Dose Optimization of BIIB107, an Anti-Alpha-4 Integrin Monoclonal Antibody, Through Population Pharmacokinetic and Pharmacodynamic Modeling.

BIIB107 is a recombinant, humanized monoclonal antibody targeting α4 integrin receptors, exhibiting a high binding affinity and strong receptor engagement potential in preclinical models, designed to prevent lymphocyte trafficking in multiple sclerosis (MS). This study aimed to characterize its pharmacokinetics (PK) and pharmacokinetic-pharmacodynamic (PK-PD) relationship using model-based approaches to inform dose optimization. A Phase 1 study (NCT04593121) was conducted in 76 healthy volunteers who received single ascending doses intravenously or subcutaneously (SC), along with multiple ascending doses SC. Population PK and PK-PD models were developed to quantify BIIB107 disposition and its effect on α4 integrin receptor saturation. A sigmoidal Emax model was used to characterize the concentration-effect relationship, and Monte Carlo simulations assessed dosing strategies for sustained α4 integrin engagement. BIIB107 exhibited nonlinear, target-mediated clearance, best described by a two-compartment model with first-order absorption and Michaelis-Menten elimination. Body weight was included in the model using allometric scaling on clearance and volume of distribution-related parameters. In a 70-kg subject, key PK parameters included clearance, 7.28 mL/h; central and peripheral compartment Vd, 3.01 and 1.18 L; terminal half-life 19.3 days; and SC bioavailability 73.8%. PK-PD analysis demonstrated dose-dependent α4 integrin saturation, with an EC50 of 0.376 µg/mL. Simulations showed that 450 mg SC every 8 weeks maintained sustained α4 integrin saturation ≥70%, the therapeutic threshold for efficacy, supporting this regimen for investigation in MS patients. These findings emphasize the value of model-informed drug development in optimizing therapeutic monoclonal antibody doses and support BIIB107's further clinical advancement.