Baloxavir Reduces Flu Symptoms and Viral Shedding

Diana Phillips

September 05, 2018

A new antiviral drug shows promise for treating acute, uncomplicated influenza — including avian and oseltamivir-resistant strains — in adults and children older than age 12 years, new research shows.

A single dose of baloxavir marboxil, a first-in-class drug that inhibits a viral protein essential for influenza replication, significantly reduced the duration of flu symptoms, duration of fever, length of time of viral shedding, and levels of virus in the nose and throat compared with placebo or oseltamivir among otherwise healthy people with the flu in two randomized controlled trials.

The findings, published online today in the New England Journal of Medicine,  are encouraging.

However, the emergence of viral escape mutants with reduced susceptibility to baloxavir provide "cause for concern," a Centers for Disease Control and Prevention (CDC) expert writes in an accompanying editorial.

Unlike neuraminidase inhibitors, which bind to the neuraminidase protein and block release of viral particles from infected cells, baloxavir inhibits the cap-dependent endonuclease protein within the flu virus, which is essential for viral replication, explain Frederick G. Hayden, MD, professor emeritus from the Department of Medicine at the University of Virginia School of Medicine in Charlottesville, and colleagues.

Following successful preclinical trials and a safety trial in which healthy volunteers received a single dose (up to 80 mg) of baloxavir without evident safety concerns, researchers conducted phase 2 and phase 3 randomized controlled trials to assess the safety and efficacy of single-dose baloxavir treatment in otherwise healthy persons with acute influenza.

The phase 2 trial was a double-blind, placebo-controlled, dose-ranging, randomized trial of single doses of baloxavir (10, 20, or 40 mg) or placebo. The trial enrolled 400 Japanese adults 20 to 64 years of age with acute influenza [predominantly A(H1N1)pdm09 virus] between December 2015 and March 2016.

The double-blind, placebo- and oseltamivir-controlled, randomized phase 3 (CAPSTONE-1) trial enrolled 1436 outpatients, 12 to 64 years of age, with influenza-like illness in the United States and Japan between December 2016 and March 2017. Patients aged 20 to 64 years were randomly assigned in a ratio of 2:1:2 to receive a single one-time oral dose of 40 or 80 mg of baloxavir according to body weight, a placebo, or 75 mg of oseltamivir twice daily for 5 days.

Patients aged 12 to 19 years were randomly assigned in a ratio of 2:1 to receive a single dose of baloxavir or a placebo. Those who weighed less than 80 kg received 40 mg of baloxavir, and those who weighed more than 80 kg received 80 mg.

The primary endpoint for both trials was the time to alleviation of symptoms, defined as the time from the start of the trial regimen to the time when all flu-related symptoms were absent or mild for at least 21.5 hours based on patient reports. Investigators also monitored time to resolution of fever, time to return to usual health, changes from baseline in virus titer, and time to cessation of viral shedding.

The results of the phase 2 dose-ranging trial demonstrated a significantly reduced time to symptom alleviation. Specifically, the median times to alleviation of symptoms in 10 mg, 20 mg, and 40 mg baloxavir-dose groups, respectively, were 54.2 hours, 51.0 hours, and 49.5 hours, all of which were significantly shorter than the time in the placebo group, at 77.7 hours. Also, the treatment groups experienced greater reductions in levels of influenza viral load at 1 and 2 days after administration of the trial regimen compared with placebo.

In the phase 3 trial, baloxavir resulted in a significantly shorter time to alleviation of symptoms compared with placebo in patients age 20 to 64 years (median difference, 25.6 hours) and those age 12 to 19 years (median difference, 38.6 hours), the authors report.

Additionally, compared with placebo, baloxavir treatment significantly reduced the following:

  • The duration of flu symptoms, by more than 1 day (median time, 53.7 hours vs  80.2 hours; P <.0001);

  • The duration of fever, by nearly 1 day (median time, 24.5 hours vs 42.0 hours; P <.0001);

  • The length of time viruses continued to be released from the body (median time of viral shedding, 24.0 hours vs 96.0 hours; P <.0001); and

  • The levels of virus in the nose and throat from 24 hours through 120 hours.

