A multivalent, easy-to-use product to mitigate and treat radiation exposure

摘要 放射性与核事故或攻击的威胁要求有效的放射医学对策 (MCM)能够减轻和治疗暴露于电离辐射的影响。造血急性辐射 综合征（HRAS）和皮肤辐射综合征（CRS）对暴露者造成严重的、危及生命的风险。 个体目前没有有效的放射缓解剂（在辐射暴露后但在组织暴露前给药） 毒性表现）或放射治疗（在组织毒性表现后施用）还没有 获得FDA批准。Fibroplate，Inc.开发了Fibrinoplate-S（FPS），一种静脉注射溶液， 纤维蛋白原包被白蛋白纳米球最初开发用于增强多种疾病的止血功能 临床环境。对受辐射啮齿动物进行的初步研究表明， 电离辐射暴露具有作为多价MCM抵抗辐射的独特潜力。特别是有人 证明FPS对辐射诱导的皮肤损伤（RSI）具有预防性质。期间 SBIR I期项目，在大鼠中进行临床前可行性研究，以证明FPS作为 治疗RSI。完成了以下几个目标：1）FPS作为预防和治疗的有效性 并证明了RSI的治疗方法。2)FPS诱导的干细胞向 观察病变。3)FPS作为中性粒细胞减少症和血小板减少症缓解剂的疗效得到证实。 4)发现FPS对细胞因子谱的调节作用。第一阶段获得的结果代表了 该SBIR II期项目的完美起点，将进行额外的临床前研究， 用于完成向FDA提交的IND提交文件包，以根据动物 功效法则。在SBIR第二阶段项目中，Fibroplate的目标是：i）证明FPS作为治疗药物的功效 在小型猪中进行RSI治疗，作为第二动物模型。ii）评估大鼠中的FPS毒理学特征， iv）扩大目前的生产工艺，以达到足以 支持临床发展。获得FDA对FPS的批准将为将其纳入 国家战略储备，作为应对辐射/核紧急情况的应急措施。 1

ABSTRACT The threat of radiological and nuclear accidents or attacks demands effective radiation medical countermeasures (MCM) able to mitigate and treat the effects of exposure to ionizing radiations. Hematopoietic acute radiation syndrome (HRAS) and cutaneous radiation syndrome (CRS) pose severe, life-threatening risks to exposed individuals. Currently no effective radio-mitigator (to be administered after radiation exposure but prior to tissue toxicity manifestation) or radio-therapeutic (to be administered after tissue toxicity manifestation) has yet received FDA approval. Fibroplate, Inc. developed Fibrinoplate-S (FPS), an intravenous injectable solution of Fibrinogen-coated Albumin nano-Spheres originally developed to augment hemostatic functions in multiple clinical settings. Preliminary studies conducted on irradiated rodents suggested that FAS administered after ionizing radiation exposure has a unique potential as a multi-valent MCM against radiations. In particular, it was demonstrated that FPS has prophylactic properties against Radiation-induced Skin Injuries (RSI). During the SBIR Phase I project, a preclinical feasibility study in rats was performed to demonstrate FPS’ efficacy as a therapeutic treatment for RSI. Several objectives were accomplished: 1) The efficacy of FPS as both prophylactic and therapeutic treatment for RSI was demonstrated. 2) An FPS-induced stem cells mobilization towards the lesion was observed. 3) The efficacy of FPS as a mitigator for neutropenia and thrombocytopenia was confirmed. 4) A regulatory effect of FPS on the cytokine profile was discovered. Results obtained in Phase I represent the perfect starting point for this SBIR Phase II project, where additional preclinical studies will be performed and used to complete an IND submission package to the FDA, to pursue FDA approval according to the Animal Efficacy Rule. In this SBIR Phase II project, Fibroplate aims at: i) Demonstrate FPS efficacy as a therapeutic treatment for RSI in minipigs, as a second animal model. ii) Assess FPS toxicology profile in rats, iii) Assess FPS stability and shelf-life, iv) Scale-up current manufacturing process to reach production volumes sufficient to sustain the clinical development. Obtaining FDA approval for FPS will pave the way for its inclusion in the Strategic National Stockpile as MCM for radiological/nuclear emergencies. 1