Inhaled IRK inhibitors as a novel therapeutic for IPF

ABSTRACTThe overall objective of this project is to develop MPX-111, an inhaled remodeling kinase inhibitor (IRKI) as a 1st-in-class, disease-modifying medicine for idiopathic pulmonary fibrosis (IPF), with superior medical benefit and improved safety and tolerability than current treatments. The main goals of this proposal are the testing of the efficacy of inhaled MPX-111 in an animal model of IPF, and inhaled toxicology 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.Metera Pharmaceuticals (Metera) in-licensed the proprietary IRKI Program from Janssen, which identified novel classes of inhaled, small molecule compounds that potently inhibit PDGFR, VEGFR and FGFR. Inhibition of these receptor tyrosine kinases is the mechanism of action of oral nintedanib which is approved for the treatment of IPF. However, nintedanib has significant safety and tolerability issues which reduce compliance and likely impact its clinical effectiveness, by limiting the doses that can be given. The IRKI Program focused on identifying compounds with the inherent pharmacological profile of nintedanib, but are optimized for local delivery to the lung, to minimize systemic exposure and reduce side-effects. Metera recently selected MPX-111 as the clinical development compound, based upon its overall biological, DMPK, physicochemical and developability profiles which are very favorable for an inhaled medicine, including high sustained lung levels in rodents after local administration, and low oral bioavailability (andlt;1%). In addition, a stable crystalline, micronized form of MPX-111 that is amenable to large-scale synthesis has been identified.In Specific Aim 1, the effects of intratracheal of MPX-111 will be compared with those of oral nintedanib in a standard model of IPF, bleomycin-induced pulmonary fibrosis in rat, using both prophylactic (to assess the impact on extracellular matrix markers) and therapeutic (to evaluate the effects on ongoing, developed disease) treatment paradigms. The plasma and lung levels of MPX-111 and nintedanib will be measured so that their PK/PD relationships can be determined. For Specific Aim 2, key inhaled toxicology and toxicokinetic studies with nebulized MPX-111 will be performed: non-GLP 7-day dose-range-finding and then GLP 28-day studies in rat and monkey, two of the species used previously to evaluate the toxicological profile of oral nintedanib. Metera will fund the rest of the IND-enabling studies required to complete an IND application.The results from this Phase II project will expand the scientific rationale for a small molecule IRKI inhibitor as an innovative, disease-modifying inhaled therapy for IPF treatment with improved safety profile compared to current oral medicines and will lay the foundation for an IND filing and the clinical development of MPX-111.Narrative Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal disease of the lung, which is estimated to affect 5 million people worldwide, and which only has an average survival of 3-5 years after diagnosis We are conducting research, including the use of disease-relevant animal models, on a new type of potential medicine, an inhaled remodeling kinase inhibitor (IRKI), for IPF that has the potential to provide superior medical benefit and improved safety (by its local delivery to the lung) compared to current treatments, and will increase survival and the quality of life for IPF patients. The results from the studies outlined in this application will be an important step towards the clinical testing of an inhaled IRKI compound in patients with the deadly disease of IPF.