GLP-1 blockbusters like semaglutide and tirzepatide are widely used for diabetes and weight loss but come with some nasty side effects like nausea and vomiting.
Scientists have now discovered that targeting a different pathway tucked deep in the brain promoted weight loss in small mammals without causing the critters gastrointestinal trouble, potentially paving the way for a new obesity drug that’s much easier to stomach.
Obese mice injected with a modified version of octadecaneuropeptide (ODN), a small protein made by cells in the hindbrain, every day for nine days consistently dropped weight. Similar effects were seen in rats and shrews, but the compound didn’t cause the typical nausea or vomiting behaviors seen with GLP-1 drugs.
The results were published in Science Translational Medicine on July 23.
Should ODN’s effects translate to humans, the protein could “serve a population of people who cannot tolerate the GLP-1 therapies,” Caroline Geisler, Ph.D., a pharmacologist at the University of Kentucky and lead author of the study, told Fierce Biotech. “That is the No. 1 issue with the GLP-1 therapies that are obviously leading the market right now: They have an over 50% discontinuation rate in large part due to the side effects.”
Geisler and her colleagues at Syracuse University and the University of Pennsylvania are now working to tweak ODN so it lasts longer in the body, she said, with the goal of hopefully starting early human trials within two or three years. Biotech startup Coronation Bio, a portfolio company of the Biosciences Research and Commercialization Center of Western Michigan University, has licensed the ODN derivatives for obesity and cardio-metabolic disease, she added, and will focus on bringing them into the clinic.
Geisler became interested in ODN because of how little attention it has received over the years, despite first being discovered in the 1980s.
“It was discovered in the heyday of scientists discovering peptide systems in the body,” Geisler explained. “But then there was a lack of tools to really follow up on better understanding what it was doing, especially in the brain.”
ODN is made by non-neuron cells called glia in the hindbrain, the part of the brain that sits at the back of the skull and controls many basic bodily functions. Glia help monitor nutrient levels in the bloodstream, and, if they detect something amiss, they send signaling molecules like ODN out to neurons to direct them to take action.
“I was really interested in how the brain was monitoring changes in nutrient status, like, how does the brain know if you have too much glucose or too little glucose?” Geisler said. “We could dive into what role ODN had in this brain region and then take that further and really look at this through the drug development lens.”
Her goal was to push and pull at the ODN pathway by activating and blocking its activity in rodent brains and watching what happened. Injecting ODN into the cerebrospinal fluid of rats suppressed the animals’ feeding activity and helped them clear glucose out of their blood, an important process for preventing high blood sugar.
But, because injecting a drug into human brains isn’t possible, the team next tested a smaller, modified version of ODN called trideca-neuropeptide (TDN) that is theoretically better able to get into the brain from the bloodstream, Geisler said. It was TDN that was given to obese mice for nine days straight, leading to regular weight loss with still no gastrointestinal side effects.
Should Geisler and her collaborators succeed at turning ODN into a non-nauseating obesity drug, there would likely be a massive market for it. Data analytics firm Evaluate Pharma recently projected that GLP-1 drugs will make up 9% of all prescription drug sales in 2030, with Eli Lilly’s Zepbound (tirzepatide) projected to earn $25.5 billion that year.
Editor's note: This story was updated at 11 a.m. ET on July 24 to add information about the licensing of ODN derivatives by Coronation Bio.