AIRFLO supports therapeutic potential of ziresovir for RSV in infants, young children

In the AIRFLO study, treatment with ziresovir – a potent, selective, orally administered RSV F protein inhibitor – leads to a greater resolution of signs and symptoms of bronchiolitis in hospitalized infants and young children with respiratory syncytial virus (RSV) infection.

“RSV is a leading cause of severe illness in infants with no effective treatment … Although RSV vaccines have been approved for use in adults ≥60 years and pregnant women, none are currently approved for use in children,” said the researchers. “In this phase III trial … treatment with ziresovir was associated with significantly greater clinical improvement and a greater viral load reduction than placebo.”

Day 3 saw greater reduction in the Wang bronchiolitis clinical score from baseline with ziresovir vs placebo (least-squares mean (LSM) change, −3.4 vs −2.7 points; difference, −0.8 points; p=0.002). According to the researchers, the differences were already evident by day 2, and the trend continued through day 6.

The changes from baseline to day 3 across all components of the bronchiolitis score were greater with ziresovir vs placebo. The between-group differences in respiratory rate, wheezing, respiratory muscle retraction, and general condition subscores were −0.18, −0.24, −0.22, and −0.18 points, respectively. [N Engl J Med 2024;391:1096-1107]

There was also a substantial drop in RSV viral load by day 5 with ziresovir vs placebo (LSM change, −2.5 vs −1.9 log₁₀ copies/mL; difference, −0.6 log₁₀ copies/mL; p=0.006). “The proportion of participants with a viral load below the lower limit of quantification increased with time and was consistently greater with ziresovir than placebo,” said the researchers.

The incidences of any adverse events (AEs) were similar between the ziresovir and placebo arms (61 percent vs 53 percent), as were the rates of grade ≥3 AEs (4 percent vs 5 percent), serious AEs (2 percent vs 4 percent), and investigator-assessed drug-related AEs (16 percent vs 13 percent).

Effective RSV-specific treatments needed

Aerosolized ribavirin is the only FDA-approved antiviral for RSV treatment. However, its use is limited to infants and young children, with marginal clinical benefit, toxicity concerns, and potential teratogenic effects. [Infect Dis Ther 2021;10:47-60; Drug Saf 2017;40:1205-1218] Palivizumab, though approved, is confined to prevention in high-risk infants, and studies have yet to ascertain the potential of nirsevimab to alter the epidemiologic features of RSV in children. [N Engl J Med 2022;386:837-846]

“For children with contraindications to antibodies, those with chronic underlying lung disease, and those with breakthrough infections, effective RSV-specific antiviral treatments are needed, especially given the RSV outbreaks reported worldwide after the COVID-19 pandemic,” the researchers stressed.

This two-part trial enrolled participants 1–24 months of age hospitalized with RSV infection. In part 1, 33 were given ziresovir, while 21 received placebo. In part 2, 256 participants were randomized 2:1 to receive ziresovir 10–40 mg (according to body weight) or placebo BID for 5 days. In the intention-to-treat (ITT) population in part 2 (61 percent ≤6 months of age, 74 percent male), the mean Wang bronchiolitis clinical score was 6.7 points, and the mean RSV viral load was 7.4 log₁₀ copies/mL. Overall, the ITT population had 244 participants, while the safety cohort had 302.

Augments current Tx armamentarium

“Overall, the results are encouraging, and further studies of ziresovir in more diverse settings and populations are warranted,” said Dr Edward Walsh from the University of Rochester in New York, US, in an accompanying editorial. [N Engl J Med 2024;391:1155-1156]

“[W]hether the measured clinical improvement will result in other clinical benefits, such as earlier hospital discharge, a reduction in discharge home with the receipt of supplemental oxygen, or limited transfer to the paediatric intensive care unit after admission, needs to be determined,” Walsh said.

He added that if confirmed, the findings may portend clinical benefits in individuals with severe immunosuppression, a group in dire need of an effective antiviral for RSV. “Thus, ziresovir offers the potential to augment the recently approved maternal vaccination and monoclonal antibody approaches for reducing the burden of RSV infection in infants.”