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A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
An oral, liver-restricted LXR inverse agonist for dyslipidemia: preclinical development and phase 1 trial
Xiaoxu Li1, Giorgia Benegiamo1, Archana Vijayakumar2
1Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Abstract:
Despite advances in lipid-lowering treatment, atherosclerotic cardiovascular disease remains the leading cause of mortality, underscoring the need to address residual risk. Targeting both the synthesis and clearance of triglyceride (TG)-rich lipoproteins is a promising approach. Liver X receptor (LXR) repression can reduce plasma TG and cholesterol and improve insulin sensitivity by suppressing de novo lipogenesis and intestinal lipid absorption and enhancing clearance of TG-rich lipoproteins, but its clinical utility remains unexplored. Here we demonstrate the role of LXR inverse agonists in lipid metabolism and metabolic diseases in preclinical models and humans. Given concerns that systemic LXR repression may impair reverse cholesterol transport, we developed TLC-2716, an orally administered, gut- and liver-restricted LXR inverse agonist. In human liver organoids modeling steatohepatitis, TLC-2716 reduced lipid accumulation and suppressed inflammation and fibrotic gene expression. In a randomized, placebo-controlled phase 1 clinical trial, 14-day treatment with TLC-2716 was well tolerated (primary endpoints) and resulted in placebo-adjusted reductions up to 38.5% in plasma TG and 61% in postprandial remnant cholesterol (secondary endpoints). In conclusion, these results highlight the tolerability and therapeutic potential of TLC-2716 as a treatment for managing dyslipidemia and reducing residual atherosclerotic cardiovascular disease risk in humans. ClinicalTrials.gov identifier: NCT05483998 .
Insights
Liver X receptor (LXR) inverse agonists, like TLC-2716, show promise for managing dyslipidemia and reducing cardiovascular disease risk by targeting triglyceride-rich lipoproteins.
Area of Science:
- Biochemistry
- Pharmacology
- Cardiovascular Medicine
Background:
- Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death despite current treatments.
- Residual risk associated with dyslipidemia necessitates novel therapeutic strategies.
- Targeting triglyceride (TG)-rich lipoproteins offers a promising approach to manage ASCVD.
Purpose of the Study:
- To investigate the role of Liver X receptor (LXR) inverse agonists in lipid metabolism and metabolic diseases.
- To evaluate the safety and efficacy of TLC-2716, a gut- and liver-restricted LXR inverse agonist, in preclinical models and human trials.
- To assess the potential of TLC-2716 in managing dyslipidemia and reducing residual ASCVD risk.
Main Methods:
- Utilized human liver organoids to model steatohepatitis and assess TLC-2716's effects on lipid accumulation, inflammation, and fibrosis.
- Conducted a randomized, placebo-controlled phase 1 clinical trial to evaluate TLC-2716's tolerability and impact on lipid profiles.
- Administered TLC-2716 orally as a gut- and liver-restricted LXR inverse agonist.
Main Results:
- TLC-2716 demonstrated reduced lipid accumulation, inflammation, and fibrotic gene expression in human liver organoids.
- Phase 1 trial showed TLC-2716 was well-tolerated over 14 days.
- Placebo-adjusted reductions of up to 38.5% in plasma TG and 61% in postprandial remnant cholesterol were observed.
Conclusions:
- TLC-2716 exhibits favorable tolerability and significant lipid-lowering effects in humans.
- This LXR inverse agonist represents a potential therapeutic agent for dyslipidemia and residual ASCVD risk.
- Further clinical development of TLC-2716 is warranted for managing metabolic diseases.
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