Mixed bag for Favipiravir antiviral in influenza
The antiviral favipiravir was associated with significant reductions in influenza viral titers and median time to cessation of virus detection, but results for time to attenuation of influenza disease were mixed, according to two international phase III trials.
The US316 trial found that favipiravir was linked to a significant reduction of 14.4 hours in the median time to disease attenuation compared to placebo (median of 84.2 versus 98.6 hours, respectively, P= 0.004), while the US317 trial found no significant difference between drug and placebo (median of 77.8 vs. 83.9 hours), reported Frederick Hayden, MD, of health system at the University of Virginia at Charlottesville, and colleagues, writing in the Journal of Infectious Diseases.
Both trials randomized otherwise healthy adults aged 18 to 80 with at least two moderate to severe flu-like symptoms and fever, and a positive test or unknown exposure to influenza. The US316 was conducted in 14 countries in the United States, Africa, Europe, Asia, Australia, and New Zealand from January 2014 to March 2015. The US317 was conducted in 10 countries and territories in the Americas from December 2013 to February 2015.
Patients were randomized 1:1 in US316 and 3:1 in US317 to receive either oral favipiravir or placebo.
In US316, the intent-to-treat population included 301 favipiravir patients and 322 placebo patients. Patients were on average 41 years old, 59% were female and 78% were Caucasian. Notably, 78% were unvaccinated for the current flu season. In US317, the intention-to-treat population included 526 favipiravir patients and 169 placebo patients.
There was no significant difference in the time to return to normal activity between the two groups in the two trials. Both trials found a significant median time to cessation of detection of infectious virus in the favipiravir group compared to the placebo group. Mean viral titers also declined more rapidly for those in the favipiravir group, the authors noted.
Regarding safety, a higher proportion of patients in the favipiravir group in both trials experienced treatment-related adverse events (AEs) – 30.7% versus 25.9%, respectively, in the US316 and 28.0% compared to 25.1% in the United States317. Diarrhea, nausea, and urinary tract infections were the most common AEs, and they were generally mild or moderate, the authors said.
They added that in the United States,316 five patients on placebo and one patient on favipiravir developed pneumonia. Serious treatment-emergent AEs included breast cancer and malignant melanoma in the placebo group and pneumonia in the favipiravir group in US316. In US317, treatment-emergent AEs in the favipiravir group included thyroid cancer, exacerbation of asthma, pneumonia, colitis, and staphylococcal bacteraemia. None of these AEs were found to be related to the study drug, the authors said.
Mean uric acid levels increased in the favipiravir group compared to baseline in the favipiravir group, but the authors noted that this “improved or disappeared” by day 15, and there was no d episodes of acute gout.
Hayden and colleagues pointed out that recipients who weighed at least 80 kg had a “more modest reduction” in time to disease attenuation, meaning that a higher dose may be needed “in some recipients to achieve reliably inhibitory concentrations,” the team wrote.
“Optimal dosing regimens for favipiravir need further investigation, particularly in heavier patients and in severe influenza,” the researchers added.
Other limitations, they said, included the lack of a direct comparison with a proven influenza antiviral and the fact that the trial did not assess participants for “the emergence of influenza variants with a reduced susceptibility to favipiravir”.
The study was funded by the Ministry of Defence.
Hayden said he served as an unpaid consultant to MediVector and Fujifilm during the clinical development of favipiravir and to other companies involved in the development of influenza therapies or vaccines: Appili, Gilead, GlaxoSmithKline, Janssen/Johnson & Johnson, MedImmune, Merck, Ridgeback, Roche/Genentech, Versatope, Vir and Visterra. He also reported that Cidara, Enanta, Shionogi, and Versatope made charitable donations for his consultation; and that Shionogi and Roche provided travel assistance for the meetings.
All other co-authors were employees of MediVector during the trial, but are no longer employees.