— TLC-6740 acquired as part of the mitochondrial protonophore program
from Gilead Sciences in 2020 and data to be presented at The Liver Meeting® 2022 —
Palo Alto, Calif. – November 2, 2022 – OrsoBio, Inc., a clinical-stage biopharmaceutical company developing treatments for severe metabolic disorders, today announced initiation of IND-enabling studies of TLC-6740, a liver-targeted mitochondrial protonophore. TLC-6740 will be initially advanced for the treatment of patients with severe lipodystrophies with a first-in-human study planned to initiate in 2023. Under the agreement with Gilead Sciences, initially signed in 2020, OrsoBio acquired TLC-6740 and an extensive library of mitochondrial protonophores, associated intellectual property, and a research license agreement with Yale University.
“Gilead Sciences built upon academic observations to discover and validate a series of liver-targeted mitochondrial protonophores for the treatment of NASH,” said Mani Subramanian, MD, PhD, Chief Executive Officer of OrsoBio. “We believe this approach holds tremendous potential not only to treat NASH, but also a broad range of metabolic disorders, including diabetes, obesity, and lipodystrophies, which collectively afflict millions of people worldwide.”
OrsoBio will present a study evaluating TLC-6740 in various preclinical models in a poster entitled “TLC-6740, a potent liver-targeted mitochondrial protonophore, has multiple metabolic benefits in preclinical models” (Abstract #2551) at AASLD’s The Liver Meeting®, November 4-8, 2022, in Washington, D.C. In this study, TLC-6740 was evaluated in vitro, in nonhuman primates, and in multiple dysmetabolic rodent models. In vitro, mild hepatic mitochondrial uncoupling with TLC-6740 was associated with metabolic benefits in multiple cell types, including AMPK activation, increased TCA cycle flux, and inhibition of de novo lipogenesis. In rodent models of NASH and insulin resistance, TLC-6740 led to weight loss, reduced liver and plasma triglycerides, and improved insulin sensitivity, without evidence of excessive systemic mitochondrial uncoupling, which can be attributed to its selective liver loading (~40x liver:plasma ratio in nonhuman primates).
“Research on mitochondrial protonophores has shown great potential for metabolic benefit, including reversal of insulin resistance, but systemic toxicities have limited clinical development to date,” 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. “Preliminary data suggest that the liver-targeted profile of TLC-6740 and related compounds has the potential to improve their safety profiles by minimizing systemic exposures and avoiding systemic uncoupling. In addition, active hepatic uptake of these compounds directly addresses the liver pathology characteristic of many metabolic disorders, including hepatic insulin resistance and steatosis.”
TLC-6740 is a novel, liver-targeted mitochondrial protonophore in development for the treatment of severe lipodystrophies and other metabolic disorders. Based on active hepatic uptake and mitochondrial protonophoric activity, TLC-6740 increases energy expenditure in hepatocytes, and is expected to have broad, systemic metabolic and cardiovascular benefits, including improved insulin sensitivity, NASH, dyslipidemia, and weight loss.
About OrsoBio, Inc.
OrsoBio, Inc. is a privately held, clinical-stage biopharmaceutical company dedicated to developing therapies to treat severe metabolic disorders, including type 2 diabetes, severe dyslipidemias, lipodystrophies, and nonalcoholic steatohepatitis. 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.
About Samsara BioCapital
Samsara BioCapital is a new breed of biotech investment fund focused on translating cutting-edge biology into new therapies to treat patients with unmet medical needs. Founded in 2016 by Srinivas Akkaraju, MD, PhD, our team of scientists, investors and entrepreneurs takes a long-term view to value creation across all stages of public and private life science companies. We believe in a collaborative, hands-on approach, working closely with entrepreneurs to harness exciting scientific advances and build leading companies. Samsara actively manages assets on behalf of endowments, foundations, and family offices. For more information, please visit www.samsaracap.com.