A Novel Drug for Septicemia Targets A1 ARs

DESCRIPTION (provided by applicant): Despite the availability of newer antimicrobial agents, improved supportive care, and the introduction of an FDA approved adjunctive therapy for sepsis, (Xigris(r), drotrecogin alfa), the mortality rate for severe sepsis and septic shock of 30-60% remains high. Endacea, Inc. (Research Triangle Park, NC) approaches sepsis with a proprietary diagnostic/biomarker to identify and a drug to then treat patients early in sepsis. This approach is based on the discovery that lipopolysaccharide (LPS)/endotoxin binds to and activates A1 adenosine receptors on human pulmonary artery endothelial cells to produce acute lung injury (ALI). With funding from NIAID (STTR Phase I grant, 1 R41 AI056603-01A1), proof of concept was demonstrated for Endacea's lead A1 adenosine receptor (AR) antagonist, L-97-1, as an adjunctive, anti-sepsis treatment in an animal model of polymicrobial sepsis, bacteremia, and endotoxemia (rat cecal ligation and puncture [CLP]). Administration of L-97-1 as a single intravenous (i.v.) infusion in high doses post-CLP improved seven day survival in a dose-dependent manner (30-40% survival) vs. controls (no treatment, 17% survival) or antibiotics alone (23% survival). In combination with antibiotics (gentamicin + ampicillin) administered as single doses, L- 97-1 significantly increased survival to 50-70% in a dose-dependent manner. Studies proposed in this revised STTR Phase II grant will extend the studies of the STTR Phase I grant in the rat CLP model of sepsis to demonstrate that in clinically relevant lower doses administered as a continuous i.v. infusion daily for three days, with and without antibiotics administered b.i.d. in repeat doses over three days, that L-97-1 is effective for the early treatment of sepsis. To demonstrate that L-97-1 is effective as an adjunctive, anti-sepsis treatment after CLP in severely ill but not moribund animals, a broad spectrum antimicrobial, ceftriaxone, will be used to cover Gram-negative and Gram-positive aerobic bacteria in combination with clindamycin to cover anaerobic bacteria. These expanded studies will evaluate the efficacy of L-97-1 at later time points after CLP to determine when benefit is lost and to compare L-97-1 to Xigris and other anti-sepsis approaches, including anti-LPS and TNF inhibitor treatments. Furthermore, these studies will be extended to include mechanistic controls to determine the efficacy of L-97-1 in an LPS-induced conscious, catheterized sepsis rat model of endotoxemia. The primary endpoints for these efficacy studies are 7 day survival, as well as the severity of ALI at 72 h and 7 days after CLP or i.v. LPS/endotoxin challenge. In this revised STTR Phase II grant, Endacea will simultaneously demonstrate whether plasma endotoxin levels as measured with Endacea's endotoxin assay and expression of A1 ARs in the lungs of rats correlate with the severity of ALI following CLP. With successful completion of the studies proposed in this revised STTR Phase II grant application, Endacea expects to attract a strategic pharmaceutical partner to license L-97-1 for further development and commercialization as an anti-sepsis therapeutic. PUBLIC HEALTH RELEVANCE: Sepsis is a medical syndrome characterized by an overwhelming systemic response to infection that can rapidly lead to shock, organ failure, and death. In the U.S. sepsis is the 10th leading cause of death overall and accounts for over 750,000 cases and 215,000 deaths each year and 17 billion in annual health care expenditures. Despite the availability of newer antimicrobial agents, improved supportive care, and introduction of an FDA approved adjunctive therapy for sepsis, Xigris(r) (drotrecogin alfa), the mortality rate for severe sepsis and septic shock of 30-60% remains high. Thus, there is a large unmet medical need for a safe, effective anti-sepsis therapy which can be used as an adjunctive therapy to antibiotics for the treatment of sepsis.