FDA Panel Backs Sofosbuvir for Hepatitis C

Troy Brown, RN

October 25, 2013

An advisory committee to the US Food and Drug Administration (FDA) voted unanimously (15-0) to recommend sofosbuvir (Gilead Sciences, Inc) in combination with ribavirin for the treatment of adults with chronic hepatitis C virus (HCV) genotypes (GT) 2 and 3 infections.

The committee also recommended (15-0) sofosbuvir in combination with pegylated interferon and ribavirin for treatment of chronic HCV in treatment-naïve adults with GT 1 and 4 infections.

Sofosbuvir is an NS5B polymerase inhibitor and the first drug in this class to be reviewed in the US. It is intended to be administered as a 400-mg oral dose once daily in combination with other drugs. The approval is momentous because it provides the first interferon-free regimen for adult patients with HCV GTs 2 and 3.

"This is a tremendous advance for patients, and I think both the sponsor and the FDA should be applauded for having gotten us here," said voting member Elizabeth Connick, MD, a professor of medicine at University of Colorado Denver, Division of Infectious Diseases, in Aurora, Colorado.

The vote follows a discussion of 4 pivotal phase 3 trials:

In patients with HCV GT 2 or 3:

  • P7977-1231 (FISSION) evaluated sofosbuvir + ribavirin (SOF + RBV) treatment for 12 weeks in treatment-naïve patients (499 patients: 256 in the SOF + RBV group; 243 in a pegylated interferon + ribavirin [PEG + RBV] group);

  • GS-US-334-0107 (POSITRON) evaluated SOF + RBV for 12 weeks in patients who were interferon intolerant, ineligible, or unwilling to take interferon (278 patients: 207 in the SOF + RBV group; 71 in the placebo group);

  • GS-US-334-0108 (FUSION) evaluated SOF + RBV for 12 or 16 weeks in treatment-experienced patients (201 patients: 103 in the SOF + RBV 12-week group; 98 in the SOF + RBV 16-week group).

In patients with HCV GT 1, 4, 5, or 6:

  • GS-US-334-0110 (NEUTRINO), evaluated SOF (400 mg once daily) + PEG (180 μg/week) + RBV (1000 or 1200 mg/day) for 12 weeks in treatment-naïve patients (N = 327).


For all 4 trials, the primary endpoint was sustained virologic response (SVR), defined as HCV RNA less than the lower limit of quantification (LLOQ) 12 weeks after stopping active treatment (SVR12).


In FISSION, the overall SVR12 rate was 67% for both groups. When they looked at the subgroups (by genotype) of the SOF + RBV group, the SVR12 rate was 95% in the subgroup of HCV genotype 2 subjects, and 56% in the subgroup of genotype 3 subjects.

In the PEG + RBV group, SVR12 rates were 78% in those with HCV GT2 and 63% in those with HCV GT3.


In POSITRON, the overall SVR12 rate was 78% in the SOF + RBV group and 0% in the placebo group. In the SOF + RBV group, SVR12 rates were 93% in those with HCV GT2 and 61% in those with HCV GT3.

Relapse was the reason for most treatment failures (HCV GT3, 38%; HCV GT2, 5%). No patients in the placebo group achieved SVR.


In FUSION, the SVR12 rate was higher in the SOF + RBV 16-week group (71%) than the SOF + RBV 12-week group (50%). Each of these was significantly higher (P < .001) when compared with the null rate of 25%. When treatment duration was increased by 4 weeks in the 12-week group, SVR12 rates in those with HCV GT2 increased from 82% to 89%, and in those with HCV GT3, SVR12 rates increased from 30% to 62%.


In NEUTRINO, overall, SVR12 was achieved by 90% of subjects compared with a historical SVR12 rate of 60%, and this was statistically significant (P < .0001). The overall relapse rate was 9%.

The SVR12 rate in those with GT1 (N = 292) was 89% (GT1a, 92%; GT1b, 82%). In those with GT4 (N = 28) the SVR12 rate was 96%. Too few subjects with GT5 and GT6 were in the clinical trial to allow for definitive dosing recommendations for those groups.


No serious or severe cardiac adverse events occurred in sofosbuvir-treated patients, and no treatment discontinuations occurred due to cardiac adverse events. Palpitations were the only Grade 2 event found in the SOF + RBV group. Eleven patients in the SOF + RBV group experienced Grade 1 events including palpitations, tachycardia, sinus bradycardia, extrasystoles, and ventricular extrasystoles.

"It's a great step forward," noted voting member Lawrence S. Friedman, MD, chair of the department of medicine at Newton-Wellesley Hospital, Massachusetts, assistant chief of medicine at Massachusetts General Hospital, a professor of medicine at Harvard Medical School, and a professor of medicine at Tufts University School of Medicine, in Boston.

"I was particularly impressed by the very favorable resistance data," said voting member Russell B. Van Dyke, MD, a professor of clinical pediatrics and head of the Section of Pediatric Infectious Diseases at Tulane University School of Medicine, New Orleans, Louisiana.

The committee was largely supportive of offering sofosbuvir in combination with pegylated interferon and ribavirin to adults with GT1 infection who are nonresponders to a previous course of pegylated interferon and ribavirin. Several members would like to see additional studies including those on long-term effects of treatment and management of complex patients.

The FDA is expected to make a decision by December 8.

The advisory committee members reported no relevant financial relationships.

US Food and Drug Administration (FDA) Antiviral Drugs Advisory Committee meeting October 25, 2013. FDA Briefing, Gilead Briefing


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