Therapeutic factor XI blockade for sepsis

 描述(申请人提供)：败血症，一种对感染的有害的全身性炎症和促凝血反应，尽管使用抗生素和疾病管理方面的重大进步，但仍然是主要的死亡原因。抗血栓药物，如肝素，可以限制感染性弥散性血管内凝血(DIC)；然而，它们会产生严重的出血副作用，并可能支持病原体的毒力，潜在地抵消了它们的抗血栓和抗炎的好处。目前还没有FDA批准的治疗严重脓毒症相关性DIC的抗血栓治疗方法。因此，存在严重的治疗缺口和对安全治疗以改善脓毒症结果的医疗需求未得到满足。我们独特的候选产品，一种可抑制激活因子XII(FXIIa)激活凝血因子XI(FXI)的单抗(人源化14E11，xisomab 3G3)，直接满足了这一关键需求。在我们的第一阶段/第二阶段先进技术SBIR期间产生的令人信服的数据表明，FXI有助于致死性脓毒症DIC和消耗性凝血障碍，并支持抑制FXI激活可能改善脓毒症预后的假设。在人类中，FXI缺乏只伴随着轻微的出血素质，而FXII缺乏没有已知的不良影响。因此，我们认为，使用3G3选择性靶向FXIIa激活FXI代表了一种全新的、更安全的全身抗凝策略，可能有助于预防或治疗严重脓毒症的血栓并发症，而不会增加出血风险，也不会干扰外部途径依赖的先天免疫。我们有望在IIB阶段开始时达到我们所有的II阶段里程碑，并已：1)证实了14E11在多菌腹膜感染和李斯特菌病中的有效性和安全性 在小鼠中，2)与抗生素建立了协同作用，3)成功地人源化了14E11(Xisomab 3G3)，4)完成了制造细胞系的开发，5)与拜耳公司建立了战略合作伙伴关系。我们已经开发了支持IND的GLP毒性协议，研究将在2014年11月拜耳医疗有限责任公司(加利福尼亚州伯克利)发布我们的毒理学批次后在Charles River Labs(里诺，内华达州)开始进行。我们还将于2015年1月与FDA举行IND前会议。这一IIB期桥梁奖，加上我们获得的配套资金，将为IND应用和临床试验的持续产品开发提供必要的支持。我们的具体目标是1)生产一批3G3的cGMP，用于GLP的稳定性和人体研究。2)准备并提交用于测试3G3在脓毒症中的应用的IND申请，以及3)在1期临床试验中评估3G3的安全性、耐受性、药代动力学和药效学。我们在IIB阶段的关键里程碑是在Xisomab 3G3的第一阶段1研究中没有剂量限制毒性。

 DESCRIPTION (provided by applicant): Sepsis, a detrimental systemic inflammatory and procoagulant response to infections, remains a leading cause of death despite antibiotics and significant advances in disease management. Antithrombotic drugs, e.g. heparins, can limit septic disseminated intravascular coagulation (DIC); however, they can produce severe bleeding side-effects and may support pathogen virulence, potentially counterbalancing their antithrombotic and antiinflammatory benefits. There are no FDA-approved antithrombotic treatments for severe sepsis- associated DIC. Consequently, there is a critical treatment gap and an unmet medical need for a safe therapeutic to improve sepsis outcomes. Our unique product candidate, a monoclonal antibody (humanized 14E11, xisomab 3G3) that inhibits coagulation factor XI (FXI) activation by activated factor XII (FXIIa), directly addresses this critical need. Compelling data generated during our Phase I/II Advanced Technology SBIR shows that FXI contributes to lethal septic DIC and consumptive coagulopathy, and supports the hypothesis that inhibition of FXI activation may improve sepsis outcomes. In humans, FXI deficiency is accompanied by only a minor bleeding diathesis, while FXII deficiency has no known adverse effects. Therefore, we propose that selectively targeting FXI activation by FXIIa using 3G3 represents a fundamentally new and safer systemic anticoagulation strategy that may be useful to prevent or treat the thrombotic complications of severe sepsis, without increasing bleeding risks or interfering with extrinsic pathway-dependent innate immunity. We are on track to reach all of our Phase II milestones by the beginning of Phase IIB, and have: 1) confirmed the efficacy and safety of 14E11 in polymicrobial peritoneal infection and in listeriosis in mice, 2) established synergy with antibiotics, 3) successfully humanized 14E11 (xisomab 3G3), 4) completed manufacturing cell line development, and 5) established a strategic partnership with Bayer AG. We have developed IND-enabling GLP toxicity protocols for studies will commence at Charles River Labs (Reno, NV) upon release of our toxicology lot by Bayer Healthcare LLC (Berkeley, CA) in Nov. 2014. We are also on track for our pre-IND meeting with FDA in Jan. 2015. This Phase IIB Bridge Award, combined with our secured matching funds, will provide essential support for continued product development towards an IND application and clinical trials. Our specific aims are to 1) Manufacture a cGMP lot of 3G3 for GLP stability and human studies. 2) Prepare and file an IND application to test 3G3 in sepsis, and 3) Evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 3G3 in a phase 1 clinical trial. Our critical milestone for Phase IIB is absence of dose- limiting toxicity in the frst phase 1 study of xisomab 3G3.