The newest treatments to fight Alzheimer’s disease (AD) are a class of therapies called anti-amyloid antibodies. These monoclonal antibodies – proteins made in a laboratory intended to stimulate the immune system – have recently been shown to slow the progression of AD by targeting amyloid plaques in the brain that feature prominently in the disease. The therapies were developed after decades of disappointing, failed clinical trials and are among the first AD treatments to be efficacious in slowing the progression of the disease.
In a review article publishing October 16, 2023 in CELL, UC San Francisco neurologist and clinical researcher Adam Boxer, MD, PhD, and Harvard neurologist Reisa Sperling, MD, review the history of clinical trials over the past 30 years in Alzheimer’s research with what was learned and how new biomarkers and clinical trial approaches are being used to find more effective treatments in a more efficient way than in the past.
While drugs such as acetylcholinesterase inhibitors and memantine have been used to treat AD for decades, but they do not reduce the accumulation of amyloid plaques and tau tangles that cause AD. Approximately 30 years ago, soon after the identification of amyloid precursor protein gene mutations, researchers thought the immune system could be trained to clear the brain of plaques was developed. But a vaccine to combat amyloid build up was abandoned shortly after human clinical trials began, due to the emergence of a severe side effect – brain inflammation that led to death in handful of patients.
“Although most Alzheimer’s trials failed over the first 20 years of anti-amyloid drug development, much was learned from these trials that couldn’t have been predicted from studies in mice or observational research in humans,” said Boxer, UCSF Endowed Professor in Memory and Aging in the department of Neurology. “In this sense, they weren’t really failures at all. New biomarkers such as brain PET scans that can measure amyloid plaques and tau tangles were also instrumental in understanding who should be treated, at what stage of disease and whether or not the drugs were actually removing amyloid as designed. It also took over a decade to understand the side effects of anti-amyloid therapy and how to manage them. These learnings can now be applied to the development of new treatments.”
The positive phase 3 clinical trials of the anti-amyloid drugs lecanemab and donanemab have ushered in a new era in Alzheimer’s disease research. Key factors in the development of these potent therapies for reducing amyloid buildup have included the selection of patients at relatively early stages of disease and the identification of biomarkers of the target pathologies, such as amyloid and tau found in PET scans, as well as insights from earlier trials.
Move toward “umbrella trials”
Currently, most AD clinical trials compare new or repurposed drugs with inactive placebo, but if lecanemab, donanemab and similar agents become widely used, it may become increasingly difficult to recruit willing trial participants and may, eventually, be considered unethical to compare novel treatments with placebo alone in symptomatic patients, according to Boxer.
He suggests that moving forward, the challenge will be to develop more effective therapies with greater efficiency. “Novel trial designs, including those testing multiple different therapies at the same time either in comparison to one another (umbrella trials) or in combination with one another, or those testing the same therapy in multiple diseases (basket trials), will accelerate clinical development. Better diversity and inclusivity in trials and the development of blood-based biomarkers are needed to help to improve access for medically underserved groups. Incentivizing innovation in both academia and industry through public-private partnerships, collaborative mechanisms and creating new career paths will be critical to build momentum.”
Given the central role of the tau protein in brain health and the abnormal nature of tau proteins in the brains of people with AD, Boxer believes efforts to target tau represent the most promising next target for AD clinical trials. “Tau is theoretically a better AD therapeutic target than amyloid because, although many years of normal cognition are possible in the setting of high brain amyloid plaque burden, the emergence of insoluble tau pathology coincides with the onset of clinical symptoms of AD and strongly predicts patterns of clinical decline.”
Trial designs such as umbrella trials, testing amyloid and tau therapies simultaneously, can save time, reduces costs and decrease the number of participants necessary to test a therapeutic hypothesis. Additionally, basket trials can test a single targeted intervention across different neurological because both AD and certain non-AD neurodegenerative syndromes, such as Progressive Supranuclear Palsy, are strongly linked to underlying tau pathology.
The new NIH supported Alzheimer’s Tau Platform Trial, led by Boxer, is an umbrella trial that will test different tau therapies in combination with an anti-amyloid therapy. It is planned to begin late next year.
“These exciting new treatment approaches will require increasing support from the NIH and philanthropic funders for public-private partnerships that can bring together the necessary partners from academia and industry to ensure their success,” according to Boxer. “The next era of AD therapeutic development has begun and seems likely to produce clinically meaningful advances at a much faster rate than in the past.”
More about the authors: Boxer directs UCSF’s Neurosciences Clinical Research Unit and the Alzheimer’s Disease and Frontotemporal Degeneration (FTD) Clinical Trials Program at the UCSF Memory and Aging Center. Co-author Sperling is director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital and is the co-principal investigator of the Harvard Aging Brain Study in Boston.
