Development of a Novel Hyaluronan Inhibitor for the Treatment of Group 3 Pulmonary Hypertension (PH)

PROJECT SUMMARY Group 3 pulmonary hypertension due to interstitial lung disease (PH-ILD) is a devastating disease. Patients with PH-ILD are perpetually short of breath and often unable to walk or even to speak in full sentences without gasping for air. Characterized by extensive changes in the extracellular matrix (ECM) and the vasculature, PH is observed

in up to 80% of patients with ILD. The severity of PH is the most significant predictor of mortality in these patients, who have an average life expectancy of only 3-4-years. Existing therapies are often ineffective, in part because they target individual cells and not the tissue remodeling that drives the disease. We desperately need new

therapies for PH-ILD. There is strong evidence from in vitro and animal models of PH that hyaluronan (HA) drives disease progression. HA, a prominent component of the ECM that fills the space between cells is overexpressed in the lungs of patients with PH and is associated with vascular remodeling, inflammation, and fibrosis. Given the role of HA

and the ECM in PH-ILD pathogenesis, HA is an attractive target, one that is currently not targeted by approved drugs or other drugs in development. 4-MU (4-methylumbelliferone) is a small molecule inhibitor of HA synthesis with the potential to treat PH-ILD. 4- MU has shown dramatic preclinical efficacy in multiple mouse models of PH. Unfortunately, 4-MU has poor

pharmacokinetics, characterized by extensive 1st pass metabolism and poor bioavailability. While 4-MU works in animal models at high dosages, we need improved formulations of 4-MU to be able to treat human PH-ILD. We have developed an approach to the formulation of 4-MU that enhances systemic delivery, reduces 1st pass

metabolism, and promotes bioavailability (H1614). Our vision is that this formulation will result in reduced dose burden and improved efficacy. To advance our program to deliver a proprietary agent for Phase 2 clinical assessment we are proposing three specific aims for this grant application: In Aim 1 we will manufacture 4-MU as an orally disintegrating tablet (ODT) using proprietary Zydis® technology

and evaluate the pharmacokinetics of the new formulation in an animal model. Then, in Aim 2 we will perform preclinical studies to identify the optimal dose of 4-MU in a rat model of PH and lung fibrosis and to define its toxicology profile to current FDA standards. Finally, in Aim 3 we will validate assays to quantitate the levels of 4-MU and HA in human serum, in order to

ensure compliance with FDA standards to support the Phase 2 human clinical trial. Completion of these studies will result in a proprietary, optimized formulation of 4-MU ready for manufacturing to support a Phase 2 clinical trial in PH-ILD (WHO Group 3). Complementary studies of toxicology, pharmacology, and human PK are to be undertaken directly by Halo Biosciences. This project has the potential

to transform the treatment not only of PH-ILD, but of other diseases characterized by inflammation and fibrosis.