A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody

Abstract

Background Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease (AD) and mild AD dementia. Methods BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer’s Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging. Results A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (−0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly. Conclusions BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer’s disease is underway. Trial registration Clinical Trials.govNCT01767311.

Significance of Oligomeric and Fibrillar Species in Amyloidosis: Insights into Pathophysiology and Treatment

“…Monoclonal antibodies against the components of amyloid deposits are also under development for the treatment of various types of systemic amyloidosis [ 10 ]. For Alzheimer’s disease, other monoclonal antibodies, including gantenerumab [ 70 ], solanezumab [ 71 ], and lecanemab [ 72 ], could also be up for approval.…”

Amyloid-β and α-Synuclein Immunotherapy: From Experimental Studies to Clinical Trials

“…After showing a favourable safety profile in two phase 1 trials, Lecanumab was tested in ongoing phase 2 trials with an adaptive Bayesian design ( Satlin et al, 2016 ). Mild-moderate AD patients based on Wechsler Memory Scale-IV Logical Memory II (WMS-IV LMII), MMSE, PET, and CSF Aβ were administered 2.5, 5, 10 mg/kg doses biweekly or monthly for 1 year ( Swanson et al, 2021 ). A dose dependent reduction in PET SUVR occurred leaving 80% amyloid negative at the end of treatment ( Swanson et al, 2021 ).…”

“…Mild-moderate AD patients based on Wechsler Memory Scale-IV Logical Memory II (WMS-IV LMII), MMSE, PET, and CSF Aβ were administered 2.5, 5, 10 mg/kg doses biweekly or monthly for 1 year ( Swanson et al, 2021 ). A dose dependent reduction in PET SUVR occurred leaving 80% amyloid negative at the end of treatment ( Swanson et al, 2021 ). While total-tau levels remained unchanged, a significant increase in CSF Aβ42 and decrease in p-tau relative to placebo occurred by 18 months ( Swanson et al, 2021 ).…”

A cross-sectional study in healthy elderly subjects aimed at development of an algorithm to increase identification of Alzheimer pathology for the purpose of clinical trial participation

“…Aβ immunotherapy could prevent (progression to) AD in healthy elderly who show evidence of amyloid pathology and could prevent (further) aggregation of neurotoxic forms of Aβ and would thereby prevent downstream effects as synaptic dysfunction, neuronal damage, and cognitive impairment [ 7 ]. However, many phase 3 anti-amyloid trials have failed to demonstrate effects on progression of cognitive decline in patients with (mild to moderate) AD, despite clear Aβ lowering effects in cerebrospinal fluid (CSF) or PET [ 8 – 12 ].…”