Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents

Hayden FG, Sugaya N, Hirotsu N, et al. N Engl J Med. 2018 Sep 6;379(10):913-23. [CrossRef] [PubMed]

Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease and has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents. The authors conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. A dose-ranging (10 to 40 mg) phase 1 placebo-controlled trial was initially conducted. This was followed by a phase 3 trial comparing baloxavir and the neuraminidase inhibitor, oseltamivir, in a single dose during the 2016-7 season. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population. 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 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 did not differ in the placebo, oseltamivir and baloxair groups. 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. The authors conclude that 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. Based on this study, The US Food and Drug Administration (FDA) approved baloxavir marboxil tablets (Xofluza, Shionogi) for the treatment of acute uncomplicated influenza in people age 12 years and older who have been symptomatic for no more than 48 hours.