oral drug reduces blood fat

A group of scientists from the Federal Polytechnic School of Lausanne (Switzerland) and the company OrsoBio has developed a orally administered compound capable of selectively inhibiting the hepatic X receptor (LXR) in the liver and intestinewhich allows triglyceride levels to be reduced without altering cholesterol protective pathways.

The compound TLC-2716 is what is known as a LXR receptor inverse agonist. Unlike a blocker (antagonist), which simply prevents the activation of the receptor, an inverse agonist causes the receptor to emit the opposite effect to what it would normally produce. The study, published in Nature Medicineis the first of its kind to be tested in humans.

The scientists began by analyzing large sets of human genetic data to determine which variant of the LXR It is related to biomarkers of elevated triglycerides in the blood. The data pointed to genetic variants of LXRa, which is highly expressed in the liver.

This was confirmed using Mendelian randomization, an efficient method that determines causal relationships between gene expression and outcomes. In this case, a causal relationship was confirmed between LXRa and metabolic disorders: increased expression of LXRa may elevate triglycerides. The findings helped select TLC-2716 as an effective compound to test against LXRa.

The study was later moved from computers to the laboratory. In models of metabolic diseases in rodents, TLC-2716 and a related compound reduced blood triglycerides and cholesterolas well as the accumulation of fat in the liver. Meanwhile, experiments with human liver organoids (miniature models of diseased liver tissue grown in the laboratory) showed the same trend, with less lipid accumulation and less inflammation and fibrosis.

The next step was security. Toxicological studies in mice and non-human primates, combined with pharmacokinetic analyses, demonstrated that TLC-2716 remains mainly in the liver and intestine. This is key, as it limits exposure to other tissues where LXR inhibition could be at risk, thus addressing the main problem in developing drugs for the treatment of metabolic diseases related to high triglyceride levels.

The clinical trial

The laboratory findings laid the foundation for a study of phase 1 randomized and placebo-controlled in healthy adults. Participants received TLC-2716 for 14 days as a single daily dose. The trial first focused on safety and tolerability, and the authors report that the drug met these primary endpoints.

But even this brief trial had clear effects: participants who received higher doses of TLC-2716 showed notable decreases in triglycerides and remaining cholesterol. At the highest doses of TLC-2716 (12 mg), triglycerides decreased up to 38.5 percentwhile remaining postprandial (after eating) cholesterol was reduced by up to 61 percent. This occurred despite the participants starting out with relatively normal lipid levels and without the use of other lipid-lowering drugs.

The treatment also accelerated triglyceride clearance by reducing the activity of two proteins that normally slow it down, ApoC3 and ANGPTL3. At the same time, the study did not detect reductions in the expression of ABCA1 and ABCG1 in blood cells, genes used here as markers linked to reverse cholesterol transport.

The trial results show that selective reduction of LXR activity in the liver and intestine by TLC-2716 could offer a new avenue, complementary to other approaches, to address high triglyceride levels and related metabolic disorders.

Phase 1 data support further clinical testing in Phase 2 studies, including in people with hypertriglyceridemia and MASLD. Larger trials will be needed, but for now, the concept has its first proof of concept in humans.