ATL146e is a synthetic small molecule developed by Adenosine Therapeutics, LLC (ATL) that acts as a selective agonist of the adenosine A2A receptor. ATL146e, sterile solution for intravenous (i.v.) bolus injection, is currently in Phase III of clinical development for use as a coronary vasodilator in pharmacodynamic stress imaging. ATL146e, when administered parenterally (intravenously, i.v.; intraperitoneally, i.p.; or subcutaneously s.c.) at much lower levels of systemic exposure (below those that elicit cardiovascular effects) exerts potent anti-inflammatory/tissue protective effects in sepsis and multiple other models of acute inflammation. Based upon its established nonclinical and clinical safety, ATL is rapidly advancing development of ATL146e for the treatment of sepsis. Accordingly, we are applying for an SBIR advanced technology grant to complete the following specific aims: 1) complete required toxicity testing for ATL146e in a second animal species to demonstrate that ATL146e is equally safe when administered as a continuous i.v. infusion compared to its administration as an i.v. bolus and 2) conduct additional pharmacodynamic testing with both ATL146e and ATL's identified lead backup compound, ATL313, in clinically-relevant mouse and rabbit models of sepsis: cecal ligation-puncture model (CLP) of polymicrobial bacteremia in mice and rabbits; and fungemia model (Candida albicans) in mice. The rationale for conduct of the additionally proposed pharmacological studies include: 1) establishment of benefit of ATL146e and ATL313 in clinically-relevant, polymicrobial models of septicemia 2) demonstrate that protective effects are not species specific (i.e. demonstrable protective effects in second nonrodent species (rabbit CLP moldel); 3) expansion of potential for use in septicemia induced by fungal infections; 4) identification of relevant cytokines that could serve as surrogate markers for monitoring clinical benefit of treatment. Since research shows that mechanisms for protection against sepsis-induced mortality by ATL146e and ATL313 relate to their broad-spectrum anti-inflammatory properties, the research proposed in this grant has direct relevance to the Small Business Bio-defense program of the National Institute for Allergy and Infectious Diseases (NIAID).
Public Health Relevance Statement: Terms: prevent; preventing; Canis familiaris; domestic dog; canine; Dogs Mammals; Dogs; Canine Species; small molecule; Adenosine; Dose; esterase; Ester Hydrolase; Bolus Infusion; Bolus; Doctor of Philosophy; PhD; Ph.D.; National Institute of Allergy and Infectious Disease; NIAID; Research Contracts; in vivo Model; Anti-inflammatory; research clinical testing; clinical test; Clinical Testing; Clinical Evaluation; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Small Business Innovation Research; SBIRS (R43/44); SBIR; Monitor; Cardiac; Development; developmental; Oral Administration; intraoral drug delivery; Oral Drug Administration; Foundations; Image; imaging; base; Goals; Grant; Half-Life; Human; Modern Man; Man (Taxonomy); Acute; Solid; Clinical; Phase; Inflammation; Injection of therapeutic agent; Injections; Evaluation; Laboratories; Lead; heavy metal lead; heavy metal Pb; Pb element; Ligation; Closure by Ligation; Toxicity Tests; Toxicity Testing; Funding; Agonist; Adenosine A2A Receptor; Adenosine A(2A) Receptor; Mortality Vital Statistics; Mortality; Mus; Murine; Mice Mammals; Mice; Mycoses; fungus infection; fungal infection; Fungus Diseases; chemokine; chemoattractant cytokine; SIS cytokines; Intercrines; Homologous Chemotactic Cytokines; Chemotactic Cytokines; Therapeutic; Animals; Drug Kinetics; Pharmacokinetics; Pharmacology; Anti-Inflammatory Agents; Antiinflammatory Agents; Antiinflammatories; Anti-Inflammatories; Plasma; Reticuloendothelial System, Serum, Plasma; Plasma Serum; Blood Plasma; Antibiotic Therapy; bacterial infectious disease treatment; bacterial disease treatment; Antibiotic Treatment; Puncture procedure; Punctures; Oryctolagus cuniculus; Rabbits Mammals; Rabbits; Domestic Rabbit; Intravenous; Research; Safety; Septicemia; septicaemia; Blood Poisoning; Solutions; Life; programs; Stress; Miniature Swine; mini pig; Minipigs; Technology; Testing; Time; Tissues; Body Tissues; Work; Week; Severities; Bacteremia; bacteraemia; Infusion procedures; Infusion; coronary vasodilator; receptor; Receptor Protein; Toxic effect; Toxicities; Sterility; sterile; Candida albicans; C.albicans; C. albicans; Disease model; disorder model; Reporting; Cardiovascular system; circulatory system; Heart Vascular; Cardiovascular system (all sites); Cardiovascular Organ System; Cardiovascular Body System; Cardiovascular; cytokine; Generations; Relative (related person); Relative; Therapeutic Intervention; intervention therapy; Fungemia; fungaemia; Pharmacodynamics; Businesses; Surrogate Markers; Modeling; Property; LOINC Axis 2 Property; Intervention; interventional strategy; Intervention Strategies; Bioavailable; Communicable Diseases; Infectious Disorder; Infectious Diseases and Manifestations; Infectious Diseases; Infectious Disease Pathway; Advanced Development; Sepsis; bloodstream infection; protective effect; antimicrobial; anti-microbial; clinically relevant; clinical relevance; mouse model
