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

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.Systemic sclerosis or scleroderma is a deadly disease of unknown etiology that has no cure. We will perform preclinical experiments to evaluate a new unique drug candidate for use as a novel scleroderma therapy.