Novel Treatment for Septicemia Targets A1 ARs

DESCRIPTION (provided by applicant): Septicemia 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. septicemia is the 10th leading cause of death overall with over 750,000 cases and 215,000 deaths each year and accounts for $17 billion in annual health care expenditures. Following its release from Gram-negative bacteria, elevated levels of endotoxin in the plasma (endotoxemia) causes acute organ damage, including acute lung injury (ALl) and death. Endacea, Inc. (Research Triangle Park, NC) is a biopharmaceutical company developing an integrated approach to Gram-negative septicemia with both a diagnostic for endotoxin and a proprietary molecule as an adjuvant treatment of Gram-negative septicemia and endotoxemia which targets a new molecular target - the A1 adenosine receptor. This approach is based on the discovery and recent report that endotoxin binds to and activates A1 adenosine receptors (AR) on human pulmonary artery endothelial cells. Previously, it was reported that A1 AR antagonists block endotoxin-induced ALl. Endacea's lead molecule A1 AR antagonist, L-97-1, is a water-soluble, small molecule with high affinity and high selectivity for the human A1 AR. The Specific Aim of this STTR Phase I grant is to demonstrate in an animal model of Gram-negative septicemia and endotoxemia that L-97-1 as an adjuvant therapy to antibiotics is more effective than antibiotics alone for the prevention and early treatment of endotoxin- induced ALl and improves outcome and mortality. In a rat cecal ligation perforation (CLP) model of Gram-negative septicemia and endotoxemia, the effect of L-97-1 on ALl at 24 and 72 hours and on mortality at 7 days (with and without antibiotics) following CLP will be investigated. Proof of concept (POC) from these feasibility animal studies will allow Endacea to apply for 1) an STTR Phase I grant to test L-97-1 as an adjuvant therapy in animal models of bioterrorism, i.e. models of endotoxin-induced ALl associated with plague, tularemia and other pathogenic Gram-negative bacteria listed as priority pathogens by NIAID and for 2) an SBIR Phase II grant to test L-97-1 as an adjuvant therapy for the prevention and early treatment of ALl in POC clinical trials in patients with suspected Gram-negative septicemia. Despite the recent introduction of an FDA approved adjuvant therapy for sepsis, XigrisTM (drotrecogin alfa), the mortality rate remains high. Thus, there is a need for new adjuvant therapies which target new targets with different mechanisms of action in the pathophysiology of sepsis, to improve the outcome for patients with sepsis. As opposed to Xigris and other proposed adjuvant therapies for sepsis, L- 97-1 targets an early event in the sepsis cascade, activation and injury to pulmonary artery endothelial cells. Endacea estimates that there were 1.2 million cases of Gram-negative septicemia in 2000 worldwide with a potential market size of $3.8 billion worldwide.