The U.S. Food and Drug Administration has approved Merck's ENFLONSIA (clesrovimab-cfor), a preventive monoclonal antibody designed to protect infants against respiratory syncytial virus (RSV) lower respiratory tract disease. The approval marks a significant advancement in RSV prevention, as ENFLONSIA becomes the first and only RSV preventive option administered using the same dose regardless of infant weight.
ENFLONSIA is indicated for neonates and infants who are born during or entering their first RSV season. The long-acting monoclonal antibody is designed to provide direct, rapid and durable protection through 5 months, spanning a typical RSV season from autumn to spring.
"RSV disease is the leading cause of infant hospitalization in the U.S. and can lead to serious respiratory conditions like bronchiolitis and pneumonia," said Dr. Octavio Ramilo, chair of the Department of Infectious Diseases at St. Jude Children's Research Hospital and investigator for the CLEVER and SMART trials. "ENFLONSIA combines dosing convenience with strong clinical data showing significant reductions in RSV disease incidence and hospitalizations, making it a promising new intervention to help protect infants from RSV."
Pivotal Trial Results Demonstrate Strong Efficacy
The FDA approval is based on results from the pivotal Phase 2b/3 CLEVER trial (MK-1654-004), which evaluated a single 105 mg dose of ENFLONSIA administered to preterm and full-term infants from birth to 1 year of age. The randomized, double-blind, placebo-controlled trial enrolled 3,614 participants, with 2,411 receiving ENFLONSIA and 1,203 receiving saline placebo.
The trial met both its primary and key secondary endpoints with statistically significant results. ENFLONSIA demonstrated a 60.5% reduction in the incidence of RSV-associated medically attended lower respiratory infections (MALRI) requiring at least one indicator of lower respiratory infection or severity compared to placebo through 5 months (95% CI: 44.2, 72.0, p<0.001). The incidence rates were 0.026 for ENFLONSIA versus 0.065 for placebo.
For the key secondary endpoint, ENFLONSIA showed an 84.3% reduction in RSV-associated hospitalizations through 5 months (95% CI: 66.7, 92.6, p<0.001), with incidence rates of 0.004 for ENFLONSIA compared to 0.024 for placebo. The data revealed increasing efficacy with increasing disease severity.
Safety Profile Comparable to Placebo
The safety profile of ENFLONSIA in the CLEVER trial was generally comparable to placebo. The most common adverse reactions were injection-site erythema occurring within 5 days post-dose (ENFLONSIA: 3.8%; placebo: 3.3%), injection-site swelling within 5 days post-dose (ENFLONSIA: 2.7%; placebo: 2.6%), and rash within 14 days post-dose (ENFLONSIA: 2.3%; placebo: 1.9%). Most adverse reactions (≥97%) were toxicity grade 1 (mild) or grade 2 (moderate).
The approval is also supported by results from the Phase 3 SMART trial (MK-1654-007), which evaluated ENFLONSIA versus palivizumab in 896 infants at increased risk for severe RSV disease. The trial demonstrated that ENFLONSIA's safety profile was generally comparable to palivizumab and consistent with the CLEVER trial results.
Unique Dosing Approach and Administration
ENFLONSIA represents a significant advancement in RSV prevention through its weight-independent dosing approach. The therapy uses a single 105 mg dose administered by intramuscular injection, regardless of infant weight. For infants born during RSV season, ENFLONSIA should be administered starting from birth. For those born outside RSV season, administration should occur prior to their first RSV season.
For infants undergoing cardiac surgery with cardiopulmonary bypass during or entering their first RSV season, an additional 105 mg dose is recommended as soon as the infant is stable after surgery.
Market Availability and CDC Recommendations
"ENFLONSIA provides an important new preventive option to help protect healthy and at-risk infants born during or entering their first RSV season with the same dose regardless of weight," said Dr. Dean Y. Li, president, Merck Research Laboratories. "We are committed to ensuring availability of ENFLONSIA in the U.S. before the start of the upcoming RSV season to help reduce the significant burden of this widespread seasonal infection on families and health care systems."
The CDC's Advisory Committee on Immunization Practices is expected to meet later this month to discuss and make recommendations for ENFLONSIA use in infants. Ordering is anticipated to begin in July, with shipments delivered before the start of the 2025-2026 RSV season.
Contraindications and Safety Considerations
ENFLONSIA should not be administered to infants with a history of serious hypersensitivity reactions, including anaphylaxis, to any component of the therapy. Healthcare providers should be aware that serious hypersensitivity reactions, including anaphylaxis, have been observed with other human immunoglobulin G1 monoclonal antibodies. If signs or symptoms of clinically significant hypersensitivity reactions occur, appropriate medications and supportive therapy should be initiated immediately.
Clinical trials demonstrated that when ENFLONSIA was administered concomitantly with routine childhood vaccines, the safety profile of the co-administered regimen was generally comparable to when ENFLONSIA and childhood vaccines were given alone.
