Quest is on for a ‘Super-Tolerable’ Weight-Loss Drug

By Deborah Borfitz

September 30, 2025 | Coming up with a medication that produces weight loss or prevents weight gain without any of the miserable side effects associated with top-selling drugs like Ozempic and Zepbound is the holy grail of every pharma company in the obesity space, according to Robert Doyle, Ph.D., Syracuse University chemistry professor and a professor of pharmacology and medicine at SUNY Upstate Medical University. About 70% of Americans are now considered overweight or obese, but relatively few of them are currently being treated with the otherwise popular weight-loss medications due in large part to side effects associated with the glucagon-like peptide-1 (GLP-1) pathway they activate in the gut and brain to achieve their effects. 

The search for alternatives began in the Doyle lab after a colleague suggested they turn their attention to astroglial cells (astrocytes), “forgotten cells” in the brain that were perhaps aiding much-studied neurons in GLP-1-related appetite suppression. “They’re really an untapped resource for potential new pathways, new targets, and even new molecules themselves that are endogenously produced,” he says.  

It was a good hunch. As described in a recent published study, it led to the creation of a molecule known as tridecaneuropeptide (TDN) that is effective in reducing food intake while avoiding the usual treatment side effects of GLP-1 drugs related to the nervous system (Science Translational Medicine, DOI: 10.1126/scitranslmed.adu6764). The synthetic peptide is thought to bypass neurons and instead target downstream pathways in astroglial support cells in the hindbrain to achieve appetite suppression and weight loss. 

TDN achieves those outcomes while acting like octadecaneuropeptide (ODN), an endogenous neuroprotective peptide made in the brain by astroglia, says Doyle. Its name refers to its composition of 18 amino acids.  

TDN is a truncated version of ODN, and Doyle and his team made hundreds of different varieties—some shorter, some longer, some with non-natural amino acids, some with different attached conjugates (lipids and polymers), and yet others with different terminal ends than a typical peptide—to come up with two that stood out in terms of meeting their functional parameters. A second, “long-acting brother” of TDN will be the subject of forthcoming work, he adds.  

Rebound Problem 

Unlike GLP-1 drugs, TDN doesn’t operate at the level of the pancreas to trigger insulin secretion. “While we are very interested in the fact that we see some glucoregulatory properties that are unique and interesting, we set out to look at this from an obesity perspective,” Doyle remarks.  

The consensus in the research community is that GLP-1 drugs are effective for managing type 2 diabetes, he says. “We can dose low enough and manage the side effects sufficiently and get wonderful metabolic outcomes.” 

Interest has shifted to the ability of GLP-1 drugs to achieve significant and often life-changing weight loss at higher doses than for managing type 2 diabetes, but at the risk of multiple, intolerable side effects for a huge cohort of patients, “the majority of which will come off the drug within three months to a year because of side effects and because drugs ... stop working,” says Doyle. They need to move to increasingly higher doses to get the same effects but can’t tolerate the escalation, so they come off the drug and rebound, quickly regaining weight. 

That “compensatory rebound” after patients stop taking the drug has set everyone’s sights on generating a better class of drug to assuage most or at least some of those side effect issues, he adds. A lot of research interest and funding is being devoted to that singular goal. 

If a higher potency drug with no side effects is realized, one concerning risk is the exacerbation of eating disorder pathology, Doyle says. It has already been flagged by the director of Penn Medicine Princeton Center for Eating Disorders as a potential, if understudied, problem with GLP-1 drugs.  

Although weight-loss drugs should only be taken under the supervision of a physician, the surge in compounding pharmacies and rise in online retailers has significantly lowered access barrier, he notes. That could create unintended problems among people desperate to lose weight for aesthetic and pathological reasons. His charge, however, is “to produce a drug that does what it’s supposed to do and is safe for human use under medical advice.” 

Optimized Version of TDN for Patients 

As a medicinal chemist, says Doyle, “I often have the answer to a question that I don’t know.” Thankfully, he has a pair of physiologist collaborators to help fill the knowledge gaps—Caroline Geisler, Ph.D., a metabolic neuroscientist at the University of Kentucky, and Matthew Hayes, Ph.D., a psychiatry professor at the University of Pennsylvania. They are both interested in the neuroendocrine pathways that drive appetite, satiety, satiation, and glucose regulation, as well as metabolic norms. 

The trio have been partnering on numerous research projects for about a decade now, and it was Geisler who first suggested they focus on the role of astrocytes, Doyle says. Together, they isolated tissue from various cell types and began examining what components were being produced and molecules were binding to receptors for communication and adhesion. 

TDN “jumped out ahead of everything else and we began to modify that molecule in the lab to make it a more druggable type of molecule ... that could be given subcutaneously,” Doyle continues. In addition to weight loss and prevention of weight gain, the metrics of success being sought were “a lack of overt side effects, [including] nausea, vomiting, malaise, low energy, changes in locomotion, and [increased] heart rate.” 

The promise of TDN has thus far been demonstrated in three pre-clinical models—obese mice, rats, and musk shrews—where the drug was injected directly into their brains, he says. Additional work to create an optimized version of the molecule that is more stable, long-acting, and able to penetrate the blood-brain barrier is underway, which could then lead to clinical studies that are now being planned. 

Treatment Trials 

The work to translate an optimized TDN candidate into the clinic is being undertaken by Coronation Bio, a year-old spinout company that has licensed intellectual property related to ODN derivatives for the treatment of obesity and cardiometabolic disease from Syracuse University and the University of Pennsylvania. Doyle is one of the scientific founders of Coronation Bio and sits on the company’s scientific advisory board. 

Coronation plans to partner with contract research organizations for much of the Investigational New Drug (IND) application enabling studies necessary to meet the requirements of the U.S. Food and Drug Administration to launch first-in-human studies, which could begin as early as 2027, he adds. Once the IND enabling studies are completed and prior to the initiation of clinical trials, a pre-IND meeting will be pursued, which is essentially a meeting with the agency to discuss the adequacy of preclinical data that shows the product is reasonably safe for initial human testing, clinical study design, product manufacturing, and the sponsor's overall regulatory strategy. 

In human study participants, it is expected that the TDN-based product candidate will be injected once a week into the abdomen, thigh, or upper arm, which is the current route and frequency of administration for Ozempic and Zepbound. Taking peptides orally is “a bridge beyond us right now,” says Doyle, although many patients surprisingly don’t seem to mind since the needles are very thin and the prefilled pen design makes administration easy to learn. 

The GLP-1 diabetes medication Rybelsus is taken orally and formulated with an absorption enhancer so the semaglutide isn’t broken down by the stomach. Many people presumed that Rybelsus would be a “gamechanger,” since its effectiveness is comparable to the injectables, Doyle says. But it has proven strangely unpopular for purposes of weight loss, he notes. Since it is taken every day as a pill, the frequency of gastrointestinal side effects can be higher. 

Patients may not realize that many groups, including his own, are “focused on making drugs that are not just safe but super-tolerable, so they can have a quality of life that is unmatched while they are being treated,” says Doyle. “Because the drugs are so tolerable, you can often dose higher, which means their prognosis is also improved.”