Clesrovimab Shows Significant Reduction in RSV Infections, Hospitalizations in Infants

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The results of the Phase IIb/III MK-1654-004 trial (NCT04767373) show that clesrovimab (Merck) produced a significant reduction in respiratory syncytial virus (RSV)-related infections and hospitalizations in infants, along with a favorable safety profile.^1,2 These data, presented at IDWeek 2024 along with interim results from the Phase III MK-1654-007 trial (NCT04938830)3, suggest the potential of the investigational extended half-life monoclonal antibody as a single-dose preventive treatment for RSV in healthy and at-risk infants, according to trial investigators.

“RSV continues to be a widespread seasonal infection that can affect both healthy and at-risk infants and is the leading cause of hospitalization for infants,” trial investigator Octavio Ramilo, MD, chair of the Department of Infectious Diseases at St. Jude’s Children’s Research Hospital, said in a press release. “The MK-1654-004 study evaluated a broad spectrum of RSV disease ranging from mild outpatient illness to severe disease requiring hospitalization. These promising results demonstrating decreased incidence of RSV disease, including hospitalizations, highlight the potential for clesrovimab to play an important role in helping to alleviate the continued burden of RSV on infants and their families.”¹

Premature infants, specifically those with chronic lung disease related to premature birth or congenital heart disease, have the greatest risk for severe RSV. Approximately 1% to 3% of children under 12 months of age are hospitalized each year due to RSV, according to data from the American Academy of Pediatrics.⁴

The development of new treatments is vital given the shortages of RSV vaccine Beyfortus (nirsevimab-alip) that plagued Sanofi and manufacturing partner AstraZeneca during the 2023–2024 RSV season. In October 2023, Sanofi announced that an unprecedented demand for Beyfortus led to a limited supply during the 2023–2024 RSV season, which prompted the CDC to issue a set of recommendations to address the shortages.^5,6

From the week of September 2, 2023, to the week of October 28, 2023, weekly RSV hospitalizations increased from 0.2 per 100,000 individuals to 1.3 per 100,000 individuals. The 2022–23 RSV season produced the highest cumulative hospitalization rates on record at 52.8 individuals per 100,000 over the 39-week season compared to 28.1 per 100,000 recorded in the 2021–22 season.⁷

Clesrovimab was designed as a passive immunization to prevent RSV and is under evaluation for healthy preterm, full-term, and at-risk infants to protect against mild, moderate, and severe RSV through their first season.

The Phase IIb/III double-blind, randomized, placebo-controlled MK-1654-004 trial analyzed the safety and efficacy of clesrovimab in healthy preterm and full-term infants from birth to one year of age entering their first RSV season. The study randomly assigned 3,632 participants in a 2:1 ratio to receive a single fixed dose of clesrovimab 105 mg via intramuscular injection on day one compared with placebo. The trial’s primary endpoints included safety and incidence of RSV-associated medically attended lower respiratory infection (MALRI) from day one to day 150 vs. placebo.

Clesrovimab achieved all of the trial’s prespecified endpoints, demonstrating consistent results across the five- and six-month time points, according to the trial investigators. Incidence of RSV-associated MALRI requiring ≥ 1 indicator of lower respiratory infection (LRI) or severity for clesrovimab vs. placebo through five months postdose was 60.4% (95% CI: 44.1, 71.9, p<0.001).

Clesrovimab reduced RSV-associated hospitalizations by 84.2% (95% CI: 66.6, 92.6, p<0.001) vs. placebo through five months and lowered RSV-associated LRI hospitalizations through five months by 90.9% (95% CI: 76.2, 96.5) vs. placebo. Further, clesrovimab lowered incidence of severe MALRI by 91.7% (95% CI: 62.9, 98.1). In terms of safety, adverse events (AEs) and serious AEs were comparable between the clesrovimab and placebo cohorts, with no treatment or RSV-related deaths reported.

