First-in-human, double-blind, placebo-controlled, single-dose...

First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer's disease

James Ferrero, et al.
Abstract

Introduction
Aducanumab (BIIB037), a human monoclonal antibody selective for aggregated forms of amyloid beta, is being investigated as a disease-modifying treatment for Alzheimer's disease (AD).
Methods

This randomized, double-blind, placebo-controlled single ascending-dose study investigated the safety, tolerability, and pharmacokinetics (PK) of aducanumab in patients with mild-to-moderate AD. Eligible patients were sequentially randomized 6:2 to aducanumab (0.3, 1, 3, 10, 20, 30, and 60 mg/kg) or placebo.
Results

The primary outcome was safety and tolerability. Doses ≤30 mg/kg were generally well tolerated with no severe or serious adverse events (SAEs). All three patients who received 60-mg/kg aducanumab developed SAEs of symptomatic amyloid-related imaging abnormalities, which completely resolved by weeks 8–15. Aducanumab C_max, AUC_0–last, and AUC_inf increased in a dose-proportional manner.
Discussion

In this single-dose study, aducanumab demonstrated an acceptable safety and tolerability profile and linear PK at doses ≤30 mg/kg (clinicaltrials.gov NCT01397539).

"Although there was an increase in plasma levels of Ab40 and Ab42 at 60 mg/kg, aducanumab did not appear
to significantly affect plasma levels of Ab40 or Ab42 at the lower doses (0.3 mg/kg to 30 mg/kg). The largely unaffected soluble Ab levels are consistent with the very low affinity of aducanumab for soluble monomeric Ab. At 60 mg/kg, both Ab40 and Ab42 also demonstrated higher baseline/pre-dose values and higher patient variability than the lower dose cohort patients, thus complicating the interpretation. No dose-dependent response was observed for change in mean ADAS-Cog 13 scores after single-dose administration of aducanumab."