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Investigational HCV regimen shows promise in two phase 3 trials
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An investigational fixed-dose combination regimen containing Sovaldi, velpatasvir and voxilaprevir for the treatment of hepatitis C virus infection resulted in high rates of SVR after 12 weeks of treatment among patients with or without compensated cirrhosis in whom previous therapy with direct-acting antiviral agents had failed, according to results of two international, phase 3 trials.
Marc Bourliére, MD, of Hospital Saint Joseph, France, and colleagues reported in The New England Journal of Medicine that the proportion of patients with HCV in whom therapy with direct-acting antiviral agents (DAAs) had failed is small; however, the number of these patients is substantial and will likely increase as more people are treated for HCV.
“This population of patients has been underrepresented in clinical trials and has limited retreatment options,” they wrote.
Therefore, the researchers conducted two phase 3 trials, POLARIS-1 and POLARIS-4, to assess the safety and efficacy of an investigational regimen containing the nucleotide polymerase inhibitor Sovaldi (sofosbuvir, Gilead Sciences), the NS5A inhibitor velpatasvir and the protease inhibitor voxilaprevir in patients with chronic HCV infection, including those with compensated cirrhosis, in whom previous therapy has failed.
In POLARIS-1, the researchers randomly assigned patients with HCV genotype 1 whose previous treatment included an NS5A inhibitor to receive a once-daily, single-tablet regimen containing 400 mg of sofosbuvir and 100 mg each of velpatasvir and voxilaprevir (n = 150) or placebo (n = 150) for 12 weeks. An additional 114 patients with other genotypes were enrolled in the sofosbuvir/velpatasvir/voxilaprevir arm.
In POLARIS-4, patients with HCV genotypes 1, 2 or 3 whose previous regimen did not include an NS5A inhibitor were assigned to receive either sofosbuvir/velpatasvir/voxilaprevir (n = 163) or Epclusa (sofosbuvir/velpatasvir, Gilead Sciences; n = 151) for 12 weeks. An additional 19 patients with HCV genotype 4 were enrolled in the sofosbuvir/velpatasvir arm.
All study participants in both trials were enrolled at more than 100 sites in the United States, Canada, New Zealand, Australia, France, Germany and the United Kingdom. Among patients who received an active treatment, 46% had compensated cirrhosis.
In POLARIS-1, the overall rate of SVR was 96% (95% CI, 93-98) among patients who received sofosbuvir/velpatasvir/voxilaprevir, which is significantly superior to a prespecified goal of 85% (P < .001), according to the researchers. Of 253 patients with an SVR, 249 returned for a 24-week visit post-treatment, and all still had an SVR. None of the patients in the placebo arm achieved an SVR.
In POLARIS-4, the overall rate of SVR was 98% (95% CI, 95-99) among those who received sofosbuvir/velpatasvir/voxilaprevir, which also was superior to the same prespecified goal as in POLARIS-1 (P < .001), and 90% (95% CI, 84-94) among those who received sofosbuvir/velpatasvir. Of 177 patients in the sofosbuvir/velpatasvir/voxilaprevir arm and 136 patients in the sofosbuvir/velpatasvir arm who had an SVR, 173 and 133 returned for the 24-week visit, and all had an SVR.
Across the study arms, the most common adverse events included headache, fatigue, diarrhea and nausea. The percentage of patients who discontinued active treatment due to adverse events was 1% or lower, the researchers reported.
“In conclusion, these results show that daily treatment with the single-tablet regimen of sofosbuvir-velpatasvir-voxilaprevir for 12 weeks is highly effective for patients infected with HCV of any genotype, with or without compensated cirrhosis, who did not have an SVR after treatment with DDA-based regimens, including NS5A inhibitors,” they wrote.
Following these data, Gilead Sciences filed a New Drug Application with the FDA for sofosbuvir/velpatasvir/voxilaprevir. According to a press release, the regimen was previously granted breakthrough therapy designation by the FDA for the treatment of patients with chronic HCV genotype 1 in whom an NS5A inhibitor-containing regimen failed. If approved, it would be the first once-daily single tablet regimen available as a salvage therapy for patients with HVC genotypes 1 through 6 infection. – by Stephanie Viguers
Disclosure: Bourliére reports receiving grant support, consulting fees, lecture fees and fees for serving on an advisory board for AbbVie, Gilead Sciences and Merck Sharp & Dohme, as well as consulting fees, lecture fees and fees for serving on an advisory board for Janssen Pharmaceutical and Bristol-Myers Squibb, and meeting fees paid for by Genfit and Intercept Pharmaceuticals. Please see the full study for a list of all other authors’ relevant financial disclosures.
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