Abstract 2329: A Randomized Double Blind, Placebo controlled Phase 1a Clinical Trial of THR-18, a PAI-1 Derived peptide, in Normal Volunteers

Background: THR-18 is an 18-mer peptide derived from the sequence of human plasminogen activator inhibitor 1 (PAI-1) that has the ability to bind at the docking site of tissue plasminogen activator (tPA) and not to its catalytic site, thereby uncoupling the beneficial clot-dissolving properties of tPA from its deleterious non-fibrinolytic effects. THR-18 is being developed as an adjunct to tPA in the treatment of acute ischemic stroke and aims to address some of the limiting properties of tPA such as limited response rate, relatively high re-occlusion rate, limited safety profile and short therapeutic window. Methods: this was a phase 1a randomized double blind, placebo controlled study aiming to asses the safety of THR-18 in healthy volunteers. Subjects were treated in five different dose and dose regimen tiers of THR-18 or placebo and were carefully monitored for the occurrence of any side effects. The pharmacokinetics profile of THR-18 in serum was also studied. Results: Pharmcokinetic studies for bolus administration of THR-18 showed a linear Cmax with a half-life of 3-7 minutes. Administration of THR-18 as a 10% bolus followed by continuous drip of the remaining 90% over 60 minutes resulted in stable plasma concentrations over 60 minutes. THR-18 was well tolerated with no severe or serious adverse events at doses of 0.25-1 mg/kg. At the dose of 0.5mg/kg and 1mg/kg, a slight and transient drop in blood pressure with orthostatic hypotension was noted. Discussion: THR-18 appears to be safe and well tolerated in healthy volunteers at doses up to 1 mg/kg. Following the encouraging safety results of THR-18 a phase 1b/2a study assessing the safety of THR-18 in stroke patients is currently ongoing.