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Cardiovascular Endocrinology

ORF30-06 - The Liver X Receptor Inverse Agonist TLC-2716 Reduces Triglycerides, Remnant Cholesterol, and Liver Fat in Patients with Severe Hypertriglyceridemia and Metabolic Dysfunction-Associated Steatotic Liver Disease

Sunday, June 14, 2026
2:30 PM - 2:45 PM CT
Location: Room W181AB



Background: Severe hypertriglyceridemia (SHTG) is associated with increased risk of acute pancreatitis, cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). TLC-2716 is a potent, oral, liver-targeted inverse agonist of liver X receptor (LXR) that lowers plasma lipids by suppressing hepatic de novo lipogenesis, enhancing triglyceride (TG)-rich lipoprotein clearance, and reducing intestinal lipid absorption. We report preliminary safety and efficacy of TLC-2716 in a Phase 2a proof-of-concept study of patients with SHTG and MASLD.

Methods: This double-blind, placebo-controlled trial (NCT06564584) enrolled overweight adults (BMI ≥28 kg/m2) with SHTG and MASLD, randomized 1:1:1 to TLC-2716 6 mg (n=10), 12 mg (n=10), or placebo (n=10) once daily for 4 weeks (W4). All participants had fasting TGs ≥350 mg/dL and MASLD by imaging and/or biopsy. The primary endpoint was the percent change from baseline (BL; Day 1) in fasting TGs at W4. Due to lipid variability, pre-specified sensitivity analyses defined BL as the mean of all pre-dose (screening and Day 1) values. Additional assessments included safety, changes in other lipids and biomarkers, including remnant cholesterol (RC), and liver fat by MRI-PDFF.

Results: 30 patients were randomized (mean age 48.8 years; 57% female; BMI 31.3 kg/m2; 23% diabetes; 17% on fibrates; 13% on statins; MRI-PDFF 15.5%). Mean (SD) plasma TGs and RC at BL were 701 mg/dL (584) and 97 mg/dL (91), respectively; 47% (n=14) had BL TGs ≥500 mg/dL. In the primary analysis, mean (95% CI) placebo-adjusted TG reductions from BL to W4 were 48% (2.7% to 92.9%; p=0.038) with 6 mg and 28% (-15.4% to 72.4%; p=0.193) with 12 mg. In a pre-specified sensitivity analysis defining BL as the mean of all pre-dose TG values, significant placebo-adjusted TG reductions were observed with both doses (6 mg: 57% [26.5% to 88.4%], p=0.001; 12 mg: 46% [15.7% to 75.9%], p=0.004). Among patients with BL TGs ≥500 mg/dL, TLC-2716 6 mg and 12 mg reduced TGs by 62% (18.5% to 105.3%; p=0.008) and 62% (14.7% to 108.3%; p=0.013) vs placebo, respectively. Placebo-adjusted RC reductions were 57% (19.7% to 94.0%; p=0.005) and 51% (13.9% to 88.8%; p=0.010), respectively. Compared to placebo, TLC-2716 (6 mg and 12 mg pooled) also reduced total cholesterol (23%, p=0.005), non-HDL-C (31%, p=0.007), and VLDL-C (58%, p< 0.001). At W4, ≥30% relative reduction from BL in liver fat by MRI-PDFF was observed in 50% (5/10), 56% (5/9), and 30% (3/10) of patients receiving 6 mg, 12 mg, and placebo, respectively. TLC-2716 was generally well tolerated, with no Grade ≥3 or serious adverse events.

Conclusion: In this 4-week, proof-of-concept study in patients with SHTG and MASLD, the liver-targeted LXR inverse agonist TLC-2716 produced clinically meaningful improvements in TGs, RC, and hepatic fat. Comparable activity at both doses supports evaluation of lower doses to optimize benefit-risk.