{"id":"doi:10.1523/eneuro.0319-23.2024","kind":"article","title":"Lecanemab and Donanemab as Therapies for Alzheimer's Disease: An Illustrated Perspective on the Data","authors":["Alberto Javier Espay","Kasper P. Kepp","Karl Herrup"],"author_count":3,"year":2024,"published":"2024-07-01","venue":"eNeuro","cited_by":97,"doi":"10.1523/eneuro.0319-23.2024","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1523/eneuro.0319-23.2024","archive_url":"https://space-kitty.com/papers/doi:10.1523/eneuro.0319-23.2024","updated":null,"pmid":"38951040","pmcid":"PMC11218032","openalex_id":"W4400188148","pdf_url":"https://www.eneuro.org/content/eneuro/11/7/ENEURO.0319-23.2024.full.pdf","abstract":"Treatment of Alzheimer's disease by targeting the antiamyloid beta (Aβ) peptide with immunotherapy has led to Food and Drug Administration approval of several new Aβ monoclonal antibodies.These approvals have come with restrictions, but the uptake of these new therapies in the clinic is expected to increase rapidly, at least in the USA.Hailed as a \"breakthrough\" by some, there has been stiff countercommentary questioning both safety and efficacy.The authors of this piece have been among those most concerned about the wisdom of releasing these drugs for clinical use.We note that the debate has been thus far largely confined to the clinical literature.With this Social Issues commentary, the authors hope to bring the basic science research community into the discussion.In 2021, despite investing tens of billions of research dollars, the field of Alzheimer's disease (AD) research was struggling.Since the approval of memantine in 2003 and the extension of donepezil for the treatment of severe AD in 2006 (Feldman et al., 2001), no new treatment for AD had made it to the regulatory approval for nearly 20 years.Worse, efforts to develop treatments based on removing amyloid from the brain had repeatedly failed in late-stage clinical trials.Then, over the succeeding 2 years, three Phase 3 clinical trials of anti-amyloid beta (Aβ) monoclonal antibodies (mAb) were completed, and their results were trumpeted as breakthroughs.First was the Biogen drug, aducanumab (marketed as Aduhelm), followed in quick succession by the Biogen/Eisai drug lecanemab (Leqembi) and the Lilly drug, donanemab.The first two were fast-tracked by the United States Food and Drug Administration (FDA), and lecanemab later received full approval for the treatment of AD.This was the first FDA-approved AD drug since the acetylcholine esterase inhibitor donepezil.As exciting as these developments appear, a comparison with the successful donepezil trial completed decades ago provides some context.The slopes between the curves of donepezil and placebo were described as diverging (Fig. 1; Rogers, 1998).This is important because it is often argued that the magnitude of the difference at the end of a clinical trial is less relevant than the situation years later.The hope is that the separation between placebo and drug will continue to grow (Doody et al., 2001).Unfortunately, long-term divergence between treatment and control never materialized for donepezil.In the recent clinical trials of the mAb, lecanemab, and donanemab, after 18 months of biweekly infusions, the difference between the curves of people on antibody and those on placebo differed by only half the difference found in the donepezil trial after 6 months.For all participants, in both treatment and placebo arms, cognition declined or worsened over the 72 week trial period.While one may hypothesize that continued divergence will Continued on next page.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Lecanemab and Donanemab as Therapies for Alzheimer's Disease: An Illustrated Perspective on the Data\" by Alberto Javier Espay, Kasper P. Kepp, Karl Herrup, https://doi.org/10.1523/eneuro.0319-23.2024, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"neurodegeneration","name":"Alzheimer's, Parkinson's & Neurodegeneration","domain_slug":"medicine"}],"cited_in_dossiers":[]}