Alzheimer's treatment trials: more investment required

Two new analyses of clinical trials point to the need for increased investment in Alzheimer's disease 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 trials in Alzheimer's drug development.

NIA Alzheimer's Clinical Trials

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in the United States, only two disease-modifying drugs have reached the market: leqembi and aducanumab (Aduhelm, now withdrawn), Kavya Shah, an MPhil candidate at the University of Cambridge in England, told the AGS meeting.

Shah presented the results of a review of NIA-funded Alzheimer's research on ClinicalTrials.gov over the past two decades. During that period, the 21st Century Cures Act of 2016 expanded NIA funding, which increased academic research into non-drug 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 U.S., with the goal of gaining insights into how federal funding could be more effectively allocated to accelerate the discovery of effective treatments for Alzheimer's disease," he said.

Shah and colleagues identified 292 intervention trials supported by the NIA from 2002 to 2023. Most 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's Alzheimer's trials over the past two decades have been pharmacological studies, and most of those were also early trials," Shah noted.

"While NIA funding has increased through federal initiatives like the 21st Century Cures Act, we have not seen a corresponding increase in the number of NIA trials investigating new drug compounds for Alzheimer's disease," he added. "Going forward, it is important to evaluate NIA's investment strategy so that it can more effectively drive the discovery of safe and effective treatments for Alzheimer's disease."

Alzheimer's Disease Drug Portfolio

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

In their assessment 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 co-authors reported that in 2024, there were 164 active trials and 127 unique treatments in the treatment pipeline, a decrease of about 10% compared with 2023.

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

Cummings attributed the decline to a lack of federal funding and a decline in 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 and Related Dementias Research Portfolio (IADRP) and its categorical system, the Common Alzheimer's and Related Dementias Research Ontology (CADRO).

In 2024, amyloid and tau targets represented 24% of all therapeutic agents in the portfolio—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 different effects on the brain," Cummings said.

"It's safe to assume that we'll see more complex biological therapies that require intravenous administration and careful monitoring for 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 small molecule disease-modifying agents, 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 each accounted for 6% of trials. Fewer phase III studies addressed tau, neurogenesis, growth factors and hormones, or circadian rhythm-related processes.

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 study in detail 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 nearly two more years for FDA review, Cummings noted. "We know that most drugs fail, but not all of them," he said, adding that even drugs that fail clinical trials "can tell us a lot."