FDA approves Epclusa (sofosbuvir/velpatasvir) for chronic hepatitis C infection

November 10, 2016

FDA approved EpclusaTM (sofosbuvir and velpatasvir, (SOF-VEL) for adults with chronic hepatitis C infection both with compensated cirrhosis or without cirrhosis as well as in combination with ribavirin for hepatitis C with decompensated cirrhosis.

Kevin W. ChamberlainHepatitis C virus (HCV) causes inflammation of the liver; chronic hepatitis C infection can lead to many long-term complications, such as bleeding, jaundice, fluid accumulation, liver failure, cancer, and death. There are at least six known distinct hepatitis C genotypes: treatment strategies and their duration are dictated by these distinct strains.

In June, FDA approved EpclusaTM (sofosbuvir and velpatasvir, (SOF-VEL) for adults with chronic hepatitis C infection both with compensated cirrhosis or without cirrhosis as well as in combination with ribavirin for hepatitis C with decompensated cirrhosis. This medication contains a fixed-dose combination of sofosbuvir and velpatasvir. These drugs inhibit the replication of HCV and are the first FDA-approved treatment for all 6 genotypes of HCV.

Efficacy

Sofosbuvir is a nucleoside [nucleotide?] analog polymerase inhibitor, whereas velpatasvir inhibits the HCV protein NS5A. The efficacy of SOF-VEL was demonstrated in a series of phase 3 clinical trials known as the ASTRAL trials involving 1,035 patients infected with various genotypes of HCV.

ASTRAL-1 was a double-blind, placebo-controlled study involving untreated and previously treated patients with chronic HCV genotype 1, 2, 4, 5, or 6. Patients were randomized in a 5:1 ratio to receive a 12-week course of either SOF-VEL or placebo (n=624 treatment and n=116 placebo). The primary outcome was sustained virological response (SVR) 12 weeks after the end of therapy. Among recipients of 12 weeks of SOF-VEL, the SVR rate was 99% (95% confidence interval [CI], 98 to >99), which was significantly superior to the pre-specified performance goal of 85% (P<0.001). None of placebo recipients had a SVR and rates of SVR were similar regardless of HCV genotype.

Follow-up studies ASTRAL-2 and ASTRAL-3 were randomized open-label studies that compared once daily SOF-VEL with the combination of sofosbuvir and ribavirin (SOF-RIB), 1:1 randomization). ASTRAL-2 was done in patients with the HCV 2 genotype over 12 weeks. ASTRAL-3 was done in patients with the HCV 3 genotype over 24 weeks. The primary endpoint in both trials was SVR 12 weeks after therapy. Among patients with HCV genotype 2, the rate of SVR in the SOF-VEL group was 99%, which was superior to the 94% rate in the SOF-RIB group (P=0.02). Among patients with HCV genotype 3, the rate of SVR in the SOF-VEL group was 95%, which was superior to the 80% rate in the SOF-RIB group (P<0.001).

 

Safety

The most common adverse events (seen in at least 10% of patients in the trials) were headache and fatigue. Other adverse events noted in the trial of patients taking SOF-VEL plus ribavirin for decompensated cirrhosis include anemia, nausea, insomnia, and diarrhea. SOF-VEL carries a warning for serious symptomatic bradycardia when co-administered with amiodarone, particularly in patients also receiving beta-blockers, or in those with underlying cardiac comorbidities or advanced liver disease. Co-administration is not recommended and cardiac monitoring is advised.

Dosing

The recommending dosage of SOF-VEL is one tablet (sofosbuvir 400mg and velpatasvir 100mg) taken once daily with or without food. The recommended dosing duration is 12 weeks for all HCV genotypes, regardless of cirrhosis severity. Ribavirin is added to SOF-VEL when HCV involves decompensated cirrhosis (Child-Pugh score of B or C) using weight-based dosing described in the package insert, divided twice daily and administered with food. No dosage adjustment of SOF-VEL is required for patients with mild or moderate renal impairment. The safety and efficacy of this medication have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or ESRD requiring hemodialysis.

Andrew Gentry, PharmD is a PGY-1 pharmacy resident at John Dempsey Hospital/UConn Health, Farmington, CT. Kevin W. Chamberlin, PharmD is associate clinical professor and assistant department head, pharmacy practice, UConn School of Pharmacy, Storrs, CT.

For more information

. Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and Velpatasvir for HCV genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med. 2015;373(27):2599-2607.

. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and Velpatasvir for HCV genotype 2 and 3 Infection. N Engl J Med. 2015;373(27):2608-2617.