The Anti-Amyloid Monoclonal Antibody Lecanemab: 16 Cautionary Notes

Article type: Article Commentary

Authors: Kepp, Kasper P.^{a; *} | Sensi, Stefano L.^{b; c} | Johnsen, Kasper B.^d | Barrio, Jorge R.^e | Høilund-Carlsen, Poul F.^{f; g} | Neve, Rachael L.^h | Alavi, Abassⁱ | Herrup, Karl^j | Perry, George^k | Robakis, Nikolaos K.^l | Vissel, Bryce^{m; n} | Espay, Alberto J.^o

Affiliations: [a] Department of Chemistry, Section of Biophysical and Biomedicinal Chemistry, Technical University of Denmark, Kongens Lyngby, Denmark | [b] Center for Advanced Studies and Technology - CAST, and Institute for Advanced Biotechnology (ITAB), University G. d’Annunzio of Chieti-Pescara, Italy | [c] Department of Neuroscience, Imaging, and Clinical Sciences, University G. d’Annunzio of Chieti-Pescara, Italy | [d] Department of Health Science and Technology, Neurobiology Research and Drug Delivery Group, Aalborg University, Aalborg, Denmark | [e] Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA, USA | [f] Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark | [g] Department of Clinical Research, University of Southern Denmark, Odense, Denmark | [h] Department of Neurology, Massachusetts General Hospital, Boston, MA, USA | [i] Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA USA | [j] Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA | [k] Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio, San Antonio, TX, USA | [l] Icahn School of Medicine at Mount Sinai Medical Center, New York, NY, USA | [m] St Vincent’s Hospital Centre for Applied Medical Research, St Vincent’s Hospital, Darlinghurst, NSW, Australia | [n] School of Clinical Medicine, UNSW Medicine & Health, St Vincent’s Healthcare Clinical Campus, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia | [o] Department of Neurology, James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati, Cincinnati, OH, USA

Correspondence: [*] Correspondence to: Kasper P. Kepp, Department of Chemistry, Section of Biophysical and Biomedicinal Chemistry, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. Tel.: +45 45 25 24 09; E-mail: [email protected].

Abstract: After the CLARITY-AD clinical trial results of lecanemab were interpreted as positive, and supporting the amyloid hypothesis, the drug received accelerated Food and Drug Administration approval. However, we argue that benefits of lecanemab treatment are uncertain and may yield net harm for some patients, and that the data do not support the amyloid hypothesis. We note potential biases from inclusion, unblinding, dropouts, and other issues. Given substantial adverse effects and subgroup heterogeneity, we conclude that lecanemab’s efficacy is not clinically meaningful, consistent with numerous analyses suggesting that amyloid-β and its derivatives are not the main causative agents of Alzheimer’s disease dementia.

Keywords: Alzheimer’s disease, amyloid-β , antibody, lecanemab, subgroup analysis

DOI: 10.3233/JAD-230099

Journal: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 497-507, 2023