Dataset Information

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.

SUBMITTER: Kaufman A

PROVIDER: S-EPMC7659583 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Kaufman Allegra A Abuqayyas Lubna L Denney William S WS Tillman Erik J EJ Rolph Tim T

Cell reports. Medicine 20200721 4

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 s ...[more]

PMID: 33205064

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Project description:PurposeTo 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.MethodsA 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.ResultsOf 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.ConclusionsIn 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 identifierNCT03466203.

Dataset Information

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

Publications

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

Similar Datasets

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