Factor XI Inhibition for the Treatment of Ischemic Stroke

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 1R43NS077600-01A1
Agency Tracking Number: R43NS077600
Amount: $315,665.00
Phase: Phase I
Program: SBIR
Awards Year: 2012
Solitcitation Year: 2012
Solitcitation Topic Code: NINDS
Solitcitation Number: PA11-096
Small Business Information
ARONORA, LLC
3500 SW BRIDLEMILE LN, PORTLAND, OR, -
Duns: 804889348
Hubzone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 PHILBERTA LEUNG
 (202) 321-4634
 philberta@aronorabio.com
Business Contact
 PHILBERTA LEUNG
Phone: (202) 321-4634
Email: philberta@aronorabio.com
Research Institution
 Stub
Abstract
DESCRIPTION (provided by applicant): One of the underlying causes of acute ischemic stroke (AIS) is the thrombotic-thromboembolic occlusion of cerebral blood vessels. Early use of tissue-type plasminogen activator (tPA, Activase(R)), currently the only FDA-approved treatment for AIS, can promote reperfusion via thrombolysis. However, tPA treatment carries a high risk of fatal intracranial hemorrhage, which is a safety concern that limits the number of stroke victims who receive tPA treatment and achieve reperfusion. In addition, re-occlusion occurs in one third of tPA-treated AIS patients, alongside clinical deterioration following the initial improvement. Thus, there is a major unmet medical need for the development of a safe and effective antithrombotic treatment that is suitable for use in AIS patients, either alone or in combination with tPA. We propose that the ideal therapeutic strategy is to block the prothrombotic activation of coagulation factor XI (FXI). In humans, elevated FXI levels are an independent risk factor for AIS, while FXI deficiency is associated with protection from AIS both in humans and in mice. Our preliminary studies suggest that using our product candidate, anti-mammalian FXI antibody 14E11, to inhibit prothrombotic FXI activationby the contact factor XIIa (FXIIa) will protect mice from AIS. Since FXII deficiency does not cause bleeding, we hypothesize that 14E11, which does not inhibit hemostatic FXI activation, has great potential for the safe treatment of AIS. In addition, we hypothesize that 14E11 can increase the long-term efficacy of tPA by enhancing its efficacy and reducing the incidence of re-occlusion. Our research objective is to determine the therapeutic potential of 14E11 to treat AIS using a mouse model of AIS. Thus, the Specific Aims for this Phase I application are to: 1) Determine the efficacy of 14E11 for improving the outcome of experimental AIS; 2) Determine the efficacy of 14E11 in combination with fibrinolytic tPA to improve the outcome of experimental AIS; and3) Determine the hemostatic safety of 14E11 alone and in combination with tPA. If successful, this Phase I project will provide evidence that the inhibition of FXI is a safe and promising therapeutic strategy to combat thrombotic AIS. Reaching our milestones will propel our project into Phase II, with the intent to initiate formal preclinical development of 14E11 for the safe treatment of AIS patients. PUBLIC HEALTH RELEVANCE: Treatment of acute ischemic stroke with the clotbuster drug tPA (Activase(R)) has serious bleeding complications, which limits its usage to less than 10% of patients. The proposed research evaluates our unique therapeutic antibody (14E11) that blocks pathological clot-promoting activation of coagulation factor XI (FXI) asa novel drug candidate for the treatment of stroke, which remains a leading cause of death and chronic disability. Since 14E11 is not expected to produce bleeding side-effects, this approach has the potential to provide a safe alternative or addition to other more dangerous antithrombotic treatments.

* information listed above is at the time of submission.

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