Factor XII Inhibitor for Surface Initiated Thrombosis

项目摘要 某些挽救生命的干预措施，如心肺转流术（CPB）、体外膜 氧合（ECMO）、血液透析或心室辅助装置（VAD）泵需要使用肝素， 保持血液流过装置和/或防止下游血栓栓塞并发症。几 其它侵入性血管手术也利用暂时抗凝，例如在假体植入期间和之后 血管移植不幸的是，抗血栓药物如肝素无意中靶向重要的 止血分子机制，并可能具有严重的剂量限制性出血毒性。因此 必须限制抗凝水平，以平衡出血和血栓形成的风险。因此，在本发明中， 装置失效和血栓形成并发症可能是频繁的和毁灭性的。我们最近的研究表明， 凝血因子XII（FXII）有助于血栓形成的进展，因此是治疗血栓形成的潜在靶点。 新型抗血栓药物。由于数据还表明FXII无助于止血， FXII缺乏症是哺乳动物中的无症状病症，FXII抑制不太可能具有显著的不良反应。 方面的影响.在这个IIB期小型市场项目中，我们将继续开发我们的创新抗凝药物 适用于ECMO和其他具有高出血风险的血栓性适应症。我们目前在 在IIB阶段开始时，我们将实现所有I/II阶段快速通道里程碑，并已：1）确认 在我们的ECMO模型中靶向FXII是抗血栓形成的，并且可以提高肝素的有效性， 止血损伤的可检测的增加，2）人源化我们的领先鼠抗FXII抗体，其现在是 命名为AB 054，和3）完成了稳定生产细胞系的开发，该细胞系用于 生产一批AB 054的毒理学产品我们还开发了IND使能GLP毒性研究方案 将在阶段开始时毒理学批次放行后在Charles River Labs（里诺，NV）开始 联合调查局这个小型市场项目，加上我们获得的配套资金，将为以下方面提供必要的支持： 继续进行产品开发，以实现IND申请和ECMO适应症的临床试验。我们 具体目的是：1）测定人源化抗FXII抗体AB 054的毒性，2）制备人源化抗FXII抗体AB 054， 用于人体研究的AB 054的cGMP批次，和3）启动1期临床试验以评估安全性、耐受性， 药代动力学和药效学。该项目的成功将推动AB 054走向 在我们提出的初始小型市场准入适应症中进行的II期人体概念验证临床试验：安全 ECMO期间的抗凝，肝素可能导致出血，并且通常无法维持器械灌注。

Project Summary Certain life-saving interventions such as cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), hemodialysis, or ventricular assist device (VAD) pumps require the use of heparin to maintain blood flow through the devices and/or to prevent downstream thromboembolic complications. Several other invasive vascular procedures also utilize temporal anticoagulation, such as during and after prosthetic vascular graft implantation. Unfortunately, antithrombotic agents such as heparin inadvertently target vital hemostatic molecular mechanisms and can have severe dose-limiting hemorrhagic toxicity. Consequently, the level of anticoagulation must be limited to balance the risk of bleeding with that of thrombosis. As a result, device failure and thrombotic complications can be frequent and devastating. Our recent studies suggest that coagulation factor XII (FXII) contributes to the progression of thrombosis, and thereby is a potential target for a new class of antithrombotic drugs. Since data also suggests that FXII does not contribute to hemostasis, and FXII deficiency is an asymptomatic condition in mammals, FXII inhibition is unlikely to have significant adverse effects. In this Phase IIB Small Market project, we will continue to develop our innovative anticoagulant drug candidate for use during ECMO and other thrombotic indications with a high bleeding risk. We are currently on track to reach all of our Phase I/II Fast-Track milestones by the beginning of Phase IIB and have: 1) confirmed that targeting FXII in our ECMO model is antithrombotic and improves the effectiveness of heparin without a detectable increase in hemostasis impairment, 2) humanized our lead murine anti-FXII antibody, which is now designated as AB054, and 3) completed development of a stable manufacturing cell line that is being used to produce a toxicology lot of AB054. We have also developed IND-enabling GLP toxicity protocols for studies that will commence at Charles River Labs (Reno, NV) upon release of our toxicology lot at the start of Phase IIB. This Small Market project, combined with our secured matching funds, will provide essential support for continued product development towards an IND application and clinical trials for the ECMO indication. Our specific aims are to: 1) determine the toxicity of the humanized anti-FXII antibody, AB054, 2) manufacture a cGMP lot of AB054 for human studies, and 3) initiate a phase 1 clinical trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AB054. Success of this project will propel AB054 towards a phase 2 human proof-of-concept clinical trial in our proposed initial small market entry indication: safe anticoagulation during ECMO, where heparin can cause bleeding and often fails to sustain device perfusion.