Preclinical development of a first in class therapeutic for treatingidiopathic pulmonary fibrosis

Abstract Fibrosis is a common end stage pathologic outcome of many diseases that is characterized by excessive accumulation of extracellular matrix proteinsloss of tissue homeostasisand ultimately organ failurePulmonary fibrosis can be particularly devastatingand is associated with significant morbidity and an overall poor survivalDisorders such as idiopathic pulmonary fibrosisIPFlead to a progressive scarring of the lung and the loss of lung functionThe limited efficacy of existing approved treatments for IPF makes it imperative that better therapeutic agents be developedIn this application we will assess the clinical utility of a highly innovative first in class therapeutic targeting plasminogen activator inhibitorPAIPAIis the physiologic inhibitor of tissue and urokinase plasminogen activatortPA and uPAIn normal physiology PAIregulates processes such as fibrinolysis and wound healingHoweverexcess PAIactivity is highly correlated with fibrotic diseases including fibrotic disease of the lungand studies in animal models of IPF suggest that the inhibition of PAIcan be an effective approach to treat this devastating diseaseMDI Therapeutics has discovered a highly effectiveoral small molecule inhibitor of PAIMDIwith efficacy demonstrated in multiple models of fibrotic diseaseincluding two different models of IPFThe studies described in this Phase I application will provide critical preclinical data necessary for the IND enabling studies that will be performed in Phase II of this SBIRThere are two specific aims with clear milestones that will effectively assess the clinical utility of this highly innovative therapeutic agentThese milestones include comparing MDIto the current standard of care for efficacy in murine models of IPFincluding a model of late stage IPFWe will also assess the tissue distribution of MDIas well as its safety in hERG and Ames studies and by metabolite analysisThe successful completion of these milestones will significantly advance this program toward commercialization by providing go no go data necessary for the IND enabling toxicology studies planned in Phase II of this SBIR Narrative Idiopathic Pulmonary FibrosisIPFis a deadly lung disease with unknown etiology that has no cureWe will perform critical preclinical studies to evaluate a newhighly innovative drug candidate as a novel IPF therapy