CHICAGO – Fibroblast growth factor 21 shows early promise as a novel therapy for a variety of metabolic disorders closely associated with type 2 diabetes.
A first-in-humans, proof-of-concept randomized trial involving 38 patients with type 2 diabetes showed that a pharmaceutically engineered variant of endogenous fibroblast growth factor 21 (FGF21) achieved "rapid and robust" improvements in lipid levels along with weight loss and reduced fasting insulin levels, Dr. Gregory A. Gaich reported at the annual scientific sessions of the American Diabetes Association.
"These results suggest that FGF21-based therapeutics may be useful for select metabolic disorders, including dyslipidemia and obesity. However, higher doses and longer periods of exposure may be required to really fully assess the potential of FGF21-based interventions in patients with type 2 diabetes," said Dr. Gaich of Eli Lilly, Indianapolis.
FGF21, discovered by Eli Lilly scientists, is a nonmitogenic member of the fibroblast growth factor family. It is involved in energy expenditure, induction of brown fat, free fatty acid oxidation, thermogenesis, and other physiologic processes. In primate and other animal studies, administration of exogenous FGF21 showed beneficial effects on lipids, body weight, and serum glucose, observations that paved the way for this randomized trial.
Participants in the 28-day, double-blind study were randomized to once-daily subcutaneous injection of the FGF21 variant, known for now as LY2405319, at 3, 10, or 20 mg or to placebo.
Subjects who received either of the two highest doses of the study drug showed 40%-50% reductions from baseline in serum triglycerides within 7 days, with maintenance of that benefit throughout the remaining 3 weeks of the trial. In contrast, reductions in LDL cholesterol occurred more gradually. By day 28, patients on the FGF21 compound at 10 or 20 mg/day showed 20%-30% reductions in LDL; however, their levels were still falling at that point, so the maximum LDL-lowering effect must await further study.
The levels of HDL cholesterol rose significantly by 15%-20% at all 3 doses of FGF21.
Body weight in the FGF21-treated patients fell by a mean of 1.7 kg. "We were delighted to see what we thought was a pretty encouraging weight loss for such a short study," Dr. Gaich commented.
Reduction in fasting plasma glucose showed a favorable dose-dependent trend that didn’t achieve statistical difference. Patients assigned to FGF21 at 20 mg/day had a 13-mg/dL greater drop over the course of the study than placebo-treated controls.
The reduction in fasting insulin levels with FGF21 was more encouraging. The effect was dose-dependent, with subjects in the 20 mg/day group exhibiting a highly significant 40% decrease from baseline.
Levels of two biomarkers followed serially in the study provide a hint as to FGF21’s mechanism of action. Levels of adiponectin, which is associated with increased insulin sensitivity, increased in dose-dependent fashion across all three groups of FGF21-treated patients and were nearly doubled at 20 mg/day compared to baseline. And levels of beta-hydroxybutyrate, a biomarker for lipid oxidation, showed across-the-board increases of 50%-90%.
No dose-dependent increase in the incidence of hypoglycemia was noted in the study. The chief safety concern was the occurrence of significant hypersensitivity reactions in two FGF21-treated patients, both in the 20 mg/day group. One patient developed a diffuse rash roughly halfway through the treatment period. The other experienced a more severe hypersensitivity reaction, including hypotension, on the second-to-last day of treatment.
Anti-LY2405319 antibodies arose in 80%-87% of patients on the drug at 10 and 20 mg/day. The clinical significance, if any, of these antibodies awaits further study. In this small initial study, there was no association between antibody production and any of the efficacy or safety parameters. Only one of the two patients with hypersensitivity reactions was antibody-positive, according to Dr. Gaich.
Dr. Gaich is an employee of Eli Lilly, which sponsored the study.