Leung P.Y.,Oregon Health And Science University |
Leung P.Y.,Aronora, Llc |
Hurst S.,Oregon Health And Science University |
Berny-Lang M.A.,Oregon Health And Science University |
And 8 more authors.
Translational Stroke Research | Year: 2012
Blood coagulation factor XI (FXI) is an established risk factor for acute ischemic stroke (AIS) and thrombosis, but is also needed for normal hemostasis. Contact factor XII (FXII), an upstream activator of FXI, also contributes to experimental stroke, but is not required for hemostasis. We investigated whether selectively inhibiting FXII-mediated FXI activation, while leaving other FXI and FXII functions intact, could improve the outcome of experimental AIS in mice. Twenty-four hours before induction of AIS by placement of a filament into the internal carotid artery for 60 min, mice were anticoagulated with an antibody directed against the apple 2 domain of FXI. This antibody selectively reduces the prothrombotic activation of FXI by FXIIa but does not affect activated FXI or hemostatic activation of FXI by thrombin, thus leaving hemostasis intact in mice and primates. In this model of AIS/reperfusion injury, mice that received the antibody before AIS displayed less ischemic damage, manifested as reduced cerebral infarction and fibrin deposition (thrombosis), increased cortical reperfusion, and improved neurological behavior. Further, the antibody-anticoagulated mice had no detectable hemostasis impairment. Consistent with the neuroprotective phenotype of FXII-deficient mice, our data suggest that a single molecular event, FXII-mediated FXI activation, contributes to the development of experimental AIS. © 2012 Springer Science+Business Media, LLC.
Tucker E.I.,Oregon Health And Science University |
Tucker E.I.,Aronora, Llc |
Verbout N.G.,Oregon Health And Science University |
Verbout N.G.,Aronora, Llc |
And 7 more authors.
Blood | Year: 2012
Severe bacterial sepsis often leads to a systemic procoagulant and proinflammatory condition that can manifest as disseminated intravascular coagulation, septic shock, and multiple organ failure. Because activation of the contact proteases factor XII (FXII), prekallikrein, and factor XI (FXI) can trigger coagulation and inflammatory responses, the contact factors have been considered potential targets for the treatment of sepsis. However, the pathogenic role of contact activation in severe infections has not been well defined. We therefore investigated whether an anticoagulant antibody (14E11) that selectively inhibits prothrombotic FXI activation by activated FXII (FXIIa) modifies the course of bowel perforation-induced peritoneal sepsis in mice. Early anticoagulation with 14E11 suppressed systemic thrombin- anti-thrombin complex formation, IL-6, and TNF-α levels, and reduced platelet consumption in the circulation and deposition in the blood vessels. Treatment with 14E11 within 12 hours after bowel perforation significantly improved survival compared with vehicle treatment, and the saturating dose did not increase tail bleeding. These data suggest that severe polymicrobial abdominal infection induces prothrombotic FXI activation, to the detriment of the host. Systemic anticoagulation by inhibiting FXI activation or FXIIa procoagulant activity during sepsis may therefore limit the development of disseminated intravascular coagulation without increasing bleeding risks. © 2012 by The American Society of Hematology.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.96M | Year: 2012
DESCRIPTION (provided by applicant): This SBIR Phase II grant will support the commercial development of an injectable biological product candidate, a unique proprietary recombinant humanized anti-factor XI monoclonal antibody (AXIMAB), towards an investigational new drug (IND) application. The lead indication for AXIMAB is severe bacterial sepsis, which is a major cause of mortality in hospitalized patients. Sepsis-associated disseminated intravascular coagulation (DIC) contributes to organ perfusion deficits, ischemia, and a systemic inflammatory response syndrome (SIRS). Antithrombotic drugs may effectively limit septic DIC; however, their antithrombotic 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 can often outweigh its benefits. There is a major unmet medical need for safer and more effective treatments, and our product candidate addresses this need by providing an alternative to APC. In primates, anticoagulation with our anti-FXI antibodies 1A6 or 14E11 is safe and antithrombotic. Our SBIR Phase I data demonstrate that anticoagulation with our universal anti-FXI antibody 14E11 improves the survival of polymicrobial peritonitis in mice, while reducing the inflammatory and coagulation responses to sepsis, and our Phase II preliminary studies show a survival benefit for mice treated with 14E11 during septic Listeriosis.We have demonstrated that 14E11 selectively inhibits factor XI (FXI) activation by factor XIIa (FXIIa). Since FXI activation by FXIIa is independent of hemostasis, using 14E11 for blocking prothrombotic FXI activation by FXIIa could translate into therapeutic anticoagulation with unprecedented safety. Since no comparable product exists, AXIMAB 14E11 would compete successfully with APC and other anticoagulants under development, including activated FXI inhibitors, and therefore has a very large market potential. The Specific Aims are to 1. Evaluate the efficacy of AXIMAB 14E11 treatment in experimental microbe-specific sepsis; 2. Determine the activity and stability of GMP-grade humanized recombinant AXIMAB batches; and 3. Determine the toxicity of humanizedAXIMAB in preclinical studies. Success of this Phase II project will support the advancement of AXIMAB into clinical studies. PUBLIC HEALTH RELEVANCE: Occlusion of blood vessels by clots significantly contributes to the high mortality rate of sepsis, and drugs that are effective against blood clots in vessels (antithrombotic drugs or blood thinners ) have only limited utility because they also aggravate the bleeding tendency (coagulopathy) that characterizes severe sepsis. 