Baloxavir marboxil, an influenza cap-dependent endonuclease inhibitor, reduces complications and speeds recovery in high-risk patients with uncomplicated influenza, according to results from the phase 3 CAPSTONE-2 trial. Baloxavir was approved in 2018 in the U.S. and Japan for treating uncomplicated influenza in otherwise healthy individuals aged 12 years and older. Dr. Michael G. Ison of Northwestern University Feinberg School of Medicine, in Chicago, and colleagues assessed the efficacy and tolerability of single-dose baloxavir, compared with placebo and five days of oseltamivir treatment, in adolescent and adult outpatients with uncomplicated influenza. The participants were at high risk of influenza-related complications by virtue of having asthma, chronic lung disease, endocrine disorders, heart disease, metabolic disorders or age 65 years or older. The study enrolled 2,184 patients, of whom 1,195 received at least one dose of study drug and had influenza confirmed by RT-PCR. The modified intention-to-treat population excluded 32 patients who were enrolled at sites that did not comply with Good Clinical Practice guidelines. The primary efficacy endpoint, time to improvement of influenza symptoms (TTIIS), was significantly shorter in the baloxavir group (median, 73.2 hours) than in the placebo group (102.3 hours, P<0.0001) and was not significantly different from that in the oseltamivir group (81.0 hours), the researchers report in The Lancet Infectious Diseases. Influenza-associated complications were significantly less common in the baloxavir group (3% of patients) than in the placebo group (10% of patients) and occurred with similar frequency in the oseltamivir group (5%). The median time to return to pre-influenza health status did not differ significantly among the three groups. Infectious virus titers declined significantly faster in the baloxavir group than in the other two treatment groups. Adverse events were fairly common (25% of baloxavir patients, 30% of placebo patients, and 28% of oseltamivir patients experienced them), but only 1% of each group withdrew from the study because of them. Polymerase acidic protein variants conferring reduced baloxavir susceptibility emerged in 5% of baloxavir recipients assessed for amino acid substitutions in the virus. "This study supports early therapy for patients at high risk of complications of influenza to speed clinical recovery and reduce complications," the authors conclude. Dr. Glenn S. Tillotson of GST Micro, in Richmond, Virginia, who wrote a linked editorial, told Reuters Health by email, "The study provides evidence of a new class of agent providing clinical efficacy in patients for whom getting it right the first time is essential. In addition to a simple regimen, it appears, at this stage, to be relatively safe. Getting antimicrobial therapy 'right the first time' is an important tenet of antimicrobial stewardship." "The superiority of single-dose baloxavir to placebo as well as its noninferiority to 5 days of oseltamivir in these challenging patients is reassuring," he said. Dr. Tillotson added, "I would like to see further studies in more compromised patients and those with organ dysfunction. Additionally, I would like to see if combination therapies can reduce the selection of resistant mutants while keeping the regimen simple." Dr. Ison did not respond to a request for comments. Shionogi funded the study and had financial relationships with all of the authors. —Will Boggs MD Source
