Non-Thrombogenic Properties of Chimeric FVIIa

嵌合 FVIIa 的非血栓形成特性

基本信息

批准号：
9199695
负责人：
Michael Griffith
金额：
$ 22.5万
依托单位：
CHIMERA BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9199695
关键词：
Address Affect Alberta province Animal Model Animals Arterial Injury Binding Biological Products Biotechnology Bleeding time procedure Brain hemorrhage Cerebral hemisphere hemorrhage Cessation of life Chimera organism Chimeric Proteins Clinical Collaborations Conditioned Culture Media Deterioration Development Dose Ear Early Intervention Effectiveness Event Exhibits Exposure to FDA approved Factor IX Growth Guidelines Hematoma Hemophilia A Hemorrhage Hemostatic Agents Heparin Hospitals Housing Human In Vitro Intracranial Hemorrhages Label Letters Life Location Marketing Medical Methods Modeling Morbidity - disease rate Nebraska Neurologic Operative Surgical Procedures Oryctolagus cuniculus Outcome Patients Phase Plasma Preparation Property Proteins Randomized Clinical Trials Rattus Recombinants Research Risk Safety Site Small Business Innovation Research Grant Testing Thromboembolism Thromboplastin Thrombosis Thrombus Time Universities Venous Work analog clinically relevant commercialization dosage ferric chloride improved intervention effect mortality novel patient population recombinant FVIIa

项目摘要

PROJECT SUMMARY/ABSTRACT Chimera BioTechnology, Inc. is a privately held startup biopharmaceutical company. The co-founders have worked together for over 35 years and believe that the proposed hemostatic agent; a novel, proprietary rFVIIa analog (designated Chimera) created by replacing the tissue factor (TF) binding Gla- and EGF1-domains of human FVIIa with the corresponding domains of human factor IX, may exhibit the procoagulant activity of NovoSeven (Novo Nordisk), but with substantially reduced thrombogenic potential. NovoSeven is safe and effective in treating bleeding events in FDA/EMA approved indications primarily affecting hemophilia patients. Although NovoSeven is not FDA approved for treating bleeding events in non-hemophiliac patients, 97% of its in-hospital use in 2008 was for unapproved, off-label clinical indications where clear evidence for an increased risk of thromboembolism has been documented. To date, off-label NovoSeven use has not been found to reduce mortality rates when used to treat uncontrolled bleeding after conventional methods have failed. Guidelines are emerging, however, that provide evidence that early intervention with NovoSeven may improve secondary morbidity outcomes that could avert subsequent life-threatening or debilitating events. We believe that the TF-dependent thrombogenicity of NovoSeven is a barrier to its safe and effective use in several clinical settings. The proposed hemostatic agent is intended to address the unmet medical need for a safe and effective agent to supplement conventional methods of controlling severe bleeding in non-hemophiliac patients. The focus of the current proposal is to obtain proof of concept evidence that the Chimera is effective in a clinically relevant animal model; we have chosen a rat intracerebral hemorrhage model that mimics in many ways the human condition where hematoma size and growth are associated with neurological deterioration and death. Positive results in the rat intracerebral hemorrhage model will provide evidence that the Chimera could be effective in treating bleeding events in non-hemophiliac patients. We also propose to obtain evidence that the TF-independent procoagulant activity of the Chimera is substantially less thrombogenic than rFVIIa using well-established rabbit models of thrombosis. Positive results in well-established rabbit models of thrombosis will provide evidence that the Chimera could be a safer alternative to rFVIIa, especially in treating severe, life-threatening bleeding events in non-hemophiliac patients. Evidence of both efficacy and safety in the proposed animal studies will warrant further development of the Chimera agent within the context of a Phase II SBIR application.

项目概要/摘要 Chimera BioTechnology, Inc. 是一家私营初创生物制药公司。联合创始人有一起工作超过 35 年，相信所建议的止血剂；一种新颖的、专有的 rFVIIa 通过替换结合组织因子 (TF) 的 Gla 和 EGF1 结构域而创建的类似物（指定为嵌合体）人 FVIIa 与人因子 IX 的相应结构域可能表现出促凝血活性 NovoSeven（诺和诺德），但显着降低了血栓形成的可能性。 NovoSeven 安全且可有效治疗 FDA/EMA 批准的主要影响血友病患者的适应症中的出血事件。尽管 NovoSeven 未获 FDA 批准用于治疗非血友病患者的出血事件，但其 97% 2008 年的院内使用是针对未经批准的、标签外的临床适应症，有明确的证据表明，血栓栓塞的风险已有记录。迄今为止，未发现标签外使用 NovoSeven 当用于治疗传统方法失败后无法控制的出血时，可降低死亡率。然而，正在出现的指南提供了证据表明 NovoSeven 的早期干预可能会改善继发性发病结果可以避免随后发生危及生命或使人衰弱的事件。我们相信 NovoSeven 的 TF 依赖性血栓形成性是其在多种临床中安全有效使用的障碍设置。所提出的止血剂旨在解决安全和止血剂未得到满足的医疗需求。补充控制非血友病患者严重出血的常规方法的有效药物。当前提案的重点是获得概念证明证据，证明 Chimera 在以下方面是有效的：临床相关动物模型；我们选择了大鼠脑出血模型来模拟许多血肿大小和生长与神经系统恶化相关的人类状况和死亡。大鼠脑出血模型中的阳性结果将提供证据表明嵌合体可有效治疗非血友病患者的出血事件。我们还建议获取证据嵌合体的不依赖于 TF 的促凝血活性比 rFVIIa 的血栓形成性要低得多使用完善的兔血栓形成模型。在完善的兔模型中取得积极结果血栓形成将提供证据表明 Chimera 可能是 rFVIIa 的更安全替代品，特别是在治疗方面非血友病患者发生严重、危及生命的出血事件。有效性和安全性的证据拟议的动物研究将保证嵌合体制剂在第二阶段SBIR申请。