OrsoBio Announces Acquisition of LXR Inverse Agonist Program for Treatment of Severe Dyslipidemias from Phenex Pharmaceuticals
Thursday, November 03, 2022
OrsoBio, Inc., a clinical-stage biopharmaceutical company developing treatments for severe metabolic disorders, today announced its acquisition of assets relating to the Liver X Receptor (LXR) inverse agonist program from Phenex Pharmaceuticals, including lead candidate TLC-2716 and associated intellectual property. The company will present preclinical data describing the efficacy of TLC-2716 in dysmetabolic rodents and human liver organoids (HLOs) at AASLD’s The Liver Meeting®, as it continues a Phase 1, first-in-human study for which data are expected in early 2023.
“TLC-2716 has demonstrated highly potent and consistent effects to improve circulating plasma triglycerides and cholesterol and to reduce hepatic steatosis in preclinical models,” said Rob Myers, MD, Chief Medical Officer of OrsoBio. “Our Phase 1 study is progressing well, and we look forward to the continued development of TLC-2716 for the treatment of severe dyslipidemias in 2023.”
TLC-2716 is a liver-targeted, inverse agonist (inhibitor) of LXR that regulates plasma triglycerides and cholesterol via multiple mechanisms, including inhibition of de novo lipogenesis (DNL), increased clearance of triglyceride- and cholesterol-rich lipoproteins, and reduced intestinal lipid absorption. The unique pharmacology of TLC-2716, namely hepatic and intestinal restriction, mitigates potential impact on peripheral reverse cholesterol transport, and supports its development for the treatment of patients with severe hypertriglyceridemia, familial hypercholesterolemia, and nonalcoholic steatohepatitis (NASH).
“The LXR pathway is central to lipid and cholesterol homeostasis. We developed TLC-2716 to be liver and intestinally restricted in order to restore lipid homeostasis in patients with dysregulation of the LXR pathway,” said Claus Kremoser, PhD, Co-Founder and Chief Executive Officer of Phenex Pharmaceuticals. “I am truly excited that OrsoBio is progressing TLC-2716 into the clinic to unlock the potential of this first-in-class compound for patients with severe dyslipidemias.”
Abstracts being presented at AASLD’s The Liver Meeting®, November 4-8, 2022, in Washington, D.C., highlight preclinical studies that demonstrate the potential of TLC-2716 to improve liver triglycerides, circulating lipids, and glucose homeostasis in dysmetabolic rodents, and to reduce the expression of genes involved in lipogenesis and steatosis in HLOs.
Abstract #2532: TLC-2716, a potent, liver-targeted, inverse agonist of the liver X receptor (LXR), demonstrates profound reductions in hepatic and plasma lipids in dysmetabolic rodent models
This study evaluated the effects of TLC-2716 on lipid metabolism in multiple preclinical models. In dysmetabolic rodents, TLC-2716 led to profound improvements in plasma and liver triglycerides, plasma cholesterol, and glucose tolerance. Additionally, in humanized chimeric liver (PXB®) mice, TLC-2716 suppressed the hepatic expression of genes involved in triglyceride and cholesterol metabolism. Due to high hepatic extraction, no impact on expression of genes involved in reverse cholesterol transport (ABCA1, ABCG1) in the circulation were observed with TLC-2716 treatment.
Abstract #4210: Enhanced lipogenesis associated with a high-risk GCKR variant (rs1260326) is effectively suppressed by TLC-2716, a novel, liver-targeted LXR inverse agonist in steatotic human liver organoids
This study utilized induced pluripotent stem cell (iPSC)-derived HLOs to evaluate the relevance of the LXR pathway in NASH, and to assess the effects of TLC-2716 on NASH-related phenotypes in HLOs from subjects with and without the glucokinase regulatory protein (GCKR) missense variant rs1260326:C>T (TT). This variant leads to increased DNL and has been associated with NASH in genome-wide association studies. The study showed upregulation of LXR expression in steatotic HLOs, and that TLC-2716 reduced the expression of lipogenic genes and lipid accumulation in HLOs from patients with and without the GCKR variant rs1260326. The data support the evaluation of TLC-2716 in NASH patients with this GCKR variant in a precision medicine approach.
