Platform technology to identify and develop first-in-class anti-fibrotic therapeutics through inhibition of collagen CP4H

Abstract There is a critical need to develop novel therapeutics to address underserved diseases which stem from abnormal fibrosis affecting multiple organ systems. Such diseases include Idiopathic pulmonary fibrosis (IPF), scleroderma skin fibrosis, kidney fibrosis resulting from chronic kidney disease (CKD), and intestinal fibrosis associated with Crohn's disease. There are effectively no good therapeutics for these diseases and together they account for over 30% of deaths worldwide. IPF alone affects 300,000 patients in the US and Europe per year, leading to more than 50,000 deaths annually. US medical costs for IPF, excluding medications, have been estimated to be ~$2 billion, with a lung transplant being the only effective therapeutic option. Mechanistically, fibrosis occurs when a maladaptive complex inflammatory response to tissue vascular injury activates the TGF- β signaling pathway, causing an upregulation of collagen I synthesis. Both FDA approved medications for IPF, pirfenidone (Esbriet®) and nintedanib (Ofev®), inhibit TGF-β induced collagen synthesis. However, these drugs only modestly impact disease progression, with severe side effects and low patient compliance. Adiutrix’s academic partners recently demonstrated that collagen synthesis during fibrosis is additionally induced by an independent mast cell (MC) mediated pathway, potentially explaining the low efficacy of drugs targeting the TGF- β pathway. They also demonstrated that both pathways converge on collagen prolyl-4 hydroxylase (C-P4H), an essential downstream rate-limiting enzyme responsible for the maturation of collagenous peptides into stable collagen. Inhibition of C-P4H corrects multiple pathological problems, including restoring normal lung function in a murine IPF model. Adiutrix is thus developing a novel anti-fibrotic compound platform to identify and develop first-in-class therapeutics targeting C-P4H activity to treat tissue remodeling and fibrosis in underserved diseases. Adiutrix has demonstrated a proof of concept with a compound that is safer than nintedanib and more potent than pirfenidone when tested in primary human lung fibroblasts, and active in a murine IPF model. In Phase I of this FastTrack Project, Adiutrix has the following Specific Aims 1) Develop 20 novel C-P4H inhibitors 2) Identify which novel C-P4H inhibitors have potential as anti-fibrotics via in vitro screening 3) Demonstrate proof of concept of C-P4H inhibition in a representative small animal model. The Go/No-go Criteria for Phase II is the successful identification of at least 2 compounds which show 60% reduction of fibrosis in the bleomycin murine model of IPF. For Phase II, Adiutrix will have the following specific aims 1) Conduct a hypothesis-driven full screen in silico search for additional C-P4H inhibitors. 2) Measure IC50 for select compounds in primary cultures of human fibroblasts from lung, skin and intestine. 3) Validate lead compounds as safe and effective anti-fibrotics via testing in animal models. Successful completion of these aims is expected to lead to much needed novel therapeutics for IPF and other fibrotic diseases and lead to significantly improved patient outcomes.