A2a Adenosine Agonist Cardiac Reperfusion Injury

描述(申请人提供)：腺苷治疗有限责任公司(ATL)成立于1999年，是一家药物发现和开发公司，开发了一系列有效和选择性的腺苷A2a受体激动剂。在STTR资金的帮助下，ATL已经开发出一种领先的腺苷A2A受体激动剂ATL-146e，目前正处于临床开发的后期阶段，用于心脏负荷成像中的冠状动脉血管扩张剂。该项目的中心目标是进一步开发ATL-146E，用于预防进展性急性心肌梗死(AMI)患者在接受直接冠状动脉支架血管重建术时发生的心脏再灌注损伤。急性心肌梗死是美国最主要的单一死因，每年有50万至70万人死于与冠状动脉疾病相关的疾病，而且只批准了一种治疗措施。我们已经证明ATL-146E对肝脏和肾脏的缺血再灌注损伤有保护作用，在小鼠、兔和犬的冠状动脉缺血再灌注损伤模型中也有保护作用。ATL146e在人体内的安全性已经在用于药理应激成像的团注给药过程中得到证实。它作为连续静脉输注给药，对再灌注损伤产生最佳的心脏保护作用，尚未进行临床研究。因此，目前的建议为在健康志愿者中持续输注ATL-146E进行安全性、药代动力学和药效学研究提供了依据。具体地说，我们将研究ATL-146E作为连续静脉输注给与接受低IV内毒素治疗的人类志愿者，以确定以下方面：1)安全性和耐受性；2)ATL-146E及其主要代谢物的药代动力学，包括稳态水平和达到稳态的时间；以及3)药效学效应(基于其抑制内毒素反应中瞬时产生的促炎细胞因子的能力)。总而言之，这项研究得出的数据将为进行后续的试点第二阶段临床试验奠定基础，该试验将在急性心肌梗死患者中进行，该试验由SBIR Fast-Track应用的第二阶段提供支持。这项试验性的第二阶段研究随后将被用作最终的第二阶段临床试验的基础，随后是最终的第三阶段临床试验和最终的市场批准。

DESCRIPTION (provided by applicant): Founded in 1999, Adenosine Therapeutics LLC (ATL) is a drug discovery and development company that has developed a family of potent and selective adenosine A2A receptor agonists. With the help of STTR funding, ATL has developed a lead adenosine A2A receptor agonist, ATL-146e, that is currently in late Phase II of clinical development for use as a coronary vasodilator in cardiac stress imaging. The central goal of this project is to further the clinical development of ATL-146e for prevention of cardiac reperfusion injury that occurs in patients with evolving acute myocardial infarction (AMI) who undergo revascularization with primary coronary stenting. AMI is the leading single cause of death in the US, accounting for 500,000- 700,000 coronary-artery disease-related deaths annually and for which only one therapeutic intervention is approved. We have demonstrated that ATL-146e protects against ischemia-reperfusion injury in liver and kidney, as well as in mouse, rabbit and canine models of coronary ischemia-reperfusion injury. The safety of ATL146e in man has been established during bolus administration that is used for pharmacological stress imaging. Its administration as a continuous IV infusion, which produces optimal cardioprotection from reperfusion injury, has not been studied clinically. Thus the current proposal provides for the conduct of a safety, pharmacokinetic, and pharmacodynamic study of ATL-146e when given as a continuous infusion in healthy volunteers. Specifically we will study ATL-146e given as a continuous IV infusion to human volunteers also treated with a low IV bolus of endotoxin to establish the following: 1) safety and tolerability; 2) pharmacokinetics of ATL-146e and its primary metabolite including steady state levels and time to steady state; and 3) pharmacodynamic effects, (based on its ability to inhibit transient production of proinflammatory cytokines that occur in response to endotoxin). Collectively, the data derived from this study will provide the foundation for the conduct of a subsequent pilot Phase II clinical trial supported by the Phase 2 portion of this SBIR Fast-Track application that will be conducted in patients with AMI. This pilot Phase II study will then be used as a basis for a definitive Phase II clinical trial, followed by a definitive Phase III clinical trial and eventual market approval.