Neutralization of α2 -antiplasmin by microplasmin: A randomized, double-blind, placebo-controlled, ascending-dose study in healthy male volunteers

• Published in: Clinical therapeutics Vol. 31; no. 8; pp. 1688 - 1706
• Main Authors: Pakola, Steve, MD, Cahillane, Geraldine, BA, Stassen, Jean-Marie, PhD, Lijnen, H. Roger, PhD, Verhamme, Peter, MD, PhD
• Format: Journal Article
• Language: English
• Published: Bridgewater, NJ Elsevier 01.08.2009
• Subjects: Biological and medical sciences; Internal Medicine; Medical Education; Medical sciences; Neurology; Pharmacology. Drug treatments; Vascular diseases and vascular malformations of the nervous system; fibrinolysis; tissue-plasminogen activator; microplasmin; plasmin; neuroprotection; α 2-antiplasmin; stroke; Neuroprotection; Cardiovascular disease; Plasmin; t-Plasminogen activator; Vascular disease; Randomization; Dose; Cerebrovascular disease; Human; Nervous system diseases; Stroke; Healthy subject; Serine endopeptidases; α2 antiplasmin; antiplasmin; Enzyme; Enzyme inhibitor; Fibrinolysis; Cerebral disorder; Peptidases; α; Plasmin inhibitor; Central nervous system disease; Placebo; Double blind study; Hydrolases; Neutralization
• ISSN: 0149-2918
• DOI: 10.1016/j.clinthera.2009.08.019

Abstract Background: Microplasmin is the isolated proteinase domain of plasmin. Administration of microplasmin has been found to neutralize α2 -antiplasmin (α2 -AP) activity, which has been associated with reduced infarct size in various preclinical models of stroke. Objectives: The goals of this first-in-man study were to investigate the ability of microplasmin to neutralize α2 -AP activity and to monitor its tolerability in healthy male volunteers. Methods: This Phase I, double-blind, placebo-controlled, ascending-dose study included 10 groups, each containing 6 subjects who were randomized to receive microplasmin or placebo in a 2:1 ratio. The study had 3 parts. In part 1, subjects received a single intravenous bolus of microplasmin 0.1, 0.5, 1, 1.5, or 2 mg/kg or placebo over 15 minutes. In part 2, subjects received a bolus of microplasmin 1 mg/kg or placebo, followed by an infusion of 1, 2, 3, or 4 mg/kg or placebo over 60 minutes. In part 3, subjects, all of whom were aged >55 years, received a bolus of mi-croplasmin 1 mg/kg or placebo, followed by an infusion of 1 mg/kg or placebo. The primary pharmaco-dynamic end point was the change in α2 -AP activity, measured at different time points up to 4 days after dosing using a chromogenic assay. All adverse events were monitored based on spontaneous reports and nondirected questioning at study visits up to the post-study visit 21 days after administration of study drug. Results: The mean (SD) age of subjects in parts 1, 2, and 3 was 30 (8), 30 (8), and 64 (8) years, respectively. All groups receiving microplasmin had a dose-dependent decrease in α2 -AP activity. In part 1, the mean maximal inhibition of α2 -AP was 11.8% (6.0%), 27.7% (4.3%), 53.0% (4.8%), 65.3% (4.3%), and 84.0% (6.0%) after bolus administration of microplasmin 0.1, 0.5, 1, 1.5, and 2 mg/kg, respectively, and 7.4% (6.9%) after administration of placebo. In part 2, the mean maximal inhibition of α2 -AP was 74.6% (11.2%), 95.5% (3.3%), 99.0% (1.0%), and 88.0% (12.5%) after bolus administration of microplasmin 1 mg/kg followed by an infusion of 1, 2, 3, and 4 mg/kg, respectively, compared with 12.9% (6.8%) after administration of placebo. In part 3, the mean maximal inhibition was 69.7% (3.4%) after bolus administration of microplasmin 1 mg/kg followed by an infusion of 1 mg/kg, compared with 8.8% (4.1%) with placebo. One subject in the highest dose group in part 1 (2 mg/kg) and 2 subjects in the highest dose group in part 2 (1 + 4 mg/kg) had an urticarial reaction. All 3 subjects also had a decrease in total hemolytic complement and an increase in complement 5a. Conclusions: Neutralization of α2 -AP activity by microplasmin was feasible in these healthy male volunteers. The urticarial reactions observed in the highest dose groups were considered dose-limiting adverse events. Further trials are needed to investigate the tolerability of this therapy and whether it is neuroprotective in patients with acute ischemic stroke.