Monday, November 25, 2024
11/25/2024
DESCRIPTION (provided by applicant): 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.
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