Safety and tolerability of BAN2401--a clinical study in Alzheimer's disease with a protofibril selective Aβ antibody

Veronika Logovinsky, Andrew Satlin, Robert Lai, Chad Swanson, June Kaplow, Gunilla Osswald, Hans Basun, Lars Lannfelt, Veronika Logovinsky, Andrew Satlin, Robert Lai, Chad Swanson, June Kaplow, Gunilla Osswald, Hans Basun, Lars Lannfelt

Abstract

Background: Several monoclonal antibodies for the treatment of Alzheimer's disease (AD) have been in development over the last decade. BAN2401 is a monoclonal antibody that selectively binds soluble amyloid β (Aβ) protofibrils.

Methods: Here we describe the first clinical study with BAN2401. Safety and tolerability were investigated in mild to moderate AD. A study design was used with staggered parallel single and multiple ascending doses, from 0.1 mg/kg as a single dose to 10 mg/kg biweekly for four months. The presence of amyloid related imaging abnormalities (ARIA, E for edema, H for hemorrhage) was assessed with magnetic resonance imaging (MRI). Cerebrospinal fluid (CSF) and plasma samples were analyzed to investigate pharmacokinetics (PK) and effects on biomarkers.

Results: The incidence of ARIA-E/H on MRI was comparable to that of placebo. BAN2401 exposure was approximately dose proportional, with a serum terminal elimination half-life of ~7 days. Only a slight increase of plasma Aβ(1-40) was observed but there were no measurable effects of BAN2401 on CSF biomarkers. On the basis of these findings Phase 2b efficacy study has been initiated in early AD.

Conclusions: BAN2401 was well-tolerated across all doses. The PK profile has guided us for selecting dose and dose regimens in the ongoing phase 2b study. There was no clear guidance for an effective dose based on biomarkers.

Trial registration number: NCT01230853 ClinicalTrials.gov Registered October 27, 2010.

Keywords: ARIA; Alzheimer's disease; Amyloid-β; Aβ; BAN2401; Clinical trial; Immunotherapy; Protofibril; mAb158.

Figures

Fig. 1
Fig. 1
Study design with overlapping SAD-MAD cohorts, where treatment periods took place in a staggered parallel manner. A cohort was initiated after review of the safety and PK data of the previous cohorts. SAD single ascending dose, MAD multiple ascending dose, PK pharmacokinetics
Fig. 2
Fig. 2
Patient disposition. SAD single ascending dose, MAD multiple ascending dose
Fig. 3
Fig. 3
a Pharmacokinetics of BAN2401, with mean serum concentration of BAN2401 in SAD cohorts. b Mean serum concentration of BAN2401 after the last dose in MAD cohorts of 0.3 – 3 mg/kg every 28 days (4 doses), or 10 mg/kg biweekly (7 doses). SAD single ascending dose, MAD multiple ascending dose
Fig. 4
Fig. 4
Mean concentrations of Aβ(1-40) versus nominal time for SAD cohorts. Aβ amyloid β, SAD single ascending dose

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