Preclinical Development of a New Drug for Treating Anemia of Chronic Inflammation

治疗慢性炎症性贫血新药的临床前开发

• 批准号: 8242247
• 负责人: Adam N. Goldfarb
• 金额: $ 24.61万
• 依托单位: CUMBERLAND PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242247
• 关键词: Aconitate Hydratase; Adverse effects; Anemia; Anemia due to Chronic Disorder; Animal Model; Arthritis; Autopsy; Biological Markers; Bone Marrow; CCL4 gene; Calcium; Cardiac; Chemistry; Chronic; Chronic Disease; Chronic Kidney Failure; Citrates; Clinical; Clinical Chemistry; Collaborations; Communication; Complete Blood Count; Cyclic GMP; Development; Development Plans; Disease; Dosage Forms; Dose; Elderly; Enzymes; Erythrocytes; Erythroid; Erythropoiesis; Erythropoietin; Foundations; Hospitals; Impairment; In Vitro; Inflammation; Inflammatory; Infusion procedures; Injectable; Interferons; Intravenous; Investigational New Drug Application; Iron; Iron deficiency anemia; Isocitrates; Kidney; Lead; Legal patent; Liver; Malignant Neoplasms; Marrow; Measures; Mediating; Medical; Metabolic; Modeling; Morbidity - disease rate; Mus; Oral; Organ; Oxygen; Pathology; Pathway interactions; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physicians' Offices; Physiological; Production; Publishing; Quality Control; Rattus; Regimen; Relative (related person); Research; Research Personnel; Resistance; Rodent Model; Route; Safety; Schedule; Second Messenger Systems; Serological; Serum; Serum Markers; Signal Pathway; Signal Transduction; Solutions; Technology; Therapeutic; Time; Tissues; Toxic effect; Tumor Necrosis Factor-alpha; Universities; Virginia; Work; autoimmune arthritis; base; behavior observation; clinical lot; clinically relevant; commercialization; cost; cytokine; design; dosage; drug candidate; human disease; improved; in vivo; intraperitoneal; intravenous injection; iron deficiency; isocitrate; macrophage; mortality; novel; novel therapeutic intervention; novel therapeutics; patient population; pre-clinical; progenitor; second messenger; tissue oxygenation

DESCRIPTION (provided by applicant): A strong unmet need exists to develop new treatments for anemias associated with chronic disease states, collectively referred to as anemia of chronic inflammation (ACI). ACI is highly prevalent in the U.S. and makes a large contribution to public morbidity and mortality. Despite billions of dollars spent annually to treat ACI patients, current therapies lack efficacy in many patients and cause potentially serious adverse effects. The mechanism for ACI involves inflammatory cytokines acting to inhibit marrow production of red cells, primarily by two interdependent pathways: (1) blocking iron transfer from macrophages to erythroid precursors (iron restriction) and (2) acting directly on the erythroid precursors to transmit inhibitory signals. Iron restriction potently sensitizes erythroid progenitors to the direct inhibitory effects of the inflammatory cytokines. Clinically, high-dose intravenous iron infusions can ameliorate anemia in ACI patients. We are developing a safe and efficacious therapy to correct anemia in these patients based on our discovery that the aconitase enzyme product, namely isocitrate, functions as a second messenger mediating iron's signal to stimulate erythropoiesis. We established the clinical utility by showing that exogenous isocitrate provided to erythroid progenitors in vitro abrogates the inhibitory effects of iron restriction and restores resistance to inflammatory cytokines. To establish clinical feasibility an commercial potential, we propose to study isocitrate's effects in the principal animal model for ACI, rats with experimentally induced chronic autoimmune arthritis. We aim to demonstrate proof-of-concept for our novel isocitrate technology by: (1) demonstrating isocitrate's curative efficacy in ACI rats using a dosing regimen per intended clinical use; (2) measuring physiological effects of isocitrate therapy on functional biomarkers of erythropoiesis to demonstrate isocitrate is effective; and (3) measuring serum biomarkers and assessing organs at necropsy for signs of systemic toxicity to demonstrate isocitrate is safe. The isocitrate technology was invented at the University of Virginia. The scientific investigators/inventors, in collaboration with Cumberland Pharmaceuticals Inc. and affiliates, are developing isocitrate as a new drug product for intravenous injection or oral dosage form to correct anemia in ACI patients. PUBLIC HEALTH RELEVANCE: Millions of people with lifelong diseases, for example those involving the kidney or cancers also have anemia. Current treatments for this type of anemia (known as anemia of chronic inflammation) are risky, expensive, and ineffective for some patient populations. In the proposed studies, we will study a new drug candidate for anemia of chronic inflammation and demonstrate that it safe and effective in an animal model relevant to the human disease.

描述（由申请人提供）：对于与慢性疾病状态相关的贫血（统称为慢性炎症性贫血（ACI））开发新的治疗方法存在强烈的未满足需求。 ACI 在美国非常流行，对公众发病率和死亡率有很大影响。尽管每年花费数十亿美元来治疗 对于 ACI 患者，目前的治疗方法对许多患者缺乏疗效，并可能导致严重的不良反应。 ACI 的机制涉及炎症细胞因子抑制红细胞的骨髓生成，主要通过两条相互依赖的途径：（1）阻止铁从巨噬细胞转移到红细胞前体（铁限制）和（2）直接作用于红细胞。 红细胞前体传递抑制信号。铁限制会导致红细胞过敏 炎症细胞因子的直接抑制作用的祖细胞。临床上，大剂量静脉输注铁剂可以改善 ACI 患者的贫血。基于我们的发现，我们正在开发一种安全有效的疗法来纠正这些患者的贫血症，因为我们发现乌头酸酶产品（即异柠檬酸）可作为介导铁信号刺激红细胞生成的第二信使。我们通过证明在体外向红系祖细胞提供外源性异柠檬酸消除了铁限制的抑制作用并恢复对炎性细胞因子的抵抗力来建立临床实用性。为了确定临床可行性和商业潜力，我们建议研究异柠檬酸在 ACI 主要动物模型（实验诱导的慢性自身免疫性关节炎的大鼠）中的作用。我们的目标是通过以下方式证明我们的新型异柠檬酸盐技术的概念验证：(1) 使用每种预期临床用途的给药方案证明异柠檬酸盐对 ACI 大鼠的疗效； (2) 测量异柠檬酸盐疗法对红细胞生成的功能性生物标志物的生理效应，以证明异柠檬酸盐是有效的； (3) 测量血清生物标志物并在尸检时评估器官的全身毒性迹象，以证明异柠檬酸是安全的。异柠檬酸技术是由弗吉尼亚大学发明的。科学研究人员/发明者与 Cumberland Pharmaceuticals Inc. 及其附属公司合作，正在开发异柠檬酸作为一种新的药物产品，用于静脉注射或口服剂型，以纠正 ACI 患者的贫血。 公共卫生相关性：数百万患有终生疾病（例如涉及肾脏或癌症的疾病）的人也患有贫血。目前针对这种类型贫血（称为慢性炎症性贫血）的治疗方法对于某些患者群体来说是危险的、昂贵的且无效的。在拟议的研究中，我们将研究一种治疗慢性炎症性贫血的新候选药物，并证明它在与人类疾病相关的动物模型中安全有效。