AKR-001, an Fc-FGF21 Analog, Showed Sustained Pharmacodynamic Effects on Insulin Sensitivity and Lipid Metabolism in Type 2 Diabetes Patients

Abstract

Experimental fibroblast growth factor 21 (FGF21) analogs can improve lipid profiles in patients with metabolic diseases. However, their effects on markers of insulin sensitivity appear to be minimal, potentially because of insufficient exposure. Systemic drug levels vary from sub-pharmacological to demonstrating pharmacodynamic effects but with dose-limiting adverse events. Here we report results from a phase 1 multiple ascending dose study of AKR-001, an Fc-FGF21 fusion protein engineered for sustained systemic pharmacologic exposure, in individuals with type 2 diabetes. With a half-life of 3–3.5 days, the peak-to-trough ratio under steady-state conditions is approximately 2 following QW dosing. AKR-001 appears to demonstrate pharmacodynamic effects on serum markers of insulin sensitivity and acceptable tolerability up to and including 70 mg QW. Positive trends in lipoprotein profile, including triglycerides, non-high-density lipoprotein (non-HDL) cholesterol, HDL-C, and apolipoproteins B and C3 are consistent with other FGF21 analogs. AKR-001’s clinical profile supports further evaluation as a treatment for metabolic diseases. FGF21 ameliorates metabolic disease in animal models but has modest effects in humans. Kaufman et al. report the pharmacokinetic, pharmacodynamic, and safety data from a phase 1 multiple ascending dose study in T2DM of AKR-001, a long-acting FGF21 analog. They show that AKR-001 exhibits positive trends in various metabolic markers.