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The antiviral agent baloxavir marboxil was safe and associated with a shorter median time to alleviation of influenza symptoms versus placebo in phase II and phase III trials, researchers found.

In the phase III trial, median time to alleviation of symptoms was 53.7 hours (95% CI 49.5-58.5) for patients on baloxavir versus 80.2 hours (95% CI 72.6-80.1, P<0.001) for patients on placebo, reported Frederick G. Hayden, MD, of the University of Virginia School of Medicine in Charlottesville, and colleagues.

However, compared with patients treated with antiviral oseltamivir (Tamiflu), median time to alleviation of symptoms was similar (53.5 hours with baloxavir versus 53.8 with oseltamivir), the authors wrote in the

They noted that baloxavir showed nanomolar antiviral activity against influenza A and B viruses in preclinical models, including "strains resistant to current antiviral agents." The authors cited antiviral resistance to other therapies as a threat, as evidenced by global circulation of oseltamivir-resistant seasonal influenza A (H1N1) viruses in 2008-2009, as well as community clusters of oseltamivir-resistant influenza A (H1N1) viruses.

In addition to animal models where baloxavir was linked with "rapid reductions in pulmonary viral loads and decreased mortality," the authors added there were no "evident safety concerns" and that the drug showed "linear pharmacokinetic characteristics and a long plasma elimination half-life" in a study of healthy volunteers.

In the phase II trial, otherwise healthy Japanese adults ages 20-64 with acute influenza were randomized to receive a 10, 20, or 40 mg dose of baloxavir or placebo. The phase III trial enrolled outpatients ages 12-64 with influenza-like illness, mostly in Japan. Adults ages 20-64 were randomized to a regimen containing a single, weight-based dose of baloxavir, or a regimen containing 75 mg of oseltamivir twice daily for 5 days, or matching placebo. Patients ages 12-19 were randomized to receive baloxavir or placebo (on day 1), with the first dose of the trial regimen under direct observation for all patients.

In the phase II trial, there were 389 patients who completed the trial. About 60% to 70% who underwent randomization were infected with influenza A (H1N1pdm09). Median time to alleviation of symptoms in all three baloxavir groups was significantly shorter than the placebo group (P=0.009, P=0.02, and P=0.005, respectively):

• 54.2 hours in 10-mg group
• 51.1 hours in 20-mg group
• 49.5 hours in 40-mg group
• 77.7 hours in placebo

The authors also noted that all three baloxavir dose groups had significantly greater reductions in influenza virus titers on days 2 and 3 versus the placebo group.

In the phase III trial, 1,366 completed the trial and 1,064 were included in the intention-to-treat infected population. Of this population, influenza A(H3N2) accounted for about 85% to 88% of infections in the three groups and over three-quarters of patients were enrolled in the study in Japan.

In addition to a significantly shorter median time to alleviation of symptoms compared with placebo, baloxavir was linked with significantly greater reduction of viral load 1 day after initiation compared with oseltamivir and placebo groups. Also, median duration of infectious virus detection was significantly shorter among the baloxavir groups (24 hours) compared with the oseltamivir group (72.0 hours) and the placebo group (96.0 hours, P<0.001 for both).

Adverse events in the phase II trial were reported in about a quarter of patients in the three baloxavir dose groups and 29.0% of patients in the placebo group. In the phase III trial, adverse events were reported in about 21% of the baloxavir group versus 24.6% of the placebo group and 24.8% of the oseltamivir group.

There were two serious adverse events in the baloxavir group (incarcerated inguinal hernia and aseptic meningitis), but they were unrelated to the trial regimen. The authors also found that adverse events considered related to the trial regimen were most common in the oseltamivir group (8.4%) versus baloxavir (4.4%) or placebo (3.9%).

In an Timothy Uyeki, MD, of the CDC in Atlanta, characterized these trials as a "first step." He specifically highlighted the significant reduction in viral replication with baloxavir treatment, saying that it suggests "the potential to reduce influenza virus spread to close contacts."

"[It] should be studied through randomized, controlled trials in households and during institutional influenza outbreaks such as in long-term care facilities," Uyeki wrote. "If a single dose is successful in reducing influenza virus transmission, baloxavir could be a useful tool for seasonal and pandemic influenza preparedness and response."

Hayden's group noted that a randomized trial for patients at high risk for influenza complications is already in progress.

The FDA granted a to baloxavir in June 2018, and an approval decision is expected in December 2018, according to Roche, the agent's co-developer along with Shionogi.