Safety of Adenosine A2a Agonist for Treatment of Sepsis

描述（由申请人提供）：ATL146e是由Adenosine Therapeutics， LLC （ATL）开发的合成小分子，作为腺苷A2A受体的选择性激动剂。ATL146e是静脉（i.v）大剂量注射用无菌溶液，目前正处于临床开发的三期，用于药效学应激成像中的冠状血管扩张剂。当ATL146e以低得多的全身暴露水平（低于引起心血管影响的水平）经肠外给药（静脉注射，静脉注射，腹腔注射，皮下注射）时，对败血症和多种其他急性炎症模型具有有效的抗炎/组织保护作用。基于其已建立的非临床和临床安全性，ATL正在迅速推进用于治疗败血症的ATL146e的开发。因此，我们正在申请SBIR先进技术补助金，以完成以下具体目标：1)在第二种动物物种中完成ATL146e所需的毒性测试，以证明ATL146e作为持续静脉输注与作为静脉注射给药同样安全；2)在临床相关的小鼠和兔子脓毒症模型中，对ATL146e和ATL确定的先导化合物ATL313进行额外的药效学测试：小鼠和兔子多微生物菌血症的盲肠结肠炎-穿刺模型（CLP）；小鼠真菌病模型（白色念珠菌）。进行额外提出的药理学研究的基本原理包括：1)在临床相关的败血症多微生物模型中建立ATL146e和ATL313的益处；2)证明保护作用不是物种特异性的(即在第二种非啮齿动物（兔CLP模型）中证明了保护作用；3)扩大用于真菌感染引起的败血症的潜力；4)鉴定相关细胞因子，作为监测治疗临床获益的替代标志物。由于研究表明，ATL146e和ATL313预防败血症引起的死亡的机制与它们的广谱抗炎特性有关，因此这项研究与美国国家过敏和传染病研究所（NIAID）的小企业生物防御计划直接相关。

DESCRIPTION (provided by applicant): 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).