LY2405319

LY2405319 is a synthetic peptide and engineered analog of human fibroblast growth factor 21 (FGF21), developed by Eli Lilly. It was designed to improve the biopharmaceutical properties of native FGF21 while retaining its metabolic activity. Modifications include an additional disulfide bond (Leu118Cys-Ala134Cys), deletion of four N-terminal amino acids, and a Ser167Ala mutation, resulting in enhanced stability and reduced proteolysis[5][6]. LY2405319 acts as an agonist/modulator at FGF receptors in the presence of the co-receptor β-Klotho, activating downstream signaling pathways that regulate glucose and lipid metabolism. In clinical studies involving obese patients with type 2 diabetes mellitus (T2DM), subcutaneous administration for 28 days led to improvements in dyslipidemia (lower LDL cholesterol and triglycerides, higher HDL cholesterol), reduced body weight, decreased fasting insulin levels, increased adiponectin levels, and favorable changes in apolipoprotein profiles[6][8]. The drug also demonstrated efficacy in preclinical models for reducing liver inflammation and fibrosis[6]. Despite these metabolic benefits—including improved lipid parameters—only modest effects on blood glucose were observed in humans[8]. Development for T2DM has not progressed beyond early clinical trials.