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学对策（MCMS） 防止因暴露于电离辐射而导致的急性组织损伤和慢性病理 意外或恐怖事件。辐射诱导炎症细胞因子，促进组织损伤 胃肠道急性辐射综合征（GI-ARS）。因为没有批准的药物来防止Gi-ARS，所以 暴露于辐射后，需要新药以治疗新药。特别是鞘脂 神经酰胺和1-磷酸盐（S1P）调节胃肠道上皮细胞存活，DNA损伤反应， 和对炎症细胞因子的反应。 S1P的合成取决于鞘氨醇激酶（SK1和SK2） 活性，因此SK是减轻GIAR的合理新分子靶标。 Apogee开发了第一个 类研究新药Opaganib（以前称为ABC294640）。 Opaganib是唯一的临床阶段 SK2的抑制剂，在临床前模型中具有广泛的抗癌和抗炎功效。第1阶段临床 对患有晚期实体瘤或多发性骨髓瘤患者的口服阿无果疗法的试验是完整的， Opaganib对前列腺癌或胆管癌患者的Opaganib的2阶段临床试验正在进行中。 此外，Opaganib改善了严重的Covid-19患者的临床结局。迄今为止， Opaganib已针对> 470名具有良好安全性的患者施用。 由于GI-ARS是由上皮细胞凋亡和过度炎症介导的，因此调节的过程 通过鞘脂，我们假设Opaganib会减少辐射暴露的GI损害 缓解GI-ARS和改善的生存率。在概念证明的研究中，生物医学高级支持 研发局和国防部，我们证明了口腔奥帕加尼布 在5％的骨头辐照后，在小鼠的GI-ARS中提供了高度显着的防止死亡率的保护 骨髓屏蔽模型。 Opaganib在辐射之前或在辐射之前或24小时后增加生存率 辐射暴露，并且在人类试验中证明是安全的水平有效。 FDA在一次预印本会议上鼓励Opaganib作为GI-ARS的MCM继续发展 根据动物批准的动物规则。确定了批准的具体要求，是 在以下针对此阶段2 SBIR项目的特定目标中解决：1。生化定义 防止辐射引起的细胞死亡和肠上皮细胞炎症的机制； 2。 辐射暴露对口腔辅助Opaganib药代动力学（PK）的影响的定义；和 3。鉴定用于未来关键动物研究的Opaganib的可评估的药效学（PD）生物标志物 和人类临床试验。本文提出的研究遵循FDA根据动物规则批准的指南 并将使Opaganib作为GI-ARS的MCM持续发展。