Rader, Daniel, Maratos-Flier, Terry, Nguyen, Amanda, Hom, Douglas, Ferriere, Michael, Li, Yifang, Kompa, Jill, Martic, Miljen, Hinder, Markus, Basson, Craig, Yowe, David, Diener, John and Goldfine, Allison (2021) LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in obese persons with modestly elevated triglycerides: A 12 Week Randomized Double Blind Placebo Controlled Study. Journal of Clinical Endocrinology and Metabolism.

Abstract

Purpose: To 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.

Methods: A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic and otherwise apparently healthy adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every four weeks for three doses.

Results: Of 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 kg/m2) 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.

Conclusions: In 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.

Item Type:	Article
Keywords:	Fibroblast growth factor 21 (FGF21), Hypertriglyceridemia, Obesity, Nonalcoholic Fatty Liver Diseases (NAFLD), Metabolism
Date Deposited:	28 Sep 2021 00:45
Last Modified:	28 Sep 2021 00:45
URI:	https://oak.novartis.com/id/eprint/45403