The FDA has granted priority review to the new drug application (NDA) for an investigational once-daily, fixed-dose combination of the nucleotide analog polymerase inhibitor sofosbuvir (SOF), approved as Sovaldi (Gilead Sciences) in December 2013, and velpatasvir (VEL), an investigational pan-genotypic NS5A inhibitor, for the treatment of chronic genotype 1–6 hepatitis C virus (HCV) infection.
Gilead Sciences filed the NDA for SOF/VEL in October 2015, and the FDA set a target action date under the Prescription Drug User Fee Act (PDUFA) of June 28, 2016. The agency also assigned SOF/VEL a breakthrough therapy designation, which is granted to investigational medications that may offer major advances in treatment over existing options.
The NDA for SOF/VEL was supported by data from four phase III clinical trials. In the ASTRAL-1, ASTRAL-2, and ASTRAL-3 studies, a total of 1,035 patients with genotype 1–6 HCV infection received 12 weeks of SOF/VEL. Among these patients, 21% had compensated cirrhosis and 28% had failed prior treatments. The ASTRAL-4 study randomly assigned 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. In all of these studies, the primary endpoint was undetectable HCV for 12 or more weeks after the end of treatment (SVR12).
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%) achieved the primary efficacy endpoint of SVR12. Of the 20 patients who did not achieve SVR12, 13 patients (1.3%) experienced virologic failure and seven did not complete an SVR12 visit (e.g., lost to follow-up). Twelve of the 13 patients with virologic failure relapsed (two genotype 1 HCV-infected patients and 10 genotype 3 HCV-infected patients). One patient had documented reinfection. No patients with genotype 2, 4, 5, or 6 HCV infection experienced 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%) treated with SOF/VEL for 12 weeks, one each in ASTRAL-1 and ASTRAL-2, discontinued treatment because of 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 plus RBV achieved higher SVR12 rates compared with patients receiving SOF/VEL alone for 12 or 24 weeks. Among genotype 1 and 3 patients treated with SOF/VEL plus RBV for 12 weeks, the SVR12 rates were 96% and 85%, respectively.
The most common adverse events across all arms of the ASTRAL-4 trial were fatigue, nausea, and headache. Anemia, a common adverse effect associated with RBV, was reported in 31% of patients in the SOF/VEL plus RBV arm, and in 4% and 3% of patients treated with SOF/VEL for 12 or 24 weeks, respectively. Treatment-emergent serious adverse events occurred in 18% of patients, and nine patients died. Most of the serious adverse events and deaths were associated with advanced liver disease.
The SOF/VEL fixed-dose combination is an investigational product, and its safety and efficacy have not been established.