New oral drug safely lowers triglycerides and other blood lipids in Phase 1 trial

In a Phase 1 clinical study, researchers led by EPFL and their partners report that a new liver- and gut-targeted oral drug can safely lower triglycerides and other blood lipids.

When we eat, our bodies convert extra calories, especially from carbs, sugar, fats, and alcohol, into molecules called "triglycerides". Triglycerides are a form of fat or "lipid", which the body stores away into its fat cells as an energy fuel for energy between meals.

But, as we all know, excess amounts of fat in the body can be dangerous, causing a condition known as "hypertriglyceridemia" ("excess triglycerides in the blood"), which significantly increases the risk of heart disease, stroke, and pancreatitis. This is why we are universally advised to make healthy lifestyle choices in diet, exercise, while particularly bad cases require medication.

Dialing down a receptor

Keeping blood fats in check depends on a careful balance. The liver and intestine release fat particles into the bloodstream, while enzymes work to break them down and clear them away. When fat production outpaces clearance, triglycerides build up, setting the stage for metabolic diseases like dyslipidemia, acute pancreatitis, and metabolic dysfunction-associated steatotic liver disease (MASLD).

One of the master switches in this system is a protein called Liver X Receptor, or LXR, which controls several genes that are involved in making and handling fats.

When LXR is active, triglycerides and cholesterol tend to rise. Dialing it down through medication seems promising, but as LXR is also involved in protective cholesterol pathways elsewhere in the body, blocking it everywhere could do more harm than good. This dilemma has held the field back for years.

A drug that specifically targets liver LXR

Now, scientists led by Johan Auwerx at EPFL and Mani Subramanian at OrsoBio have addressed this problem with an orally administered compound that can repress the activity of LXR specifically in the liver and gut to lower triglycerides without disrupting the body's protective cholesterol pathways.

The compound, TLC‑2716, is what is known as an "inverse agonist" for the LXR. Unlike a "blocker" ("antagonist") that merely stops a receptor from being activated, an "inverse agonist" makes the receptor signal the opposite effect to what it would normally do.

The study, which is published in Nature Medicine, is the first of this type to be tested in humans.

Combing genetic datasets to find the right receptor variant

The scientists began by analyzing large human genetics datasets to determine which LXR variant is related to biomarkers for elevated triglycerides in the blood. The data pointed to the genetic variants within LXRα, which is highly expressed in the liver.

This was further confirmed through "Mendelian randomization", a powerful method that determines causal relationships between gene expression and outcomes. In this case, it confirmed a causal link between LXRα and metabolic disorders: higher LXRα expression can drive triglycerides upward.

The findings helped select TLC‑2716 as an effective compound to test against LXRα.

Testing the compound

The study then moved from computers into the lab. In rodent models of metabolic disease, TLC‑2716 and a related compound lowered triglycerides and cholesterol in the blood and reduced fat accumulation in the liver. Meanwhile, experiments in human liver organoids (miniature lab-grown models of diseased liver tissue), showed the same trend, with less lipid buildup and lower inflammation and fibrosis.

Next was safety. Toxicology studies in mice and non-human primates, combined with pharmacokinetic analyses, showed that TLC‑2716 largely stays in the liver and gut. This is key, as it limits exposure to other tissues where inhibiting LXR could be risky, thus addressing the main problem of developing drugs for treating metabolic diseases related to high triglycerides in the body.

The clinical trial

The lab findings set the stage for a randomized, placebo-controlled Phase 1 study in healthy adults. Participants received TLC‑2716 for 14 days given as a single dose per day and the trial focused first on safety and tolerability, and the authors report that the drug met these primary endpoints.

But even this short trial had clear effects: participants who received higher doses of TLC‑2716 showed notable drops in triglycerides as well as remnant cholesterol. At the highest doses of TLC‑2716 (12mg), triglycerides fell by up to 38.5%, while postprandial ("after eating") remnant cholesterol dropped by as much as 61%. This happened despite participants starting with relatively normal lipid levels and without the use of other lipid-lowering drugs.

The treatment also sped up 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 blood-cell expression of ABCA1 and ABCG1, genes used here as markers linked to reverse cholesterol transport.

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. The 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 human proof of principle.