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Review
. 2023 Oct 26;186(22):4757-4772.
doi: 10.1016/j.cell.2023.09.023. Epub 2023 Oct 16.

Accelerating Alzheimer's therapeutic development: The past and future of clinical trials

Adam L Boxer  1 , Reisa Sperling  2
Affiliations
Review

Accelerating Alzheimer's therapeutic development: The past and future of clinical trials

Adam L Boxer et al. Cell. .

Abstract

Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of the anti-Aβ antibodies lecanemab and donanemab. Why did it take 30 years to achieve these successes? Developing potent therapies for reducing fibrillar amyloid was key, as was selection of patients at relatively early stages of disease. Biomarkers of the target pathologies, including amyloid and tau PET, and insights from past trials were also critical to the recent successes. Moving forward, the challenge will be to develop more efficacious therapies with greater efficiency. Novel trial designs, including combination therapies and umbrella and basket protocols, will accelerate clinical development. Better diversity and inclusivity of trial participants are needed, and blood-based biomarkers may help to improve access for medically underserved groups. Incentivizing innovation in both academia and industry through public-private partnerships, collaborative mechanisms, and the creation of new career paths will be critical to build momentum in these exciting times.

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Conflict of interest statement

Declaration of interests Adam Boxer has served as a consultant to AGTC, Alector, Alzprotect, Amylyx, Arkuda, Arrowhead, Arvinas, Aviado, Boehringer Ingelheim, Denali, Eli Lilly, GSK, Humana, Life Edit, Merck, Modalis, Oligomerix, Oscotec, Roche, Transposon and Wave. He has received research support from Biogen and Eisai for serving as a site investigator for clinical trials, as well as from Regeneron. He has received research support from the National Institutes on Aging: NIH U19AG063911, R01AG073482, R56AG075744, R01AG038791, RF1AG077557, R01AG071756, U24AG057437; Rainwater Charitable Foundation, Bluefield Project to Cure FTD, GHR Foundation, Alzheimer’s Association, Association for Frontotemporal Degeneration, Gates Ventures, Alzheimer’s Drug Discovery Foundation, UCSF Parkinson’s Spectrum Disorders Center and the University of California Cures AD Program. Reisa Sperling has served as a consultant to AC Immune, Acumen, Alector, Bristol Myers Squibb, Genentech, Ionis, Janssen, Oligomerix, Prothena, Roche, Shionogi and Vaxxinity. Her spouse has been a consultant to Merck and Novartis. She has received research funding from the National Institute on Aging, NIH: P01AG036694, U24AG057437; R01AG063689; R01AG054029; R01AG061848; Alzheimer’s Association, GHR Foundation, Gates Ventures, an Anonymous Foundation, Accelerating Medicines Partnership FNIH, and public partnership trial funding from Eli Lilly, and Eisai.

Figures

Figure 1.
Figure 1.. Insights from past clinical trials and new approaches.
(Top panel) Insights from past biomarker development and clinical trials. (Middle panel) New trial designs and priorities to accelerate clinical development. (Bottom panel) Bar represents percent estimates based on autopsy cohorts of clinical AD cases with pure AD (ATN pathology without co-pathology), AD with co-pathology (e.g., ATN plus vascular, α-synuclein and/or TDP-43) and relative percentage of Early Onset AD (EOAD; first symptoms before age 65).
Figure 2.
Figure 2.. History of Aβ immunotherapy.
(A) Timeline from discovery of amyloid precursor protein (APP) mutations as a cause of early onset AD, nonclinical proof of concept in PDAPP mouse model, showing selected clinical trial programs and biomarker discoveries (green boxes) discussed in the text through the present day lecanemab and donanemab programs. Timeline is not meant to be comprehensive and does not include many important biomarker and clinical trial programs. PiB = Pittsburgh Compound B [first widely used amyloid PET ligand]; P-tau181 and 217 = phosphorylated tau at residues 181 or 217; ASO= antisense oligonucleotide; IPMS = immunoprecipitation mass spectrometry. Clinical trial dates from clinical trials.gov: NCT00112073, NCT00574132, NCT02760602, NCT00905372, NCT01900665, NCT01677572, NCT01760005, NCT01998841, NCT02008357, NCT02484547, NCT02477800, NCT03114657, NCT02670083, NCT03367, NCT03186989, NCT03887455, NCT04437511, NCT04468659, NCT05310071. (B) Amyloid plaque reduction is correlated with clinical benefit. Treatment versus placebo difference in change in CDR-SB correlated with amyloid PET centiloid difference in change over time with various anti-Aβ mAbs including lecanemab (Lec), aducanumab (Adu), donanemab (Dona) and solanezumab (Sola). Note that solanezumab Phase 3 estimates are from previous Phase 3 studies in sporadic AD, as well as the A4 Study and subset of DIAN-TU study that was conducted in a preclinical (asymptomatic) AD population. Crenezumab (Cren) estimates includes the API Study in preclinical AD population. Adapted with recent updates from similar depictions in. ,
Figure 3:
Figure 3:. Stages of clinical development for typical AD new molecular entity drugs.
Nonclinical refers to in vitro, cell culture and animal model studies prior to moving forward with first in human clinical trials through an Investigational New Drug (IND) or equivalent process.
Figure 4.
Figure 4.. Amyloid and tau biomarker changes in relation to symptom onset with predicted effects of amyloid and tau targeted therapies in current and planned trials.
(A) Hypothetical pattern of soluble and insoluble amyloid and tau biomarker changes in relationship to symptom onset based on work from the Dominantly Inherited Alzheimer’s Network (DIAN; Barthelemy et al, 2019) modified from a slide presented at AD/PD2022 by Dr. Randall Bateman. (B) Representation of biomarker and cognitive changes after treatment with lecanemab or donanemab in recent Phase 3 studies. (C) Predicted biomarker changes if current A3–45 (AHEAD) study is positive. (D) Predicted biomarker changes if planned Alzheimer’s Tau Platform (ATP) study is positive. (E) Predicted biomarker changes if a hypothetical “A2” even earlier intervention study to prevent “amyloid positivity” succeeds.
See this image and copyright information in PMC

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