OrsoBio Announces Nature Medicine Publication Establishing Clinical and Mechanistic Validation of First-in-Class LXR Inverse Agonist TLC-2716 for the Treatment of Serious Metabolic Diseases

Findings confirm translation from human genetics, organoid systems, and preclinical models to Phase 1 clinical findings

MENLO PARK, Calif.–(BUSINESS WIRE)–#NatureMedicine—OrsoBio, Inc. (“OrsoBio” or “the Company”), a clinical-stage biopharmaceutical company developing treatments for obesity and related metabolic disorders, today announced the publication in Nature Medicine of first-in-human, Phase 1 clinical data, and supporting translational evidence validating TLC-2716, an oral liver-targeted inverse agonist of Liver X Receptor (LXR).

The publication reports favorable safety and tolerability, along with robust lipid-lowering activity of TLC-2716 in healthy volunteers, with close concordance to human genetic evidence and results from human liver organoids, dysmetabolic rodent models, and non-human primates. Collectively, these data demonstrate successful translation of liver-restricted LXR inhibition from preclinical systems to humans.

TLC-2716 is currently being evaluated in a Phase 2a clinical trial in patients with severe hypertriglyceridemia (SHTG) and metabolic dysfunction-associated steatotic liver disease (MASLD) (NCT06564584), with topline data expected in the first half of 2026. Together, these highly prevalent metabolic disorders afflict more than 80 million Americans, with incidence expected to grow rapidly in the coming decades.¹

“The positive results from our first-in-human study validate LXR as a therapeutic target and highlight the unique liver and gut-restricted pharmacology of TLC-2716 for the treatment of diseases driven by excessive lipid production,” said Mani Subramanian, MD, PhD, Chief Executive Officer of OrsoBio. “By improving key lipid parameters and reducing hepatic fat, TLC-2716 has the potential to address severe hypertriglyceridemia, elevated remnant cholesterol, and MASH—major contributors to cardiovascular morbidity and mortality.”

Liver X receptors are oxysterol-activated nuclear hormone receptors that play a central role in triglyceride and cholesterol homeostasis.² TLC-2716 is an oral, liver-targeted LXR inverse agonist designed to modulate plasma triglycerides and cholesterol through multiple complementary mechanisms, including suppression of hepatic de novo lipogenesis, enhanced clearance of triglyceride- and cholesterol-rich lipoproteins, and reduced intestinal lipid absorption.

Preclinical studies described in the publication and presented at The Liver Meeting® demonstrated consistent improvements in lipid and metabolic parameters across multiple disease-relevant models. Treatment with TLC-2716 reduced plasma and hepatic triglycerides, lowered plasma cholesterol, and improved glucose tolerance in dysmetabolic rodents, with findings observed in human liver organoids (HLOs). In humanized chimeric liver (PXB®) mice, TLC-2716 selectively modulated hepatic lipid metabolism while sparing peripheral LXR activity, consistent with its liver-restricted pharmacology. Further, it was well tolerated in toxicology studies in mice and non-human primates.

“Our extensive analyses of human genetic data support liver-restricted LXR inhibition to treat lipids disorders and MASH,” said Johan Auwerx, MD, PhD, Professor at the École Polytechnique Fédérale de Lausanne (EPFL), Switzerland. “These findings not only validate the underlying mechanism, they also demonstrate strong concordance with the safety and lipid-lowering effects of TLC-2716 observed across animal models, human organoids, and the Phase 1 clinical study. As OrsoBio advances clinical development of TLC-2716, I anticipate continued evidence supporting the benefits of LXR inhibition across a broad range of cardiometabolic diseases.”

The randomized, double-blind, placebo-controlled, Phase 1 trial (NCT05483998) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single- and multiple-ascending doses of TLC-2716 in 100 healthy volunteers. Treatment for up to 14 days resulted in clinically meaningful, dose-dependent reductions versus placebo across multiple atherogenic lipid parameters, including triglycerides (up to 39%), remnant cholesterol (up to 61%), VLDL-C (up to 34%), LDL-C (up 17%), and LDL particles (up to 37%), along with decreases in apolipoprotein C3 and ANGPTL3, key regulators of lipoprotein clearance. TLC-2716 was well tolerated, with no serious adverse events reported and all treatment-related adverse events mild in severity.

About TLC-2716

TLC-2716 is a potent, oral, small-molecule, liver-targeted, inverse agonist of the Liver X Receptor (LXR). By modulating key pathways involved in lipid homeostasis—including de novo lipogenesis, lipoprotein clearance, and intestinal lipid absorption—TLC-2716 has the potential to treat a range of serious metabolic diseases. TLC-2716 is being evaluated in a Phase 2a study (NCT06564584) to understand its effects on plasma lipids, liver fat, and noninvasive markers of liver disease severity in patients with hypertriglyceridemia and MASLD.

About OrsoBio, Inc.

OrsoBio, Inc. is a privately held, clinical-stage biopharmaceutical company dedicated to developing therapies to treat obesity and obesity-associated disorders, including type 2 diabetes, MASH, and severe dyslipidemias. 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.

¹ Le P, Tatar M, Dasarathy S, et al. Estimated Burden of Metabolic Dysfunction–Associated Steatotic Liver Disease in US Adults, 2020 to 2050. JAMA Netw Open. 2025;8(1):e2454707. doi:10.1001/jamanetworkopen.2024.54707.

² Griffett K and Burris TP. Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases. Front Med. 2023 Feb 2:10:1102469. doi: 10.3389/fmed.2023.1102469.

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