1687-P: Sequential Combination of the Mitochondrial Protonophore (MP) TLC-6740 with Semaglutide Normalizes Body Weight and Preserves Lean Mass in DIO Mice

Introduction and Objective: TLC-6740, a liver-targeted MP, regulates body weight via increased energy expenditure and is complementary to incretins that reduce food intake. We evaluated weight loss with a sequential combination of ‘6740 and semaglutide (SEMA), and ‘6740 maintenance therapy post SEMA discontinuation (D/C) in diet-induced obese (DIO) mice. Methods: Male DIO mice were treated with ‘6740 (6 wk), ‘6740 (3 wk) followed by combo with SEMAlow (3 wk), or ‘6740 post D/C of SEMAhigh (3 + 3 wk). Body weight (BW), fat (FM) and lean mass (LM), and oral glucose tolerance (oGTT) were assessed. Results: ‘6740 caused significant BW (-18%, 6 wk) and FM loss (-52%) without altering LM vs vehicle, while SEMAhigh reduced BW (-24%), FM (-67%), and LM (-16%). ‘6740+SEMAlow combo was well tolerated and further lowered BW, FM, and oGTT AUC (-33%, -77%, and -28%), but did not affect LM (Fig A). Post SEMAhigh D/C, ‘6740 maintained BW and FM loss similarly to mice continuing on SEMAhigh, unlike mice switched to vehicle (Fig B). ‘6740 maintenance also blunted the worsening of glucose tolerance post SEMAhigh D/C vs vehicle. Conclusion: In DIO mice, ‘6740 combo with SEMAlow was more efficacious than SEMAhigh, maintained weight loss post SEMA D/C, and was LM neutral. These data support evaluation of ‘6740 in combo with incretins in obesity and associated metabolic disorders. N. Sroda: Employee; OrsoBio, Inc. M. Sharma: None. E. Murakami: Employee; OrsoBio, Inc. C. Logan: None. S. Weng: Employee; OrsoBio, Inc. B.J. Kirby: Employee; OrsoBio, Inc, Gossamer Bio, Inc. Consultant; Lilac Therapetutics, TERNS Pharmaceuticals, Actio Biosciences, SiteOne Therapeutics, IconOVir Bio, Recludix Pharma. R.P. Myers: Employee; OrsoBio, Inc. Stock/Shareholder; OrsoBio, Inc. M. Subramanian: Employee; OrsoBio, Inc. G.I. Shulman: Advisory Panel; Novo Nordisk. Consultant; Ionis Pharmaceuticals. Research Support; AstraZeneca, Merck & Co., Inc, ESPERION Therapeutics, Inc., Novo Nordisk. Advisory Panel; OrsoBio, Inc. A. Vijayakumar: Employee; OrsoBio, Inc.