TP508: A New Drug for Mitigating Lethal Effects of Radiatin Exposure

描述(由申请人提供)：随着最近日本反应堆的辐射释放和世界各地核爆炸可能性的增加，迫切需要开发有效的药物应对措施，这些措施可以在暴露后提供，以防止辐射导致的死亡。除了这一需要，当辐射与损伤(RCI)相结合时，死亡率显著增加。因此，必须开发和储存用于减轻辐射和RCI影响的试剂，以备紧急使用。我们认为，目前正在进行临床试验的治疗糖尿病足部溃疡和骨折的新型多肽药物TP508(柔沙拉肽醋酸酯)可能由于其加速伤口愈合和对血管内皮细胞的独特有益作用而防止RCI引起的死亡。第一阶段研究表明，TP508局部应用于创面或照射后注射，可恢复受照射动物的正常创面愈合，防止辐射诱导的IL-6上调，并减轻RCI诱导的死亡率。暴露后注射TP508也延缓了致死剂量辐射后的死亡率和菌血症的发生。第二阶段将侧重于优化TP508配方，以便局部和系统地提供，并改进这些配方，以增加其稳定性和在核灾难后使用的潜力。具体目标包括比较和优化配方，测试稳定的多肽，并通过测量死亡率的降低、内皮功能的保护和伤口愈合的恢复来选择最佳给药方式。在与FDA举行会议后，将外包更多的GLP安全性、有效性和最终配方稳定性研究，以满足FDA在《动物规则》豁免下对TP508批准的具体要求。在第二阶段完成后，TP508产品(S)应准备好进行关键的动物规则疗效试验，并加速批准紧急储存，以减轻核辐射和RCI的影响。

DESCRIPTION (provided by applicant): With recent radiation release from reactors in Japan and increasing probability of nuclear detonation somewhere in the world, there is a critical need for development of effective medicinal counter-measures that can be delivered after exposure to prevent radiation-induced mortality. Adding to this need, mortality increases significantly when radiation is combined with injury (RCI). Agents to mitigate effects of radiation and RCI must therefore be developed and stockpiled for emergency use. We proposed that TP508 (rousalatide acetate), a novel peptide drug currently in clinical trials for healing diabetic foot ulcers and fractures, may prevent RCI-induced mortality based on its acceleration of wound healing and its unique beneficial effects on vascular endothelial cells. Phase 1 studies demonstrated that TP508 applied topically to wounds or delivered by post-exposure injection, restored normal wound healing in irradiated animals, prevented radiation-induced up-regulation of IL-6, and mitigated RCI-induced mortality. Post-exposure TP508 injection also delayed mortality and the onset of bacteremia following a lethal dose of radiation. Phase 2 will focus on optimization of TP508 formulations for topical and systemic delivery and refinement of these formulations to increase their stability and potential for use following a nuclear disaster. Specifc Aims include comparisons and optimization of formulations, testing stabilized peptides, and selecting best modes of delivery by measuring mitigation of mortality, protection of endothelial function and restoration of wound healing. Following a meeting with the FDA, additional GLP safety, efficacy and final formulation stability studies will be outsourced to meet specific FDA requirements for TP508 approval under the "Animal Rule" exemption. Upon completion of Phase 2, TP508 product(s) should be ready for pivotal Animal Rule efficacy trials and accelerated approval for emergency stockpiling to mitigate effects of nuclear radiation and RCI.