In the dynamic realm of biopharma, GLP-1 receptor agonists are blazing a trail. Originally designed to combat type 2 diabetes and obesity, these remarkable drugs are now captivating the industry’s attention for their multifaceted potential. From addressing nonalcoholic fatty liver disease and cardiovascular issues to battling addiction, GLP-1 receptor agonists are becoming game-changers. The most recent revelation? Their role in the quest to conquer Alzheimer’s disease.
“It’s more than meets the eye with GLP-1,” explains Christian Hölscher, co-founder and chief scientific officer at Kariya Pharmaceuticals, also a professor of neuroscience at Henan University of Chinese Medicine in China. “Initially associated with diabetes, its capabilities extend far beyond that. It’s almost serendipitous that its potential for Alzheimer’s is now emerging as well.” Kariya Pharmaceuticals and other forward-thinking companies are now leading the charge in exploring these drugs’ neurodegenerative possibilities.
At its core, GLP-1 is a hormone responsible for regulating insulin secretion after meals. It induces feelings of fullness and prompts cells to absorb glucose from the bloodstream, making it a potent treatment for diabetes and obesity. Yet, GLP-1 isn’t confined to the pancreas—it’s also naturally produced in the central nervous system, predominantly in the brainstem. What’s more, its receptors are dispersed throughout various brain regions, including critical areas like the striatum and nucleus accumbens.
Considering that the brain, although only a small portion of our total body weight, consumes a whopping 20% of our energy resources, the significance of glucose cannot be overstated, as explained by Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF).
“Aging brings an inevitable rise in insulin resistance across the entire body,” he notes, pointing out that cells become less responsive to glucose, which could spell trouble. “When neurons, especially those linked to learning and memory, face a glucose deficit, they malfunction and, over time, succumb to neurodegeneration.”
The journey of GLP-1 receptor agonists is just beginning, and their potential to revolutionize Alzheimer’s treatment is an exciting frontier that holds immense promise.
Alzheimer’s disease, often dubbed “type 3 diabetes,” is entangled with insulin resistance as a contributing factor. In a 2022 review article published in Frontiers in Endocrinology, the notion that drugs targeting GLP-1 for type 2 diabetes (T2D) might also hold the key to Alzheimer’s treatment is explored.
GLP-1 receptor agonists have demonstrated their prowess in reducing neuroinflammation and oxidative stress, two well-known culprits in Alzheimer’s disease. Additionally, they exhibit neurotrophic effects in animal models of Alzheimer’s, as outlined by the authors. However, they cautiously note that further clinical trials are needed to substantiate these findings.
The 2023 International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (AD/PD) featured a poster presentation shedding light on the encouraging outcomes of the Phase II ELAD study. This trial assessed Novo Nordisk’s liraglutide in mild to moderate Alzheimer’s, with the Alzheimer’s Drug Discovery Foundation (ADDF) providing pivotal funding. Howard Fillit, co-founder and chief science officer at ADDF, emphasized the organization’s long-standing interest in this pathway.
In Alzheimer’s, the brain gradually shrinks, and cells wither away. However, liraglutide administered to patients in the study substantially slowed this atrophy, as observed through MRI volume and cognition measurements. Christian Hölscher, co-author of the poster, hailed this trial as “a clear proof of concept” for the potential of GLP-1 receptor agonists in slowing Alzheimer’s progression.
Novo Nordisk, which markets the GLP-1 receptor agonist semaglutide as Rybelsus for T2D, initiated two Phase III trials in 2021—EVOKE and EVOKE Plus—to investigate the drug’s impact on early-stage Alzheimer’s in roughly 3,700 individuals. These trials are currently underway, with an expected completion date in September 2025.
However, there’s a twist: Drugs like liraglutide and semaglutide were initially designed to remain in the bloodstream, which is beneficial for diabetes but less so for Alzheimer’s since drugs need to reach the brain. At Kariya Pharmaceuticals, Christian Hölscher has engineered drugs designed to penetrate the brain, exhibiting promising effects in preclinical studies.
These molecules feature an additional component—a glucose-dependent insulinotropic polypeptide (GIP), working synergistically with GLP-1. This dual mechanism mirrors Eli Lilly’s Mounjaro, marketed for T2D and currently under investigation for its potential against obesity. Kariya is set to embark on a Phase I trial in September, eagerly advancing the frontiers of Alzheimer’s research.
A Combination Candidate
The Cognitive Hurdle: Unveiling the Potential of GLP-1 for Alzheimer’s and Brain-Related Diseases
In the quest to harness GLP-1’s potential against Alzheimer’s and other brain disorders, a peculiar challenge looms large—psychological inertia. According to Christian Hölscher, when conversing with Alzheimer’s experts, GLP-1 remains a little-known entity, overshadowed by the relentless focus on amyloid. This phenomenon mirrors the inverse scenario in diabetes research, where GLP-1 is widely recognized, but its neurological implications are less explored, creating a disparity that hampers research funding.
However, should clinical results continue to validate GLP-1’s promise, it offers distinct advantages over anti-amyloid antibodies, Hölscher suggests. GLP-1 drugs are tried-and-true in terms of safety, administration is straightforward, and there’s no need for IV injections as with antibodies.
Moreover, it need not be an either-or proposition. As Howard Fillit points out, GLP-1 drugs could seamlessly complement anti-amyloid therapies, such as Eisai and Biogen’s recently approved Leqembi (lecanemab) or Lilly’s investigational donanemab. This synergy arises from the non-overlapping mechanisms of action between GLP-1 and anti-amyloid drugs.
In clinical trials, Leqembi demonstrated a 27% reduction in clinical decline among individuals with mild to moderate Alzheimer’s, while donanemab curtailed decline by up to 36% in early symptomatic Alzheimer’s patients. While these findings represent meaningful progress and a significant breakthrough, Fillit underscores that there’s still a long journey ahead. The ultimate aspiration is to achieve a 100% slowdown and even prevention of Alzheimer’s, he emphasizes.