Assoc Scientific Director, Clinical Pharmacology Biogen, United States
Objectives: BIIB107 is a recombinant, humanized monoclonal antibody targeting α4 integrin, a key mediator of lymphocyte trafficking across the blood-brain barrier in multiple sclerosis (MS)1. The objective of this analysis was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of BIIB107 using population-based modeling and to identify a subcutaneous (SC) dosing regimen that ensures sustained receptor engagement for future evaluation in MS patients.
Methods: Data were collected from a Phase 1, first-in-human (FIH) study (NCT04593121) in 76 healthy volunteers receiving single ascending doses (SAD) or multiple ascending doses (MAD) of BIIB107 administered intravenously or subcutaneously. A population PK model was built using NONMEM, employing a two-compartment structure with first-order absorption and Michaelis-Menten elimination to describe target-mediated drug disposition2. Covariate effects, including body weight, were explored using stepwise model selection3. PD was modeled with a sigmoidal Emax function linking BIIB107 concentration to α4 integrin saturation, a validated surrogate for efficacy1,4. Monte Carlo simulations tested fixed and weight-based SC dosing regimens for their ability to maintain ≥70% α4 saturation, the efficacy threshold derived from natalizumab experience4.
Results: The final PK model adequately captured BIIB107 disposition. For a 70-kg subject, clearance was 7.28 mL/h, with central and peripheral volumes of 3.01 and 1.18 L, respectively. Terminal half-life was 19.3 days, and SC bioavailability was 73.8%. Body weight was the only significant covariate affecting PK. The PD model yielded an EC50 of 0.382 µg/mL and a maximum receptor saturation of 83.8%, with no additional covariate effects. Simulations demonstrated that a 450 mg SC dose every 8 weeks maintained sustained α4 integrin saturation above 70%, with 360 mg and 600 mg Q8W included for dose-ranging5. Flat dosing showed equivalent exposure and PD profiles to a weight-based regimen (4.5 mg/kg), simplifying clinical implementation6.
Conclusions: BIIB107 exhibits nonlinear PK consistent with target-mediated monoclonal antibody clearance and a strong concentration-saturation relationship for α4 integrin. PK-PD modeling supports 450 mg SC Q8W as the optimal regimen balancing efficacy and convenience. Compared to natalizumab, BIIB107 may enable a less frequent SC regimen with similar or superior receptor engagement4,7. These findings illustrate the value of model-informed drug development in optimizing biologic dosing strategies.
Citations: 1. Hartung HP et al., Neurology. 1995;45: S22–S32. 2. Ryman JT, Meibohm B. CPT Pharmacometrics Syst Pharmacol. 2017;6(9):576–588. 3. Jonsson EN, Karlsson MO. Pharm Res. 1998;15(9):1463–1468. 4. Muralidharan KK et al., J Clin Pharmacol. 2017;57(8):1017–1030. 5. Gabrielsson J, Weiner D. Pharmacokinetic and Pharmacodynamic Data Analysis. 4th ed. 2007. 6. Dirks NL, Meibohm B. Clin Pharmacokinet. 2010;49(10):633–659. 7. Polman CH et al., N Engl J Med. 2006;354(9):899–910.
Keywords: Pharmacokinetics/pharmacodynamics, alpha-4 integrin, population modeling
