The science does not yet support regulatory approval of amyloid‐targeting therapies for Alzheimer's disease based solely on biomarker evidence

Abstract

Amyloid load reduction is an unvalidated surrogate for clinical benefit. Amyloid-targeting antibodies have demonstrated efficacy in both amyloid reduction and slowing cognitive decline due to AD at the mild cognitive impairment (MCI) and mild dementia stages. However, no individual-level mediation analysis has been released to demonstrate that the clinical efficacy of amyloid-targeting antibodies is associated with and mediated by the reduction of amyloid load. According to Prentice's criteria for surrogacy it is, therefore, not scientifically justifiable to use amyloid-positron emission tomography (PET) as a surrogate clinical endpoint.2 Beginning with the use of flecainide for myocardial infarction in the 1980s based on inferred “effectiveness” against ventricular tachycardia (a risk factor of sudden coronary death), there are too many examples in medicine of the risks of relying on unvalidated surrogate markers. The 1991 CAST trial demonstrated that flecainide actually worsened outcomes for patients with myocardial infarction.3 Specific biological requirements for amyloid-targeting treatments are not specified. Aisen et al. suggest interpreting “robust plaque lowering” measured by positron emission tomography (PET) (<15–20 Centiloids) as a reason for drug approval.1 Their reasoning is based on the large proportion of patients becoming amyloid-PET-negative in the lecanemab4 and donanemab5 trials. Notably, in the four aducanumab6 and gantenerumab7 trials, a lower proportion achieved this biological target, and in three, no clinical impact was observed (Table 1). Achieving amyloid-PET negativity depends on the amyloid PET threshold, the patient's baseline amyloid load, the conformation of amyloid-beta being targeted, the duration of treatment, and the antibody dose used. Table 1 reports amyloid baselines and reductions across studies, accounting for high variability in the placebo groups. Despite gantenerumab's lack of clinical efficacy, the “robust plaque lowering” defined as risk ratios of amyloid-PET negativity compared to the placebo group might have led to its approval. These complexities make it unclear how to define biological thresholds of efficacy. The evaluation of clinical benefit is specific to each population. There has been vigorous debate on the risks and benefits of amyloid-targeting antibodies in AD at the MCI and mild dementia stages, as exemplified by the European Medicines Agency and the US Veteran's Administration decisions to exclude subgroups at risk for ARIA, and the Australian Therapeutic Goods Administration refused lecanemab approval. For the care of the asymptomatic amyloid-positive population, this debate is likely to be even more intense. These individuals have an increased risk of developing cognitive impairment, but many with low levels of amyloid pathology will remain cognitively unimpaired during their lifetime8 and the clinical meaningfulness of amyloid reduction will therefore depend on individuals’ characteristics and clinical trajectories.9 Approval without demonstrating the clinical benefit of intervention (for example, reducing incident cognitive impairment) will, therefore, make it impossible to meaningfully assess the risk-benefit ratio because there will be no clinical benefit, just biomarker reduction. As highlighted 25 years ago by Robert Temple, Senior Advisor at the United States Food and Drug Administration (FDA), a drug that affects a surrogate endpoint unlinked to clinical benefit cannot be considered safe, as its risk-benefit ratio would be infinite.10 Post-approval demonstration of clinical benefit using registries and matching with historical cohorts will not suffice. These approaches will introduce numerous biases and reduce the quality of scientific evidence to guide the care of an asymptomatic amyloid-positive person. Current evidence indicates that approving amyloid-targeting therapies solely based on plaque lowering is not scientifically justified. While we all strive to accelerate drug development for AD, it is essential to use adequate clinical trial datasets for AD at the MCI and mild dementia stages to support surrogacy validation so that effective therapies are accurately identified. It will also be valuable to explore additional candidate surrogate markers beyond amyloid clearance, both in imaging and fluids, particularly those more closely linked to neurodegeneration and symptom progression. Establishing clear thresholds for biomarker modification would be crucial to ensure that any future drug approved based on surrogate markers would be highly likely beneficial. For asymptomatic individuals, a first positive prevention trial based on clinical endpoints is mandatory. This hypothetical dataset will, hopefully, enable the validation of an effective surrogate endpoint for this specific population. Treatment: 77% Placebo: 0.5% 176 (95% CI 56.9–545.0) Treatment: 68% Placebo: 16% 4.2 (95% CI 3.1–5.9) Treatment: 31% Placebo: 8% 3.9 (95% CI 2.0–7.5) Treatment: 48% Placebo: 5% 8.9 (95% CI 3.7–21.3) Treatment: 28% Placebo: 2% 25 (95% CI 3.5–182.8) Treatment: 27% Placebo: 0% The authors have nothing to report. Author disclosures are