Therapeutic factor XI blockade for sepsis

 描述（由申请人提供）：脓毒症是一种对感染的有害全身炎症和促凝血反应，尽管使用了抗生素，疾病管理也取得了重大进展，但脓毒症仍然是导致死亡的主要原因。抗血栓药物（如肝素）可限制脓毒性弥散性血管内凝血（DIC）;然而，它们可产生严重的出血副作用，并可能支持病原体毒力，可能抵消其抗血栓和抗血栓益处。对于严重脓毒症相关DIC，尚无FDA批准的抗血栓治疗。因此，存在严重的治疗差距和对安全治疗的未满足的医疗需求，以改善脓毒症结局。我们独特的候选产品是一种单克隆抗体（人源化14 E11，xisomab 3G 3），可通过激活因子XII（FXIIa）抑制凝血因子Xi（FXi）的激活，直接满足了这一关键需求。在我们的I/II期先进技术SBIR期间生成的令人信服的数据表明，FXI导致致死性脓毒性DIC和消耗性凝血病，并支持抑制FXI活化可能改善脓毒症结局的假设。在人类中，FXI缺乏症仅伴有轻微的出血素质，而FXII缺乏症没有已知的不良反应。因此，我们提出，使用3G 3选择性靶向FXIIa激活FXI代表了一种全新且更安全的全身抗凝策略，可用于预防或治疗严重脓毒症的血栓性并发症，而不会增加出血风险或干扰外源性途径依赖性先天免疫。我们有望在IIB期开始时达到所有II期里程碑，并已：1）证实了14 E11在多种微生物腹膜感染和淋病中的疗效和安全性 在小鼠中，2）建立了与抗生素的协同作用，3）成功人源化14 E11（xisomab 3G 3），4）完成了生产细胞系开发，5）与Bayer AG建立了战略合作伙伴关系。我们已经制定了IND使能GLP毒性方案，研究将在Bayer Healthcare LLC（Berkeley，CA）于2014年11月放行我们的毒理学批次后在Charles River Labs（里诺，NV）开始。我们也将在2015年1月与FDA举行IND前会议。该IIB期桥梁奖与我们获得的配套资金相结合，将为IND申请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3G 3的cGMP批次，用于GLP稳定性和人体研究。2)准备并提交IND申请，以测试3G 3在脓毒症中的作用，以及3）在1期临床试验中评估3G 3的安全性、耐受性、药代动力学和药效学。我们IIB期的关键里程碑是在第一项xisomab 3G 3 I期研究中没有剂量限制性毒性。

 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.