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- ß signaling pathway, causing an upregulation of collagen I synthesis. Both FDA approved medications for IPF, pirfenidone (Esbriet®) and nintedanib (Ofev®), inhibit TGF-ß 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- ß 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 , 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.
Public Health Relevance Statement: Narrative Fibrotic diseases affect multiple organ systems and cause about 30% of all deaths worldwide; however, no effective therapies exist. Adiutrix will develop a platform to identify a range of compounds targeting a key step in the fibrosis pathway. New therapies and significantly improved patient outcomes are expected from this project. Terms: <4 Hydroxyproline; Actins; Active Sites; Address; Affect; Ag element; Animal Model; Animal Models and Related Studies; Assay; Binding; Binding Site Domain; Binding Sites; Bioassay; Biological Assay; Bleo; Bleomycin; Body System; Body Tissues; Bone-Derived Transforming Growth Factor; Cell-Extracellular Matrix; Cessation of life; Chemicals; Chronic Kidney Failure; Chronic Renal Disease; Chronic Renal Failure; Clinical; Collagen; Combining Site; Complex; Crohn disease; Crohn's; Crohn's disease; Crohn's disorder; Death; Development; Disease; Disease Progression; Disorder; Drug Targeting; Drugs; ECM; Enzyme Gene; Enzymes; Esbriet; Europe; Exclusion; Extracellular Matrix; FDA approved; Fibroblasts; Fibrosing Alveolitis; Fibrosis; Gene Transcription; Genes; Genetic Transcription; Granulomatous Enteritis; Human; Hydroxyproline; Hypoxia Inducible Factor; Immune Diseases; Immune Disorders; Immune Dysfunction; Immune System Diseases; Immune System Disorder; Immune System Dysfunction; Immune System and Related Disorders; Immunodeficiency and Immunosuppression Disorders; Immunologic Diseases; Immunological Diseases; Immunological Dysfunction; Immunological System Dysfunction; In Vitro; In vivo analysis; In-bleomycin; Inflammatory Response; Intestinal; Intestinal Fibrosis; Intestines; Involuntary Muscle; Lead; Ligand Binding Domain; Lung; Lung Grafting; Lung Parenchyma; Lung Respiratory System; Lung Tissue; Lung Tissue Fibrosis; Lung Transplantation; Marrow Mast Cell; Measures; Mediating; Medical Care Costs; Medication; Mice; Mice Mammals; Milk Growth Factor; Modeling; Modern Man; Modification; Molecular Interaction; Murine; Mus; Nebulizer; Ofev; Oral; Organ; Organ System; Oxyproline; Pathologic; Pathway interactions; Patient Compliance; Patient outcome; Patient-Centered Outcomes; Patient-Focused Outcomes; Patients; Pb element; Peptides; Peptidyl Prolyl Hydroxylase; Pharmaceutical Preparations; Phase; Pirfenidone; Platelet Transforming Growth Factor; Procollagen Prolyl 4-Hydroxylase; Procollagen-Proline Dioxygenase; Production; Proline Hydroxylase; Proline, 2-Oxoglutarate 4-Dioxygenase; Prolyl 4-Hydroxylase; Prolyl Hydroxylase; Protocollagen Prolyl Hydroxylase; Pulmonary Fibrosis; Pulmonary Graft; Pulmonary Transplant; Pulmonary Transplantation; RNA Expression; Reactive Site; Safety; Scleroderma; Series; Signal Pathway; Silver; Skin; Smooth Muscle; Structure of parenchyma of lung; Surgical wound; System; TGF B; TGF-beta; TGF-ß; TGFbeta; TGFß; Testing; Therapeutic; Tissue Basophils; Tissues; Transcription; Transforming Growth Factor beta; Transforming Growth Factor-Beta Family Gene; Up-Regulation; Upregulation; Wound Repair; analog; antifibrotic agent; antifibrotic medication; antifibrotic therapy; antifibrotic treatment; bowel; chronic kidney disease; cost; cutaneous fibrosis; dermal fibrosis; dermatosclerosis; design; designing; developmental; diffuse interstitial pulmonary fibrosis; drug efficacy; drug/agent; effective therapy; effective treatment; eleocolitis; enzyme substrate; exosome; fibrosis in the lung; fibrotic skin; heavy metal Pb; heavy metal lead; idiopathic pulmonary fibrosis; improved; in silico; in vivo evaluation; in vivo testing; indium-bleomycin; inhibitor; injury to the vasculature; interest; kidney fibrosis; lung fibrosis; lung function; lung transplant; mast cell; mastocyte; medical college; medical costs; medical expenses; medical schools; model of animal; mouse model; murine model; nebulization; nebulize; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; nintedanib; novel; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapeutics; novel therapy; pathway; patient adherence; patient cooperation; patient oriented outcomes; prevent; preventing; pulmonary; pulmonary function; regional enteritis; renal fibrosis; response; school of medicine; screening; screenings; side effect; skin fibrosis; stem; technology platform; technology system; therapeutic target; therapeutically effective; vascular injury; wound healing; wound recovery; wound resolution
