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Baloxavir marboxil (Xofluza) was approved by the FDA on October 24, 2018, after expedited review, to treat acute uncomplicated influenza infection in patients 12 years of age and older. Approval was based primarily on two randomized, controlled, manufacturer-sponsored studies involving a total of 1836 patients, to whom medication was administered within 48 hours of flu symptom onset (NEJM JW Infect Dis Nov 2018 and N Engl J Med 2018; 379:913). Baloxavir was compared with placebo in one trial and with placebo or the neuraminidase inhibitor oseltamivir (given twice daily for 5 days) in the other trial. In both trials, self-reported symptom relief was earlier in the baloxavir group than in the placebo group (about 54 hours vs. 80 hours; relief with baloxavir was faster in younger than in older patients). Onset of symptom relief was similar with baloxavir versus oseltamivir. Few side effects (primarily gastrointestinal) occurred in any study group but were more common with oseltamivir than with baloxavir.
Viral load in respiratory secretions was lower at 24 hours with baloxavir than with oseltamivir or placebo, an effect that might correlate with decreased person-to-person transmission. However, even in this relatively small trial group, some mutation-based emergence of resistance to baloxavir was evident. Relative replication and transmissibility competence of the mutant viruses are unknown.
FDA approves new drug to treat influenza [press release]. Silver Spring, MD: U.S. Food and Drug Administration; Oct 24, 2018. (https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624226.htm)
Hayden FG et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med 2018 Sep 6; 379:913. (https://doi.org/10.1056/NEJMoa1716197)
Comment
In considering the release of the first new anti-influenza drug in almost 20 years, it is worthwhile to recall that this is the hundredth anniversary of the 1918 influenza pandemic that resulted, over the subsequent 3 years, in about as many deaths as have resulted from AIDS in the 37 years it has been recognized. Previous to baloxavir, two drug classes were available for influenza treatment and prevention. The adamantanes (amantadine and rimantadine), discovered serendipitously, were effective against only type A influenza virus and acted via viral uncoating. Emergence of viral resistance during the 2005–2006 influenza season has rendered these drugs virtually useless. Inhibitors of viral neuraminidase, which facilitates separation of daughter viruses from the infected cell, are active against both types of flu viruses and can be used for prophylaxis as well as treatment. Baloxavir functions through inhibition of an endonuclease involved in viral RNA replication, so it should be effective against avian flu viruses that require this process, and there should be no cross-resistance with the other antivirals. The single-dose pill is 40 mg; two pills are suggested for those weighing >80 kg.
Given the known morbidity and mortality of influenza, there are reasons to be excited about the development and approval of this new anti-influenza drug. However, we have no data yet on its efficacy in severe or life-threatening influenza, or on how readily flu viruses will become resistant if the drug is widely used. The price of this drug, which appears pegged to the list price of a 10-pill regimen of oseltamivir, may prove an obstacle to ubiquitous use. Most important, annual vaccination is still the key to minimizing the morbidity and mortality of influenza.