Amyloid-Directed Antibodies: Past, Present, and Future

Issue title: Therapeutic Trials in Alzheimer’s Disease: Where Are We Now?

Guest editors: Paula I. Moreira, Jesus Avila, Daniela Galimberti, Miguel A. Pappolla, Germán Plascencia-Villa, Aaron A. Sorensen, Xiongwei Zhu and George Perry

Article type: Review Article

Authors: Noorda, Keith^a | Noorda, Kevin^a | Sabbagh, Marwan N.^b | Bertelson, John^c | Singer, Jonathan^{d; e} | Decourt, Boris^{d; f; *}

Affiliations: [a] School of Medicine, University of Nevada, Las Vegas, NV, USA | [b] Alzheimer’s and Memory Disorders Division, Barrow Neurological Institute, Phoenix, AZ, USA | [c] Department of Neurology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; and The University of Texas Health at Austin, Austin, TX, USA | [d] Department of Pharmacology and Neuroscience, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA | [e] Department of Psychological Sciences, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA | [f] Roseman University of Health Sciences, Las Vegas, NV, USA

Correspondence: [*] Correspondence to: Boris Decourt, PhD, Director, Laboratory on Neurodegeneration and Translational Research, Department of Pharmacology and Neuroscience, School of Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, Room 5C169, STOP 6592, Lubbock, TX 79430, USA. Tel.: +1 806 743 1012; Fax: +1 806 743 2744; E-mail: [email protected].

Abstract: Background:Alzheimer’s disease (AD) is the most common neurodegenerative disorder in patient demographics over 65 years old causing debilitating cognitive impairment. Most commonly, AD is diagnosed clinically as “probable AD”, and definitive diagnosis is confirmed through postmortem brain autopsies to detect extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau tangles. The exact mechanism causing AD is still unknown, but treatments for AD have been actively investigated. Currently, immunotherapies have shown substantial promise in reducing the pathologic and clinical signs of AD. Objective:This review aims to evaluate passive immunotherapies deemed to have promise for further development and use in the treatment of AD. Methods:Immunotherapies were selected via a narrative review of medications that have potential clinical effectiveness with a status of FDA accepted, FDA fast-track, FDA status pending, or emerging therapies poised to pursue FDA approval. Results:This review has yielded two anti-Aβ monoclonal antibodies (mAb) that are currently fully FDA approved, one mAb granted FDA fast-track status, two therapies on hold, three discontinued medications, and three promising emerging therapies. Conclusions:We conclude that, in the near future, passive immunotherapies will be the preferred and evidence-based method of treatment for AD with the presence of brain Aβ deposits for both symptom management and potential slowing of disease progression. Specifically, lecanemab and donanemab will require further clinical studies to optimize patient selection based on safety profiles. Despite some key limitations, these two drugs are paving the way for disease-modifying treatments in patients displaying early signs of amyloid pathology.

Keywords: Alzheimer’s disease, amyloid plaques, clinical trials, FDA approval, passive immunotherapy

DOI: 10.3233/JAD-240189

Journal: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S3-S22, 2024