Infectious Disease

Favipiravir shows significant antiviral effects but misses mark in phase 3 flu trials

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Disclosures:
Hayden reports serving as an unpaid consultant to Medivector and Fujifilm during the clinical development of favipiravir and to other companies involved in developing influenza therapeutics or vaccines including Appili, Gilead, GSK, Janssen/J&J, MedImmune, Merck, Ridgeback, Roche/Genentech, Versatope , Vir and Visterra, as well as receiving donations for consulting and/or travel fees from Cidara, Enanta, Shionogi, and Versatope. Epstein and all other authors report being Medivector employees at the time of the trials.

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Although favipiravir showed significant antiviral effects in two phase 3 influenza trials, the clinical efficacy results differed between the trials “for unclear reasons,” researchers reported in The Journal of Infectious Diseases.

“The favipiravir regimen used in the clinical program showed significant antiviral effects in uncomplicated seasonal influenza in both trials, but the primary clinical endpoint — the difference in time to alleviation of a composite of influenza symptoms — did not achieve the 24-hour difference compared to placebo mandated by FDA and was less that the effects observed in earlier pivotal studies of oseltamivir,” Carol Epstein, MD, cofounder and former owner of MediVector, and Frederick G. Hayden, MD, professor of medicine and pathology at the University of Virginia School of Medicine, told Healio in a joint email.

Epstein and Hayden said preclinical studies and the two clinical trials summarized in the article were funded by the US Department of Defense “in efforts to develop an oral antiviral which would be effective against all influenza viruses including those resistant to oseltamivir, as well as potentially diseases caused by other RNA viruses.”

The development program was conducted by MediVector in partnership with favipiravir’s inventor, Toyama Chemical, with the goal of obtaining an FDA approval for favipiravir an experimental antiviral that has been shown to improve survival rates of patients with Ebola as an influenza treatment.

Based on the results of the phase 3 trials and following a consultation with the FDA, however, the sponsors decided not to seek approval, which “would have enabled stockpiling of favipiravir for emergency use,” Epstein and Hayden said.

Epstein, Hayden and colleagues randomly assigned otherwise healthy adults with influenza-like symptoms and fever to receive 1,800 mg of favipiravir twice daily on day 1, then 800 mg twice daily on days 2 to 5, or placebo. This was done in two studies: US316, in which patients were matched in a 1:1 ratio; and US317, in which patients were matched in a 3:1 ratio. The primary efficacy endpoint was time to illness alleviation.

In both studies, researchers found that favipiravir was associated with reduced viral titers, RNA load area under the curve over days 1 to 5, and median times to the end of virus detection (P < .001).

However, in US316, favipiravir was associated with a 14.4-hour reduction in time to illness alleviation compared with placebo (84.2 vs. 98.6 hours; P = .004), but in US317, favipiravir did not significantly reduce time to alleviation (77.8 vs .83.9 hours).

“Oral favipiravir … is an effective inhibitor of seasonal influenza virus replication at the doses studied. However, the dose used in the clinical program may not have been high enough,” Epstein and Hayden said. “Further studies of higher dose oral regimens in outpatients and in hospitalized patients with severe influenza, combination therapy with other antivirals like oseltamivir or baloxavir, as well as the development of an intravenous formulation, are warranted.”

One limitation of the trials was that they did not compare favipiravir to a “proven” influenza antiviral, the researchers noted.

“The antiviral effects observed in these trials are generally similar to those reported for oseltamivir in uncomplicated influenza but less than observed with baloxavir,” they wrote. “An obvious strategy to enhance potency would be the use of antiviral combinations, and in vitro studies indicate that favipiravir shows synergistic effects with oseltamivir for influenza A viruses.”

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