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Two new assessments of clinical trials pointed to the need for more investment in Alzheimer's disease treatments.

At the 2024 (AGS) scientific meeting, researchers evaluated Alzheimer's trials funded by the National Institute on Aging (NIA) over a 20-year period. Another analysis, published in , provided a comprehensive look at active trials in the Alzheimer's drug pipeline.

NIA Alzheimer's Trials

While $3.5 billion are spent annually in the U.S. on federally sponsored Alzheimer's research, only two disease-modifying treatments -- lecanemab (Leqembi) and aducanumab (Aduhelm, now discontinued) -- have come to market, said Kavya Shah, an MPhil candidate of the University of Cambridge in England, at the AGS meeting.

Shah presented results of a review of NIA-funded Alzheimer's studies on from the past two decades. During this period, the 21st Century Cures Act of 2016 expanded NIA funding, which increased academic non-pharmacologic trials initially and later increased new drug trials, he noted.

"We conducted this study to learn more about clinical trials funded by the NIA -- a major funder of Alzheimer's research in the U.S. -- with the hopes of revealing insights into how federal funding can be better allocated to accelerate the search for effective Alzheimer's treatments," he said.

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

Of the 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 novel.

"Less than one-third of NIA-funded Alzheimer's trials over the past two decades were pharmacological studies, and most of these were also early-stage trials," Shah observed.

"While NIA funding has been increased by federal initiatives such as the 21st Century Cures Act, we haven't seen a corresponding increase in the number of NIA-funded trials studying novel drug compounds for Alzheimer's," he added. "In the future, it is important to evaluate the NIA's investment strategy so it can more effectively drive the search for safe and effective treatments for Alzheimer's disease."

Alzheimer's Drug Pipeline

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

In their assessment published in , Jeffrey Cummings, MD, ScD, of the University of Nevada Las Vegas, and co-authors reported that the 2024 treatment pipeline included 164 active trials and 127 unique treatments, about a 10% decrease from 2023.

There were 88 new chemical entities in the 2024 pipeline, a drop of about 13% from the previous year, the researchers said. Overall, 39 treatments in the 2024 pipeline were repurposed agents approved for other diseases, similar to 2023.

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

The researchers accessed data on studies registered with ClinicalTrials.gov through the and its categorical organization 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 Alzheimer's pipeline agents targeted neuroinflammation.

Combination therapies including pharmacodynamic combinations, pharmacokinetic combinations, and combinations aimed at enhancing penetration of the blood-brain barrier were evident in the 2024 pipeline, the researchers noted.

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

"One prediction we can make with confidence is that we should be prepared for more complex biological therapies that require intravenous infusion and vigilant monitoring for side effects, more like cancer therapies," he added.

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

Of treatments in phase III trials, 34% targeted neurotransmitter systems, 22% targeted amyloid-related processes, and 12% evaluated synaptic plasticity or neuroprotection. Studies of metabolic and bioenergetic targets, inflammation, or proteostasis each represented 6% of phase III trials. Smaller numbers of phase III studies addressed tau, neurogenesis, growth factors and hormones, or circadian rhythm-related processes.

The 2024 pipeline also included 90 phase II trials assessing 81 drugs, and 26 phase I studies testing 25 agents.

"Eight of the drugs with reported data from phase II for this year are all anti-inflammatory drugs, and the biomarkers included in the trials will allow us to dissect the importance of the individual aspects of inflammation," Cummings noted.

It takes a decade to advance an investigational drug from phase I to phase II, and then nearly 2 more years for FDA review, Cummings pointed out. "We know that most drugs fail, but not all of them," he said, adding that even drugs that fail in clinical trials "can still tell us a lot."

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