Phase II Dose Selection for Alpha Synuclein–Targeting Antibody Cinpanemab (BIIB054) Based on Target Protein Binding Levels in the Brain

Abstract

This modeling and simulation analysis was aimed at selecting doses of cinpanemab (BIIB054), a monoclonal antibody targeting aggregated α-synuclein, for a phase II study in Parkinson’s disease (PD). Doses and regimens were proposed based on anticipated target concentration in brain interstitial fluid (ISF); in vitro/in vivo data on the affinity of monoclonal antibodies to the target protein; and safety, tolerability, and pharmacokinetic data (1–135 mg/kg intravenous administration) from a phase I single ascending dose (SAD) study. A population pharmacokinetic modeling approach was used to select intravenous doses of 250, 1,250, and 3,500 mg every 4 weeks, to maintain 50%, 90%, and > 90% of target binding in ISF of PD participants. A favorable safety profile from the SAD study—which showed that cinpanemab was generally well-tolerated at doses up to 90 mg/kg, supported by modeling and simulations of the anticipated safety margins—allowed implementation of a fixed-dose approach.