Safety of A2A Adenosine Agonist for Treatment of Sepsis

描述(申请人提供)：ATL146e是由腺苷治疗公司(ATL)开发的一种合成小分子，作为腺苷A2a受体的选择性激动剂。ATL146e静脉无菌输液(静脉注射)团注，目前处于临床开发的第三阶段，用于药效负荷成像中的冠状动脉血管扩张剂。ATL146e，肠外给药(静脉注射；腹膜内注射；或皮下注射)在较低水平的全身暴露(低于引发心血管效应的水平)，在脓毒症和多种其他急性炎症模型中发挥强大的抗炎/组织保护作用。基于已确定的非临床和临床安全性，ATL正在迅速推进用于治疗脓毒症的ATL146e的开发。因此，我们正在申请SBIR先进技术赠款，以实现以下具体目标：1)在第二个动物物种中完成所需的ATL146e毒性测试，以证明ATL146e作为连续静脉注射时同样安全。将输液与静脉注射进行比较。(2)对ATL146e和ATL已确定的先导备份化合物ATL313进行额外的药效学测试，用于临床相关的小鼠和兔败血症模型：小鼠和兔的盲肠结扎-穿刺法(CLP)的多菌菌血症模型；以及小鼠的真菌血症模型(白色念珠菌)。另外建议进行的药理学研究的理由包括：1)确定ATL146e和ATL313在临床相关的多菌败血症模型中的益处；2)证明保护作用不具有物种特异性(即在第二非啮齿动物物种(兔CLP模型)中可证明的保护作用)；3)扩大用于治疗真菌感染引起的败血症的潜力；4)确定可用作监测临床治疗效益的替代标记物的相关细胞因子。由于研究表明，ATL146e和ATL313对脓毒症所致死亡的保护机制与它们的广谱抗炎特性有关，因此这项拨款中提议的研究与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).