Clesrovimab shows comparable safety to palivizumab in high-risk infants across 2 RSV seasons

Infants at increased risk for severe respiratory syncytial virus (RSV) disease who received clesrovimab (ENFLONSIA; Merck) had a safety profile comparable to that of palivizumab during their first RSV season, while children who remained at elevated risk tolerated a higher dose of clesrovimab during a second RSV season, according to findings from the phase 3 SMART trial published in JAMA Pediatrics.

How did clesrovimab perform compared with palivizumab in high-risk infants?

The randomized, partially masked trial enrolled 997 infants at 110 sites across 27 countries and territories. Eligible participants included infants with prematurity, chronic lung disease of prematurity, or hemodynamically significant congenital heart disease who qualified for RSV prophylaxis. During the first RSV season, infants received either a single 105-mg dose of clesrovimab followed by placebo or monthly palivizumab. Children who remained at increased risk entered a second RSV season and received an open-label 210-mg dose of clesrovimab.

The primary outcome was safety. During the first RSV season, adverse events occurred in 75.3% of infants who received clesrovimab and 79.6% of those who received palivizumab. Serious adverse events were reported in 24.5% and 27.5% of participants, respectively. No cases of anaphylaxis or hypersensitivity were reported in either treatment group, and no serious adverse events were considered related to clesrovimab.

Among the 276 children who received clesrovimab during their second RSV season, 67.4% experienced at least 1 adverse event. Injection-site pain was the most common local reaction, and no treatment-related serious adverse events or anaphylaxis were reported.

"The primary endpoint in the study was regarding safety, and the safety demonstrated that the safety profile of ENFLONSIA was similar to that of the comparator in the study," Anushua Sinha, MD, MPH, senior principal scientist at Merck Research Laboratories, said in an interview. "The comparator was palivizumab."

What did the SMART trial show during a second RSV season?

The investigators also evaluated RSV-associated disease. Through 150 days after dosing during the first RSV season, RSV-associated medically attended lower respiratory infection occurred in 3.2% of infants receiving clesrovimab and 3.4% receiving palivizumab. RSV-associated hospitalization rates were 1.0% and 1.7%, respectively.

Investigators reported that pharmacokinetic findings in both RSV seasons were consistent with earlier studies, with serum concentrations similar to those observed in the phase 2b/3 CLEVER trial. According to the authors, these data support extrapolating efficacy findings from healthy infants enrolled in CLEVER to the higher-risk population studied in SMART.

Sinha highlighted the pharmacokinetic findings as another key result.

"The pharmacokinetic results, which is to say, the ENFLONSIA serum concentrations achieved for these infants and children in both RSV season one and RSV season 2 were similar to those observed in healthy infants in that phase 2b/3 CLEVER study," Sinha said. "Another term we use is PK bridging. It supports extrapolation of clinical efficacy from that CLEVER trial to the infants and children in SMART."

What do the findings mean for pediatric RSV prevention?

The investigators noted that clesrovimab offers a single-dose approach during an RSV season, whereas palivizumab requires monthly administration. In the discussion, the authors wrote that a single-dose regimen may reduce the likelihood of missed doses in this high-risk population.

Sinha also discussed the potential clinical implications of a once-per-season approach.

"Palivizumab required monthly dosing, and the reality of that was adherence to any care regimen can be challenging when multiple healthcare visits are required," Sinha said. "We're now in the long-acting RSV prevention epoch. You know, ENFLONSIA only requires a once-per-season prevention approach, and that means these children's care regimen can be simplified."

Although the study supports the safety of clesrovimab during a second RSV season in children who remain at increased risk, the authors acknowledged that the trial did not include a comparator group during the second season and was not powered to demonstrate noninferiority for efficacy outcomes.

Reference

Zar HJ, Bont L, Manzoni P, et al; SMART (MK-1654-007) Study Group. Clesrovimab in infants at increased risk for severe disease during 2 RSV seasons: a randomized clinical trial. JAMA Pediatrics. Published online July 20, 2026. doi:10.1001/jamapediatrics.2026.2760.