OrsoBio to Present Phase 1 Data for the Liver-Targeted Mitochondrial Protonophore TLC-6740 in Development for the Treatment of Obesity at ObesityWeek® 2023

OrsoBio, Inc., a clinical-stage biopharmaceutical company developing treatments for severe metabolic disorders, today announced preliminary safety and pharmacokinetic (PK) data from the single ascending dose (SAD) portion of an ongoing Phase 1 trial of TLC-6740, a liver-targeted, mitochondrial protonophore. This study is exploring the safety and efficacy of TLC-6740 as an oral, first-in-class treatment for obesity and obesity-associated diseases, including diabetes and nonalcoholic steatohepatitis (NASH).

Increasing cellular energy expenditure by mitochondrial uncoupling is a validated approach to weight loss, however, toxicity due to systemic uncoupling (e.g., increased body temperature) has restricted its clinical use. To circumvent these potential toxicities, TLC-6740 was developed to be actively taken up by hepatocytes (liver cells), thereby avoiding high plasma exposures. In addition, by targeting the liver?a key organ governing whole body energy metabolism?TLC-6740 has multiple potential metabolic benefits, including weight loss and improvements in NASH, insulin resistance, lipids, and cardiovascular risk.

"Preliminary results from this Phase 1 study are very promising and support the safety of liver-targeted mitochondrial uncoupling with TLC-6740," said Rob Myers, MD, Chief Medical Officer of OrsoBio. "Modeling of plasma and liver concentrations upon multiple dosing suggests that high systemic exposures of TLC-6740 will be avoided, providing large safety margins compared with thermogenic exposures in preclinical studies, while efficacious exposures will be achieved at low doses. We look forward to confirming these findings in the multiple ascending dose (MAD) cohorts of this study, and to generating additional data to support the potential of TLC-6740 to treat obesity and its comorbidities."

OrsoBio will present preliminary results from its first-in-human study of TLC-6740 at ObesityWeek®, an international conference for obesity researchers and clinicians, in Dallas, Texas, October 14-17, 2023.

Abstract #418: Preliminary Human Safety and PK of the Liver-Targeted Mitochondrial Protonophore TLC-6740

Poster Session: Tuesday, October 17, 2023 (11:45 a.m. - 1:15 p.m.)

The randomized, double-blind Phase 1 trial (NCT05822544) is designed to evaluate the safety, tolerability, PK, and pharmacodynamics of single and multiple ascending doses of TLC-6740 for up to 10 days in healthy subjects. In cohorts treated with single doses of TLC-6740 (3, 6, 15, 30, 60, and 120 mg), only mild and non-serious adverse events (AEs) were reported. No AEs were considered related to treatment and there were no clinically significant laboratory abnormalities or changes in vital signs (e.g., temperature) or ECG parameters, supporting the safety and tolerability of TLC-6740. The PK profile of TLC-6740 includes a prolonged half-life (17 to 46 hours), supporting once-daily, oral dosing. Due to liver targeting, plasma concentrations are projected to remain >80-fold below exposures associated with hyperthermia in preclinical studies, providing large safety margins for human use. The results also suggest that low doses of TLC-6740 will reach therapeutic exposures, supporting its potential efficacy for obesity and associated disorders.

"With the growing burden of obesity and obesity-associated diseases, development of safe, effective oral therapies that are complementary to existing therapies, such as GLP-1 receptor agonists, will help address the tremendous unmet medical need for patients with severe metabolic disorders," said Gerald Shulman, MD, PhD, MACP, MACE, FRCP, the George R. Cowgill Professor of Medicine and Professor of Cellular and Molecular Physiology at Yale School of Medicine, Co-Director of the Yale Diabetes Research Center, and scientific advisor to OrsoBio. "These preliminary human data suggest that TLC-6740 has the potential to be a highly safe and effective mitochondrial protonophore based on the novel approach of liver targeting."

About TLC-6740

TLC-6740 is a novel, oral, liver-targeted mitochondrial protonophore in development for the treatment of obesity and obesity-associated diseases, including diabetes and NASH. Based on active hepatic uptake and mitochondrial protonophore activity, TLC-6740 increases energy expenditure in hepatocytes, and is expected to have broad, systemic metabolic and cardiovascular benefits, including weight loss, and improved insulin sensitivity, NASH, and dyslipidemia. Preclinical data presented at AASLD's The Liver Meeting® in 2022 showed that dysmetabolic rodents treated with TLC-6740 achieved dose-dependent reductions in body weight and improvements in glucose tolerance and liver and plasma triglycerides. Moreover, due to active hepatic uptake, plasma exposures of TLC-6740 are limited, serving to enhance its therapeutic safety. The safety, tolerability, PK, and pharmacodynamic activity of multiple ascending doses of TLC-6740 for up to 10 days in healthy subjects are being evaluated in an ongoing Phase 1 study (NCT05822544).

About OrsoBio, Inc.

OrsoBio, Inc. is a privately held, clinical-stage biopharmaceutical company dedicated to developing therapies to treat severe metabolic disorders, including obesity, type 2 diabetes, NASH, and severe dyslipidemias. The company was co-founded by Mani Subramanian, MD, PhD, former Therapeutic Area Head for Liver Diseases at Gilead Sciences, and Samsara BioCapital. OrsoBio currently has four programs in clinical and preclinical development with first-in-class compounds that address central pathways in energy metabolism. For more information, please visit www.orsobio.com.