The multicenter, randomized, partially blinded, controlled MK-1654-007 trial compared the safety, efficacy, and pharmacokinetics of clesrovimab vs. palivizumab in infants and children with an elevated risk for severe RSV disease entering their first RSV season. Participants were randomly assigned in a 1:1 ratio to receive clesrovimab or monthly palivizumab in their first season, while eligible participants were administered clesrovimab in their second RSV season.

At the time of the interim analysis, investigators enrolled 901 participants in the trial. The primary endpoint of MK-1654-007 is the safety and tolerability of clesrovimab compared with palivizumab in their first RSV season, with secondary endpoints that include incidence of RSV-associated MALRI that required ≥1 indicator of LRI or severity, and RSV-associated hospitalizations through day 150.

Interim data demonstrated that clesrovimab has a comparable safety profile to palivizumab, with no drug-related serious AEs reported at the time of the analysis. Incidence rates of RSV-associated MALRI requiring ≥ 1 indicator of LRI or severity were 3.6% in the clesrovimab cohort compared to 1.3%, in the palivizumab cohort and RSV-associated hospitalizations were 3.0% in the clesrovimab cohort compared to 1.5% in the palivizumab cohort through five months.

“The breadth of data presented at IDWeek highlight the potential for clesrovimab to help lessen the significant impact RSV can have on infants and their families, as well as the strain on healthcare systems due to high infection and hospitalization rates,” said Paula Annunziato, MD, senior vice president, infectious diseases and vaccines, Global Clinical Development, Merck Research Laboratories, said in a press release. “These clinically meaningful findings also reinforce the potential for clesrovimab to be the first and only immunization designed to protect both healthy and at-risk infants using the same dose, regardless of weight. We look forward to continuing to discuss these data with health authorities around the world with the goal of making clesrovimab available for infants as early as the 2025-26 RSV season.”¹

References

1. Merck’s Clesrovimab (MK-1654), an Investigational Respiratory Syncytial Virus (RSV) Preventative Monoclonal Antibody, Significantly Reduced Incidence of RSV Disease and Hospitalization in Healthy Preterm and Full-term Infants. News release. Merck. October 17, 2024. Accessed October 18, 2024. https://www.merck.com/news/mercks-clesrovimab-mk-1654-an-investigational-respiratory-syncytial-virus-rsv-preventative-monoclonal-antibody-significantly-reduced-incidence-of-rsv-disease-and-hospitalization-in-heal/

2. Efficacy and Safety of Clesrovimab (MK-1654) in Infants (MK-1654-004). ClinicalTrials.gov. Updated July 16, 2024. Accessed October 18, 2024. https://clinicaltrials.gov/study/NCT04767373

3. Clesrovimab (MK-1654) in Infants and Children at Increased Risk for Severe Respiratory Syncytial Virus (RSV) Disease (MK-1654-007). ClinicalTrials.gov. Updated October 15, 2024. Accessed October 18, 2024. https://clinicaltrials.gov/study/NCT04938830?intr=Clesrovimab&rank=3

4. FDA Approves New Drug to Prevent RSV in Babies and Toddlers. News release. FDA. July 17, 2023. Accessed October 18, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-prevent-rsv-babies-and-toddlers

5. Limited Availability of Nirsevimab in the United States—Interim CDC Recommendations to Protect Infants from Respiratory Syncytial Virus (RSV) during the 2023–2024 Respiratory Virus Season. US Centers for Disease Control and Prevention. News release. October 24, 2023. Accessed October 18, 2024. https://emergency.cdc.gov/han/2023/han00499.asp

6. Sanofi Beyfortus Statement. Sanofi. News release. October 24, 2023. Accessed October 18, 2024. https://www.news.sanofi.us/Sanofi-Beyfortus-Statement

7. What is the state of RSV in the United States? USA Facts. Website. December 5, 2023. Accessed October 18, 2024. https://usafacts.org/articles/what-is-the-state-of-rsv-in-the-united-states/