A single dose of a new influenza drug can significantly shorten the duration of the illness in teens and adults, according to a study. The article reports the results of two multi-centre, double-blind, randomised clinical trials.
Both found that the drug, baloxavir marboxil, shortened the duration of flu symptoms by about one day and more quickly cleared virus compared with placebo in otherwise healthy teens and adults. The larger, phase 3 trial also found that baloxavir’s effect on symptoms was similar to that of a five-day course of oseltamivir but that baloxavir had significantly greater antiviral potency. The studies identified no important side effects.
“Baloxavir shows remarkable antiviral potency in uncomplicated influenza, and if approved by the US Food and Drug Administration (FDA), it would be an important addition to our treatment options for influenza,” said researcher Dr Frederick G Hayden, of the University of Virginia School of Medicine. “Of note, because baloxavir has a novel antiviral action in inhibiting the endonuclease of the virus, the drug is inhibitory for influenza A and B viruses including those that may be resistant to currently available drugs.”
The first trial was conducted in Japan in 2016 and evaluated the drug’s safety and effectiveness in 389 adults, ages 20 to 64. Study participants received either the drug or a placebo. Median flu symptom duration among those who received the drug was 23.4 to 28.2 hours shorter than among participants who received the placebo. (Baloxavir, developed by drug company Shionogi, was approved for use in Japan in children and adults in February 2018.)
The second study was conducted in the US and Japan in the 2016-17 influenza season. It compared baloxavir with both a placebo and an approved drug, oseltamivir, in 1,064 otherwise healthy study participants ages 12 to 64, with proven influenza. The median time to resolution of flu symptoms was 26.5 hours shorter among those who received baloxavir than the 80.2 hours reported among those who were given placebos. Baloxavir and oseltamivir produced similar reductions in symptom duration, but baloxavir required only a single dose compared with the standard five-day oseltamivir regimen.
“Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms and was superior to both oseltamivir and placebo in reducing the viral load one day after initiation of the trial regimen,” the researchers note in their paper.
In both trials, the rate of adverse events reported by study participants was similar regardless of whether participants had been given a placebo or baloxavir.
To become available in the US, baloxavir would need approval from the FDA. The drug was accepted for priority review by the FDA in June, so that a decision is expected by 24 December at the latest.
The drug was tested for its safety and effectiveness among flu sufferers with a higher risk of complications during the past influenza season, but the results of that testing have not yet been formally presented.
Studies of its effectiveness in hospitalised influenza patients, likely in combination with other influenza antivirals, and in preventing transmission of influenza virus are planned.
Background: Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.
Methods: We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016–2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.
Results: In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.
Conclusions: Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed.
Frederick G Hayden, Norio Sugaya, Nobuo Hirotsu, Nelson Lee, Menno D de Jong, Aeron C Hurt, Tadashi Ishida, Hisakuni Sekino, Kota Yamada, Simon Portsmouth, Keiko Kawaguchi, Takao Shishido, Masatsugu Arai, Kenji Tsuchiya, Takeki Uehara and Akira Watanabe