Merck reports positive Phase III SMART data for Enflonsia in second RSV season

Edited by Robert McTiernan··3 min read

Merck & Co., (NYSE: MRK) announced positive second-season findings from the global Phase III SMART study evaluating Enflonsia (clesrovimab) in infants and children at increased risk for severe respiratory syncytial virus (RSV) disease. The preventive, long-acting monoclonal antibody targeting the RSV F protein met key trial criteria by achieving serum concentrations over a second RSV season similar to those seen in healthy infants in a previous pivotal trial, supporting efficacy extrapolation for this vulnerable group.

Trial specifics

The Phase III SMART trial (MK-1654-007) was a randomized, partially blind, palivizumab-controlled study evaluating the safety, efficacy, and pharmacokinetics of Enflonsia. The patient population included early or moderate preterm infants, as well as infants with chronic lung disease of prematurity or congenital heart disease. During the first RSV season, participants were randomized to receive either a single 105 mg dose of Enflonsia or monthly palivizumab via intramuscular injection. In the second season, eligible children under two years of age remaining at increased risk received an additional open-label 210 mg dose of Enflonsia, administered as two 105 mg injections.

The trial measured monoclonal antibody serum concentrations as a secondary endpoint, demonstrating that levels achieved in children during their second RSV season were similar to those in healthy infants from the Phase IIb/III CLEVER study. Through Day 180 of the second season, the incidence rates for RSV-associated medically attended lower respiratory infection and RSV-associated hospitalization among the treated children were 7.3% and 3.0%, respectively. The company reported that safety was generally consistent with observations from the first season, with no drug-related serious adverse events. Solicited adverse events reported within five days post-dose included irritability (13.0%), somnolence (8.7%), and decreased appetite (6.9%).

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The company said it plans to share the second-season results with the US FDA and global regulatory authorities to evaluate an expanded indication for children at increased risk for severe RSV disease through their second RSV season. Executives noted that the data position Enflonsia as an important potential option to protect young children remaining at high risk, and regulatory filings to broaden access are currently underway globally.

Enflonsia is an extended half-life monoclonal antibody engineered to provide direct, passive immunization against RSV by binding to the viral fusion (F) protein. By targeting this mechanism, the antibody prevents the virus from entering host cells, offering rapid and durable protection across a typical five-month RSV season without relying on an active infant immune response. This approach is highly relevant to disease biology, as infants often lack robust immune defenses against RSV, which frequently leads to severe bronchiolitis and pneumonia. Enflonsia was approved by the US FDA in 2025 for the prevention of RSV lower respiratory tract disease in newborns and infants entering their first RSV season, utilizing a single 105 mg dose regardless of patient weight.

The pediatric RSV prevention landscape features multiple established products aimed at reducing severe lower respiratory tract disease. Key competitors include:

  • Sanofi and AstraZeneca’s Beyfortus (nirsevimab), a long-acting monoclonal antibody also directed against the RSV F protein, is widely approved for the prevention of RSV lower respiratory tract disease in neonates and infants during their first RSV season, as well as for vulnerable children up to 24 months of age entering their second season. While Beyfortus and Enflonsia share a similar mechanism of action, Beyfortus relies on weight-based dosing (50 mg or 100 mg) for infants in their first season, whereas Enflonsia employs a universal single dose.
  • Pfizer’s Abrysvo, a bivalent RSV prefusion F vaccine approved for administration to pregnant individuals at 32 to 36 weeks of gestation. This active immunization strategy aims to protect infants from birth through six months of age via the transplacental transfer of maternal antibodies, offering an alternative systemic approach to direct infant monoclonal antibody administration.