OrsoBio to Present Phase 1 Data for the Liver-Targeted LXR Inverse Agonist TLC-2716 in Development for Severe Hypertriglyceridemia and NASH at AHA’s Scientific Sessions 2023

MENLO PARK, Calif.–()–OrsoBio, Inc., a clinical-stage biopharmaceutical company developing treatments for severe metabolic disorders, today announced initial safety, pharmacokinetic (PK), and pharmacodynamic data from its first-in-human, Phase 1 study of TLC-2716, a liver-targeted inverse agonist (inhibitor) of the Liver X Receptor (LXR). TLC-2716 is in clinical development as a potential treatment for severe hypertriglyceridemia (SHTG) and nonalcoholic steatohepatitis (NASH).

Liver X receptors are oxysterol-activated nuclear hormone receptors that regulate triglyceride and cholesterol homeostasis.1 TLC-2716 is an oral, liver-targeted inhibitor of LXR that modulates plasma triglycerides and cholesterol by multiple mechanisms, including inhibition of de novo lipogenesis, increased clearance of triglyceride- and cholesterol-rich lipoproteins, and reduced intestinal lipid absorption. In data presented at AASLD’s The Liver Meeting®, TLC-2716 demonstrated highly potent and consistent improvements in plasma triglycerides and cholesterol and hepatic steatosis in preclinical models.

“The results of this Phase 1 study are very promising and support the safety, tolerability, and potential efficacy of TLC-2716,” said Rob Myers, MD, Chief Medical Officer of OrsoBio. “While prior studies2,3 with systemic LXR agonists demonstrated adverse effects on plasma lipids and hepatic steatosis, liver-targeted LXR inhibition with TLC-2716—the opposite approach—demonstrated dose-dependent improvements in atherogenic lipids, including plasma triglycerides, LDL-C, LDL particles, and apolipoprotein B in this study. Based on these encouraging data in healthy volunteers, we are initiating a Phase 2a study to evaluate TLC-2716 in patients with SHTG and concomitant hepatic steatosis, with data expected in early 2024.”

The company will present results from its first-in-human study of TLC-2716 at the American Heart Association’s Scientific Sessions in Philadelphia, Pa., November 11-13, 2023.

Abstract #Mo3209: Safety, Pharmacokinetics, and Lipid Lowering Effects of the Oral, Liver-Targeted Liver X Receptor (LXR) Inverse Agonist TLC-2716 in Healthy Volunteers

Poster Session: Monday, November 13, 2023 (1:30 – 2:45 p.m.)

The randomized, double-blind, placebo-controlled Phase 1 trial (NCT05483998) assessed the safety, tolerability, PK, and pharmacodynamics of single and multiple ascending oral doses of TLC-2716 in healthy volunteers. TLC-2716 treatment for up to 14 days was well tolerated; no serious adverse events (AE) were reported, and all treatment-related AEs were mild in severity. TLC-2716 treatment led to significant, dose-dependent improvements in atherogenic lipid parameters, including triglycerides, LDL-C, LDL particles, and apolipoprotein B, as well as reductions in apolipoprotein C3 and ANGPTL3, important inhibitors of lipoprotein lipase-mediated lipoprotein clearance. Notably, due to active hepatic uptake and limited systemic exposures, TLC-2716 did not adversely affect peripheral reverse cholesterol transport. The results support the ongoing development of TLC-2716 in patients with metabolic disorders including SHTG and NASH.

About TLC-2716

TLC-2716 is a potent, oral, small-molecule, liver-targeted, inverse agonist of the Liver X Receptor (LXR). Based on modulation of key mechanisms involved in lipid homeostasis, including de novo lipogenesis, clearance of lipoproteins, and intestinal lipid absorption, TLC-2716 has potential as a treatment for SHTG and NASH. TLC-2716 will be evaluated in a Phase 2a study to understand its effects on plasma lipids, liver fat, and noninvasive markers of liver disease severity in patients with SHTG and hepatic steatosis.

About OrsoBio, Inc.

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

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1 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.

2 Kirchgessner TG, et al. Beneficial and adverse effects of an LXR agonist on human lipid and lipoprotein metabolism and circulating neutrophils. Cell Metab. 2016 Aug 9; 24:223-33.

3 Groot PHE, et al. Synthetic LXR agonists increase LDL in CETP species. J Lipid Res. 2005 Oct; 46:2182-91.

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