Relative to oseltamivir, baloxavir treatment resulted in similar median time to alleviation of symptoms (median, 53.5 hours for baloxavir vs 53.8 hours for oseltamivir; P = .7560) and similar time to resolution of fever reduction (median, 24.4 hours vs 24.0 hours; P = .9225), respectively.

However, baloxavir treatment was associated with significantly reduced viral shedding duration (24.0 hours vs 72.0 hours; P < .0001) and significantly lower levels of virus in the nose and throat at 24 hours and 72 hours.

"It is unclear why the time to alleviation of symptoms was similar in the baloxavir group and the oseltamivir group even though baloxavir showed greater antiviral activity," the authors write. "The findings suggest that the symptom benefit of antiviral agents may have a ceiling in self-limited influenza illness in adults, perhaps because viral replication levels are decreasing by the time of presentation and illness pathogenesis is linked to host proinflammatory responses."

Overall, baloxavir was well-tolerated and had a lower incidence of adverse events reported (20.7%) compared with placebo (24.6%) or oseltamivir (24.8%). The  most common adverse events were diarrhea (3%), bronchitis (2.6%), nausea (1.3%), and sinusitis (1.1%).

"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," the authors write.

The drug, which is being fast-tracked by the US Food and Drug Administration, was approved for use in Japan earlier this year.  

Reduced Susceptibility

With respect to viral escape mutations, the emergence of variants 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, the authors report. While not unexpected given that "[a]ll influenza-specific antiviral agents lead to the emergence of resistant variants," according to the authors, the findings warrant ongoing characterization of the frequency, replication competence, and transmission fitness of clinical isolates with reduced susceptibility to baloxavir, they stress.

It is because of this potential for the emergence of drug-resistant viral mutations that editorialist Timothy M. Uyeki, MD, MPH, MPP, from the Influenza Division of the CDC's National Center for Immunization and Respiratory Diseases in Atlanta, Georgia, urges caution in interpreting the study results.

"[I]n both trials, baloxavir treatment induced the emergence of viral escape mutants with reduced susceptibility through changes from isoleucine to other amino acids at position 38 (I38) of the gene encoding PA [polymerase acidic]," he writes. "The issue for public health is whether these influenza viruses with reduced susceptibility to baloxavir are transmissible, and surveillance for I38T and other markers will be needed."

Uyeki suggests the studies reported here should be considered a "first step," with future research focused on safety and efficacy of the drug in patients at higher risk for flu complications. "These include persons at higher risk for influenza complications because of age (young children and elderly persons), pregnancy, or chronic coexisting medical conditions," he writes.

Uyeki also indicates the need for additional studies to determine the following:

  • The clinical benefit of administering baloxavir treatment more than 48 hours after illness onset to high-risk outpatients and those hospitalized with severe influenza complications, including critical illness;

  • Pharmacokinetic and pharmacodynamic behavior to inform appropriate dosing and to determine whether additional baloxavir doses are beneficial in patients with severe influenza;

  • Whether combination treatment with oseltamivir and baloxavir can provide greater clinical benefit than oseltamivir monotherapy in high-risk groups with seasonal influenza, as well as in hospitalized patients with zoonotic influenza, such as those with avian influenza A(H7N9) virus infection; and

  • Whether baloxavir can successfully treat patients with neuraminidase inhibitor–resistant influenza virus infection.

"The significant reduction in influenza viral replication with baloxavir treatment suggests the potential for reducing influenza virus spread to close contacts and should be studied through randomized, controlled trials in households and during institutional influenza outbreaks such as in long-term care facilities," Uyeki writes. "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. Further clinical, virologic, and transmission studies, and global surveillance for influenza viruses with reduced drug susceptibility, will inform the usefulness of baloxavir for clinical use and public health benefit."

Both trials were funded by Shionogi, and multiple authors reported a financial relationship to Shionogi. In addition, several authors report multiple types of financial relationships with numerous companies. For the full disclosure please see the journal website. Uyeki has disclosed no relevant financial relationships.

N Engl J Med. 2018;379:913-923, 975-977. Abstract, Editorial

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