Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents

N Engl J Med. 2018 Sep 6;379(10):913-923. doi: 10.1056/NEJMoa1716197.

Abstract

Background: Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.

Methods: We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.

Results: 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 median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). 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 were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. 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.

Conclusions: 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. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354 .).

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antiviral Agents / administration & dosage*
  • Antiviral Agents / adverse effects
  • Antiviral Agents / therapeutic use
  • Child
  • Double-Blind Method
  • Endonucleases / antagonists & inhibitors
  • Female
  • Humans
  • Influenza, Human / drug therapy*
  • Influenza, Human / virology
  • Intention to Treat Analysis
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Oseltamivir / therapeutic use*
  • Oxazines / administration & dosage*
  • Oxazines / adverse effects
  • Pyridines / administration & dosage*
  • Pyridines / adverse effects
  • Thiepins / administration & dosage*
  • Thiepins / adverse effects
  • Triazines / administration & dosage*
  • Triazines / adverse effects
  • Viral Load
  • Virus Replication / drug effects
  • Young Adult

Substances

  • Antiviral Agents
  • Oxazines
  • Pyridines
  • Thiepins
  • Triazines
  • Oseltamivir
  • baloxavir
  • Endonucleases

Associated data

  • ClinicalTrials.gov/NCT02954354