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 often outweigh its benefits. The lack of safe and effective sepsis treatments represents a major unmet medical need that we address with the development of a new antithrombotic molecule, a therapeutic anti-factor XI antibody that does not cause bleeding and thus provides a safe alternative to APC for treating the coagulopathic complications of sepsis.1
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.51M | Year: 2012
DESCRIPTION (provided by applicant): Thrombotic cardiovascular diseases including venous thromboembolism (VTE), deep vein thrombosis (DVT), myocardial infarction, and ischemic stroke, remain leading causes of death and disability in the U.S. 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 in some patients. Consequently, there is a significant and urgent unmet medical need for safer antithrombotic treatment alternatives. The proposed research will continue the development of an antithrombotic antibody against coagulation factor XI (AXIMAB 1A6) for the safe prevention and treatment of acute venousthrombosis. We have reached our Phase I milestones: 1) Establishing a minimum saturating dose of 1A6 (0.1mg/kg, iv) that is antithrombotic in baboons, 2) Showing that 1A6 has significant antithrombotic effects that are comparable to a high interventional dose of the low-molecular-weight heparin enoxaparin (Lovenox(R), 1mg/kg, iv), and 3) Verifying that the antithrombotic dose of AXIMAB 1A6 produces no measurable hemostatic impairment, in contrast to enoxaparin, which increases bleeding in the baboons. During Phase I we also discovered that 1A6 is more effective than our other prototype AXIMAB antibody 14E11 at limiting thrombus development under arterial shear flow conditions and during tissue factor initiated venous-type thrombosis. The difference in efficacy is likely related to distinct FXI molecular pathways that are targeted by the two antibodies. We therefore propose to continue the commercial development of AXIMAB 1A6 as our hemostatically safe and effective antithrombotic drug candidate. We have successfully advanced AXIMAB product development and are now prepared to further move AXIMAB towards clinical trials for the short-term prevention and treatment of acute DVT and VTE. The Specific Aims for this Phase II project that will be necessary to supportthe development of AXIMAB 1A6 through an investigational new drug (IND) application are to: 1) Evaluate the activity and efficacy of recombinant humanized AXIMAB 1A6, 2) Characterize manufactured GMP-grade humanized AXIMAB 1A6 formulations, and 3) Determine the dose-limiting toxicity of GMP-grade humanized AXIMAB 1A6 in preclinical studies. The AXIMAB approach represents a fundamentally new anticoagulation concept since the contribution of FXI to pathological coagulation appears to far outweigh its role innormal hemostasis. Thus, AXIMAB could represent an effective antithrombotic strategy that is exceptionally safe. Success of this Phase II research and achievement of our critical milestones will lead directly into the next stage of product development that will consist of IND preparation and filing, followed by the initiation of phase 1 clinical studies to safely prevent and treat acute venous thrombosis and thromboembolism. PUBLIC HEALTH RELEVANCE: While anticoagulant drugs (blood thinners) improve the outcome of blood clot related diseases (heart attack, stroke, and venous thrombosis), their usefulness is compromised by potentially severe bleeding-related side effects. Consequently, there remains an urgent unmet medical need for safer anticoagulant treatments. The proposed research addresses this need by continuing the development of a new antithrombotic antibody drug candidate AXIMAB (Anti-Factor XI Monoclonal Antibody), which has been shown in definitive primate studies to potently inhibit thrombotic blood vessel occlusion without increasing bleeding, and thus provides a safe and effective alternative for treating and preventing thrombosis.
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.
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 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
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 ...
Aronora, Llc | Entity website
Our Drug Candidates Aronoras unique product candidates address the unmet medical need for safe and early field treatment and prevention of cardio-vascular emergencies, including stroke, heart attack, and severe infection associated bleeding due to consumptive coagulopathy (disseminated intravascular coagulation, DIC). Our products are intended for use when antithrombotic therapy could result in survival and other critical outcome benefits, but current antithrombotic drugs on the market pose too high a risk of bleeding and are therefore not used ...