The recent failure of Novo Nordisk’s GLP-1 drug semaglutide in a Phase III trial for Alzheimer’s disease has prompted discussion among experts about the future direction of treatment. While the trial did not achieve its primary goal, the drug did show an effect on certain biomarkers associated with Alzheimer’s, leading some to believe that combination therapies may be necessary to achieve clinical benefits.
Coya Therapeutics CEO Arun Swaminathan commented on the results, saying he was encouraged by a 10% improvement in key Alzheimer’s markers. Swaminathan told BioSpace, “Coya has always predicted that alone, [GLP-1s] won’t work. That’s been our whole hypothesis, is that you got to combine it with something else.”
Analysts from BMO Capital Markets described the outcome as “clearly disappointing” but suggested further research could be valuable. In their reaction to the November data readout, BMO wrote, “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. 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.”
The discontinuation of Novo Nordisk’s extension of the Phase III EVOKE program leaves open questions about who will pursue future studies. The approval of antibody treatments such as Biogen’s Leqembi and Eli Lilly’s Kisunla has shifted attention toward combination approaches similar to those used in cancer therapy.
Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), said in December: “These agents are only about 30%, 35% at most [effective] at slowing the course of the disease. 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.”
Swaminathan expressed interest in testing Coya's COYA-301—an agent designed to reduce inflammation—in combination with GLP-1 drugs. Coya is developing COYA-301 both alone and as part of COYA-302, which adds another immunotherapy component. COYA-302 is currently being tested for amyotrophic lateral sclerosis (ALS), but Coya aims to expand into trials for Alzheimer's and other neurodegenerative diseases.
According to Swaminathan, reaching a 20%–25% improvement in relevant biomarkers could translate into meaningful clinical outcomes. He noted that collaboration would be needed for such trials: “I would not write off GLP-1,” he said.
The challenge of finding effective Alzheimer’s treatments is underscored by recent setbacks involving different therapeutic approaches. BMO analysts noted that each attempt contributes valuable scientific knowledge: “They’re all actually, in a way, advancing science in a fantastic way that I think we’re going to start seeing breakthroughs come,” Swaminathan added.
Attention within neuroscience is increasingly focused on inflammation as a driver of neurodegenerative diseases. Data presented by Novo Nordisk at last year’s Clinical Trials on Alzheimer’s Disease conference showed improvements in plasma high sensitivity C-reactive protein—a marker linked to inflammation—in patients treated during EVOKE trials.
Fillit stated: “My personal view is that inflammation is a very important target in this illness, both systemic and neuroinflammation.” Swaminathan agreed that addressing inflammation might be key: “You’re seeing a consistent pattern that addressing inflammation is the way to maybe address neurodegenerative diseases,” he said.
There are now more than 30 active clinical trials targeting anti-inflammatory pathways in Alzheimer’s disease; ADDF has invested in some of these efforts—including those run by Coya Therapeutics and Therini Bio.
The importance placed on inflammation was reinforced when Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi received the Nobel Prize in Physiology or Medicine for their work on immune tolerance—a discovery relevant to understanding inflammatory processes involved in neurodegeneration.
Swaminathan concluded: “I really don’t think it’s even a hypothesis anymore. It has been proven that that is the trigger.” As Coya moves forward with its programs and seeks partners for combination studies, full data from EVOKE trials are awaited for further insights into GLP-1 drugs’ role against Alzheimer’s disease.
“That,” Swaminathan said, “will give us a lot of insights on how potentially we could move forward with this combination.”
