Merck Shares Encouraging Second-Season Data for Enflonsia in High-Risk Children Facing RSV

Merck — known as MSD outside the United States and Canada — has announced positive new findings from the Phase 3 SMART trial evaluating its RSV preventive therapy, Enflonsia (clesrovimab). The data were presented during an oral session at RSVVW’26, the 9th conference of the Respiratory Syncytial Virus Foundation in Rome, Italy.

The new results focus on children under 2 years of age who remain at increased risk for severe respiratory syncytial virus (RSV) disease as they enter their second RSV season — a particularly vulnerable group that often includes children with chronic lung disease (CLD) or congenital heart disease (CHD).

Why RSV Protection Matters Beyond the First Season?

RSV is one of the leading causes of infant hospitalization worldwide. While all infants are susceptible, the risks are significantly higher for babies born prematurely or those with underlying medical conditions. Many of these children face continued vulnerability even after their first RSV season.

The Phase 3 SMART trial (MK-1654-007) evaluated the safety, efficacy, and pharmacokinetics of Enflonsia across two RSV seasons. Earlier interim results from Season 1 helped support FDA approval of Enflonsia in June 2025 for use in newborns and infants entering their first RSV season.

Now, second-season data suggest the therapy may extend protection to children who remain at high risk beyond infancy.

What the Second-Season Data Showed?

Children eligible for RSV Season 2 in the SMART study received an open-label 210 mg dose of Enflonsia (administered as two 105 mg injections). Nearly all of these participants had chronic lung disease or congenital heart disease.

Key findings include:

• Safety profile remained consistent with what was observed in the first RSV season.
• The most commonly reported side effects within five days of dosing were mild and included:
  • Irritability (13.0%)
  • Somnolence (8.7%)
  • Decreased appetite (6.9%)
  • Injection site pain (4.3%)
  • Fever (1.1%)
• No drug-related serious adverse events (SAEs) were reported.

Importantly, antibody levels achieved in these higher-risk toddlers were comparable to levels seen in healthy infants in the earlier Phase 2b/3 CLEVER trial (MK-1654-004). This supports the scientific rationale for extending efficacy to children entering their second RSV season.

Among children who received Enflonsia in Season 2:

• RSV-associated medically attended lower respiratory infection (MALRI) occurred in 7.3% of participants.
• RSV-related hospitalizations were reported in 3.0%.

Researchers noted that these rates reflect the children’s higher baseline risk and the ongoing RSV burden seen in the post-COVID pandemic era.

How Enflonsia Works?

Enflonsia is a long-acting monoclonal antibody designed to provide passive immunization against RSV lower respiratory tract disease. Unlike vaccines that stimulate the immune system to produce antibodies, monoclonal antibodies provide direct, immediate protection.

The therapy:

• Is administered as a single fixed dose (105 mg/0.7 mL prefilled syringe) regardless of infant weight.
• Is designed to protect for approximately five months, covering a typical RSV season.
• Has a 30-month shelf life, offering practical advantages for health systems.

For infants born during RSV season, dosing is recommended within the first week of life. Those born outside the season should receive it shortly before RSV activity begins. An additional dose may be given following cardiac surgery with cardiopulmonary bypass.

Expert Perspective

Dr. Paolo Manzoni, an investigator in the SMART trial and Head of Maternal–Infant Medicine at the University of Torino Hospital Degli Infermi in Italy, emphasized that nearly all children who received Enflonsia in their second RSV season had serious underlying conditions.

“These new findings from SMART demonstrate the potential of Enflonsia to help protect these vulnerable children, who may require an additional dose for their second RSV season,” he noted.

Dr. Macaya Douoguih, vice president and therapeutic area head of global clinical development at Merck Research Laboratories, added that the company aims to expand access globally for eligible infants and high-risk children.

What Comes Next?

Merck plans to share the second-season data with the U.S. Food and Drug Administration and other global regulatory authorities as it seeks an expanded indication for children who remain at high risk during their second RSV season.

Currently, Enflonsia is approved in the United States, Canada, and several other countries for infants entering their first RSV season, with additional regulatory filings underway worldwide.

The Bigger Picture

RSV continues to pose a significant global health challenge, particularly for infants and toddlers with prematurity, chronic lung disease, or congenital heart disease. While preventive options have expanded in recent years, there remains a meaningful unmet need for therapies that protect both healthy infants and high-risk children beyond their first RSV season.

With these new SMART trial findings, Enflonsia may represent an important step forward in extending protection to some of the most medically vulnerable young children.

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