Stroke activates the nuclear enzyme poly (ADP-ribose) polymerase (""""""""PARP""""""""), triggering cells to undergo necrosis and inflammation. Inotek's ultrapotent clinical PARP inhibitor (""""""""INO-1001') profoundly reduces tissue necrosis and neurologic dysfunction in transient and permanent ischemic rat stroke models. Our data are in agreement with genetic deletion studies in stroked mice, which demonstrate > 80% neuroprotection in MCA occlusion models. We now propose a clinical study of INO-1001 to confirm tolerability, pharmacokinetics, and safety in a population with acute stroke. ? Based on clinical studies of INO-1001 in healthy subjects, we expect that INO-1001 will be ? Well-tolerated and safe, and maintain therapeutic drug plasma concentrations for 24 hours after a ? single bolus. We will test this hypothesis by carrying out a prospective, open-label multi-center study ? of n=30 subjects presenting with a clinical diagnosis and CT confirmation of acute non-lacunar ? ischemic stroke. A dose-escalation is planned, structured in cohorts of n=10 subjects per dose level. ? Subjects will be continuously monitored and observed for alterations in vital signs, physical exam, ? electrocardiogram, metabolic status, and clinical chemistries, hematologic and coagulation ? parameters, and plasma drug concentration. Whilst clinical outcome will be recorded, this is not ? intended to be a therapeutic trial, and wall include stable patients, who are able to consent themselves ? and report symptoms, with more detailed pharmacokinetic and tolerability monitoring than would ? be typical in a large multi-center investigation of efficacy. In a follow-on Phase 2 SBIR, we will carry ? out a pivotal study of INO-1001 in 900 patients to establish efficacy in a population with acute ? non-lacunar ischemic stroke. We will assess the effect of INO-1001 on 1) brain infarction, as ? quantitated by MRI, and 2) neurologic dysfunction, as assessed at baseline, 4 days, I week, 2 weeks, ? and I month by (a) NIHSS modified Rankin and Barthel score. ? ?
