Opaganib as a Medical Countermeasure for Gastrointestinal Acute Radiation Syndrome

项目摘要 NIAID的辐射对策计划正在寻求医疗对策（MCM）， 预防因暴露于电离辐射而导致的急性组织损伤和慢性病变， 意外或恐怖事件。辐射诱导炎性细胞因子，促进组织损伤，包括 胃肠道急性放射综合征（GI-ARS）。因为没有批准的药物来预防GI-ARS， 强烈需要用于辐射后治疗的新药。尤其是鞘脂 神经酰胺和鞘氨醇1-磷酸（S1 P），调节GI上皮细胞存活，DNA损伤反应， 和对炎症细胞因子的反应。S1 P的合成依赖于鞘氨醇激酶（SK 1和SK 2） 活性，因此SK是减轻GI-ARS的合理的新分子靶标。Apogee开发了第一个 研究新药opaganib（以前称为ABC 294640）。Opaganib是唯一的临床阶段 在临床前模型中具有广泛的抗癌和抗炎功效。1期临床 对晚期实体瘤或多发性骨髓瘤患者口服施用Opaganib的试验已经完成， opaganib在前列腺癌或胆管癌患者中的2期临床试验正在进行中。 此外，opaganib改善了严重Covid-19高度受损患者的临床结局。到目前为止， opaganib已被给予>470名患者，具有良好的安全性。 由于GI-ARS是由上皮细胞凋亡和过度炎症介导的， 通过鞘脂，我们假设opaganib将减少辐射暴露引起的GI损伤， 减轻GI-ARS并提高生存率。在生物医学高级研究所支持的概念验证研究中， 研究和发展管理局和国防部，我们证明了口服opaganib 在5%骨中照射后，对小鼠中GI-ARS的死亡率提供高度显著的保护 骨髓屏蔽模型在放射前或放射后24小时给药时，Opaganib增加了存活率。 辐射暴露，并且在人体试验中已证明安全的水平下有效。 在IND前会议上，FDA鼓励继续开发opaganib作为GI-ARS的MCM 根据动物法规进行监管审批。确定了批准的具体要求， 第二阶段SBIR项目的具体目标如下：1.生物化学的定义 针对肠上皮细胞中辐射诱导的细胞死亡和炎症的保护机制; 2. 定义辐射暴露对口服给予的opaganib的药代动力学（PK）的影响;以及 3.确定用于未来关键动物研究的opaganib的可评估药效学（PD）生物标志物 和人体临床试验。本文提出的研究遵循FDA指南，根据动物规则获得批准 并将使opaganib作为GI-ARS的MCM继续发展。

PROJECT ABSTRACT The Radiation Countermeasures Program of the NIAID is seeking medical countermeasures (MCMs) to prevent acute tissue damage and chronic pathologies resulting from exposure to ionizing radiation from an accidental or terroristic event. Radiation induces inflammatory cytokines that promote tissue damage including Gastrointestinal Acute Radiation Syndrome (GI-ARS). Because there are no approved drugs to prevent GI-ARS, there is an intense need for new drugs for therapy following exposure to radiation. Sphingolipids, particularly ceramides and sphingosine 1-phosphate (S1P), regulate GI epithelial cell survival, the DNA damage response, and responses to inflammatory cytokines. Synthesis of S1P is dependent on sphingosine kinase (SK1 and SK2) activity, and so SKs are rational new molecular targets to mitigate GI-ARS. Apogee has developed the first-in- class Investigational New Drug opaganib (previously called ABC294640). Opaganib is the only clinical-stage inhibitor of SK2 and has broad anticancer and anti-inflammatory efficacy in preclinical models. Phase 1 clinical trials of orally-administered opaganib to patients with advanced solid tumors or multiple myeloma are complete, and Phase 2 clinical trials of opaganib in patients with prostate cancer or cholangiocarcinoma are in progress. Additionally, opaganib improved clinical outcome for highly compromised patients with severe Covid-19. To date, opaganib has been administered to >470 patients with a favorable safety profile. Because GI-ARS is mediated by epithelial cell apoptosis and excessive inflammation, processes regulated by sphingolipids, we hypothesized that opaganib will decrease GI damage from radiation exposure leading to mitigation of GI-ARS and improved survival. In Proof-of-Concept studies supported by the Biomedical Advanced Research and Development Authority and the Department of Defense, we demonstrated that oral opaganib provides highly significant protection against mortality from GI-ARS in mice following irradiation in a 5% bone marrow-shielded model. Opaganib increased survival when administered either prior to radiation or 24 hr after radiation exposure and was efficacious at levels that have been demonstrate safe in human trials. In a pre-IND meeting, the FDA encouraged the continue development of opaganib as an MCM for GI-ARS under the Animal Rule for regulatory approval. Specific requirements for approval were identified, and are addressed in the following Specific Aims for this Phase 2 SBIR project: 1. Definition of the biochemical mechanism(s) for protection against radiation-induced cell death and inflammation in intestinal epithelial cells; 2. Definition of the effect of radiation exposure on the pharmacokinetics (PKs) of orally-administered opaganib; and 3. Identification of assessable pharmacodynamic (PD) biomarkers for opaganib for future pivotal animal studies and human clinical trials. The studies proposed herein follow FDA guidance for approval under the Animal Rule and will enable continued advancement of opaganib as an MCM for GI-ARS.