Therapeutic factor XI blockade for sepsis

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 E xisomab G 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 G 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 confirmed the efficacy and safety of E in polymicrobial peritoneal infection and in listeriosis in mice established synergy with antibiotics successfully humanized E xisomab G completed manufacturing cell line development and 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 We are also on track for our pre IND meeting with FDA in Jan 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 Manufacture a cGMP lot of G for GLP stability and human studies Prepare and file an IND application to test G in sepsis and Evaluate the safety tolerability pharmacokinetics and pharmacodynamics of G in a phase clinical trial Our critical milestone for Phase IIB is absence of dose limiting toxicity in the frst phase study of xisomab G 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 andquot blood thinnersandquot 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