Terns’ ex-MASH drug cuts fat, not muscle or food intake, in GLP-1 combo in mice

Terns’ ex-MASH drug cuts fat, not muscle or food intake, in GLP-1 combo in mice

Terns Pharmaceuticals’ prediction that its shelved metabolic dysfunction-associated steatohepatitis (MASH) drug TERN-501 could be effective against obesity in a combination treatment appears to be playing out, at least preclinically.

Mice with diet-induced obesity that were given TERN-501 in combination with semaglutide, the active ingredient in Novo Nordisk’s Ozempic and Wegovy, lost 33% of their body weight over six weeks of daily treatment, new data presented June 23 at the American Diabetes Association’s Scientific Sessions showed.

In comparison, mice that were given semaglutide alone lost 26% of their body weight.

The data showed that weight loss from the TERN-501-semaglutide combination wasn’t statistically different from that induced by tirzepatide, Eli Lilly’s dual GLP-1/GIP dual receptor agonist that is commercialized as Zepbound and Mounjaro. Mice treated with tirzepatide lost 35% of their body weight over the study period, per Terns’ data.

Intriguingly, mice that received the TERN-501-semaglutide combination ate just as much as obese controls, indicating that its effects come from altering metabolic adaptation—that is, how the body responds to weight loss—rather than appetite suppression. Unlike other weight loss drugs, the combo didn’t eat away at the animals’ lean muscle mass. In fact, Mice given TERN-501 and semaglutide ended the study with less fat and more muscle than the ones in the semaglutide-only group.

Furthermore, it appeared that the combo was more effective in animals that had higher body masses than those with lower ones, adding more weight to the idea that its benefits come from TERN-501’s effects on metabolic rate. This makes sense given TERN-501’s mechanism of action—the drug is a selective agonist of thyroid hormone receptor-beta (THR-β), a protein that regulates important components of energy expenditure.

“These results suggest that TERN-501, a potent and highly selective THR-β agonist, may be an ideal combination partner for GLP-1 therapies and may offer broader metabolic benefits compared to either treatment alone,” Terns’ researchers concluded on the poster they presented at the conference.

This is the second set of preclinical data showing that TERN-501 is effective against obesity in combination with semaglutide. Terns presented the first evidence at an investor event last summer, showing that the combo led to a 25% to 30% weight reduction in mice.

In a note about the new data, Mizuho managing director of research Graig Suvannavejh, Ph.D., called the results an “incremental positive” for Terns. The company has another obesity candidate, TERN-601, in a phase 1 clinical trial and expects results in the second half of this year.

The new data “points to another potential role for [TERN-501] and … builds excitement ahead of initial phase 1 data for TERN-601,” Suvannavejh said in the note.

On the same day, Viking Therapeutics presented positive preclinical data at the ADA conference for its obesity program. In a poster presentation, the company showed that its dual agonists of the amylin and calcitonin receptors (DACRAs) were effective at reducing body weight and improving blood glucose levels in a mouse model of diet-induced obesity.

Mice that were given daily doses of a Viking DACRA for 24 days lost 10% of their body weight by the end of the study period, and their blood glucose levels were 24% lower than baseline.

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