Lecanemab (BAN2401): an anti–beta-amyloid monoclonal antibody for the treatment of Alzheimer disease

ABSTRACT

Introduction

Nearly a dozen monoclonal antibodies (mAbs) directed against beta-amyloid (Aβ) have been developed for the treatment of Alzheimer disease (AD), and most of these mAbs are undergoing clinical trials. Newer mAbs have targeted more specific Aβ types. Lecanemab Eisai has a high affinity for large and soluble Aβ protofibrils. Data from phase 2 clinical trials have suggested the possibility of a robust efficacy signal and manageable risk of amyloid-related imaging abnormalities (ARIAs). Lecanemab is currently being studied in phase 3 trials.

Areas covered

This article briefly reviews mAbs that target Aβ in AD and discusses the biology, mechanism of action, and targets of lecanemab.

Expert opinion

mAbs that target Aβ are an important focus of therapeutic development for AD, with several soon to be considered for US Food and Drug Administration approval. The experience of aducanumab informs the development of other mAbs, such as lecanemab. One consideration is the conformation of Aβ targets. Targeting monomeric species has not resulted in robust clinical efficacy, whereas targeting Aβ in the form of oligomers, protofibrils, and plaques has shown evidence of slowing clinical decline. Another consideration is that mAbs will require safety monitoring for ARIAs.

KEYWORDS:

• Alzheimer disease
• ARIA
• beta-amyloid
• clinical trials
• monoclonal antibody
• neuroinflammation
• protofibrils

Article highlights

• Lecanemab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody

• Lecanemab selectively binds to soluble Aβ aggregate species and is selective for Aβ protofibrils

• In a dose dependent manner, lecanemab shows directional concordance between amyloid clearance and slowing of clinical decline

• The phase 3 Clarity study recapitulates the phase 2 findings of slowing of clinical decline with the mAB meeting its prespecified endpoint on the Clinical Dementia Rating—Sum of Boxes

• ARIA occurred in 12.6% of the treated population, with less than 3% experiencing symptomatic ARIA

Box 1. Drug summary

Drug Name (generic): Lecanemab

Phase (for indication under discussion): 3

Indication (specific to discussion): Mild cognitive impairment and mild dementia due to Alzheimer’s disease

Pharmacology Description/ MOA: Lecanemab selectively binds to soluble Aβ aggregate species and is selective for Ab protofibrils

Route of Administration: Intravenous

Chemical Structure: Lecanemab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody

Pivotal Trial(s)- Clarity AD [van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, Froelich L, Katayama S, Sabbagh M, Vellas B, Watson D, Dhadda S, Irizarry M, Kramer LD, Iwatsubo T. Lecanemab in early Alzheimer’s disease. N Engl J Med. 29 November 2022. doi: 10.1056/NEJMoa2212948. Epub ahead of print. PMID: 36,449,413.]

Abbreviations

Aβ, beta-amyloid; AD, Alzheimer disease; ADAS-Cog, Alzheimer’s Disease Assessment Scale–Cognitive Subscale; ADCOMS, Alzheimer’s Disease Composite Score; APP, amyloid precursor protein; ARIA, amyloid-related imaging abnormalities; CDR-SB, Clinical Dementia Rating—Sum of Boxes; CSF, cerebrospinal fluid; ED90, effective dose 90%; FDA, US Food and Drug Administration; mAb, monoclonal antibody; PET, positron emission tomography

Acknowledgments

We thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript preparation.

Declaration of interest

MN Sabbagh discloses ownership interest (stock or stock options) in NeuroTau, Inc., Optimal Cognitive Health Company, uMETHOD, Athira Pharma, Inc., Cognoptix, Inc., Cortexyme, Seq Biomarque, and EIP Pharma; consulting for Alzheon, Inc., Biogen Idec, GmbH, Genentech (Roche Group), Acadia Pharmaceuticals, Inc., T3D Therapeutics, Inc., Eisai Co., Ltd., Eli Lilly and Co., and KeifeRx. G Vitek and B Decourt declare no conflict of interest at the time this publication was written.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by grants from the National Institutes of Health (NIH): NIH R01AG059008, NIH P30 AG072980, and NIH R01AG073212.