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Ziresovir produced significantly greater clinical improvement, decreased viral load, and reduced the Wang bronchiolitis clinical score compared to placebo in the treatment of infants and young children hospitalized with respiratory syncytial virus (RSV) infection, according to the results of the Phase III AIRFLO trial (NCT04231968) published by The New England Journal of Medicine.1,2 In a prior Phase II trial (NCT02654171), ziresovir, a potent, selective, orally bioavailable RSV F protein inhibitor, was found to be well tolerated in hospitalized RSV‐infected infant patients, while also lowering viral load and Wang Respiratory Score.3
“Preclinical toxicity, pharmacokinetic, and metabolic studies suggested that the drug is a suitable candidate for clinical development,” the study authors wrote. “A recent phase 2 trial involving 72 participants 1 to 24 months of age showed that treatment with ziresovir was associated with greater reductions in the RSV viral load and in scores representing signs and symptoms than placebo, with no evident safety concerns.”1
RSV infections lead to an estimated 3.6 million hospitalizations per year with approximately 97,200 to 124,900 deaths reported in children aged 5 years and younger worldwide, the majority of which occur in developing countries. FDA-approved RSV vaccines are indicated for use in adults aged 60 years or older and in pregnant individuals; however, there are no approved vaccines indicated for children. The FDA has approved aerosolized ribavirin to treat RSV infection in infants and young children, but the study authors noted the drug has limited efficacy, an unfavorable safety profile, and potential teratogenic effects.1
The multicenter, double-blind, randomized, placebo-controlled AIRFLO trial was conducted in China with participants aged 1 to 24 months who were hospitalized for RSV infection. Patients were randomly assigned in a 2:1 ratio to receive either ziresovir at a dosing range of 10 to 40 mg based on body weight or placebo, administered twice per day for five days. The trial’s primary endpoint was the change from baseline to day three in Wang bronchiolitis clinical score.
The trial’s intention-to-treat cohort enrolled 244 patients with confirmed RSV infection administered at least one dose of ziresovir or placebo, whereas the safety cohort enrolled 302 patients administered at least one dose of ziresovir or placebo.
Results of the trial showed that a decrease from baseline in Wang bronchiolitis clinical score at day three was significantly higher in patients administered ziresovir compared to placebo (−3.4 points [95% confidence interval {CI}, −3.7 to −3.1] vs. −2.7 points [95% CI, −3.1 to −2.2]; difference, −0.8 points [95% CI, −1.3 to −0.3]; P=0.002). Further, the decrease in RSV viral load at day five was higher in patients administered ziresovir compared to placebo (−2.5 vs. −1.9 log10 copies per milliliter; difference, −0.6 log10 copies per milliliter [95% CI, −1.1 to −0.2]). Investigators also reported improvements in prespecified patient subgroups, including those with a baseline bronchiolitis score of at least eight and in those aged 6 months or younger.
In terms of safety, 16% of patients administered ziresovir experienced adverse events (AEs) compared to 13% of those administered placebo. The most frequently reported AEs that investigators linked to either ziresovir or placebo were diarrhea (4% and 2%, respectively), increased liver-enzyme level (3% and 3%, respectively), and rash (2% and 1%, respectively).
“In this trial, we found that ziresovir treatment in infants and young children who were hospitalized with RSV infection resulted in a significantly greater resolution of signs and symptoms associated with RSV infection as well as greater decrease in the viral load than placebo,” the study authors wrote. “These initial findings warrant further evaluation in an international, phase 3 trial of ziresovir treatment for RSV infection.”1
References
1. Zhao S, et al. Ziresovir in Hospitalized Infants with Respiratory Syncytial Virus Infection. Published September 25, 2024. N Engl J Med 2024;391:1096-1107. DOI: 10.1056/NEJMoa2313551. Vol. 391 No. 12.
2. A Study of AK0529 in Chinese Infants Hospitalized With RSV (AIRFLO). ClinicalTrials.gov. Updated February 13, 2024. Accessed October 3, 2024. https://clinicaltrials.gov/study/NCT04231968
3. Huang LM, et al. Safety and efficacy of AK0529 in respiratory syncytial virus-infected infant patients: A phase 2 proof-of-concept trial. Influenza Other Respir Viruses. 2023 Jul 25;17(7):e13176. doi: 10.1111/irv.13176. PMID: 37502622; PMCID: PMC10368966.