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PORTLAND, OR, United States

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 309.53K | Year: 2011

DESCRIPTION (provided by applicant): Thrombotic cardiovascular diseases including venous thromboembolism, myocardial infarction, and ischemic stroke, remain leading causes of death and disability in the US. Although effective antithrombotic agents are available, these drugs inadvertently target vital hemostatic molecular mechanisms and can produce severe dose-limiting hemorrhagic toxicity, thereby limiting their use. Consequently, there is a significant and urgent unmet medical need for safe antithrombotictreatment alternatives. The proposed research will determine whether monoclonal antibodies against coagulation factor XI (AXIMABs) hold promise for the safe prevention and treatment of acute thrombosis. Initially we will study the unique proprietary antibody 14E11, which targets the apple 2 domain of coagulation factor XI (FXI) and prevents its activation by factor XIIa (FXIIa). To justify eventual clinical development and commercialization, we will first establish in primates the hemostatic safety and antithrombotic efficacy of 14E11 compared with the market leader for relevant indications, low-molecular- weight heparin (enoxaparin). The proposed research has three specific aims. Aim 1: to prepare and characterize neutralizing 14E11 for preclinical productcandidate evaluation. The quantitative milestone for Aim 1 is to establish the minimum saturating dose of 14E11 that produces effective anticoagulation for at least 24 hours in baboons. Aim 2: to determine the efficacy of 14E11 compared with enoxaparin ina baboon venous thrombosis model. The quantitative milestone for Aim 2 is to document a significant antithrombotic effect of 14E11, at a saturating dose, that is comparable to that achieved by a clinically relevant dose of enoxaparin. Aim 3: to determine the hemostatic safety of 14E11 in aspirin-treated baboons. The quantitative milestone for Aim 3 is to demonstrate that 14E11 produces significantly less hemostatic impairment (bleeding) versus that seen in enoxaparin-treated baboons that are hemostaticallycompromised by aspirin. While our initial focus will be on the AXIMAB 14E11, an additional AXIMAB molecule, 1A6, which targets the apple 3 domain of FXI and prevents activation of FIX by FXIa, will also be evaluated as an alternative to 14E11. The AXIMAB approach represents a fundamentally new anticoagulation concept since clinical and experimental evidence suggests that blocking FXI activation by FXIIa will not produce side-effects that could limit effective dosing. Thus AXIMABs could represent a new antithrombotic strategy that is thrombus-specific and exceptionally safe. After successful completion of Phase I, the company will seek additional capital, either through Phase II or through private financing, to commence with the preclinical development program and advance AXIMAB into formal product development for acute thromboembolism indications. PUBLIC HEALTH RELEVANCE: Acute thrombotic blood vessel occlusion is a highly prevalent disorder with severe consequences, including death and chronic morbidity syndromes. While anticoagulant drugs (blood thinners) improve the outcome of diseases that are caused by blood clots, their usefulness is compromised by potentially severe bleeding- related (hemorrhagic) side-effects that restrict therapeutic dosing options. Accordingly, there remains an urgent unmet medical need for safer antithrombotic treatments. The proposed research addresses this need by evaluating a new product candidate, an antithrombotic antibody that targets a coagulation factor that contributes to blood vessel occlusion but is non-vital for normal blood coagulation necessary to arrest bleeding. Since the antibody is not expected to produce hemorrhagic side-effects, this approach could provide an effective yet safer alternative to currently marketed parenteral anticoagulants. 1

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 315.67K | Year: 2012

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.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.77M | Year: 2010

