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

TP508：一种减轻辐射暴露致死效应的新药

• 批准号: 8534018
• 负责人: Darrell H. Carney
• 金额: $ 81.04万
• 依托单位: CHRYSALIS BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534018
• 关键词: Acceleration; Acetates; Acute; Animals; Attenuated; Bacteremia; Biological Availability; Blast Cell; Bone Marrow; Cessation of life; Clinical Trials; Critical Pathways; Dermal; Development; Diabetic Foot Ulcer; Disasters; Dose; Drug Formulations; Drug Kinetics; Earthquakes; Emergency Situation; Exposure to; FDA approved; Film; Foot Fracture; Functional disorder; Genetic; Glycolic-Lactic Acid Polyester; Goals; Government; Healed; Hour; Human; Humidity; Hydrogels; In Vitro; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Interleukin-6; Intramuscular; Investigational Drugs; Japan; Laboratories; Life; Measures; Microspheres; Modeling; Mus; Nuclear; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase III Clinical Trials; Probability; Radiation; Radiation Syndromes; Rattus; Route; Safety; Saline; Sepsis; Stem cells; Sterile coverings; Testing; Thick; Topical application; Toxicology; Up-Regulation; Vascular Endothelial Cell; Vascular Endothelium; Whole-Body Irradiation; Wound Healing; animal efficacy; animal rule; base; body system; combat; crypt cell; cytokine; efficacy trial; healing; in vivo; intestinal crypt; intravenous injection; meetings; mortality; novel; phase 1 study; prevent; radiation effect; reproductive; restoration; safety study; safety testing; subcutaneous; wound

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.

描述（由申请人提供）：随着最近日本反应堆的辐射释放以及世界某个地方核爆炸的可能性增加，迫切需要开发有效的药物对抗措施，这些措施可以在暴露后提供，以防止辐射诱导的死亡。除此之外，当辐射与损伤（RCI）结合时，死亡率显着增加。因此，必须开发和储存减轻辐射和放射性核素干扰影响的制剂，以备紧急使用。我们提出，TP 508（醋酸罗格列酮），一种新的肽类药物，目前在临床试验中愈合糖尿病足溃疡和骨折，可能会防止RCI诱导的死亡率基于其加速伤口愈合和其独特的有益作用，对血管内皮细胞。1期研究表明，TP 508局部应用于伤口或通过暴露后注射递送，恢复了受辐射动物的正常伤口愈合，防止了辐射诱导的IL-6上调，并减轻了RCI诱导的死亡率。暴露后注射TP 508也延迟了致死剂量辐射后的死亡率和菌血症发作。第二阶段将集中于优化TP 508制剂的局部和全身给药，并改进这些制剂，以提高其稳定性和在核灾难后使用的潜力。具体目标包括制剂的比较和优化、稳定肽的测试以及通过测量死亡率的减轻、内皮功能的保护和伤口愈合的恢复来选择最佳递送模式。在与FDA开会后，将外包额外的GLP安全性、有效性和最终制剂稳定性研究，以满足FDA在“动物规则”豁免下对TP 508批准的特定要求。在第2阶段完成后，TP 508产品应准备好进行关键的动物规则有效性试验，并加速批准紧急储存，以减轻核辐射和RCI的影响。