2869-LB: Increasing Energy Expenditure with the Liver-Targeted Mitochondrial Protonophore TLC-6740 Enhances Weight Loss and Metabolic Benefits in Combination with Tirzepatide in Obesity: A Phase 2a Study

Introduction and Objective: Obesity results from an imbalance between energy intake and expenditure, yet incretins primarily reduce appetite. TLC-6740 is a liver-targeted mitochondrial protonophore designed to increase energy expenditure. We evaluated TLC-6740 combined with tirzepatide (TZP) in a Phase 2a proof-of-concept study in obesity. Methods: In this double-blind trial (NCT05822544), 55 adults with obesity (BMI ≥30 kg/m2) without diabetes were randomized 3:2 to once-weekly TZP (5 mg SC) plus either daily oral TLC-6740 180 mg (n=33) or placebo (n=22) for 24 weeks (W24). The primary endpoint was safety and key efficacy endpoint was percent change in weight from baseline (BL) to W24. Exploratory assessments included glycemic parameters and liver fat and body composition by MRI. Results: At BL, mean body weight was 109.2 kg; 60% were female. At W24, mean weight change was -8.8% with TZP plus placebo and -13.3% with TZP plus TLC-6740, an additional 4.5% weight loss with the combination (p=0.018, ITT), which also produced greater improvements in insulin, HOMA-IR, liver tests, adiponectin, and hsCRP. In an MRI substudy, TZP plus TLC-6740 (n=25) vs TZP plus placebo (n=12) produced greater reductions in visceral adipose tissue (-24.8% vs -15.9%; p=0.052) and total adipose tissue without affecting lean mass. Among participants with BL liver fat ≥5% (MASLD), MRI-PDFF decreased -60.6% with TLC-6740 (n=13) vs -44.0% with placebo (n=7; p=0.12). TLC-6740 plus TZP was well tolerated. AEs led to discontinuation in 3 participants (14%) on placebo and none on TLC-6740; Grade ≥2 AEs (59% vs 49%) and GI AEs (55% vs 48%) were similar. Conclusion: The liver-targeted mitochondrial protonophore TLC-6740 combined with TZP was well tolerated and produced greater weight loss and metabolic benefits than TZP alone. These findings support combining incretins with therapies that increase energy expenditure to improve weight loss and metabolic outcomes in obesity. Disclosure R. Huss: Employee; Current; OrsoBio, Inc. E. Gane: None. A. Letica: None. J. Kerr: None. S. Smith: None. S. Zenhari: Employee; Current; OrsoBio, Inc. J. Sur: Employee; Current; OrsoBio, Inc. S. Weng: Employee; Current; OrsoBio, Inc. Stock/Shareholder; Current; OrsoBio, Inc. E. Murakami: Employee; Current; OrsoBio, Inc. Stock/Shareholder; Current; OrsoBio, Inc. B.J. Kirby: Employee; Current; OrsoBio. Consultant; Current; Actio BioSciences, SiteOne Therapeutics, Lilac Therapeutics. Consultant; Ended; Terns Pharmaceuticals. Consultant; Current; Recludix Pharma, Eurofarma. Employee; Ended; Gossamer Bio. S. Chahal: None. M. Schneider: Employee; Current; Antaros Medical. A. Vijayakumar: Employee; Current; OrsoBio, Inc. G. Shulman: Consultant; Current; Novo Nordisk A/S. Research Support; Current; Novo Nordisk A/S. Other - collaboration; Current; Ionis Pharmaceuticals. Advisory Panel; Current; ESPERION Therapeutics, Inc. Research Support; Current; Novo Nordisk Foundation. Advisory Panel; Current; Orsobio. Research Support; Current; Orsobio. Advisory Panel; Current; Village S.S.D. G. Subramanian: Employee; Current; OrsoBio. R.P. Myers: Employee; Current; OrsoBio, Inc.