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

该项目将为一种新的治疗性小分子药物提供关键的临床前数据。 纤溶酶原激活物抑制物1(PAI-1)对弥漫性皮肤系统性疾病的潜在治疗作用 硬化症合并间质性肺疾病(dcSSc-ILD)。SSC是一种毁灭性的疾病 病因不明，目前没有批准的疾病修饰治疗；肺纤维化 间质性肺病是导致弥漫性肺间质细胞癌死亡的主要原因。在此阶段II中 我们将进一步开发一种高度创新的一流治疗药物MDI-2517。PAI-1 是组织的生理性抑制物和尿激酶型纤溶酶原激活剂(tPA和uPA)。在……里面 正常生理状态下，PAI-1调节纤溶和伤口愈合等过程。然而， PAI-1的高表达与肺、肾、心脏和肾脏的纤维化疾病有关 对于这个应用程序来说，使用SSC非常重要。这种联系导致了人们认识到PAI-1 直接与病理有关，抑制它可能是治疗的有效方法 纤维性疾病。MDI治疗公司已经确定了一种高效的口服活性小分子 PAI-1抑制剂在多种纤维化疾病模型中的疗效，包括肺纤维化 和SSC。本第二阶段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。确实有 具有明确里程碑的两个具体目标，旨在推动MDI-2517向 研究新药(IND)申请，随后进行人类首个阶段1 临床研究将在第三阶段通过争取私人风险资本投资获得资金。

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.