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 <5% of victims. Recently, major advance has been
made with proven efficacy from endovascular mechanical thrombectomy in combination with
tPA. Despite this, <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.
