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.

PUBLIC HEALTH RELEVANCE: Blood clots significantly contribute to the high death rate associated with sepsis, a life-threatening complication of infections. However, drugs that are effective against blood clots (antithrombotic drugs or "blood thinners") have limited overall effectiveness in sepsis, primarily because they also aggravate the bleeding tendency that accompanies severe sepsis. There is no FDA-approved antithrombotic drug for sepsis, representing a treatment gap and major unmet medical need that we now address with the development of a new antithrombotic drug that does not increase bleeding, and thus provides a new approach for treating the blood clotting complications of sepsis. 1