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 venous thrombosis. 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 support the 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 in normal 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
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44HL106919-03
Application #
8536930
Study Section
Special Emphasis Panel (ZRG1-VH-F (10))
Program Officer
Warren, Ronald Q
Project Start
2011-01-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$992,422
Indirect Cost
Name
Aronora, LLC
Department
Type
DUNS #
078698200
City
Portland
State
OR
Country
United States
Zip Code
97239
Garland, Kathleen S; Reitsma, Stéphanie E; Shirai, Toshiaki et al. (2017) Removal of the C-Terminal Domains of ADAMTS13 by Activated Coagulation Factor XI induces Platelet Adhesion on Endothelial Cells under Flow Conditions. Front Med (Lausanne) 4:232
Puy, Cristina; Tucker, Erik I; Matafonov, Anton et al. (2015) Activated factor XI increases the procoagulant activity of the extrinsic pathway by inactivating tissue factor pathway inhibitor. Blood 125:1488-96
Sparkenbaugh, Erica M; Chantrathammachart, Pichika; Wang, Shaobin et al. (2015) Excess of heme induces tissue factor-dependent activation of coagulation in mice. Haematologica 100:308-14
Matafonov, Anton; Leung, Philberta Y; Gailani, Adam E et al. (2014) Factor XII inhibition reduces thrombus formation in a primate thrombosis model. Blood 123:1739-46
Puy, C; Tucker, E I; Wong, Z C et al. (2013) Factor XII promotes blood coagulation independent of factor XI in the presence of long-chain polyphosphates. J Thromb Haemost 11:1341-52
Tormoen, Garth W; Recht, Olivia; Gruber, András et al. (2013) Phosphatidylserine index as a marker of the procoagulant phenotype of acute myelogenous leukemia cells. Phys Biol 10:056010
Crosby, Jeffrey R; Marzec, Ulla; Revenko, Alexey S et al. (2013) Antithrombotic effect of antisense factor XI oligonucleotide treatment in primates. Arterioscler Thromb Vasc Biol 33:1670-8
Tucker, Erik I; Verbout, Norah G; Leung, Philberta Y et al. (2012) Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis. Blood 119:4762-8