A New Drug Therapy for Advanced Heart Failure

晚期心力衰竭的新药物疗法

• 批准号: 10216334
• 负责人: R Mark Van Allen
• 金额: $ 101.87万
• 依托单位: CORNOVUS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216334
• 关键词: Action Potentials; Adverse effects; Animal Model; Area; Award; Biological Assay; Canis familiaris; Cardiac; Cardiac Myocytes; Cardiology; Cavia; Cell Line; Chemistry; Chromatography; Clinical Research; Clinical Trials; Collaborations; Column Chromatography; Connecticut; Conscious; Crystallization; Cyclic GMP; Development; Diabetes Mellitus; Digestive System Disorders; Disease Progression; Dose; Drug Formulations; EFRAC; Ethers; Filtration; Formulation; Funding; Galactose; Genes; Glucose; Goals; Grant; Heart; Heart Diseases; Heart Rate; Heart failure; HepG2; Human; In Vitro; Infarction; Institutes; Investigational Drugs; Investigational New Drug Application; Ion Channel; Ions; Kidney; Kidney Diseases; Knowledge; Laboratories; Laboratory Research; Lead; Liquid substance; Medical; Membrane Potentials; Mitochondria; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Nucleosides; Nucleotides; P2X-receptor; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Pharmacotherapy; Positioning Attribute; Privatization; Procedures; Process; Product Approvals; Property; Rattus; Reaction; Research; Ribose; Safety; Scheme; Science; Shapes; Systolic heart failure; Testing; Therapeutic; Therapeutic Index; Toxic effect; Toxicology; United States Food and Drug Administration; United States National Institutes of Health; Universities; Ventricular; Work; base; blood pressure reduction; cardioprotection; chemical synthesis; clinical lot; cytotoxicity; drug development; drug efficacy; extracellular; first-in-human; healing; improved; indium arsenide; insight; medical schools; mortality; new therapeutic target; novel strategies; novel therapeutics; preclinical efficacy; preclinical safety; pressure; programs; receptor; safety study; scale up; small molecule; stoichiometry

PROJECT SUMMARY Current therapy for advanced heart failure (HF) is limited and new treatment is needed since the mortality and morbidity of subjects with this form of heart disease remain high. Effort aimed at enhanced healing of failing heart by cardioprotection represents a novel approach. The specific background for the proposed project is that we have identified the endogenous cardiac P2X receptor as a new therapeutic target for cardioprotection. The cardiac P2X4 receptor is an essential and important subunit of the endogenous cardiac P2X receptor. A small molecule drug substance MRS2339 activating cardiac P2X receptors has proven preclinical efficacy in animal models of advanced HF and is without safety concerns in the Investigational New Drug (IND)- enabling studies in rat and dog. Cornovus is a company, in collaboration with its academic partner University of Connecticut School of Medicine’s cardiology research laboratory and Laboratory of Bioorganic Chemistry of the National Institute of Diabetes, Digestive and Kidney Diseases of NIH, is well-positioned to apply for an IND to the Food and Drug Administration (FDA) should the proposal is awarded. The objective of the grant is to further develop process chemistry for bulk cGMP manufacturing of the clinical lot of MRS2339 and its drug product based on the current formulation as well as to perform FDA-requested in vitro studies on cardiac ion channels and on potential mitochondrial toxicity by MRS2339 and its metabolite MRS1873. Cornovus has already improved the scale-up process chemistry in producing hundred gram quantity for GLP safety studies and has ruled out any effect on the human ether-à-go-go-related gene (hERG) ion channel by both compounds. The proposed studies should add to scientific knowledge on the chemistry and pharmacology of both compounds and may also yield new insights into the science of nucleotide and nucleoside. The proposal should also satisfy the regulatory requirements to move this new drug into first-in-human clinical study, as we anticipate new benefit to patients with advanced HF.

项目摘要 目前对晚期心力衰竭（HF）的治疗是有限的，需要新的治疗，因为 患有这种心脏病的患者的死亡率和发病率仍然很高。努力旨在 通过心脏保护增强衰竭心脏的愈合代表了一种新的方法。具体 该项目的背景是，我们已经确定了内源性心脏P2 X 受体作为心脏保护的新治疗靶点。心脏P2 X4受体是一种 内源性心脏P2 X受体的必需和重要亚基。小分子药物 激活心脏P2 X受体物质MRS 2339在动物中已被证明具有临床前功效 晚期HF模型，并且在试验性新药（IND）中没有安全性问题- 从而能够在大鼠和狗中进行研究。Cornovus是一家公司，与其学术机构合作， 康涅狄格大学医学院心脏病学研究实验室的合作伙伴， 国立糖尿病、消化和肾脏研究所生物有机化学实验室 美国国立卫生研究院的疾病，是很好的位置申请IND的食品和药物管理局 (FDA)如果该提案被授予。赠款的目的是进一步发展进程， 临床批次MRS 2339及其制剂的散装cGMP生产化学 基于目前的配方，以及进行FDA要求的体外心脏研究， MRS 2339及其代谢物MRS 1873对线粒体离子通道和潜在毒性的影响。 Cornovus已经改进了生产百克的放大工艺化学， GLP安全性研究的数量，并排除了对人体乙醚-à-go-go相关 基因（hERG）离子通道。拟议的研究应增加科学 这两种化合物的化学和药理学知识，也可能产生新的 对核苷酸和核苷科学的深刻见解。建议书亦须符合 监管要求将这种新药投入首次人体临床研究，因为我们 预期对晚期HF患者有新的获益。