Despite the definitive failure of Novo Nordisk’s semaglutide in Alzheimer’s, biotech executives, analysts and other industry experts see potential in more testing of GLP-1s for the neurodegenerative disease, particularly in a combination approach.
The failure of Novo Nordisk’s GLP-1 semaglutide in treating Alzheimer’s disease was pretty definitive. But the blockbuster obesity drug did affect the biomarkers underlying the devastating neurodegenerative disease and experts say it’s just a matter of finding the right combination of therapies to push that into a clinically effective regimen.
Coya Therapeutics CEO Arun Swaminathan, for one, did not see a complete failure in the Phase III results from the EVOKE program. The executive was heartened by the 10% improvement on key markers of Alzheimer’s and thinks that result could easily be boosted into the therapeutic range with a drug like COYA-301.
“Coya has always predicted that alone, [GLP-1s] won’t work,” Swaminathan told BioSpace. “That’s been our whole hypothesis, is that you got to combine it with something else.”
Swaminathan is not alone in that view. BMO Capital Markets analysts, who dubbed the semaglutide trial “clearly disappointing,” were open to the possibility of more testing.
“GLP-1 treatment for Alzheimer’s remains an interesting pursuit with positive biomarkers from EVOKE/EVOKE+ potentially providing more potential for clinical benefit in the long term,” BMO wrote in reaction to the November readout. “Results clearly represent a step back in what could have been a breakthrough for the field, but future study may still be necessary to further understand how results may differ with presymptomatic treatment over a longer time horizon.”
It’s unclear if Novo will be the one to do that work. The company discontinued an extension of the Phase III EVOKE program.
After antibodies like Leqembi and Kisunla finally broke through in Alzheimer’s, gaining approval as disease-modifying options, experts like Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation, began to turn to the idea of combination approaches, much like in cancer care.
These agents “are only about 30%, 35% at most [effective] at slowing the course of the disease,” Fillit told BioSpace in December. “It’s clear we need other pathways and other drugs to get to a much higher rate of efficacy with the equivalent or better safety profile in a setting of precision medicine with the right biomarkers and combination therapy.”
Could GLP-1s do the trick?
Swaminathan would be happy to offer Coya’s services for testing a combination approach. COYA-301 is a low-dose IL-2 agent that promotes the survival of Tregs to reduce inflammation. Coya is developing the agent alone for Alzheimer’s and in combination as COYA-302, which adds a CTLA-4 immunoglobulin to boost the function of regulatory T cells. COYA-302 is currently being tested in a Phase II trial for amyotrophic lateral sclerosis, but Coya is aiming to expand clinical testing into Alzheimer’s, frontotemporal dementia and Parkinson’s disease.
If a GLP-1 can spur a 10% improvement in Alzheimer’s biomarkers, such as indicators of inflammation in the brain, Swaminathan reasons that adding another drug on top of that could move the needle into a therapeutic and clinically beneficial range.
“That magical number that people have in their head is 20% to 25% movement in these markers can translate to a clinical outcome,” he said.
Coya will need a partner to test the theory, preferably one with a GLP-1 in its portfolio. This could be done in smaller clinical trials.
“I would not write off GLP-1,” Swaminathan concluded.
From Theory to Fact
The Alzheimer’s space has seen a lot of failures. The Coya CEO pointed to recent hits to the tau theory in Alzheimer’s, such as Johnson & Johnson’s posdinemab not slowing the decline of the disease in a Phase II study.
This kind of activity is simply a reminder of how tough developing drugs for the disease is, BMO said in a Nov. 24 note. And for Swaminathan, every step—positive or negative—adds to a greater understanding of the disease.
“They’re all actually, in a way, advancing science in a fantastic way that I think we’re going to start seeing breakthroughs come,” he said.
In particular, neuroscience in general is beginning to zero in on inflammation as a driver of these difficult degenerative diseases.
Patients in the EVOKE trials experienced improvements in plasma high sensitivity C-reactive protein (hs-CRP), a key marker of inflammation, according to a detailed presentation by Novo at the Clinical Trials on Alzheimer’s Disease (CTAD) conference in November.
“My personal view is that inflammation is a very important target in this illness, both systemic and neuroinflammation,” Fillit said.
Swaminathan noted that while Fillit and others have been saying this for decades, now the biopharma world—and the clinical data—is catching on in a meaningful way.
“You’re seeing a consistent pattern that addressing inflammation is the way to maybe address neurodegenerative diseases,” he said. “I think more and more companies are going to start pivoting towards that and away from just focusing on plaque removal.”
Indeed, according to Fillit, there are over 30 other active clinical trials in Alzheimer’s with anti-inflammatory targets—including those being run by Coya and Therini Bio, both of which ADDF has invested in.
The pivot to inflammation was also backed up by the 2025 Nobel Prize award in physiology or medicine for Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi, who discovered peripheral immune tolerance and its role in preventing the immune system from harming the body. The October award helped turn 2025 into “a spotlight year for the inflammation hypothesis around neurodegeneration,” Swaminathan said.
“I really don’t think it’s even a hypothesis anymore,” he continued. “It has been proven that that is the trigger.”
For now, Coya is moving ahead with its programs and searching for partners. Swaminathan will be keeping an eye out for the release of full data from the EVOKE trials to glean more learnings into GLP-1’s potential role in Alzheimer’s.
“That,” he said, “will give us a lot of insights on how potentially we could move forward with this combination.”
