Pulmonology · Medical Literature
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 (EC50) at the end of the dosing interval (90% above the EC90 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.
Clinical relevance
Depemokimab represents a novel ultra-long-acting anti-IL-5 biologic with enhanced receptor binding affinity that enables twice-yearly subcutaneous dosing — a significant departure from existing monthly or bimonthly biologics in type 2 inflammatory disease. This population PK/PD analysis, drawing from seven Phase I and Phase III trials (including SWIFT-1/-2 for asthma and ANCHOR-1/-2 for CRSwNP), addresses the critical clinical need to understand whether a 26-week dosing interval provides sustained pharmacological suppression of eosinophilic inflammation. Pulmonologists and rhinologists managing severe eosinophilic asthma and CRSwNP should attend to these data as they directly inform dosing confidence, patient selection, and the absence of need for dose individualization.
Key findings
1. Predicted geometric mean half-life of depemokimab was 47 days, conferring an extended pharmacokinetic profile consistent with its twice-yearly dosing design and resulting in negligible drug accumulation across dosing intervals. 2. A single subcutaneous dose of depemokimab 100 mg rapidly suppressed blood eosinophil count (BEC) to less than 25% of baseline, confirming rapid and potent IL-5 pathway inhibition early in the dosing cycle. 3. All participants maintained trough depemokimab concentrations above the EC50 at the end of the 26-week dosing interval, with 90% of participants sustaining concentrations above the EC90 level — indicating near-maximal pharmacodynamic coverage throughout the full dosing interval. 4. A small, clinically contextualized rise in BEC was observed toward the end of the 26-week dosing interval, though concentrations remained above EC90 in 90% of patients, suggesting this rebound is unlikely to be clinically meaningful for the majority of treated individuals. 5. Population PK/PD modeling was conducted across 961 participants (PK) and 1,324 participants (PK/PD), drawn from three Phase I and four Phase III studies across two indications (asthma and CRSwNP), providing a robust and generalizable dataset. 6. No clinically relevant covariates — intrinsic (e.g., age, weight, renal/hepatic function) or extrinsic (e.g., concomitant medications) — were identified as significantly affecting either the PK or PK/PD model, supporting a universal fixed-dose strategy without individualized adjustment.
Practice implications
Clinicians can prescribe depemokimab 100 mg subcutaneously every 26 weeks (twice yearly) without dose adjustment based on patient-specific factors such as body weight, age, organ function, or concomitant therapies, as no clinically relevant covariates were identified in this large population PK/PD analysis. The demonstration that trough concentrations exceed EC90 in 90% of patients at the end of the dosing interval provides pharmacodynamic justification for the 6-month interval and should reinforce adherence counseling — patients and providers can be reassured that eosinophil suppression is sustained well beyond the midpoint of the dosing cycle. For patients with severe eosinophilic asthma or CRSwNP who struggle with adherence to monthly biologic regimens, depemokimab's twice-yearly schedule represents a clinically meaningful option, with BEC serving as an accessible biomarker to confirm pharmacodynamic response if needed.