The Future of AD Clinical Trials with the Advent of Anti-Amyloid Therapies: An CTAD Task Force Report.

BACKGROUND

Aducanumab (ADUHELMTM) was approved for the treatment of Alzheimer's disease (AD) in the US. This approval was supported by an effect on the cerebral amyloid plaque load and evidence of cognitive efficacy to be confirmed in post-marketing trials. Other anti-amyloid antibodies are under investigation in phase III (donanemab, lecanemab, gantenerumab) and have shown preliminary evidence of a cognitive benefit in phase II trials. Although these agents target a small segment of patients with mild cognitive impairment due to AD or mild AD dementia, their advent will change the design of future clinical trials both for anti-amyloid and non-amyloid drugs. These changes will promote the selection of patients in clinical trials by amyloid and tau biomarkers that identify patients with appropriate biology and may follow the treatment response to approved amyloid antibodies. The use of these agents creates the opportunity to test combined drug therapies and to conduct comparative assessments with innovative therapies and newly approved drugs available in clinical practice. Blood-based AD biomarkers should be implemented in research and could facilitate the recruitment into clinical trials. Anti-amyloid antibodies will have positive (e.g., more early diagnosis) and negative impacts (some subjects will be reluctant to participate in trials and risk assignment to placebo) on AD trials in the immediate future. We present the results of the CTAD Task Force on this topic, in Boston, November 6, 2021.

Déclaration de conflit d'intérêts

The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work. Dr. Delrieu has received payment/honoraria from Biogen (presentation for Biogen in 2021); has participated on a Data Safety Monitoring Board or Advisory Board for French board for Roche in 2020-2022. Dr. Bateman is Director of DIAN–TU and Principal Investigator of DIAN–TU001. He receives research support from the NIA of the NIH, DIAN–TU trial pharmaceutical partners (Eli Lilly and Company, F. Hoffman La Roche Ltd, Janssen, Eisai, Biogen and Avid Radiopharmaceuticals), Alzheimer’s Association, GHR Foundation, Anonymous Organization, DIAN–TU Pharma Consortium (active: Biogen, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann La Roche Ltd/Genentech; previous: AbbVie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, United Neuroscience), NfL Consortium (Hoffman La-Roche, Biogen, AbbVie, and Bristol Meyer Squibb) and Tau SILK Consortium (Eli Lilly and Company, Biogen and AbbVie) . He has been an invited speaker for the Korean Dementia Association and American Neurological Association and a consultant for Amgen, Hoffman La-Roche and Eisai. D.H., is an inventor on patents for one of the treatments (solanezumab), which was tested in the DIAN clinical trials. If solanezumab is approved as a treatment for Alzheimer’s disease or Dominantly Inherited Alzheimer’s Disease, Washington University and Dr. Holtzman will receive part of the net sales of solanezumab from Eli Lilly, which has licensed the patents related to solanezumab from Washington University. Dr. N. Sabbagh: consulting fees (Alzheon, Neurotrope, Biogen, Cortexyme, Danone, Regeneron, Roche-Genentech, Stage 2 Innovations, Acadia); stock or stock options (Brain Health Inc, NeuroReserve, NeuroTau, Optimal Cognitive Health Company, uMethod Health,Versanum, Athira). Dr. Cummings has provided consultation to AB Science, Acadia, Alkahest, AlphaCognition, ALZPath, Annovis, AriBio, Artery, Avanir, Biogen, Cassava, Cerevel, Clinilabs, Cortexyme, Diadem, EIP Pharma, Eisai, GatehouseBio, GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Lexeo, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Otsuka, PharmacotrophiX, PRODEO, Prothena, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, Unlearn AI, Vaxxinity, VigilNeuro, Zai Laboratories pharmaceutical, assessment, and investment companies. He is supported by NIGMS grant P20GM109025; NINDS grant U01NS093334; NIA grant R01AG053798; NIA grant P20AG068053; NIA grant R35AG71476; Alzheimer’s Disease Drug Discovery Foundation (ADDF); and the Joy Chambers-Grundy Endowment.