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OBJECTIVE-Metabolic activation of the innate immune system governed by interleukin(IL)-1β contributes to β-cell failure in type 2 diabetes. Gevokizumab is a novel, human-engineered monoclonal anti-IL-lß antibody. We evaluated the safety and biological activity of gevokizumab in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS-In a placebo-controlled, dose-escalation study, a total of 98 patients were randomly assigned to placebo (17 subjects) or gevokizumab (81 subjects) at increasing doses and dosing schedules. The primary objective of the study was to evaluate the safety profile of gevokizumab in type 2 diabetes. The secondary objectives were to assess pharmacokinetics for different dose levels, routes of administration, and regimens and to assess biological activity.
RESULTS-The study drug was well tolerated with no serious adverse events. There was one hypoglycemic event whereupon concomitant insulin treatment had to be reduced. Clearance of gevokizumab was consistent with that for a human IgG^sub 2^, with a half-life of 22 days. In the combined intermediate-dose group (single doses of 0.03 and 0.1 mg/kg), the mean placebo-corrected decrease in glycated hemoglobin was 0.11, 0.44, and 0.85% after 1,2 (P = 0.017), and 3 (P = 0.049) months, respectively, along with enhanced C-peptide secretion, increased insulin sensitivity, and a reduction in C-reactive protein and spontaneous and inducible cytokines.
CONCLUSIONS-This novel IL-1β-neutralizing antibody improved glycemia, possibly via restored insulin production and action, and reduced inflammation in patients with type 2 diabetes. This therapeutic agent may be able to be used on a once-every-month or longer schedule.
Diabetes Care 35:1654-1662, 2012
Onset of type 2 diabetes occurs when pancreatic β-cells fail to adapt to the increased insulin demand caused by insulin resistance. Morphological and therapeutic intervention studies have uncovered an inflammatory process in islets of patients with type 2 diabetes characterized by the presence of cytokines, immune cells, ß-cell apoptosis, amyloid deposits, and fibrosis. This is attributed to a pathological activation of the innate immune system by metabolic stress and is governed by interleukin (IL)-I signaling (1-4).
Based on the above-described islet inflammation with a predominant role for IL- Iß, we initiated clinical trials of IL-I antagonism in type 2 diabetes. In a proofof-concept study, the naturally occurring antagonist of IL- Iß, IL-I receptor agonist (IL-IRa), was tested in a placebo-controlled study of 70 patients (5). At...