Expanding the Treatment Window for the FDA-Approved Radiation Countermeasure Nplate.

introductionRecent shifts in the geopolitical landscape, including the threat of nuclear conflict and the proliferation of nuclear materials, have heightened concerns about radiological emergencies. Acute radiation syndrome (ARS) is a major health consequence of such events, but effective medical countermeasures (MCMs) remain limited. Although several compounds have been approved as mitigators to treat ARS, there is currently no FDA-approved drug that can be used as a prophylaxis-administered before exposure to prevent or lessen the effects of radiation. One key mitigator is Nplate (romiplostim), a thrombopoietin receptor agonist currently approved for use as soon as possible after expected or confirmed exposure to myelosuppressive doses of radiation (2 Gray (Gy)). However, there is growing interest in expanding its utility beyond this narrow window. Our current research suggests that administering Nplate at later time points (e.g., 48 or 72 hours postexposure) could still provide a significant survival benefit. Furthermore, its potential as a prophylaxis is being explored, which could offer a vital layer of protection for first responders and military personnel in high-risk environments. This expansion would address a critical gap in current medical readiness and increase resilience in a radiologically contaminated environment. MATERIALS AND

methodsThe efficacy of Nplate as both a mitigator and prophylaxis for ARS was evaluated in 2 separate studies using C57BL/6 mice. The first study used the Armed Forces Radiobiology Research Institute (AFRRI) cobalt-60 gamma irradiator to simulate nuclear fallout. Nplate was administered as a mitigator at 24, 48, and 72 hours postirradiation and as a prophylaxis at 6 and 12 hour preirradiation. The second study utilized the AFRRI Training, Research, Isotope, General Atomic (TRIGA) reactor to mimic nuclear detonation with mixed neutron-gamma radiation. All experiments were conducted under the oversight of the Uniformed Services University of the Health Sciences (USUHS) Institutional Animal Care and Use Committee (IACUC).

resultsWhen used as a mitigator for delayed administration, Nplate significantly enhanced the survival of both male and female subjects in a dose-dependent manner. In addition to improved survival rates, Nplate treatment led to the recovery of deficiencies in blood cell counts, an increase in colony-forming units (CFUs) in bone marrow, and a notable increase in megakaryocytes in sternal sections. Similarly, and even more pronounced, results were seen when Nplate was used as a prophylaxis. Prophylactic use resulted in a greater increase in overall survival, underscoring its potential to protect against the damaging effects of radiation.

conclusionsThe data presented in this manuscript provides compelling evidence to support the expanded use of Nplate as a MCM against radiation exposure. Our findings demonstrate that Nplate's efficacy extends beyond its current approved use, remaining effective as a mitigator when administered at 24, 48, and even 72 hours postirradiation. Furthermore, the studies show that Nplate is a potent prophylaxis, offering significant protection for military personnel and first responders in the event of a radiological or nuclear incident. This data will be used to support continued interactions with the FDA to broaden Nplate's indications.