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.