A Phase 1 clinical study has indicated that a new oral drug, TLC‑2716, developed by researchers from EPFL and their partners, safely lowered triglycerides and other blood lipids. The compound, which specifically targets the liver and gut, is an inverse agonist for the Liver X Receptor (LXR), a protein involved in fat production. The study met its primary safety and tolerability endpoints and observed significant reductions in triglycerides and postprandial remnant cholesterol in healthy adult participants.
Understanding Triglycerides and Associated Risks
Triglycerides are a form of fat stored in the body for energy. Elevated levels, a condition known as hypertriglyceridemia, are associated with an increased risk of heart disease, stroke, acute pancreatitis, dyslipidemia, and metabolic dysfunction-associated steatotic liver disease (MASLD). These conditions often arise when the body's production of fat particles surpasses their clearance by enzymes, leading to triglyceride accumulation.
The Liver X Receptor (LXR) is a protein that regulates genes involved in fat synthesis and processing. While activating LXR typically increases triglyceride and cholesterol levels, a broad reduction of LXR activity across the body could disrupt beneficial cholesterol pathways.
TLC‑2716: A Targeted Therapeutic Approach
Scientists, including Johan Auwerx at EPFL and Mani Subramanian at OrsoBio, developed TLC‑2716 to address this challenge. This orally administered compound acts as an 'inverse agonist' for LXR, meaning it represses LXR activity. Crucially, TLC‑2716 specifically targets LXRα in the liver and gut, aiming to reduce triglycerides without affecting protective cholesterol pathways in other tissues.
Research began with the analysis of human genetic datasets, which identified LXRα as a variant linked to elevated blood triglycerides. This causal relationship was further supported by Mendelian randomization. Pre-clinical studies involving rodent models and human liver organoids demonstrated that TLC‑2716 reduced triglycerides, cholesterol, and fat accumulation in the liver, alongside decreased inflammation and fibrosis. Toxicology studies in mice and non-human primates indicated that the drug primarily remained within the liver and gut, limiting systemic exposure.
Phase 1 Clinical Trial Outcomes
A randomized, placebo-controlled Phase 1 study, published in Nature Medicine, was conducted with healthy adults who received TLC‑2716 daily for 14 days. This trial marked the first human test of this type of compound. The study met its primary endpoints for safety and tolerability.
Participants who received higher doses of TLC‑2716 exhibited reductions in blood lipids. Triglyceride levels decreased by up to 38.5% (at the 12mg dose), and postprandial remnant cholesterol levels were reduced by up to 61%. These effects were observed despite participants having relatively normal baseline lipid levels and not using other lipid-lowering medications.
Mechanism of Action and Future Directions
The treatment was found to accelerate triglyceride clearance by reducing the activity of ApoC3 and ANGPTL3 proteins, which typically slow this process. The study did not detect reductions in the expression of ABCA1 and ABCG1 genes in blood cells, which are associated with reverse cholesterol transport, suggesting the drug did not disrupt these beneficial pathways.
These findings suggest that the selective reduction of LXR activity in the liver and gut by TLC‑2716 offers a potential therapeutic strategy for managing high triglycerides and related metabolic disorders. The Phase 1 data support further clinical testing in Phase 2 studies, including those for individuals with hypertriglyceridemia and MASLD.