Myocardin-related transcription factor (MRTF) pathway modulators as a novel, disease-modifying oral medicine for idiopathic pulmonary fibrosis (IPF)

Abstract The overall objective of this project is for OncoArendi Therapeutics (OAT) to develop a myocardin-related transcription factor (MRTF) pathway inhibitor as a novel, disease-modifying oral medicine for idiopathic pulmonary fibrosis (IPF), with superior medical benefit and improved safety and tolerability compared to current treatments. The main goal of this Phase I proposal is the selection of a compound to enter IND-enabling studies. IPF is a chronic, progressive and fatal fibrotic lung disease, with a median survival of 3-5 years after diagnosis. Current treatment options for IPF are limited with minimal efficacy and significant tolerability issues. It is estimated that about 5 million people worldwide suffer from IPF. Thus, IPF represents a serious, common disease with a massive unmet medical need for new medicines that will improve morbidity and mortality. Literature reports have provided evidence that the MRTF pathway is critical to the initiation and progression of fibrosis, and underpins the various processes that are responsible for fibrosis. One of the current standard- of-care treatments for IPF, pirfenidone, inhibits MRFT activation, albeit in very high concentrations. Thus, selective and potent MRTF pathway inhibitors offer an innovative strategy to attenuate fibrosis. OAT has identified MRTF pathway inhibitors, with the most potent compound, OAT-5116, having an IC50 of 50 nM in the primary screening assay, involving inhibition of MRTF/SRF dependent luciferase assay on transfected HEK293 T cells. OAT-5116 is >1000-fold more potent than pirfenidone (IC50 >100 µM) in this assay. The two key Aims of this proposal are: Specific Aim 1: Lead Optimization to identify a Clinical Development Candidate (CDC). A detailed Medicinal Chemistry strategy has been developed to synthesize and test novel analogs of the current chemical pharmacophore, and address the developability liabilities of the lead compound, OAT- 5116, including poor oral pharmacokinetic profile in rodents, high plasma protein binding, and hERG potassium channel inhibition. All the relevant in vitro and in vivo biological and DMPK assays have been established. The ultimate goal of these studies is the selection of a CDC compound with the appropriate biological, chemical, DMPK and developability characteristics to progress into IND-enabling studies. Specific Aim 2: Effects of the CDC in the Bleomycin-induced Model of IPF in Mouse. The dose-response effects of oral administration of the CDC compound will be examined in the bleomycin-induced pulmonary fibrosis model in mouse, the gold-standard rodent model of IPF. The compound will be administered using a therapeutic treatment paradigm and its effects will be compared with those of oral pirfenidone, a current treatment for IPF. The results from this Phase I application will expand the scientific rationale for an MRTF pathway inhibitor as an innovative, disease-modifying oral therapy for IPF, and lay the foundation for the future clinical development of the optimized compound that OAT selects for progression to IND-enabling studies.