Terns' former MASH drug reduces fat, preserves muscle and appetite in GLP-1 combo for mice

Terns Pharmaceuticals' shelved drug TERN-501, initially aimed at metabolic dysfunction-associated steatohepatitis (MASH), is showing promise in preclinical trials as a potential treatment for obesity when used in combination with semaglutide. Semaglutide is the active ingredient in Novo Nordisk’s Ozempic and Wegovy. Recent data unveiled at the American Diabetes Association’s Scientific Sessions on June 23 demonstrated that mice with diet-induced obesity lost 33% of their body weight over six weeks when treated daily with the combination of TERN-501 and semaglutide.

For comparison, mice given only semaglutide saw a 26% reduction in their body weight. Additionally, the weight loss from the TERN-501 and semaglutide combination was not significantly different from that induced by tirzepatide, a dual GLP-1/GIP receptor agonist commercialized by Eli Lilly under the brand names Zepbound and Mounjaro. Mice treated with tirzepatide lost 35% of their body weight during the study period.

Interestingly, the study found that mice receiving the TERN-501 and semaglutide combination consumed as much food as obese control mice. This suggests the weight loss effects stem from changes in metabolic adaptation rather than appetite suppression. Unlike some other weight loss drugs, the combination did not cause muscle loss. In fact, mice in this group ended the study with more muscle and less fat compared to those treated only with semaglutide.

The findings also indicated that the combination was more effective in animals with higher body mass, supporting the theory that TERN-501’s benefits are linked to its effects on metabolic rate. TERN-501 works by activating thyroid hormone receptor-beta (THR-β), a protein crucial for regulating energy expenditure. According to Terns’ researchers, these results suggest that TERN-501 may be an ideal partner for GLP-1 therapies, offering broader metabolic benefits than either treatment alone.

This is the second set of preclinical data supporting the effectiveness of TERN-501 in combination with semaglutide for obesity treatment. Last summer, Terns Pharmaceuticals presented initial evidence at an investor event, showing that the combination led to a 25% to 30% weight reduction in mice.

Graig Suvannavejh, Ph.D., Mizuho's managing director of research, described the new data as an "incremental positive" for Terns. The company is also testing another obesity candidate, TERN-601, which is currently in a phase 1 clinical trial with results expected in the latter half of this year. Suvannavejh noted that the new data bolsters the potential role of TERN-501, generating anticipation for the initial phase 1 data for TERN-601.

On the same day, Viking Therapeutics shared positive preclinical data at the ADA conference for its obesity treatment program. The company demonstrated that its dual agonists of the amylin and calcitonin receptors (DACRAs) were effective in reducing body weight and improving blood glucose levels in a mouse model of diet-induced obesity. Mice treated with a Viking DACRA daily for 24 days lost 10% of their body weight and experienced a 24% reduction in blood glucose levels from baseline.

These promising developments in obesity research indicate potential new treatments that can offer broader metabolic benefits without compromising lean muscle mass, making them significant in the fight against obesity and related metabolic disorders.