Alzheimer's Treatment Trials: Big Investment Required

Two new analyzes of clinical trials highlight the need for increased investment in Alzheimer's treatments.

At the 2024 American Geriatrics Society (AGS) Scientific Meeting, researchers evaluated Alzheimer's disease clinical trials funded by the National Institute on Aging (NIA) over a 20-year period. Another analysis, published in the journal Alzheimer's and Dementia: Translational Research and Clinical Interventions, provided a comprehensive overview of active Alzheimer's disease drug development trials.

NIA Alzheimer's Disease Clinical Trial

Although $3.5 billion is spent annually on federally sponsored Alzheimer's disease research in the United States, only two disease-modifying drugs have reached the market: lecamemab (Leqembi) and aducanumab (Aduhelm, now discontinued), said Kavya Shah, MPhil candidate from the University of Cambridge in England, at the AGS meeting.

Shah presented the results of a review of NIA-funded Alzheimer's disease research on ClinicalTrials.gov over the past two decades. During this period, the 21st Century Cures Act of 2016 expanded funding for the NIA, which increased the amount of academic research into nondrug treatments and subsequently increased the number of new drug trials.

"We conducted this study to learn more about clinical trials funded by the NIA—the primary source of funding for Alzheimer's disease research in the United States—with the goal of identifying insights into how federal funding can be more effectively allocated to speed the search for effective treatments. Alzheimer's disease," he said.

Shah and colleagues identified 292 intervention trials supported by NIA from 2002 to 2023. The majority studied behavioral (41.8%) or drug (31.5%) interventions.

Among NIA-sponsored drug trials, the most common targets were amyloid (34.8%), neurotransmitters other than acetylcholine (16.3%), and the cholinergic system (8.7%). About a third (37%) of the drug compounds tested were new.

"Less than a third of the NIA Alzheimer's disease trials over the past two decades have been pharmacological studies, and most of these have also been early trials," Shah noted.

"Although NIA funding has been increased through federal initiatives such as the 21st Century Cures Act, we have not seen a corresponding increase in the number of NIA trials studying new drug compounds for Alzheimer's disease," he added. "Moving forward, it will be important to evaluate NIA's investment strategy so that it can more effectively drive the search for safe and effective treatments for Alzheimer's disease."

Medicine portfolio for Alzheimer's disease

The annual review reported a decline in the number of trials, drugs and new chemical entities in the Alzheimer's therapeutic pipeline in 2024, but a similar number of repurposed agents.

In an evaluation study published in the journal Alzheimer's and Dementia: Translational Research and Clinical Interventions, Jeffrey Cummings, MD, ScD, of the University of Nevada, Las Vegas, and his co-authors reported that there were 164 active trials and 127 unique treatments in the treatment pipeline in 2024, a decrease of approximately 10% compared to 2023.

There were 88 new chemical compounds in the portfolio in 2024, a 13% decrease from the previous year, the researchers reported. Overall, 39 treatments in the 2024 portfolio were repurposed agents approved for other diseases, similar to 2023.

Cummings attributed the decline to a lack of federal funding and declining private investment from the biopharmaceutical industry. "Simply put, we need more investment from government and pharmaceutical companies to combat this trend of declining clinical trials," he said.

The researchers obtained data on studies registered on ClinicalTrials.gov through the International Alzheimer's Disease and Related Dementias Research Portfolio (IADRP) and its categorization system, Common Alzheimer's and Related Dementias Research Ontology (CADRO).

In 2024, amyloid and tau targets represented 24% of all therapeutic agents in the pipeline—16% for amyloid and 8% for tau. Overall, 19% of agents in the portfolio target neuroinflammation.

Combination therapies, including pharmacodynamic combinations, pharmacokinetic combinations and combinations aimed at improving blood-brain barrier penetration, were present in the 2024 portfolio, the researchers noted.

"There are a large number of drugs in the portfolio that have very diverse effects on the brain," Cummings said.

“It is safe to assume that we will see more complex biological therapies that require intravenous administration and careful monitoring of side effects, similar to cancer therapies,” he added.

In 2024, there were 48 studies evaluating 32 drugs in phase III trials for Alzheimer's disease. Of these, 37% were disease-modifying small molecules, 28% were disease-modifying biologics, 22% were neuropsychiatric agents, and 12% were cognitive enhancers.

Of the treatments in phase III trials, 34% targeted neurotransmitter systems, 22% targeted amyloid-related processes, and 12% assessed synaptic plasticity or neuroprotection. Studies of metabolic and bioenergetic targets, inflammation or proteostasis accounted for 6% each. Fewer phase III studies focused on tau, neurogenesis, growth factors and hormones, or processes related to circadian rhythms.

The 2024 portfolio also included 90 Phase II studies evaluating 81 drugs and 26 Phase I studies testing 25 agents.

“The eight drugs reporting phase II data this year are all anti-inflammatory drugs, and the biomarkers included in the studies will allow us to drill down into the importance of individual aspects of inflammation,” Cummings noted.

It takes a decade to advance an experimental drug from phase I to phase II, and almost another 2 years for FDA review, Cummings noted. "We know that most drugs fail, but not all of them fail," he said, adding that even drugs that fail clinical trials "can tell us a lot."