AKR-001, an Fc-FGF21 Analog, Showed Sustained Pharmacodynamic Effects on Insulin Sensitivity and Lipid Metabolism in Type 2 Diabetes Patients
Open accessAbstract
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.
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All FGF21 analogues consistently have a pronounced ability to decrease plasma triglyceride levels, in many cases by as much as ~70%.
“all analogues consistently have a pronounced ability to decrease plasma triglyceride levels, in many cases by as much as ~70% (refs. 81,87–91).”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
Effects of different FGF21 compounds on glucose homeostasis and insulin sensitivity vary: some do not significantly affect insulin sensitivity, while others significantly increase it in people with type 2 diabetes.
“some compounds do not significantly affect insulin sensitivity81, while others significantly increase insulin sensitivity in people with type 2 diabetes87,88.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
The magnitude of glucose-lowering effects of FGF21 analogues is clearly lower in humans than rodents.
“the magnitude of the glucose-lowering effects of FGF21 analogues is clearly lower in humans than rodents81,87–91, perhaps because of differences in brown adipose tissue metabolism between species65.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
Two other FGF21 analogues AKR-001 and pegbelfermin have not been found to significantly decrease body weight in people with obesity or type 2 diabetes.
“two other FGF21 analogues, AKR-001 (also known as efruxifermin)88 and pegbelfermin89,90, have not been found to significantly decrease body weight in people with obesity or type 2 diabetes.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
FGF21's triglyceride-lowering effects are mediated by altered adipose and liver metabolism: accelerated lipoprotein catabolism, suppression of postprandial lipolysis, decreased hepatic ER and oxidative stress, and increased beta-oxidation of lipids in the liver.
“Pharmacological administration of FGF21 or FGF21 analogues exerts lipid-lowering effects through accelerated lipoprotein catabolism108, suppression of postprandial lipolysis in adipose tissues88, decreased hepatic endoplasmic reticulum and oxidative stress109,110, and increased beta-oxidation of lipids in the liver62”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
Clinical studies in patients with obesity and type 2 diabetes have found FGF21-analogue administration markedly induces plasma adiponectin levels.
“clinical studies in patients with obesity and type 2 diabetes have found that FGF21-analogue administration markedly induces plasma adiponectin levels81,87–89”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
Most adverse effects associated with FGF21-analogue administration are gastrointestinal.
“most adverse effects associated with FGF21-analogue administration are gastrointestinal81,87,88.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
In humans, administration of FGF21 analogues has conflicting effects on bone turnover: PF-05231023 increases markers of bone turnover, whereas AKR-001 and pegbelfermin have not.
“PF-05231023 has been found to increase markers of bone turnover in humans81, whereas AKR-001 (ref. 88) and pegbelfermin89 have not.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
Administration of FGF21 analogues AKR-001 and pegbelfermin in humans with NASH results in marked absolute decreases in liver fat (up to 70%) and significant amelioration of liver fibrosis.
“Administration of the FGF21 analogues AKR-001 (ref. 88) and pegbelfermin89 in humans with NASH results in marked absolute decreases in liver fat (up to 70%) and significant amelioration of liver fibrosis88,89.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
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- Authors
- Kaufman, A., Abuqayyas, L., Denney, W. S., Tillman, E. J., & Rolph, T.
- Affiliations
- Amgen (United States) (US)
- Corresponding author
- Rolph, Tim
- Venue
- Cell Reports Medicine
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 1
- Issue
- 4
- Pages
- 100057
- ISSN
- 2666-3791 (ISSN-L)
- PMC
- PMC7659583
- OpenAlex
- W3044370932
- Cited by
- 131
- References
- 82
- Citations by year
- 2026: 12 · 2025: 24 · 2024: 25 · 2023: 21 · 2022: 26 · 2021: 19 · 2020: 4
- FWCI
- 5.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports Medicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Pfizer
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- FGF21 analogs, type 2 diabetes, insulin sensitivity, lipid metabolism, pharmacodynamics, pharmacokinetics, lipoprotein profile, triglycerides, non-HDL cholesterol, apolipoprotein B, apolipoprotein C-III, tolerability
- MeSH terms
- Adult, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Fibroblast Growth Factors, Humans, Insulin, Insulin Resistance, Lipids, Male, Middle Aged, Obesity, Recombinant Fusion Proteins, Triglycerides, United States, Placebo Effect, Lipid Metabolism
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