DESCRIPTION (provided by applicant): Stroke and heart attack are the leading causes of mortality and grave morbidity. The goal of this Fast-Track STTR grant application is to enable preclinical investigation of WE-thrombin, a bioengineered protein C activator enzyme for the treatment of severe, acute thrombotic diseases, in particular ischemic stroke. WE- thrombin is a fundamentally new thrombosis-specific agent that may act in part by increasing the surface concentration of endogenous activated protein C (APC), which is an anticoagulant, profibrinolytic, and cytoprotective enzyme. Unlike any other antithrombotic drug, WE-thrombin is virtually inactive in the center of the blood stream or in static wound blood. WE-thrombin is a well-defined and far-advanced drug candidate, with antithrombotic efficacy and hemostatic safety verified in definitive primate studies. The proposed research will generate information for an Investigational New Drug (IND) application for WE- thrombin. Existing antithrombotic and thrombolytic drugs, such as recombinant tissue plasminogen activator (TPA) cause bleeding and, thus, cannot be used at their fully effective doses. In addition, TPA needs to be administered within the first 3 hours following onset of ischemic stroke. Since only a small percentage of stroke patients qualify for treatment in this narrow time frame, TPA is seldom administered. Thus, relevant to the mission of NIH, there is an urgent need for better drugs for stroke and other acute thrombotic diseases. The project addresses this need directly with WE-thrombin, which has shown outcome benefits compared to TPA in treating experimental acute ischemic stroke in preliminary studies using mice. Phase I has been designed to create pharmaceutically acceptable formulations of WE- thrombin that can be administered beyond the 3-hour treatment window of TPA in stroke. The 3 specific aims of Phase I are to develop a stable, injectable formulation of WE-thrombin (Aim 1) and to determine its efficacy (Aim 2) and safety (Aim 3) in comparison to TPA when administered in mice with advanced experimental acute ischemic stroke (AIS). Demonstration of efficacy and safety of WE-thrombin in AIS is the milestone that will move WE-thrombin development into Phase II, during which pharmaceutical GMP- grade (good manufacturing practice) WE-thrombin will be obtained and evaluated in vitro (Aims 4 and 5) and subsequently tested in IND-enabling studies to determine its dose-limiting toxicity and potential side effects (Aim 6). Successful completion of Phase II will be defined as a preclinical safety and efficacy data package - and sufficient amount of formulated drug that is suitable for clinical studies. After Phases I and II, an IND application will be submitted, and upon FDA approval, WE-thrombin will be taken into clinical development. PUBLIC HEALTH RELEVANCE: Blood clots that block blood flow can cause acute heart attack and stroke that both remain among the three leading causes of death and severe chronic disability in the U.S., in part due to limited safety of clot-preventing and clot-removing drugs. The relevance of the proposed project to public health is that it is intended to develop a therapeutic agent (product) for safely interrupting and/or removing blood clots in acute thrombotic diseases. The new recombinant therapeutic enzyme - WE-thrombin - is a first-of-its-kind thrombosis-specific drug candidate that has the potential to represent a breakthrough in antithrombotic therapy for ischemic stroke. WE- thrombin has already been shown to be effective in treating experimental blood clots (thrombosis) in large primates - it is now intended to offer a safe and effective alternative to existing drugs that all had failed to fundamentally improve the morbidity and mortality of stroke, primarily due to their bleeding side effects.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 297.49K | Year: 2010

DESCRIPTION (provided by applicant): This Phase I SBIR grant will support the initial commercial development of a single dose injectable biological product candidate, recombinant humanized anti-factor XI monoclonal therapeutic anticoagulant antibody, towards an investigational new drug (IND) application. The lead indication is severe bacterial sepsis, which is among the leading causes of mortality among hospitalized patients. Ischemia contributes to the pathogenesis of sepsis-associated disseminated intravascular coagulation (DIC) and systemic inflammatory response syndrome (SIRS). Antithrombotic drugs may be effective; however, their most potent doses can produce severe bleeding side effects. Apart from antibiotics, the only FDA-approved treatment for severe sepsis is the anticoagulant enzyme recombinant activated protein C (APC, Xigris(r)), but the bleeding side effects of APC outweigh its benefits in less severe cases. Our product candidate addresses a major medical need with a safe and effective alternative to APC. The molecular target is coagulation factor XI (FXI). FXI deficiency improves the survival of experimental polymicrobial peritonitis in mice, and preliminary data suggest that anticoagulation by antibody inhibition of FXI produces similar benefits. FXI inhibition may also be anti-inflammatory by reducing bradykinin liberation. Antibody inhibition of FXI represents a fundamentally new method of anticoagulation because FXI is part of the contact pathway where the molecular mechanisms of hemostasis and thrombosis converge. In primates, anticoagulation by antibody inhibition of FXI is antithrombotic for more than a week, and hemostatically safer than heparin or aspirin. No comparable drugs exist, and thus if AXIMAB is successfully developed, it would have significant market potential. The Specific Aims are to 1. Prepare neutralizing mouse anti-mouse FXI monoclonal antibody (mAXIMAB); 2. Determine the efficacy of mAXIMAB in septic mice; and 3. Determine the hemostatic safety of mAXIMAB in na ve mice. Positive results will support the hypothesis that pharmacological inhibition of FXI is beneficial in sepsis. PUBLIC HEALTH RELEVANCE: Thrombotic occlusion of blood vessels in sepsis causes ischemia and contributes to the high mortality rate of severe systemic inflammatory response syndrome. Antithrombotic drugs that could be effective produce severe bleeding side effects, which render them less than useful. Apart from antibiotics, the only FDA approved treatment for severe sepsis is the antithrombotic enzyme, recombinant activated protein C (APC, Xigris(r)), but bleeding side effects outweigh its benefits in less severe sepsis cases. We address this major medical need with a new antithrombotic antibody product candidate to provide a safe and effective alternative to APC.

Aronora, Llc | Entity website

AB022 A recombinant protein (monoclonal antibody) that selectively inhibits the intrinsic blood coagulation cascade upstream of coagulation factor XI (F11). AB022 is in pre-clinical development for emergency antithrombotic use in conditions that are intrinsically accompanied with thrombosis and bleeding, such as major surgeries, fractures, crushing and head injuries ...

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