A single ascending dose study of bapineuzumab in patients with Alzheimer disease

Abstract

The safety, tolerability, and pharmacokinetics (PKs) of bapineuzumab (AAB-001), a humanized monoclonal antibody to amyloid beta, were evaluated in patients with mild-to-moderate Alzheimer disease in a phase 1, randomized, third-party unblinded, placebo-controlled, single ascending dose trial. Thirty patients received bapineuzumab infusion of 0.5, 1.5, or 5 mg/kg or placebo (6 active, 2 placebo for 0.5 and 1.5-mg/kg cohorts; 10 active, 4 placebo for 5.0-mg/kg cohort). Three patients in the highest dose cohort (5.0 mg/kg) developed magnetic resonance imaging abnormalities consistent with vasogenic edema, predominantly high signal abnormalities on fluid-attenuated inversion recovery sequences, all of which resolved over time. Plasma amyloid beta was elevated from baseline, peaking approximately 24 hours after infusion. PK analysis demonstrated a half-life of 21 to 26 days, supporting a 13-week dosing interval for bapineuzumab. This small, single-dose study demonstrated the safety profile and PK characteristics of bapineuzumab and was used to design later safety and efficacy trials.

FIGURE 1

Patient disposition.

FIGURE 2

Transverse fluid-attenuated inversion recovery (FLAIR) and gradient-echo (T2*) magnetic resonance imaging scans showing emergence and resolution of left frontal abnormality on FLAIR 4, 7, and 12 weeks after bapineuzumab administration, with associated dot-like hypointense lesion on T2*, representing a focus of associated microhemorrhage.

FIGURE 3

Mean (± SE) bapineuzumab serum concentrations for the 3 doses administered in this study.

FIGURE 4

Mean change (± SE) from baseline in the mean MMSE scores at week 16 for the 3 dose groups in the study and the pooled placebo patients (zero dose). **1.5 mg/kg versus pooled placebo; P = 0.047. MMSE indicates Mini-Mental State Examination.