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 inhibitorPAIas a potential treatment for diffuse cutaneous systemic sclerosis with associated interstitial lung diseasedcSSc ILDSSc is a devastating disease of unknown etiology with no currently approved disease modifying treatmentslung fibrosisinterstitial lung diseaseILDis the leading cause of mortality in dcSScIn this application we will assess the clinical utility of a highly innovative first in class therapeuticPAIis the physiologic inhibitor of tissue and urokinase plasminogen activatortPA and uPAIn normal physiology PAIregulates processes such as fibrinolysis and wound healingHoweverelevated expression of PAIis associated with fibrotic diseases of the lungkidneyheartand importantly for this applicationwith SScThis association has led to the recognition that PAIcontributes directly to pathologyand that its inhibition may be an effective approach to treat fibrotic diseaseMDI Therapeutics has identified a series of highly effectiveorally activesmall molecule inhibitors of PAIwith efficacy in multiple models of fibrotic diseaseincluding pulmonary fibrosis and SScThe studies described in this Phaseapplication will compare the two top candidate molecules in this seriesMDIand MDIwith the primary goal of selecting the clinical candidate molecule for the IND enabling studies that will be performed in Phaseof this SBIRThere are two specific aims with clear milestones that will effectively assess the clinical utility of these highly innovative first in class therapeuticsThese milestones include comparing the two clinical candidates for efficacy in a murine model of SSc relative to the current treatment optionsdirect comparison of their pharmacokinetics propertiesand their safety inday multi dose toxicology studiesThe successful completion of these milestones will significantly advance this program toward commercialization by identifying a single lead clinical candidate to be selected for API synthesis and for the IND enabling toxicology studies planned in Phaseof this SBIR Systemic sclerosis or scleroderma is a deadly disease of unknown etiology that has no cureWe will perform preclinical experiments to evaluate new unique drug candidates for a novel scleroderma therapy