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.
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.