Repurposing an EU Therapeutic for Hemoglobinopathies

重新利用欧盟治疗血红蛋白病的药物

• 批准号: 10910749
• 负责人: Sharie Haugabook
• 金额: $ 166.83万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10910749
• 关键词: Address; Adhesions; Adult; Anemia; Birth; Blood Vessels; Brain; Canada; Cell Death; Cessation of life; Chronic; Clinical; Clinical Pharmacology; Clinical Trials; Compensation; Data; Defect; Development; Disease; Drug Interactions; Drug Kinetics; Erythrocytes; European Union; Excretory function; Fatigue; Fetal Hemoglobin; Formulation; Genes; Genetic Diseases; Goals; Health; Heart; Hemoglobin; Hemoglobin A; Hemoglobin concentration result; Hemoglobinopathies; Investigational Drugs; Investigational New Drug Application; Lead; Lung; Metabolism; Mutation; Organ; Oxygen; Pharmaceutical Preparations; Pharmacology Study; Phase; Point Mutation; Polymers; Production; Proteins; Recommendation; Sampling; Sickle Cell Anemia; Sickle Cell Trait; Symptoms; Therapeutic; Therapeutics for Rare and Neglected Diseases; Toxicology; United States Food and Drug Administration; absorption; beta Globin; beta Thalassemia; dimer; disability; drug repurposing; effective therapy; efficacy study; fetal; manufacture; targeted treatment; thalassemia intermedia

The oxygen-carrying hemoglobin protein (Hemoglobin A or HbA) is a tetrameric molecule, comprising two paired alpha-chain/beta-chain protein dimers. Beta-thalassemia is caused by mutations that result in insufficient production of the beta-globin protein, whereas sickle cell disease is caused by a point mutation in the beta-globin protein that causes the hemoglobin tetramers to form rigid polymers that deform the red blood cell, causing early cell death, abnormal adhesion to blood vessels and resulting widespread organ damage. HbA is the adult form of hemoglobin, produced mostly after birth. At earlier developmental stages, fetal forms of hemoglobin (HbF) are expressed. Importantly, these fetal globin proteins can replace the abnormal adult beta-globin proteins found in sickle cell disease and compensate for the absence of adult beta-globin proteins in beta-thalassemia. Although fetal globin expression stops shortly after birth, the drug PB-04 can reactivate expression of the fetal-stage beta-globin gene. This activation may lead to production of sufficient levels of HbF to mitigate the beta-hemoglobinopathies. The goal of this project is to repurpose this drug, currently in use in the European Union and Canada for another indication, for treatment of the hemoglobin disorders beta-thalassemia and sickle cell disease. The TRND team completed pharmacology and efficacy studies to recapitulate key data generated by the collaborator. The team received recommendations from the Food and Drug Administration (FDA) regarding the proposed studies required to support the filing of an Investigational New Drug (IND) application via pre-IND interactions. Pharmacokinetic, bioanalytical, ADME (absorption, distribution, metabolism, excretion) and IND-enabling toxicology studies were completed, as were formulation and manufacturing of the drug product. These data and materials enabled the collaborator to file regulatory applications, which were cleared by both the US FDA and Health Canada, to begin clinical trials for beta thalassemia intermedia. The TRND team continued to support) manufacturing of the drug product, and clinical pharmacology efforts. An additional batch of GMP drug product was manufactured, and clinical pharmacology support to address clinical sample analyses for the ongoing Phase 1b/2a clinical trial which is near completion.

携带氧气的血红蛋白蛋白（血红蛋白A或HBA）是四聚体分子，包括两个配对的α-链/β链蛋白二聚体。 β-阿无血石症是由突变引起的，这些突变导致β-珠蛋白的产生不足，而镰状细胞疾病是由β-蛋白质蛋白中的点突变引起的，该突变会导致血红蛋白四聚体形成刚性聚合物，从而形成刚性细胞，从而导致细胞死亡，从而导致早期死亡，并损害了血液的衰减，从而造成了血液的衰减。 HBA是血红蛋白的成年形式，主要在出生后产生。在较早的发育阶段，表达了血红蛋白（HBF）的胎儿形式。重要的是，这些胎儿球蛋白蛋白可以替代在镰状细胞疾病中发现的异常成年β-珠蛋白蛋白，并补偿β-核亚无血症中不存在成年β-珠蛋白。尽管胎儿球蛋白表达在出生后不久停止，但药物PB-04可以重新激活胎儿β-珠蛋白基因的表达。这种激活可能会导致产生足够水平的HBF来减轻β-亚属细胞病。该项目的目的是将目前在欧盟和加拿大使用的药物重新利用，以治疗血红蛋白疾病β-地中海贫血和镰状细胞病。 TRND团队完成了药理学和功效研究，以概述合作者生成的关键数据。该小组收到了食品药品监督管理局（FDA）的建议，内容涉及支持通过预先互动提交研究性新药（IND）申请所需的拟议研究。药代动力学，生物分析，ADME（吸收，分布，新陈代谢，排泄）和毒理学研究完成，药物的制定和制造。这些数据和材料使合作者能够提交由美国FDA和加拿大卫生部清除的监管应用程序，以开始对βthalassemia Intermedia进行临床试验。 TRND团队继续支持）制造药品和临床药理学工作。生产了一批GMP药物，并支持临床药理学支持，以解决正在进行的1B/2A期临床试验的临床样本分析，该试验即将完成。