A New Drug Therapy for Advanced Heart Failure

项目概要 目前对晚期心力衰竭 (HF) 的治疗有限，需要新的治疗方法，因为 患有这种心脏病的受试者的死亡率和发病率仍然很高。努力的目标 通过心脏保护来促进衰竭心脏的愈合代表了一种新颖的方法。具体的 拟议项目的背景是我们已经确定了内源性心脏 P2X 受体作为心脏保护的新治疗靶点。心脏 P2X4 受体是 内源性心脏 P2X 受体的必需且重要的亚基。小分子药物 MRS2339激活心脏P2X受体的物质已在动物身上证明临床前疗效 晚期心力衰竭模型，并且在研究性新药 (IND) 中不存在安全问题 - 使研究能够在大鼠和狗身上进行。 Cornovus 是一家公司，与其学术界合作 合作伙伴康涅狄格大学医学院心脏病学研究实验室和 国立糖尿病·消化·肾脏研究所生物有机化学实验室 NIH 的疾病，有能力向食品药品监督管理局申请 IND （FDA）如果该提案获得批准。赠款的目的是进一步开发流程 MRS2339 临床批次及其药品的批量 cGMP 生产化学 基于当前的配方以及执行 FDA 要求的心脏体外研究 离子通道以及 MRS2339 及其代谢物 MRS1873 潜在的线粒体毒性。 Cornovus 已经改进了生产百克的放大工艺化学 GLP 安全研究的数量，并排除了对人类以太相关的任何影响 两种化合物的基因（hERG）离子通道。拟议的研究应增加科学性 有关这两种化合物的化学和药理学的知识，也可能产生新的结果 对核苷酸和核苷科学的见解。该提案还应满足 监管要求将这种新药纳入首次人体临床研究，因为我们 预计晚期心力衰竭患者将获得新的益处。

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.