OR22-05 Weight Loss and Change in Body Composition in a DIO Mouse Model by the Combined AMPK and Mitochondrial Activator, ATX-304, Alone, in Combination With Semaglutide, and After Semaglutide Withdrawal

Abstract Disclosure: E.J. Schneider: Amplifier Therapeutics AB (affiliated employee), Cambrian BioPharma, Inc (employee, shareholder). J.A. Hall: Amplifier Therapeutics AB (employee, shareholder). G. Bor: Gubra (employee). D. Jacobs: Amplifier Therapeutics AB (employee), Cambrian BioPharma, Inc (shareholder). J.G. Peyer: Amplifier Therapeutics AB (director); Cambrian BioPharma Inc (employee, shareholder, director). R. Thieroff-Ekerdt: Amplifier Therapeutics AB (director), Cambrian BioPharma, Inc (employee, shareholder). Background: ATX-304 (ATX) is a novel, peripherally restricted, oral small molecule AMPK and mitochondrial activator in clinical development for obesity. In diet-induced obesity (DIO) animal models, ATX increases energy expenditure and results in significant weight loss without a reduction in food intake. Additionally, ATX shows beneficial effects on glucose and lipid metabolism, cardiovascular function, and exercise endurance. Methods: ATX coadministration with semaglutide (sema) was investigated in 2 experiments: (A) during and (B) after treatment with sema in a mouse DIO model (C57Bl/6JRj mice on a high fat diet (HFD) for 17-18 weeks; N=8/group). (A) Mice were treated subcutaneously (sc) with 1 (low) or 3 (high) nmol/kg sema for 3 days or sc vehicle. Starting on day 4, animals were treated with oral ATX formulated in HFD, ATX + sema, sema alone, or control HFD for 28 days or until reaching maximally tolerated weight loss according to animal use protocols. (B) Mice were treated with 3 nmol/kg sc sema or vehicle for 28 days. Sema was discontinued, and animals were treated with 3 different oral doses of ATX in HFD, or HFD alone, for 14 days. Body weight, food intake, and body composition by EchoMRITM were measured in both experiments. Results: (A) Animals dosed with ATX alone demonstrated -21% weight loss after 28 days. ATX + sema-low and ATX + sema-high both resulted in -27% weight loss after 15 days. At the same time point, sema alone resulted in -14% (low) and -19% (high) weight loss, respectively. The magnitude of weight loss at day 15 in combination triggered a dose reduction in all sema groups to 10% of the starting dose. Upon dose reduction, sema only groups became hyperphagic and regained weight to baseline levels over the following 17 days. Animals on reduced-sema + ATX maintained -27% weight reduction despite hyperphagia. EchoMRITM at 32 days revealed that weight loss in both ATX and ATX + sema groups was attributable to fat mass with no reduction in lean mass. Body composition in sema-only groups was similar to control. (B) Animals dosed with sema alone for 28 days demonstrated -20% weight loss with a reduction in both fat and lean mass compared to controls. After sema withdrawal, animals became hyperphagic. Treatment with ATX for 14 days demonstrated a dose-dependent prevention of weight regain, with animals in the highest dose continuing to lose weight (-26% vs baseline), without further loss of lean mass. Conclusions: Based on results from this mouse model, ATX is a promising new weight loss agent with complementary effects to incretins, including preservation of lean mass. ATX may be useful as monotherapy, in coadministration, or as weight maintenance therapy in patients discontinuing incretins. Presentation: Sunday, July 13, 2025