1886-LB: Safety, PK, and Preliminary Efficacy of the Liver-Targeted Mitochondrial Protonophore TLC-6740—A Phase 1 Study

Background: Mitochondrial uncoupling is a validated approach to weight loss, however, toxicity due to systemic uncoupling has restricted clinical use. To enhance safety, TLC-6740 was developed as a liver-targeted protonophore (40x liver/plasma ratio) for the treatment of obesity. Methods: In this randomized, double-blind Ph 1 study (NCT05822544), healthy subjects received single (SAD; n=48) or multiple ascending doses (MAD; n=60) of TLC-6740 (3-120 mg) PO once daily for 10 days (n=6-8 active vs n=2 placebo/group) while fasting. Eight subjects received TLC-6740 15 mg fasted and then fed to evaluate food effect. Results: In the MAD cohorts, the proportion of subjects with adverse events (AEs) was 58% with placebo and 50-88% with TLC-6740. All AEs were mild except 3 moderate AEs unrelated to treatment (anal fissure, 30 mg; heating pad burn, 120 mg; viral illness, placebo). No drug-related discontinuations, lab abnormalities, or temperature increases were observed. TLC-6740 had a median steady-state half-life of 18-33 hrs; AUC and Cmax increased in a dose-dependent manner with no impact of food or body weight. TLC-6740 caused significant, dose-dependent reductions in serum total and LDL-C (Figure). Conclusion: In this Ph 1 study, the liver-targeted protonophore TLC-6740 was well tolerated and led to dose-dependent improvements in lipids, supporting its potential for treatment of obesity. Disclosure E. Gane: None. R.S. Huss: None. J. Sur: Employee; OrsoBio, Inc. E. Murakami: Employee; OrsoBio, Inc. S. Weng: Employee; OrsoBio, Inc. B.J. Kirby: Consultant; OrsoBio, Inc. A. Shah: Consultant; OrsoBio, Inc. G.I. Shulman: None. M. Subramanian: Board Member; OrsoBio, Inc. A. Vijayakumar: Employee; OrsoBio, Inc. R.P. Myers: Employee; OrsoBio, Inc.