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某处核爆炸的可能性增加，迫切需要开发有效的药物应对措施，可以在暴露后提供，以防止辐射引起的死亡。此外，当辐射合并损伤（RCI）时，死亡率显著增加。因此，必须开发和储存减轻辐射和RCI影响的药剂，以备紧急使用。我们提出，TP508（醋酸rousalatide acetate）是一种新型肽药物，目前正在临床试验中用于治疗糖尿病足溃疡和骨折，基于其加速伤口愈合和对血管内皮细胞独特的有益作用，可能预防rci诱导的死亡。1期研究表明，TP508局部应用于伤口或暴露后注射，可恢复受辐射动物的正常伤口愈合，阻止辐射诱导的IL-6上调，并减轻rci诱导的死亡。暴露后注射TP508也延迟了致死剂量辐射后的死亡率和菌血症的发生。第二阶段将重点优化TP508配方，用于局部和系统给药，并改进这些配方，以提高其稳定性和核灾难后的使用潜力。具体目标包括比较和优化配方，测试稳定肽，并通过测量降低死亡率，保护内皮功能和恢复伤口愈合来选择最佳递送模式。在与FDA召开会议后，将外包额外的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”豁免下批准TP508的特定要求。在第二阶段完成后，TP508产品应准备好进行关键的动物规则有效性试验，并加速批准紧急储备，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. PUBLIC HEALTH RELEVANCE: Following a nuclear detonation the combination of radiation and traumatic injury is expected to be much more deadly that radiation alone. We have demonstrated that TP508, a novel peptide drug in human clinical trials, mitigates effects of whole body radiation and radiation combined with injury on mortality, wound healing, and dysfunction of multiple organ systems. In Phase 2, we will optimize TP508 formulations for topical and systemic delivery and complete FDA requirements to allow TP508 to begin pivotal trials to reduce mortality from nuclear radiation exposure.