An MRI scan of the human brain
There may be no hotter trend in biopharma right now than GLP-1 receptor agonists. Currently approved to treat type 2 diabetes and obesity, this drug class has also shown potential in other indications, from nonalcoholic fatty liver disease and cardiovascular disease to addiction, and recent studies suggest it may help tackle another big target—Alzheimer’s disease.

“[GLP-1] does all kinds of things in the body,” Christian Hölscher, co-founder and chief scientific officer at Kariya Pharmaceuticals and a professor of neuroscience at the Henan University of Chinese Medicine in China, told BioSpace. “It’s just a coincidence that they found an effect in diabetes first.” Kariya and other companies are now pursuing the use of these drugs to treat neurodegeneration.

GLP-1 is a hormone that stimulates insulin secretion after eating, enabling a feeling of fullness and triggering cells to take up glucose from the blood. GLP-1 agonists mimic the effects of this hormone, making them an effective treatment for diabetes and obesity. But GLP-1 is also produced in the central nervous system, predominantly in the brainstem, and its receptors are expressed in multiple regions of the brain, including the striatum and nucleus accumbens.

Glucose is the body’s primary energy supplier—and though the brain only makes up only 2% to 3% of the body’s total weight, it consumes about 20% of those energy resources, Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), told BioSpace.

“There’s no doubt there’s increasing insulin resistance with aging across the whole body,” he said, meaning cells fail to take up glucose in response to the hormone. “When there’s sub-optimal glucose and highly active neurons have limited access to energy, they dysfunction and ultimately die on a chronic basis.” The most active neurons are in regions of learning and memory, Fillit said, making them more susceptible to glucose deprivation and, ultimately, neurodegeneration.

Howard Fillit

Recent Research

Alzheimer’s disease is sometimes called type 3 diabetes because insulin resistance is known to be a contributing factor. A review article published in 2022 in Frontiers in Endocrinology posits that drugs that target GLP-1 to treat type 2 diabetes (T2D) could potentially treat Alzheimer’s as well.

GLP-1 receptor agonists have shown the ability to reduce neuroinflammation and oxidative stress—well-recognized contributors to Alzheimer’s disease—and provide neurotrophic effects in animal models of Alzheimer’s, the authors write, while cautioning that this needs to be verified by further clinical trials.

A poster presentation at the 2023 International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (AD/PD) highlighted positive results from one such trial, the Phase II ELAD study, which assessed Novo Nordisk’s liraglutide in mild to moderate Alzheimer’s. ADDF, which Fillit said has been “very interested” in this pathway for many years, was involved in funding the trial.

In Alzheimer’s disease, the brain shrinks over time and cells die, Hölscher, a co-author on the poster, told BioSpace. Biomarker analysis of the study showed that this shrinking process was “much reduced, he said. Patients who received liraglutide had slower reduction in MRI volume and cognition compared to placebo, the authors wrote in the poster abstract. Hölscher called the study “a clear proof of concept” that a GLP-1 receptor agonist can help slow Alzheimer’s progression.

In 2021, Novo Nordisk—which also markets the GLP-1 receptor agonist semaglutide as Rybelsus for T2D—launched two Phase III trials, EVOKE and EVOKE Plus, studying the drug in approximately 3,700 people with early-stage Alzheimer’s disease. In an email sent to BioSpace, a Novo representative said that the trials are ongoing but declined to comment further for this article. The EVOKE trials are expected to be completed in September 2025.

Christian Hölscher

Hölscher noted that drugs like liraglutide and semaglutide were not designed to treat diseases of the brain. “They’re actually designed to stay in the blood, which is good for diabetes but bad for Alzheimer’s because a drug that stays in the blood doesn’t get into the brain.”

At Kariya, Hölscher has designed drugs to be taken up into the brain that he said show much better effects in preclinical studies. The molecules also have a second component: a glucose-dependent insulinotropic polypeptide (GIP), a hormone he said “works hand-in-hand” with GLP-1. This dual mechanism of action is the same as Eli Lilly’s Mounjaro, currently marketed for T2D and being tested for its effect on obesity. Kariya expects to begin a Phase I trial in September.

 

A Combination Candidate

Hölscher said the biggest barrier to the uptake of GLP-1 as an approach to Alzheimer’s—and other diseases of the brain—is psychological. “When you talk to people who work in Alzheimer’s, they have never heard of GLP-1,” he said. “It’s still amyloid, amyloid, amyloid.” This dilemma also exists in reverse in the diabetes space, where he said researchers “know everything about GLP-1, but they don’t know anything about the brain.” Combined, this makes it difficult to win research dollars, he noted.

But providing that the mechanism continues to bear out in the clinic, there are advantages to GLP-1 drugs over anti-amyloid antibodies, Hölscher said. “We know that the drugs are safe, they’re easy to apply, and you don’t need IV injections as with the antibodies.”

It also doesn’t need to be one approach or the other. As Fillit noted, GLP-1 drugs would be “very good candidates to be delivered in combination” with an anti-amyloid drug like Eisai and Biogen’s recently approved Leqembi (lecanemab) or Lilly’s investigational donanemab, because there is no overlap in the mechanism of action.

In its confirmatory trial, Leqembi was shown to reduce clinical decline in mild to moderate Alzheimer’s by 27%, while donanemab reduced decline in early symptomatic Alzheimer’s by up to 36%. While calling these results “meaningful” and “a big breakthrough,” Fillit said it is obviously not enough. “We want to get to 100% slowing and even prevention,” he said.

Source: https://www.biospace.com/article/coveted-glp-1-drugs-show-early-promise-in-alzheimer-s-disease-/
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