available in the Supporting information. During the past 3 years, Dr. Planche was a local unpaid investigator or sub-investigator for clinical trials granted by NovoNordisk, Biogen, TauRx Pharmaceuticals, Janssen, Green Valley Pharmaceuticals, and Alector. He received consultant fees for animal studies from Motac Neuroscience Ltd, outside the submitted work. He received grants from the Agence Nationale de la Recherche, Fondation Recherche Alzheimer and Fondation PSP France. Dr. Schindler has served on scientific advisory boards on biomarker testing and education for Eisai and Novo Nordisk and has received speaking fees for presentations on biomarker testing from Eisai, Eli Lilly, and Novo Nordisk. Dr. Knopman serves on Data Safety Monitoring Boards for (1) the Dominantly Inherited Alzheimer Network Treatment Unit study for which he receives personal compensation; (2) a study of nicorandil for the treatment of hippocampal sclerosis of aging sponsored by the University of Kentucky (no compensation); (3) a study of varenicline in Parkinson disease sponsored by the University of Michigan (no compensation); and (4) a study of lamotrigine for mild cognitive impairment sponsored by Johns Hopkins (no compensation). He was a site investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California, and is currently a site investigator in a trial in frontotemporal degeneration with Alector. He has served as a consultant for Roche, Biovie, Linus Health, and Alzeca Biosciences but receives no personal compensation from any of the sponsors. Dr. Frisoni has received funding through the Private Foundation of Geneva University Hospitals from: A.P.R.A. – Association Suisse pour la Recherche sur la Maladie d'Alzheimer, Genève; Fondation Segré, Genève; Ivan Pictet, Genève; Race Against Dementia Foundation, London, UK; Fondation Child Care, Genève; Fondation Edmond J. Safra, Genève; Fondation Minkoff, Genève; Fondazione Agusta, Lugano; McCall Macbain Foundation, Canada; Nicole et René Keller, Genève; Fondation AETAS, Genève; has received funding through the University of Geneva or Geneva University Hospitals: for IISSs from ROCHE Pharmaceuticals OM Pharma EISAI Pharmaceuticals Biogen Pharmaceuticals and Novo Nordisk; has received funding for competitive research projects from: H2020, Innovative Medicines Initiative (IMI), IMI2, Swiss National Science Foundation, and VELUX Foundation; has received consulting fees from: Biogen, Diadem, Roche; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from: Biogen, Roche, Novo Nordisk, GE HealthCare. Dr. Galasko has served as a consultant for Eisai, Inc. Dr. Grill reports research support from NIA, Alzheimer's Association, BrightFocus Foundation, Biogen, Eli Lilly, Genentech, and Eisai. He has consulted for SiteRx. He receives personal income for editorial service to Alzheimer's & Dementia and has received travel support from the Alzheimer's Association. Within a 48 months time frame, Dr. Schneider reports grants from NIH R01 AG054434 (Delivery of Essential Fatty Acids to the Brain in Alzheimer's disease), P30 AG066530 (USC ADRC), R01 AG062687, R01 AG051346, R01 AG055444, P01 AG02350, R01 AG053267 (DIAN-TU), R01 AG074983 (Aβ and tau vaccines), R01 AG063826, State of California CADC 15-10291; grants and personal fees from Eli Lilly/Avid, grants and personal fees from Roche/Genentech; grants/contracts from Eisai, Biogen, and Biohaven; grants from Washington University, St. Louis/ NIA DIAN-TU, grants from UC San Diego ADCS, personal fees from Neurim, Ltd (Israel), Cognition Therapeutics, Corium, Immunobrain Checkpoint, Ltd (Israel), Alpha-cognition, BioVie, Lexeo, Lighthouse, AC Immune (Suisse), Athira, GW Research (UK, Jazz, USA), Merck, Otsuka (USA), Pharmatrophix, Linus Health, Lundbeck, Novo Nordisk, Muna (Denmark), Ono Ltd, Vivli.org, outside the submitted work; and from The Della Martin Foundation endowment. In the past 12 months or coming 12 months, Dr. Karlawish has or will receive compensation from Linus Health (scientific advisory board) and Biogen (consultation). Independent of this work, Dr. Villain received research support from Fondation Bettencourt-Schueller, Fondation Servier, Union Nationale pour les Intérêts de la Médecine (UNIM), Fondation Claude Pompidou, Fondation Alzheimer, Banque Publique d'Investissement and Fondation pour la Recherche sur l'Alzheimer; travel grant from the Movement Disorders Society, Merz-Pharma, UCB Pharma, and GE Healthcare SAS; is an unpaid local principal investigator or sub-investigator in NCT04241068 and NCT05310071 (aducanumab, Biogen), NCT05399888 (BIIB080, Biogen), NCT03352557 (gosuranemab, Biogen), NCT04592341 (gantenerumab, Roche), NCT03887455 (lecanemab, Eisai), NCT03828747, and NCT03289143 (semorinemab, Roche), NCT04619420 (JNJ-63733657, Janssen – Johnson & Johnson), NCT04374136 (AL001, Alector), NCT04592874 (AL002, Alector), NCT04867616 (bepranemab, UCB Pharma), NCT04777396 and NCT04777409 (semaglutide, Novo Nordisk), NCT05469360 (NIO752, Novartis), is an unpaid national coordinator for NCT05564169 (masitinib, ABScience), NCT (AD04, ADvantage Therapeutics GmbH); has given unpaid lectures in symposia organized by Eisai and the Servier Foundation; has been an unpaid expert for Janssen – Johnson & Johnson Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Topics & Concepts