Population Pharmacokinetics and Pharmacodynamics of Depemokimab in People with Asthma and Chronic Rhinosinusitis with Nasal Polyps

Abstract Depemokimab is the first ultra‐long‐acting biologic with enhanced interleukin‐5 (IL‐5) binding affinity, high potency, and extended half‐life, enabling twice‐yearly dosing. Depemokimab has demonstrated efficacy and safety in patients with asthma and chronic rhinosinusitis with nasal polyps. These analyses aimed to characterize the pharmacokinetic/pharmacodynamic (PK/PD) profile of depemokimab. Data from three Phase I studies (NCT03287310/NCT05140200/NCT05602025) and four Phase III studies (SWIFT‐1/‐2: NCT04719832/NCT04718103; ANCHOR‐1/‐2: NCT05274750/NCT05281523) were used to develop a PK model for depemokimab and PK/PD model for blood eosinophil count (BEC) reduction, a key biomarker of type 2 inflammation. Participants received subcutaneous depemokimab or placebo (one dose in Phase I [2‐300 mg in NCT03287310; 100 mg or 300 mg in NCT05140200/NCT05602025] and two 100 mg doses in Phase III) and ≥1 post‐first‐dose PK/PD (BEC) observation. PK analysis included 961 participants and PK/PD analysis included 1324 participants. Predicted geometric mean half‐life was 47 days, with negligible accumulation in PK. Depemokimab 100 mg rapidly reduced BEC to <25% of baseline, with a small increase observed at the end of the 26‐week dosing interval. No clinically relevant covariates were identified for either model. All participants had trough depemokimab concentrations above the half maximal effective concentration (EC 50 ) at the end of the dosing interval (90% above the EC 90 level). PK/PD modeling showed that single‐dose depemokimab 100 mg provides durable BEC reduction throughout a 26‐week dosing interval, suggesting sustained suppression of IL‐5 activity. These data support twice‐yearly recommended dosing for depemokimab 100 mg, with no dose adjustments required based on intrinsic or extrinsic factors.