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（派-1）作为弥漫性皮肤系统性 硬化伴相关间质性肺病（dcSSc-ILD）。SSc是一种毁灭性的疾病， 病因不明，目前尚无获批的疾病缓解治疗;肺纤维化 间质性肺病（ILD）是dcSSc死亡的主要原因。在第二阶段 我们将进一步开发一种高度创新的一流治疗药物MDI-2517。派-1 是组织和尿激酶纤溶酶原激活物（tPA和uPA）的生理抑制剂。在 正常生理派-1调节诸如纤维蛋白溶解和伤口愈合的过程。然而，在这方面， 派-1的表达升高与肺、肾、心脏的纤维化疾病相关， 对于此应用程序来说，重要的是使用SSc。这种关联导致人们认识到派-1 直接导致病理学，并且其抑制可能是一种有效的治疗方法。 纤维化疾病MDI Therapeutics已经确定了一种高效，口服活性的小分子药物， 派-1抑制剂在多种纤维化疾病模型中有效，包括肺纤维化 的SSc。本II期申请中描述的研究将提供关键安全性， 毒理学数据以及当前治疗方案的体内比较研究。有 两个具体目标，明确规定了旨在推动MDI-2517向提交 研究性新药（IND）申请，随后进行首次人体I期试验 第三阶段的临床研究将通过获得私人风险资本投资来资助。

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.