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

Abstract

Summary 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: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases

“…In addition to directly enhancing energy uptake in adipose tissue, FGF21 potently stimulates secretion of adiponectin from adipocytes (44,100,225,236,242,243). Increased levels of adiponectin in non-human primates and humans with metabolic disease (type 2 diabetes, obesity and NASH) have been consistently observed following treatment with various FGF21 analogs (183,(244)(245)(246). As an adipokine, adiponectin signals from adipose tissue to distal tissues including liver (247).…”

“…Increased levels of corticotropin-releasing hormone or corticosterone/cortisol with FGF21 or FGF21 analog treatment have been reported in rodents, but not in non-human primates nor in any human studies (183,293,313). Likewise, reports of FGF21 increasing water intake and blood pressure in rodents, potentially by stimulating sympathetic pathways (313, 314) do not appear to translate consistently to humans, with one study (293) but no others (183,(244)(245)(246)315) suggesting an effect. The lack of effect is consistent with blood pressure phenotypes of humans with FGF21 genetic variants.…”

FGF19 and FGF21 for the Treatment of NASH—Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human

“…In a Phase 1b trial of 4 weeks duration 7–140 mg of Efruxifermin lowered plasma TG and LDLc and increased HDLc. Postprandial decrease in FFA was also observed in subjects treated with Efruxifermin ( 206 ). Efruxifermin also lowered BG and glycosylated HbA1c and an increase in insulin sensitivity was observed at the 70 mg once weekly dosing.…”

“…While a handful of FXR agonist are in late stage clinical trials (17) there is currently only one FGF19 analogue in clinical development and as described previously it is important to separate the mitogenic signaling from the metabolic action of FGF19. Aldafermin NGM282 (Aldafermin) is a non-mitogenic FGF19 analogue with 5-amino acid deletion (P24-S28) and 3 amino acids substitutions at critical positions (A30S, G31S, H33L) within the amino terminus (183,206). The analogue is not protracted, and once daily subcutaneous dosing is required.…”

“…NGM282 (Aldafermin) is a non-mitogenic FGF19 analogue with 5-amino acid deletion (P24-S28) and 3 amino acids substitutions at critical positions (A30S, G31S, H33L) within the amino terminus ( 183 , 206 ). The analogue is not protracted, and once daily subcutaneous dosing is required.…”