An oxysterol drug candidate, Oxy210, for inhibition of pulmonary fibrosis through targeting hedgehog and TGFβ signaling

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ABSTRACT Idiopathic Pulmonary Fibrosis (IPF) is a chronic interstitial lung disease, characterized by progressive, irreversible scarring of lung tissue and declining lung function, terminating in respiratory failure. Median patient survival is limited to 3-5 years post diagnosis. Two currently available therapies, Pirfenidone and Nintedanib, only slow the progression of the disease and have not greatly reduced IPF mortality or significantly improved quality of life in IPF patients since they were approved in 2014. Hence, new and improved IPF drug candidates are urgently needed. IPF disease progression is driven in significant part through inappropriate reactivation of embryonic cellular signaling pathways, such as the Transforming Growth Factor beta (TGFβ) and Hedgehog (Hh) signaling pathways. In fact, Pirfenidone and Nintedanib act in part through modestly blocking these signaling pathways. At MAX BioPharma, we are developing novel, proprietary, oxysterol-based antagonists of aberrant cellular signaling that may have disease modifying properties in human IPF and other fibrotic diseases. This application covers an oxysterol-based drug candidate, Oxy210, a dual inhibitor of Hh and TGFβ signaling that ameliorates hepatic fibrosis and inflammation in a humanized mouse model of non-steatohepatitis (NASH). In this application, we present encouraging preliminary data from in vitro studies with Oxy210, demonstrating its inhibitory effects on proliferation and pro-fibrotic gene expression in a normal pulmonary fibroblast cell line (IMR- 90) and an IPF patient-derived cell line (LL97A). Oxy210 has anti-inflammatory effects in LPS-treated macrophages through direct inhibition of Toll-Like Receptor (TLR4), TLR2, and AP-1, and does not interfere with the anti-inflammatory effects of TGFβ. Preliminary findings show the promising potential of Oxy210 to inhibit bleomycin-induced pulmonary pathology in vivo in mice. We propose to further characterize Oxy210 in relevant in vitro and in vivo models of IPF. Specifically, we propose to address the following specific aims: Aim 1. Elucidation of the effects of Oxy210 on myofibroblast differentiation and activation of primary pulmonary fibroblasts from normal lungs and from IPF patients in vitro. Aim 2. Identification of the effects of Oxy210 on lung fibrosis, fibroblast activation, and macrophage phenotypes at different stages of disease progression using RNA sequencing in bleomycin-treated mice. Aim3. Examination of Oxy210 safety using in vitro Ames, Cytochrome P450 inhibition, and off-target activity studies. We anticipate that data from the proposed studies will evaluate the potential of Oxy210 as a drug candidate for further development and targeting of IPF. Compared to existing therapies, Oxy210 may be more effective and safer as a standalone therapy or when used in combination with existing therapies for treating IPF.