Gilead Sciences, Inc., a biopharmaceutical company, 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 per cent had compensated cirrhosis and 28 per cent 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.
Complete results from all four studies will be presented at future scientific conferences.
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 per cent) 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.
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 per cent) 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 per cent and 85 per cent, 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 per cent of patients in the SOF/VEL+RBV arm and in 4 per cent and 3 per cent of patients treated with SOF/VEL for 12 or 24 weeks, respectively. Treatment emergent serious adverse events occurred in 18 per cent of patients and nine patients died. The majority of serious adverse events and deaths were associated with advanced liver disease.
"The ASTRAL study results demonstrate that a 12-week course of therapy with the first fixed-dose combination of two pan-genotypic compounds can provide high cure rates for patients with all HCV genotypes," said Norbert Bischofberger, Ph.D., executive vice president of research and development and chief scientific officer at Gilead.
"We are pleased to have now brought forward our second single tablet regimen for HCV infection that complements Harvoni, our first single tablet regimen approved specifically for patients with genotype 1 infection and which could eliminate the need for HCV genotype testing. We look forward to advancing the regulatory submissions for the SOF/VEL fixed-dose combination."
The US Food and Drug Administration 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.
The SOF/VEL fixed-dose combination is an investigational product and its safety and efficacy have not yet been established.
The double-blind, placebo-controlled ASTRAL-1 trial enrolled 740 patients with chronic genotype 1, 2, 4, 5 or 6 HCV infection randomized to SOF/VEL or placebo for 12 weeks.
The open-label ASTRAL-2 study evaluated the use of SOF/VEL or SOF+RBV for 12 weeks in 266 genotype 2 HCV-infected patients.
The open-label ASTRAL-3 study evaluated the use of SOF/VEL for 12 weeks or SOF+RBV for 24 weeks in 552 genotype 3 HCV-infected patients.
The ASTRAL-1 study met its primary endpoint of statistical superiority to the pre-specified SVR12 goal of 85 per cent (p<0.001). ASTRAL-2 and ASTRAL-3 also met their respective endpoints. In ASTRAL-2, the SVR12 rate among genotype 2 HCV-infected patients receiving SOF/VEL for 12 weeks was statistically superior to the SVR12 rate for patients receiving SOF+RBV for 12 weeks (p=0.018). In ASTRAL-3, the SVR12 rate among genotype 3 HCV-infected patients receiving SOF/VEL for 12 weeks was statistically superior to that of patients treated with SOF+RBV for 24 weeks (p<0.001).
The open-label ASTRAL-4 study evaluated the use of SOF/VEL with or without RBV for 12 weeks and SOF/VEL for 24 weeks in 267 HCV-infected patients with Child-Pugh class B cirrhosis, regardless of genotype.