LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in Obese Adults With Modest Hypertriglyceridemia

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 adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses.

Results: Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with 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 homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin 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 nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted.

Clinicaltrials.gov identifier: NCT03466203.

Keywords: fibroblast growth factor 21 (FGF21); hypertriglyceridemia; metabolism; nonalcoholic fatty liver diseases (NAFLD); obesity.

Figure 1.

The CONSORT flow diagram provides a summary of study progress from screening through analysis, by treatment arm.

Figure 2.

Effects of LLF580 and placebo are shown for fasting plasma lipids including percent of baseline by treatment group for (A) triglycerides, (B) total cholesterol, (C) low-density lipoprotein (LDL) cholesterol, and (D) high-density lipoprotein (HDL) cholesterol. LDL-cholesterol concentrations were measured directly. (-●-, black) LLF580, (-●-, gray) placebo. The mixed model repeated measures framework described in the statistical methods was used for the log ratio to baseline and the 95% CIs that resulted are shown.

Figure 3.

Effects of LLF580 and placebo are shown for hepatic measures including (A) hepatic fat fraction (%) assessed by magnetic resonance imaging performed fasting at baseline (day 0) and postdose (day 85) by spaghetti plots of individual patients assigned to LLF580 (left) or placebo (right). The difference in change in mean hepatic fat fraction between LLF580 and placebo with 95% CIs is provided. Hepatic fat is considered normal below 5% and elevated above 8%, with boundaries shown by dashed lines. (B) The percent of participants with than 30% (■, gray) or greater than or equal to 30% (■, black) reduction in hepatic fat less are shown for LLF580 (left) and placebo (right) groups. Change from baseline for (C) alanine aminotransferase (ALT), (D) aspartate transaminase (AST), and (E) pro-peptide of type III collagen (Pro-C3) (-●-, black) LLF580, (-●-, gray) placebo. The mixed model repeated measures framework described in the statistical methods was used for the log ratio to baseline and the 95% CIs that resulted are shown.