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Pharmacologic Suppression of Reperfusion Injury Following Endovascular Thrombectomy In Stroke.

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41NS110252-01A1
Agency Tracking Number: R41NS110252
Amount: $475,175.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 102
Solicitation Number: PA18-575
Timeline
Solicitation Year: 2018
Award Year: 2019
Award Start Date (Proposal Award Date): 2019-09-15
Award End Date (Contract End Date): 2021-08-31
Small Business Information
4650 S FOREST ST
Englewood, CO 80113-6100
United States
DUNS: 079124042
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 DAVID WARNER
 (919) 684-6633
 warne002@mc.duke.edu
Business Contact
 JAMES CRAPO
Phone: (303) 221-3201
Email: jdc@crapodenver.com
Research Institution
 DUKE UNIVERSITY
 
2200 W MAIN ST, SUITE 820
DURHAM, NC 27705-4673
United States

 Nonprofit college or university
Abstract

Ischemic stroke is a leading cause of death and disability in the United States. This often is
attributable to thrombus formation at an atherosclerotic plaque or thromboembolism. Patients
who present within 4.5 hours of symptom onset are eligible for thrombolysis with tissue
plasminogen activator (tPA). This serves andlt;5% of victims. Recently, major advance has been
made with proven efficacy from endovascular mechanical thrombectomy in combination with
tPA. Despite this, andlt;50% of treated patients have a good recovery. Basic and clinical science
indicate that abrupt restoration of oxygen delivery to ischemic tissue causes reperfusion injury
that amplifies/propagates adverse cascades initiated by the initial ischemic insult. There has
been widespread call for pharmacologic intervention to mitigate reperfusion injury. The
mechanistic basis for reperfusion injury is diverse, but fundamentally associated with rapid
onset dysfunction of intracellular mechanisms responsible for regulation of oxygen metabolism.
This leads to oxidative stress, inflammation, apoptosis, blood-brain barrier disruption and tissue
damage. We are working closely with chemists who have synthesized manganese porphyrins
(MnP). MnP have been highly characterized and serve as potent catalytic oxidoreductants. MnP
have extraordinary efficacy to favorably modulate redox-mediated activation of transcription
factors (e.g., NF-kB, Nrf2) and MAPK and phosphatases. MnP also serve as potent catalytic
reductants of reactive oxygen/nitrogen species. We have repeatedly shown enduring
improvement in experimental stroke long-term outcome after therapeutic MnP dosing. The lead
MnP, BMX-001, now in human trials as a radioprotectant for normal tissue in the context of
radiotherapy for brain malignancy, has achieved GMP synthesis, scale-up technology, and
requisite preclinical toxicological screening. Based on highly encouraging pilot data, we propose
BMX-001, given at endovascular thrombectomy reperfusion onset, as an adjunct
pharmaceutical to optimize endovascular thrombectomy outcome. In Phase 1, we will define
optimal dosing and maximal ischemia duration before reperfusion and treatment onset that
retains efficacy, measure long-term functional outcome in aged, metabolic syndrome, and
spontaneously hypertensive rats, define interactions with tPA activity, and obtain independent
laboratory efficacy validation. A Clinical Trial Consulting Team, consisting of independent stroke
experts, will work in collaboration with Biomimetix to monitor go/no-go end-points and develop
protocols for human dose-escalation trials.PROJECT NARRATIVE
Stroke treatment has been revolutionized by advance of endovascular thrombectomy, yet andgt;50% of
stroke patients undergoing thrombectomy fail to recover independent status due to damaged brain.
This Phase I STTR proposes execution of a series of preclinical efficacy assessments of BMX-001, as
an adjunct to endovascular thrombolysis to salvage injured brain and improve outcome. Successful
completion of this Phase I STTR will provide the appropriate foundation for design and implementation
of Phase 2 clinical trials of BMX-001 in endovascular thrombectomy stroke patients.

* Information listed above is at the time of submission. *

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