Single-Dose Baloxavir Marboxil Improves Influenza Recovery Rates, Safety

Frederick G. Hayden, MD

Selective endonuclease inhibitor baloxavir marboxil, a promising investigative therapy for patients with influenza A and B virus infections—including antiviral-resistant strains—has reported efficacy and safety benefits in a phase 2 and phase 3 trial.

Investigators, led by Frederick G. Hayden, MD, of the Division of Infectious Diseases and International Health, University of Virginia Health System, conducted 2 randomized, double-blind, placebo-controlled trials to compare the antiviral agent versus oseltamivir in otherwise healthy patients with influenza (flu). The positive benefits of baloxavir marboxil indicates the therapy could join an antiviral therapy market in need of new agents in response to treatment-resistant strains.

As investigators noted, M2 ion-channel inhibitors—along with neuraminidase inhibitors—are the most common class of therapies for the flu. But circulating viruses are now predominately resistant to M2 ion-channel inhibitors, and previous influenza seasons such as in 2008-2009 have shown that antiviral resistance to neuraminidase inhibitors have become more prevalent as well.

As a small-molecule prodrug of a selective polymerase acidic protein (PA) inhibitor, baloxavir marboxil has potential to target the crucial polymerase complex evident in resistant flu strains.

“In murine models of seasonal influenza and avian influenza A(H5N1) or A(H7N9), orally administered baloxavir was associated with rapid reductions in pulmonary viral loads and decreased mortality,” investigators wrote. “In an ascending single-dose study involving healthy volunteers, baloxavir was administered up to the highest dose tested (80 mg) without evident safety concerns, and it showed linear pharmacokinetic characteristics and a long plasma elimination half-life.”

And now, a single-dose form of the treatment has been associated with acute flu benefits.

For the phase 2 trial, investigators conducted a double-blind, placebo-controlled, dose-ranging, randomized trial (ratio 1:1:1:1) of single-dose baloxavir (10, 20 and 40 mg) or placebo. Japanese adults aged 20-64 years old with acute influenza were enrolled from December 2015 through March 2016.

Of the 400 patients randomized, 389 completed the trial. A majority of patients (61% to 71%) were infected with the influenza A(H1N1)pdm09 virus. Patients treated with single-dose baloxavir reported significantly shorter median time to symptom alleviation (54.2 hours in 10 mg, 51.0 hours in 20 mg, and 49.5 mg in 40 mg) than patients treated with placebo (77.7 hours [ P = .009, P = .02, P = .005, respectively]). All 3 baloxavir dose groups also reported significantly greater reductions in influenza virus titers on days 2 and 3 versus patients treated with placebo (P < .001).

The treatment group also reported fewer mean adverse events (23% to 27%) versus patients on placebo (29%), with no significant differences in rates of specific events between treatment groups.

In the phase 3 trial (CAPSTONE-1)—a double-blind, placebo- and oseltamivir-controlled, randomized trial involving 1436 patients aged 12-64 years old with influenza-like illness in the US and Japan&mdash;investigators randomized patients aged 20-64 years old 2:2:1 to single oral dose baloxair (40 mg for those weighing <80 kg; 80 mg for those weighing >80 kg), twice-daily 75 mg oseltamivir, or matching placebos, for 5 days.

Patients aged 12-19 years old were randomly assigned 2:1 to either one-day baloxavir or matching placebo.

Of the 1366 patients to have completed the trial, 1064 were included in the intention-to-treat infected population. Similar to the phase 3 trial, median time to symptom alleviation was shorter in the baloxavir group than in the placebo group in both the intention-to-treat infected population (53.7 hours vs 80.2 hours, P < .001) and intention-to-treat population (65.4 vs 88.6, P < .001).

By day 2, investigators noted a more rapid alleviation of symptoms with baloxavir than with placebo. A shorter time to alleviation of symptoms with baloxavir than with placebo was observed in both adolescents (median difference, 38.6 hours; P = .006) and adults (median difference, 25.6 hours; P < .001).

The median time to fever resolution was shorter with baloxavir (24.5 hours) than with placebo (42.0 hours [P < .001]), and the therapy was also associated with significantly more rapid declines in infectious viral load than placebo or oseltamivir.

Adverse events were reported in 20.7% of baloxavir patients, 24.6% of placebo patients, and 24.8% of oseltamivir patients. A pair of serious adverse events reported by patients administered baloxavir (incarcerated inguinal hernia, aseptic meningitis) were not considered treatment-related.

Though investigators noted differences in time to symptom alleviation between patients enrolled in Japan versus the US, they hypothesized the disparity was related to differences of healthcare-seeking behavior or symptom reporting procedures. That said, baloxavir was associated with similar clinical benefits in both countries.

With a randomized, controlled trial involving patients at high risk for flu complications currently underway, investigators concluded that baloxavir may provide an option for patients with uncomplicated influenza.

“The antiviral effects that were observed with baloxavir in patients with uncomplicated influenza provide encouragement with respect to its potential value in treating complicated or severe influenza infections,” investigators wrote. “Baloxavir has shown synergistic antiviral effects with neuraminidase inhibitors in vitro. Such combinations could be studied clinically to determine whether they reduce the risk of resistance emergence and enhance clinical efficacy.”

The study, “Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents,” was published online in the New England Journal of Medicine.