The ultimate goal of our project is to develop novel therapeutics effective in idiopathic pulmonary fibrosis, a chronic, progressive and fatal fibrotic lung disease, of unknown etiology. It occurs primarily in adults over 50, with a median survival of 2.5 years after diagnosis. Present treatment options for IPF are sub-optimal. Specifically, the two recently FDA-approved drugs, Nintedanib and Pirfenidone, have significant tolerability issues and limited efficacy. Clearly, there remains a significant unmet medical need for novel medicines treating IPF, with improved clinical benefit and safety profile compared to current drugs. LPAR1 has been implicated in the development of IPF given its role in mediation of fibroblast recruitment, vascular leak, and endothelial barrier dysfunction in animal models. In the bleomycin mouse model of pulmonary fibrosis, LPAR1-deficient mice show reduced levels of fibroblast recruitment and decreased vascular permeability, indicating a protective role of decreased LPA signaling. Furthermore, levels of LPA are elevated in BAL samples of patients with IPF, supporting the clinical relevance of this signaling pathway in IPF development. BMS-986020, a small molecule LPAR1 antagonist was advanced to clinical testing in IPF patients. In which its efficacy was compared with placebo in patients with a confirmed diagnosis of IPF. In the primary end point analysis, BMS-986020 600 mg bid significantly reduced the rate of decline in FVC from baseline to week 26 when compared with patients receiving placebo thus suggesting that LPA antagonism may offer a benefit in treatment of IPF and provide clinical validation for the target. BMS-986020, however led to dose-related increases in liver enzymes were observed in several patients with three cases of cholecystitis leading to cholecystectomy in these patients and early termination of the trial. The presumed hepatobiliary toxicity, as manifested by treatment-related SAEs of cholecystitis was determined to be compound-specific and not target related. Epigen has identified several potent and selective LPAR1 antagonists with pre-clinical efficacy in other fibrotic disease models which do not show cholestatic risk in human cellular hepato-toxicity models compared to BMS-986020. Among these are lead compound EPGN696 and backup EPGN2154. Both compounds demonstrate improved bioavailability relative to BMS-986020 and are without cholestatic risk potential in a c- DILI bioassay. We propose to evaluate these compounds for IPF by testing their efficacy in the bleomycin model. In addition, the levels and functional roles of LPAR1 in normal and IPF lungs and disease-relevant human cells will be further determined. A positive outcome of this study will trigger IND-enabling activities and initiation of clinical trials for a compound class that is clinically validated for IPF, but devoid of cholestatic risk.
The objective of this work is to evaluate the preclinical efficacy of EPGN696 and EPGN2154, small molecule antagonists of the LPA1 receptor, a potential treatment for idiopathic pulmonary fibrosis, a significant cause of mortality.
