Opaganib as a Medical Countermeasure for Gastrointestinal Acute Radiation Syndrome

奥帕加尼作为胃肠道急性辐射综合症的医学对策

• 批准号: 10758903
• 负责人: Charles D Smith
• 金额: $ 85.22万
• 依托单位: APOGEE BIOTECHNOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10758903
• 关键词: Accidents; Acute; Address; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Apoptosis; Authorization documentation; Autophagocytosis; Biochemical; Biological Availability; Biological Markers; Bone Marrow; Cell Cycle Arrest; Cell Death Induction; Cell Survival; Cell physiology; Ceramides; Cholangiocarcinoma; Chronic; Clinical; Clinical Trials; DNA Damage; DNA Repair; DNA lesion; Department of Defense; Development; Dose; Down-Regulation; Drug Kinetics; Epithelial Cells; Event; Exposure to; Future; Generations; Goals; Human; Induction of Apoptosis; Inflammation; Inflammatory; Interleukin-6; Investigational Drugs; Ionizing radiation; Malignant neoplasm of prostate; Mediating; Methods; Modeling; Molecular Target; Multiple Myeloma; Mus; NF-kappa B; National Institute of Allergy and Infectious Disease; Oral; Oral Administration; Outcome; Pathology; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Plasma; Pre-Clinical Model; Process; Production; Proteins; Qualifying; Radiation; Radiation Accidents; Radiation Dose Unit; Radiation Induced DNA Damage; Radiation Protection; Radiation Toxicity; Radiation exposure; Radiation induced damage; Role; Safety; Sampling; Signal Pathway; Small Business Innovation Research Grant; Solid Neoplasm; Sphingolipids; TNF gene; Testing; Tissues; Toxicology; animal rule; anti-cancer; authority; c-myc Genes; cell killing; chemical stability; cytokine; drug development; efficacy study; emergency preparedness; gastrointestinal; improved; in vitro activity; in vivo; inhibitor; intestinal epithelium; irradiation; liquid chromatography mass spectrometry; medical countermeasure; mortality; novel therapeutics; pharmacodynamic biomarker; pharmacologic; pre-Investigational New Drug meeting; prevent; programs; radiation countermeasure; radiation effect; radioprotected; repaired; research and development; response; severe COVID-19; sphingosine 1-phosphate; sphingosine kinase

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.

项目摘要 NIAID 的辐射对策计划正在寻求医疗对策 (MCM)，以 预防因暴露于电离辐射而引起的急性组织损伤和慢性病变 意外或恐怖事件。辐射会诱导炎症细胞因子，促进组织损伤，包括 胃肠道急性辐射综合症（GI-ARS）。因为没有批准的药物可以预防 GI-ARS， 迫切需要用于治疗暴露于辐射后的新药物。鞘脂类，特别是 神经酰胺和 1-磷酸鞘氨醇 (S1P)，调节胃肠道上皮细胞存活、DNA 损伤反应， 以及对炎症细胞因子的反应。 S1P 的合成依赖于鞘氨醇激酶（SK1 和 SK2） 活性，因此 SK 是减轻 GI-ARS 的合理新分子靶点。 Apogee 开发了首个 类研究新药 opaganib（以前称为 ABC294640）。 Opaganib是唯一处于临床阶段的 SK2 抑制剂，在临床前模型中具有广泛的抗癌和抗炎功效。一期临床 针对晚期实体瘤或多发性骨髓瘤患者口服奥帕加尼的试验已经完成， 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 改善了患有严重 Covid-19 的高度受损患者的临床结果。迄今为止， 奥帕加尼已被用于超过 470 名患者，且安全性良好。 由于 GI-ARS 是由上皮细胞凋亡和过度炎症介导的，因此过程受到调节 通过鞘脂，我们假设奥帕加尼将减少辐射暴露导致的胃肠道损伤，从而导致 缓解 GI-ARS 并提高生存率。在生物医学高级支持的概念验证研究中 研究与发展局和国防部，我们证明了口服奥帕加尼 对小鼠 5% 骨照射后的 GI-ARS 死亡提供非常显着的保护 骨髓屏蔽模型。在放疗前或放疗后 24 小时给药时，Opaganib 可提高生存率 辐射暴露，并且在人体试验中已证明安全的水平下是有效的。 在 IND 前会议上，FDA 鼓励继续开发 opaganib 作为 GI-ARS 的 MCM 根据动物规则获得监管批准。确定了批准的具体要求，并 该第 2 阶段 SBIR 项目的具体目标如下： 1. 生化的定义 防止肠上皮细胞辐射诱导的细胞死亡和炎症的机制； 2. 辐射暴露对口服奥帕加尼药代动力学（PK）影响的定义；和 3. 鉴定可评估的奥帕加尼药效学 (PD) 生物标志物，用于未来的关键动物研究 和人体临床试验。本文提出的研究遵循 FDA 动物规则批准指南 并将推动奥帕加尼作为 GI-ARS 的 MCM 的持续发展。