TLC-2716 Achieves Primary Endpoints in Phase 2a Trial in Patients With SHTG and MASLD

TLC-2716, an oral, liver-targeted liver X receptor (LXR) inverse agonist in development by OrsoBio, has met its primary efficacy endpoint in patients with severe hypertriglyceridemia (SHTG) and metabolic dysfunction-associated steatotic liver disease (MASLD).1

Announced on February 10, 2026, OrsoBio announced positive topline results from a phase 2a proof-of-concept study evaluating TLC-2716 in reducing fasting triglyceride and improving remnant cholesterol and hepatic fat. This was a randomized, double-blind, placebo-controlled study including once-daily oral doses of TLC-2716 6 mg or 12 mg for 4 weeks.1

“These Phase 2a data provide compelling clinical validation of LXR inverse agonism as a differentiated therapeutic strategy for severe metabolic disorders,” Rob Myers, MD, chief medical officer and head of development for OrsoBio, said in a statement. “The substantial reductions in triglycerides, remnant cholesterol, and other atherogenic lipids – along with improvements in liver fat and a favorable safety profile – support the potential of TLC-2716 to become a meaningful therapeutic option for patients with diseases driven by excessive lipid production, including SHTG, [metabolic dysfunction-associated steatohepatitis (MASH)], and elevated remnant cholesterol.”1

TLC-2716 is an oral, small-molecule, liver-targeted, inverse LXR agonist, designed to modulate key pathways connected to lipid homeostasis. The drug targets de novo lipogenesis, lipoprotein clearance, and intestinal lipid absorption. Liver X receptors are oxysterol-activated nuclear hormone receptors, typically modulating plasma triglycerides and cholesterol via several complementary mechanisms.1

In total, the study included a 4-week screening period, a 4-week treatment period, and a 2-week follow-up period. Investigators included patients with a body mass index (BMI) ≥28 kg (61.7 lb)/m2 and a fasting triglyceride ≥350 mg/dL without diabetes or with diabetes and HbA1c <9.5% at screening. Additionally, patients were required to have a diagnosis of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) within 5 years of screening based on hepatic imaging and be normotensive or without uncontrolled hypertension, which was defined as systolic blood pressure >155 mmHg and/or diastolic blood pressure >90 mmHg at screening.2

Patients were excluded if they had HbA1c ≥9.5% at screening, weight loss >5% during the 90 days before screening, a positive test for human immunodeficiency virus antibody, hepatitis B surface antigen, or hepatitis C antibody, or a medical history of liver disease other than NAFLD/NASH. Additionally, those with unstable cardiovascular disease, a history of intestinal resection or malabsorptive conditions, or the presence of severe peptic ulcer, gastroesophageal reflux disease, or other gastric acid hypersecretory conditions at screening, among other criteria.2

A total of 30 adults with overweight and fasting triglycerides ≥350 mg/dL with evidence of MASLD via imaging or biopsy were enrolled. These patients were then randomly assigned to TLC-2716 6 mg, 12 mg, or matched placebo. The primary endpoints were the relative percent change in fasting triglycerides at week 4 and incidence of treatment-emergent adverse events. Both were measured up to day 28 of the study.1,2

Ultimately, TLC-2716 demonstrated consistent improvements across total cholesterol, non-HDL cholesterol, and VLDL cholesterol. Investigators determined that these data support continued evaluation. These data follow a recent publication of first-in-human phase 1 clinical data, which demonstrated clinical and mechanistic validation of TLC-2716 across human genetics and organoid systems.1

“We look forward to presenting a comprehensive dataset at a future scientific conference to provide a more detailed characterization of the therapeutic profile of TLC-2716,” Myers said. “These results support continued development of TLC-2716 across multiple severe metabolic disorders, which collectively affect millions of patients worldwide.”1

References

1. OrsoBio, Inc. OrsoBio Announces Positive Topline Phase 2a Data for LXR Inverse Agonist TLC-2716 in Severe Hypertriglyceridemia and Metabolic Liver Disease. BusinessWire. February 10, 2026. Accessed February 10, 2026. https://www.businesswire.com/news/home/20260210425918/en/OrsoBio-Announces-Positive-Topline-Phase-2a-Data-for-LXR-Inverse-Agonist-TLC-2716-in-Severe-Hypertriglyceridemia-and-Metabolic-Liver-Disease

2. OrsoBio, Inc. Phase 2a Study of Safety, Tolerability, and Efficacy of TLC-2716 in Subjects With Hypertriglyceridemia and NAFLD. ClinicalTrials.gov Identifier: NCT06564584. Updated April 3, 2025. Accessed February 10, 2026. https://clinicaltrials.gov/study/NCT06564584