Therapeutic factor XI blockade for sepsis

治疗败血症的 XI 因子阻断

• 批准号: 9481478
• 负责人: Andras Gruber
• 金额: $ 35.97万
• 依托单位: ARONORA, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-13 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9481478
• 关键词: Abdomen; Address; Adult; Adverse effects; Anti-Inflammatory Agents; Antibiotic Therapy; Antibiotics; Anticoagulants; Anticoagulation; Blood Coagulation Disorders; Blood coagulation; Cause of Death; Cell Line; Clinical Trials; Coagulation Process; Complication; Cyclic GMP; Data; Death Rate; Development; Disease Management; Disease susceptibility; Disseminated Intravascular Coagulation; Dose; Dose-Limiting; Double-Blind Method; Drug Kinetics; Effectiveness; FDA approved; FXII deficiency; Factor XI; Factor XI Deficiency; Factor XII; Factor XIIa; Freezing; Funding; Grant; Healthcare; Hemorrhage; Hemostatic Agents; Hemostatic function; Heparin; Howard Temin Award; Human; Impairment; Infection; Inflammatory; Investigational Drugs; Investigational New Drug Application; Ischemic Stroke; Lead; Licensing; Life; Listeriosis; Measurable; Medical; Methods; Minor; Monoclonal Antibodies; Mus; Natural Immunity; Outcome; Pathway interactions; Patients; Peritoneal; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Placebo Control; Primates; Productivity; Protein C; Protocols documentation; Randomized; Risk; Rivers; Safety; Schedule; Secure; Sepsis; Small Business Innovation Research Grant; Sterility; Technology; Testing; Therapeutic; Thrombosis; Thrombus; Toxic effect; Toxicology; Virulence; activated Protein C; base; commercialization; expiration; human study; improved; manufacturing scale-up; meetings; mouse model; murine antibody; novel strategies; pathogen; patient subsets; phase 1 study; preclinical development; preclinical study; prevent; product development; prototype; public health relevance; response; safety testing; septic; synergism; volunteer

 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.

 描述（由适用提供）：败血症是对感染的有害全身性炎症性和引起的反应，仍然是死亡抗生素的主要原因，并且在疾病管理方面取得了重大进展。抗血栓药物，例如肝素可以限制败血症传播血管内凝血（DIC）；但是，它们可以产生严重的出血副作用，并可能支持病原体病毒，并可能抵消其抗血栓形成和抗炎益处。对于严重的败血症DIC，没有FDA批准的抗血栓治疗。因此，存在关键的治疗差距，并且需要对安全疗法改善败血症结局的医疗需求。我们独特的候选产品，一种单克隆抗体（人源化14E11，Xisomab 3G3），该抗体通过活化因子XII（FXIIA）抑制凝血因子XI（FXI）激活，直接解决了这一关键需求。在我们的I/II阶段高级技术SBIR中产生的引人注目的数据表明，FXI有助于致命的败血性DIC和紧凑型凝血病，并支持以下假设：抑制FXI激活可以改善败血症的结果。在人类中，FXI缺乏症仅伴随着次要出血的素质，而FXII缺乏症没有已知的不良反应。因此，我们建议使用3G3选择性靶向FXI激活FXI激活，这是一种从根本上新的，更安全的系统性抗凝策略，可能对预防或治疗严重败血症的血栓形成并发症可能有用，而不会增加出血风险或干扰外部途径依赖于依赖于依赖于依赖的先天性的天生免疫。我们有望在IIB开始之前达到所有II期里程碑 在小鼠中，2）与抗生素建立协同作用，3）成功人性化14E11（Xisomab 3G3），4）完成制造细胞系的开发，5）与拜耳AG建立了战略合作伙伴关系。我们已经开发了研究的GLP毒性方案，用于研究将在2014年11月11日由拜耳医疗保健有限责任公司（贝克利，加利福尼亚州）发行我们的毒理学领域的查尔斯河实验室（Reno，NV）。试验。我们的具体目的是1）生产GLP稳定性和人类研究的CGMP批次为3G3。 2）在败血症中准备并提交IND应用程序以测试3G3，3）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。我们对IIB期的关键里程碑是在Xisomab 3G3的第1阶段研究中没有剂量限制毒性。