LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in obese adults with modest hypertriglyceridemia.

Abstract

PURPOSE\nTo evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction.\n\n\nMETHODS\nA multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300\xa0mg or placebo subcutaneously every four weeks for three doses.\n\n\nRESULTS\nOf 64 randomized study participants, 61 (mean±SD: age 45±11 years, 49% male, 80/15/5% Caucasian/African American/Other, BMI 36.1±3.8\xa0kg/m 2) received LLF580 (n=30) or placebo (n=31) at 7 research sites in the USA. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, LDL-cholesterol 12%, and increased HDL-cholesterol 36% compared to placebo (all P<0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P<0.001) was also demonstrated, in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P<0.05). Insulin and C-peptide levels and insulin resistance by HOMA-IR were all lower, and adiponectin higher with LLF580 treatment compared to placebo, while fasting glucose and HbA1c were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects.\n\n\nCONCLUSIONS\nIn obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and non-alcoholic fatty liver disease. Assessments of longer-term safety and efficacy are warranted.