Although potent antithrombotic agents are available, all of these drugs inadvertently target vital hemostatic molecular mechanisms, resulting in dose-limiting hemorrhagic toxicity that restrict their use. Due to a lack of safe thromboprophylaxis, thrombotic blood vessel occlusions continue to be extremely prevalent, and result in a wide range of severe disease conditions that remain the leading causes of death and severe chronic disability in the U.S. Consequently, there is a significant and urgent unmet medical need for a safer antithrombotic treatment that is effective when used alone or can safely improve the efficacy of existing antithrombotic drugs. The proposed research will continue the development of our unique, and highly specific humanized anti-factor XI (FXI) monoclonal antibody (AXIMAB), termed xisomab 3G3, for the safe prevention and treatment of thrombosis. We have already reached and exceeded our Phase II SBIR milestones by: 1) Demonstrating that the humanized AXIMAB 3G3 binds to FXI and inhibits baboon and human FXI procoagulant activity in vitro, and that doses as low as 0.2 mg/kg are antithrombotic in disease models, 2) Producing ~300 grams of 3G3, formulated and sterile-filled, with ongoing shelf-life stability (?24-months at 4C), and 3) Determining the no observed adverse effect level (NOAEL) for 3G3 in GLP grade toxicity studies, which was found to be >50-fold above the maximum anticipated pharmacological effect dose. These data have led to the submission of Aronora's first investigational new drug (IND) application to the FDA, which was subsequently accepted on May 5th, 2017. Our phase 1 first-in-human study began on June 6th, 2017, with no adverse events associated with 3G3 noted in the first dosing cohort (0.1 mg/kg). This Phase IIB Bridge Award, combined with our secured matching funds, will provide essential support for continued product development towards advanced proof-of-concept clinical studies.
The specific aim for this project is to initiate a phase 2a clinical trial evaluating the safety and early antithrombotic efficacy of xisomab 3G3 in end stage renal disease (ESRD) patients on hemodialysis (HD). The milestone for success will be to demonstrate that the FXI antibody xisomab 3G3 is safe in this small group of hemodialysis patients when incorporated into the standard hemodialysis procedure. The xisomab 3G3 approach represents a fundamentally new anticoagulation concept since the contribution of FXI and the contact system to pathological coagulation appears to far outweigh its role in normal hemostasis. Therefore, 3G3 could be an effective antithrombotic strategy that is exceptionally safe. Success of this Phase IIB research and achievement of our critical and final milestone will lead directly into the next stage of product development consisting of licensing our drug candidate to Bayer AG, who will take on the ultimate responsibility of performing subsequent and definitive trials in HD and other indications to the benefit of patients who are in desperate need of safe thromboprophylaxis.
While anticoagulant drugs (blood thinners) improve the outcome of blood clot related diseases (e.g. heart attack, stroke, venous thrombosis) or procedures (e.g. kidney dialysis, cardiopulmonary bypass), 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 clinical development of a new antithrombotic drug candidate, xisomab 3G3, which has been shown in definitive primate studies to potently inhibit blood clot formation without increasing bleeding, and thus may safely enhance the effectiveness of current anticoagulants or provide a safe and effective treatment alternative.
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