A new study in Nature Medicine reports early clinical data on TLC-2716, an investigational oral drug designed to lower triglyceride-rich lipoproteins by acting mainly in the liver and gut. The drug is a liver X receptor inverse agonist, developed to improve lipid profiles while limiting systemic exposure.
Triglycerides and remnant cholesterol are increasingly recognized as clinically relevant risk markers, particularly in patients with residual cardiovascular risk despite standard lipid-lowering therapy. These measures are commonly checked in practice alongside low-density lipoprotein cholesterol (LDL-C) when evaluating dyslipidemia, metabolic syndrome, and cardiometabolic risk.
The researchers described a development program that included preclinical testing and a randomized, placebo-controlled phase 1 study in healthy volunteers, wrote lead study author Xiaoxu Li, PhD, of École Polytechnique Fédérale de Lausanne, and colleagues. In animal models, TLC-2716 reduced triglycerides and total cholesterol and lowered expression of liver genes linked to lipogenesis. The researchers also reported that short-term safety lab testing in animals did not show signs of liver injury.
In the phase 1 trial, 100 healthy participants were enrolled across single-ascending dose and multiple-ascending dose cohorts. In the multiple-dose portion, participants received TLC-2716 at doses of 0.5 mg, 2 mg, 6 mg, or 12 mg once daily for 14 days, or placebo.
Following 14 days of treatment, the strongest lipid effects were seen at the 6 mg and 12 mg doses. Compared with placebo, triglycerides decreased by up to approximately 38%. Postprandial remnant cholesterol also decreased, with reductions reported up to approximately 61%. The study also reported improvements in other lipid markers used in clinical assessment, including non–high-density lipoprotein cholesterol (non-HDL-C) and LDL particle number.
Because this was a phase 1 trial, the primary goal was safety and tolerability rather than long-term clinical benefit. The researchers reported no serious adverse events, no treatment discontinuations, and no clinically concerning changes in safety lab results, electrocardiogram findings, or vital signs during the short study period. Reported side effects were mostly mild and included headache and gastrointestinal symptoms.
Larger and longer studies will be needed to determine how durable these effects are and whether they translate into improved clinical outcomes.
Disclosures can be found in the study.
Source: Nature
