Development of a small molecule inhibitor of PAI-1 for the treatment of diffuse cutaneous systemic sclerosis

开发用于治疗弥漫性皮肤系统性硬化症的 PAI-1 小分子抑制剂

基本信息

批准号：
10004564
负责人：
James Craig Hartman
金额：
$ 74.7万
依托单位：
MDI THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004564
关键词：
Affinity Animal Genetics Biological Biological Markers Bleomycin Capital Cessation of life Chronic Cicatrix Clinical Clinical Research Collagen Complex Cutaneous Data Development Diffuse Disease Dose Etiology Extracellular Matrix Failure Family Fibrinolysis Fibronectins Fibrosis Formulation Funding Goals Heart Diseases Human Genetics Hydrophobicity In Vitro Interstitial Lung Diseases Investigational Drugs Investigational New Drug Application Investments Kidney Diseases Lead Lung diseases Modeling Monoclonal Antibodies Mus Mycophenolate Natural Products Oral Organ Pathology Patients Pharmaceutical Preparations Pharmacologic Substance Phase Physiological Physiology Pirfenidone Plasma Plasminogen Activator Inhibitor 1 Plasminogen Activator Interaction Plasminogen Inactivators Play Privatization Process Progress Reports Protease Inhibitor Pulmonary Fibrosis Rare Diseases Role Safety Sampling Scleroderma Secure Serine Proteinase Inhibitors Serpins Small Business Innovation Research Grant Snails Specificity Structure System Systemic Scleroderma Therapeutic Tissues Toxicology Transgenic Organisms Urokinase Vitronectin clinical candidate cofactor comparative efficacy drug candidate effective therapy experimental study first-in-human high throughput screening human disease in vivo in vivo Model inhibitor/antagonist innovation interest member method development mortality mouse model novel novel therapeutics pre-clinical preclinical study skin disorder small molecule small molecule inhibitor success therapeutic target wound healing

项目摘要

This project will provide critical preclinical data for a novel therapeutic small molecule inhibitor of plasminogen activator inhibitor 1 (PAI-1) as a potential treatment for diffuse cutaneous systemic sclerosis with associated interstitial lung disease (dcSSc-ILD). SSc is a devastating disease of unknown etiology with no currently approved disease-modifying treatments; lung fibrosis (interstitial lung disease, ILD) is the leading cause of mortality in dcSSc. In this phase II application we will further develop a highly innovative first in class therapeutic, MDI-2517. PAI-1 is the physiologic inhibitor of tissue and urokinase plasminogen activator (tPA and uPA). In normal physiology PAI-1 regulates processes such as fibrinolysis and wound healing. However, elevated expression of PAI-1 is associated with fibrotic diseases of the lung, kidney, heart, and importantly for this application, with SSc. This association has led to the recognition that PAI-1 contributes directly to pathology, and that its inhibition may be an effective approach to treat fibrotic disease. MDI Therapeutics has identified a highly effective, orally active, small molecule inhibitor of PAI-1 with efficacy in multiple models of fibrotic disease, including pulmonary fibrosis and SSc. The studies described in this Phase II application will provide critical safety and toxicology data as well as in vivo comparator studies with current treatment options. There are two Specific Aims with clearly defined Milestones aimed at advancing MDI-2517 toward filing an Investigational New Drug (IND) application and subsequently conducting first-in-human Phase 1 clinical studies which will be funded in Phase III by securing private venture capital investment.

该项目将为新型治疗性小分子抑制剂提供关键的临床前数据纤溶酶原激活物抑制剂 1 (PAI-1) 作为弥漫性皮肤全身性皮肤病的潜在治疗方法硬化症相关间质性肺疾病 (dcSSc-ILD)。 SSc 是一种毁灭性的疾病病因不明，目前尚无批准的疾病缓解治疗方法；肺纤维化（间质性肺病，ILD）是 dcSSc 死亡的主要原因。在这个第二阶段我们将进一步开发高度创新的一流治疗药物 MDI-2517。 PAI-1 是组织和尿激酶纤溶酶原激活剂（tPA 和 uPA）的生理抑制剂。在正常生理 PAI-1 调节纤维蛋白溶解和伤口愈合等过程。然而， PAI-1 表达升高与肺、肾、心脏和肺的纤维化疾病相关对于此应用程序来说，重要的是 SSc。这种关联使人们认识到 PAI-1 直接影响病理学，抑制它可能是治疗的有效方法纤维化疾病。 MDI Therapeutics 已鉴定出一种高效、口服活性的小分子 PAI-1 抑制剂，对多种纤维化疾病模型（包括肺纤维化）有效和科学硕士。本二期申请中描述的研究将提供关键的安全性和毒理学数据以及与当前治疗方案的体内比较研究。有两个具有明确定义里程碑的具体目标，旨在推进 MDI-2517 提交申请研究性新药 (IND) 申请并随后进行首次人体 1 期试验临床研究将通过私人风险投资来资助第三阶段。