Background: Pathologically, AD is defined by the presence of extracellular neuritic plaques containing amyloid beta (Aβ) and intracellular neurofibrillary tangles. The leading hypothesis proposes that the driving force behind the disease process is the abnormal accumulation of Aβ resulting from an imbalance between Aβ production and Aβ clearance in the brain. Thus targeting fibrillar amyloid is expected to reduce A β accumulation and attenuate the course of AD. BIIB037 is a unique, fully human monoclonal antibody that is highly selective for fibrillar beta amyloid and preferentially targets parenchymal plaques over vascular forms. The purpose of the present study was to characterize the pharmacokinetics of BIIB037 in mild to moderate AD patients in a single dose-escalation trial. Methods: Seven cohorts each consisting of 8 patients with mild to moderate AD randomized 3:1 to BIIB037 or placebo were evaluated. BIIB037 doses were 0.3, 1.0, 3.0, 10.0, 20.0, 30.0 and 60 mg/kg. Eligible patients were between 55-85 years old, met NINCDS-ADRDA criteria for probable AD, and had a MMSE between 14-26. Serial blood samples were collected for up to 24 weeks post-dose and serum concentrations determined by ELISA. Pharmacokinetics were estimated by best fit two-compartment model. Results: A total of 48 patients have thus far completed the study and were included in the PK analysis. Dosing of the 60 mg/kg cohort is on-going. BIIB037 exposures (AUC inf) were linear throughout the dosage range. The mean serum half-life was approximately 18 days and was consistent between 1 mg/kg and 30 mg/kg doses. The coefficient of variance for both AUC inf and serum half-life was generally less than 30%. Conclusions: BIIB037 demonstrates predictable pharmacokinetics including dose-dependent exposure linearity and low variability.
Ferrero, J., Stella, H., Leitermann, K., Mikulskis, A., Song, T., & Sevigny, J. (2013). P1-348: Pharmacokinetics of BIIB037 in people with mild-to-moderate Alzheimer’s disease (AD) participating in a phase 1 dose-escalation trial. Alzheimer’s & Dementia, 9, P285–P285. https://doi.org/10.1016/j.jalz.2013.05.574