Fibrosis is a common end-stage pathologic outcome of many diseases that is characterized by excessive accumulation of extracellular matrix proteins, loss of tissue homeostasis, and ultimately organ failure. Pulmonary fibrosis can be particularly devastating, and is associated with significant morbidity and an overall poor survival. Disorders such as idiopathic pulmonary fibrosis (IPF) lead to a progressive scarring of the lung and the loss of lung function. The limited efficacy of existing approved treatments for IPF makes it imperative that better therapeutic agents be developed. In this application we will assess the clinical utility of a highly innovative first in class therapeutic targeting plasminogen activator inhibitor-1 (PAI-1). 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, excess PAI-1 activity is highly correlated with fibrotic diseases including fibrotic disease of the lung, and studies in animal models of IPF suggest that the inhibition of PAI-1 can be an effective approach to treat this devastating disease. MDI Therapeutics has discovered a highly effective, oral small molecule inhibitor of PAI-1, MDI-2517, with efficacy demonstrated in multiple models of fibrotic disease, including two different models of IPF. The 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 SBIR. There are two specific aims with clear milestones that will effectively assess the clinical utility of this highly innovative therapeutic agent. These milestones include comparing MDI-2517 to the current standard of care for efficacy in murine models of IPF, including a model of late-stage IPF. We will also assess the tissue distribution of MDI-2517, as well as its safety in hERG and Ames studies and by metabolite analysis. The 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.
Idiopathic Pulmonary Fibrosis (IPF) is a deadly lung disease with unknown etiology that has no cure. We will perform critical preclinical studies to evaluate a new, highly innovative drug candidate as a novel IPF therapy.