In a recent Phase 1 clinical trial, researchers from EPFL and their collaborators have demonstrated that a new oral drug, TLC‑2716, can safely reduce triglycerides and other blood lipids. The findings were published in Nature Medicine.
Triglycerides are fat molecules formed when the body converts excess calories from sources such as carbohydrates, sugar, fats, and alcohol. While they serve as an energy reserve, elevated levels can lead to hypertriglyceridemia—a condition associated with increased risk of heart disease, stroke, and pancreatitis.
The balance of blood fats relies on the interplay between the liver and intestine releasing fat particles into the bloodstream and enzymes breaking them down. When this process is disrupted, triglyceride levels rise, contributing to metabolic diseases including dyslipidemia and metabolic dysfunction-associated steatotic liver disease (MASLD).
A key regulator in this system is the Liver X Receptor (LXR), a protein that controls genes involved in fat metabolism. Activating LXR increases triglyceride and cholesterol levels. However, blocking LXR throughout the body can interfere with protective cholesterol pathways.
To address this challenge, Johan Auwerx at EPFL and Mani Subramanian at OrsoBio led a team to develop TLC‑2716—an orally administered compound designed to suppress LXR activity specifically in the liver and gut. This targeted approach aims to lower triglycerides without affecting beneficial cholesterol functions elsewhere in the body.
TLC‑2716 acts as an "inverse agonist" for LXR. Unlike traditional blockers that prevent receptor activation, inverse agonists induce the opposite effect of normal receptor signaling.
The research began by analyzing large human genetic datasets to identify which LXR variants are linked to high triglyceride biomarkers. The analysis pointed to genetic variants within LXRα—a form highly expressed in the liver. Mendelian randomization further confirmed that higher expression of LXRα is causally related to increased triglyceride levels.
Based on these findings, TLC‑2716 was selected for further testing against LXRα. In rodent models of metabolic disease, TLC‑2716 reduced both blood triglycerides and cholesterol while decreasing fat accumulation in the liver. Experiments using human liver organoids showed similar reductions in lipid buildup along with decreased inflammation and fibrosis.
Safety assessments included toxicology studies in mice and non-human primates as well as pharmacokinetic analyses. These indicated that TLC‑2716 remains largely confined to the liver and gut—minimizing exposure elsewhere in the body where inhibiting LXR could pose risks.
The preclinical results led to a randomized, placebo-controlled Phase 1 study involving healthy adults who received daily doses of TLC‑2716 for 14 days. The primary focus was safety and tolerability; according to researchers, "the drug met these primary endpoints."
Participants given higher doses experienced significant reductions in both triglycerides (up to 38.5%) and remnant cholesterol (up to 61%). These effects were observed even though participants had normal baseline lipid levels and were not taking other lipid-lowering medications.
The treatment also accelerated triglyceride clearance by reducing proteins ApoC3 and ANGPTL3 that normally slow this process. No changes were detected in markers related to reverse cholesterol transport (ABCA1 and ABCG1).
According to the authors: "The trial's results show that selectively reducing LXR activity in the liver and gut by TLC‑2716 may offer a new way, complementary to other approaches, to tackle high triglycerides and related metabolic disorders." They add: "The Phase 1 data support further clinical testing in Phase 2 studies, including in people with hypertriglyceridemia and MASLD." Larger trials will be necessary before broader use is considered.
