The preclinical discovery and development of depemokimab for severe eosinophilic asthma

Severe eosinophilic asthma is driven by interleukin (IL)-5-mediated type 2 inflammation and frequently requires long-term biologic therapy. Depemokimab was designed to achieve sustained IL-5 neutralization with a twice-yearly dosing schedule, addressing key unmet needs related to treatment burden and adherence. This review summarizes the molecular design, preclinical pharmacology, model-informed drug development (MIDD) strategy, Phase I-III clinical trial program, and regulatory approvals of depemokimab in asthma and chronic rhinosinusitis with nasal polyps. Depemokimab exemplifies how rational antibody engineering, including Fc modification and high-affinity IL-5 binding, can enable sustained pharmacodynamic activity and ultra-long-acting cytokine inhibition. A twice-yearly dosing regimen may offer advantages in terms of treatment adherence, patient convenience, and long-term disease control. The application of MIDD approaches facilitated efficient clinical development and supported the progression of pivotal trials, potentially shortening development timelines by approximately two to three years. Although efficacy and safety data are encouraging, longer-term real-world evidence will be necessary to better define immunogenicity, rare adverse events, and adherence patterns. Comparative effectiveness studies of depemokimab versus other approved anti-IL-5 therapies and type 2-targeted biologics will be critical to establish its relative clinical value. Further investigation into additional eosinophilic diseases, pediatric populations, and diverse healthcare settings may expand its therapeutic utility, positioning depemokimab as a representative example of next-generation long-acting biologics that target cytokine-mediated inflammatory diseases.