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

Allegra Kaufman, Lubna Abuqayyas, William S Denney, Erik J Tillman, Tim Rolph, Allegra Kaufman, Lubna Abuqayyas, William S Denney, Erik J Tillman, Tim Rolph

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.

Trial registration: ClinicalTrials.gov NCT01856881.

Conflict of interest statement

A.K. is a shareholder of Amgen and was an employee of Amgen at the time of this study. L.A. is an employee and shareholder of Amgen. W.S.D. is a consultant to Akero Therapeutics. E.J.T. is a shareholder and employee of Akero Therapeutics. T.R. is a co-founder, shareholder, and employee of Akero Therapeutics and shareholder of Pfizer. Akero Therapeutics has licensed exclusive rights to patents relating to AKR-001’s composition and use.

© 2020 The Author(s).

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Summary of the Trial Design See also Figure S1.
Figure 2
Figure 2
PK Profile of AKR-001 in Type 2 Diabetic Patients (A and B) Median serum concentration of intact AKR-001 following (A) weekly (QW) and (B) once every 2 weeks (Q2W) dose regimens.
Figure 3
Figure 3
Effect of AKR-001 on Markers of Glycemic Control and Lipid Metabolism (A–H) Concentration change from baseline of fasted-state (A) glucose, (B) insulin, (C) C-peptide, (D) glucagon, (E) HOMA-IR, (F) HDL cholesterol, (G) non-HDL cholesterol, and (H) triglycerides by study day for placebo (n = 7–9), 21 mg (n = 5–6), and 70 mg (n = 5–6) QW dose cohorts. Data are presented as least-squares mean ± 95% confidence intervals. See also Figure S2.

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