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. 2025 Jun 30:157:107995.
doi: 10.1016/j.cct.2025.107995. Online ahead of print.

Evaluation of a monoclonal antibody against respiratory syncytial virus, clesrovimab, in infants and children: Comprehensive rationale and study design for the late-stage clinical trials

Anushua Sinha  1 , Radha A Railkar  2 , Luis Castagnini  2 , Andrea Guerra  2 , Andrea Likos  2 , Jeannine Lutkiewicz  2 , Brian M Maas  2 , Xiaowei Zang  2 , Brad A Roadcap  2 , Yoonyoung Choi  2 , Georges J Nahhas  2 , Carmen S Arriola  2 , Louis Bont  3 , Paolo Manzoni  4 , Octavio Ramilo  5 , Flor M Muñoz  6 , Lyn Finelli  2 , Andrew W Lee  2
Affiliations

Evaluation of a monoclonal antibody against respiratory syncytial virus, clesrovimab, in infants and children: Comprehensive rationale and study design for the late-stage clinical trials

Anushua Sinha et al. Contemp Clin Trials. .

Abstract

Background: Respiratory syncytial virus (RSV) is a leading cause of infant morbidity and mortality. Clesrovimab is a half-life-extended, RSV neutralizing monoclonal antibody for the prevention of RSV disease in infants. This article describes the methodology that enabled the acceleration of two pivotal late-stage clinical trials, CLEVER (MK-1654-004; NCT04767373) and SMART (MK-1654-007; NCT04938830), for the evaluation of clesrovimab.

Methods: CLEVER is a placebo-controlled phase 2b/3 study in healthy preterm and full-term infants, evaluating the efficacy and safety of clesrovimab for the prevention of RSV-associated medically attended lower respiratory tract infection (RSV-MALRI) and RSV-associated hospitalization. SMART is a phase 3 palivizumab-controlled study evaluating the safety, tolerability, and efficacy of clesrovimab, compared with palivizumab, for the prevention of RSV-associated MALRI and RSV-associated hospitalization in infants and children at increased risk of severe RSV disease. Dose selection in these studies was informed using a model-based meta-analysis of phase 1 and 2 clesrovimab trial data. Program acceleration was enabled by designing CLEVER seamlessly, to rapidly progress from phase 2b to phase 3. Additionally, efficacy was extrapolated to the SMART population, based on pharmacokinetic bridging between CLEVER and SMART.

Conclusion: The methodology of the accelerated late-stage development of clesrovimab, including the model-informed dose selection approach, the seamless enrollment in the phase 3 portion of CLEVER, and the extrapolation of efficacy from the population in CLEVER to the population in SMART, may be used to inform future trial designs where acceleration is needed to address an unmet medical need.

Keywords: Drug development; Modeling; Monoclonal antibody; Pediatrics; Respiratory infections; Respiratory syncytial virus.

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Conflict of interest statement

Declaration of competing interest AS, RAR, LC, AG, AL, JL, BMM, XZ, BAR, YC, GJN, CSA, LF, and AWL are/were employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may hold stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. LB is an employee of University Medical Center, Utrecht (UMCU). UMCU has received major funding from AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics, and minor funding for consultation, Data and Safety Monitoring Board membership or invited lectures by Ablynx, Bavarian Nordic, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, and Janssen. PM has received consultation, Data and Safety Monitoring Board membership or invited lectures fees from Pfizer, MSD, Sanofi, Moderna, Enanta, GSK, and AstraZeneca, and research grants from the Italian Drug Agency (AIFA). OR has received research grants from the National Institutes of Health, Bill & Melinda Gates Foundation, MSD, and Janssen Pharmaceuticals; fees for participation in advisory boards from MSD, Sanofi, Moderna, and Pfizer; and fees for educational lectures from Pfizer, AstraZeneca, Merck, and Sanofi. FMM has received advisory and consultation fees and served in Data Safety Monitoring Boards from MSD, Moderna, Pfizer, Sanofi, and AstraZeneca.

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