decompensated cirrhosis (Child-Pugh class B) to receive 12 weeks of SOF/VEL with or without ribavirin (RBV), or 24 weeks of SOF/VEL. The primary endpoint for all studies was SVR12. Treatment (N) Genotypes 1,2,4,5,6 19 percent (121/624) with cirrhosis SOF/VEL ( 624 ) 12 weeks Overall: 99% (618/624 ) GT1: 98% (323/328) GT2: 100% (104/104) GT4: 100% (116/116) GT5: 97% (34/35) GT6: 100% (41/41) Genotype 2 14 percent (38/266) with cirrhosis SOF/VEL (134) 12 weeks 99% (133/134) SOF+RBV (132) 12 weeks 94% (124/132) Genotype 3 30 percent (163/552) with cirrhosis SOF/VEL (277) 12 weeks 95% (264/277) SOF+RBV (275) 24 weeks 80% (221/275) Genotypes 1-6 All with Child-Pugh class B (decompensated) cirrhosis SOF/VEL (90) 12 weeks 83% (75/90) SOF/VEL+RBV (87) 12 weeks 94% (82/87) SOF/VEL (90) 24 weeks 86% (77/90) Of the 1,035 patients treated with SOF/VEL for 12 weeks in the ASTRAL-1, ASTRAL-2 and ASTRAL-3 studies, 1,015 (98 percent) achieved the primary efficacy endpoint of SVR12. Of the 20 patients who did not achieve SVR12, 13 patients (1.3 percent) experienced virologic failure and seven did not complete an SVR12 visit (e.g., lost to follow-up). Twelve of the 13 virologic failure patients relapsed (two genotype 1 HCV-infected patients and 10 genotype 3 HCV-infected patients). There was one patient with documented reinfection. No patients with genotype 2, 4, 5 or 6 HCV infection had virologic failure.
The intent-to-treat SVR12 rates observed in the ASTRAL studies are summarized in the table below. Complete results from all four studies will be presented at future scientific conferences.
Study
Population
Duration
SVR12 Rates
ASTRAL-1*
ASTRAL-2
ASTRAL-3
ASTRAL-4
* 116 patients received placebo (SVR12=0%)
Patients treated with SOF/VEL for 12 weeks in these three studies had similar adverse events compared with placebo-treated patients in ASTRAL-1. Two patients (0.2 percent) treated with SOF/VEL for 12 weeks, one each in ASTRAL-1 and ASTRAL-2, discontinued treatment due to adverse events. The most common adverse events were headache, fatigue and nausea.
In ASTRAL-4, patients with Child-Pugh class B cirrhosis receiving SOF/VEL+RBV achieved higher SVR12 rates than patients receiving SOF/VEL for 12 or 24 weeks. Among genotype 1 and 3 patients treated with SOF/VEL+RBV for 12 weeks, the SVR12 rates were 96 percent and 85 percent, respectively.
The most common adverse events across all arms of ASTRAL-4 were fatigue, nausea and headache. Anemia, a common side effect associated with RBV, was reported in 31 percent of patients in the SOF/VEL+RBV arm and in 4 percent and 3 percent of patients treated with SOF/VEL for 12 or 24 weeks, respectively. Treatment emergent serious adverse events occurred in 18 percent of patients and nine patients died. The majority of serious adverse events and deaths were associated with advanced liver disease.
The FDA has assigned the SOF/VEL fixed-dose combination a Breakthrough Therapy designation, which is granted to investigational medicines that may offer major advances in treatment over existing options.
