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

Abstract 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.