Novel PPARa/d Dual Agonist ETI-039 to Treat Pulmonary Fibrosis
Abstract
Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible lung disease of unknown cause that is characterized by scarring (fibrosis) of the lungs, breathing difficulties, shortness of breath, and eventual loss of lung function. Currently, an estimated 1 in 200 adults over age 60 in the U.S. has pulmonary fibrosis and each year 50,000 new cases are diagnosed. Only 39% of IPF patients survive up to 5 years and every year 40,000 Americans die from the disease. The Food and Drug Administration (FDA) has approved two therapies for IPF – nintedanib and pirfenidone – however, these drugs only slow the progression of disease and are very expensive, costing up to $94,000 per patient per year by one recent estimate. In this project, we aim to tackle IPF by testing a molecule that our team at Epitracker first discovered and then chemically improved to allow it to interact better with specific cellular components of the lungs (fibroblasts and macrophages) to help keep the lining of our airways healthy. The proposal matches up with the Fiscal Year 2019 Peer Reviewed Medical Research Program Topic Area “Pulmonary Fibrosis” and the call to develop innovative treatments that can potentially arrest IPF so that patients are less likely to die from their condition. If successful, our studies could lead to a breakthrough new therapy for reversing the devastating consequences of this illness. The drug compound we propose testing is ETI-039, which was originally derived from a natural molecule present in the human body. It binds to specific receptors present on cells in our lungs, called peroxisome proliferator-activated receptors, or PPARs. Literature supports PPARs’ role in treating IPF: drugs that bind to PPARs have been shown to block cellular processes in the lung that lead to scarring, and PPARs are known to reduce inflammation, which helps restore damaged cells in the airways. In clinical trials, drugs that bind to PPARs have shown promise in treating conditions similar to IPF, but currently available PPAR-based drugs have not been ideally optimized to target lung fibrosis. Study Objectives: We aim to put ETI-039 through a series of rigorous tests in order to determine whether the compound can resolve lung scarring and airway inflammation in a mouse model of PF without producing negative effects. We have previously demonstrated that ETI-039 is effective in resolving fibrosis in human lung cells and that the compound can achieve concentrations that are likely to produce beneficial effects in humans. Based on these data, we hypothesize that ETI-039 will reduce scarring in mice that have developed PF and that the results will show improved outcomes when compared to nintedanib or pirfenidone. We further anticipate that the compound will pass a set of tests demonstrating its stability and safety, steps which are necessary for the FDA to approve ETI-039 as an Investigational New Drug (IND). Specific Aims and Study Design: Our research will: (1) identify doses at which ETI-039 is active; (2) measure its ability to resolve lung scarring in mice with PF compared to nintedanib and pirfenidone; (3) develop methods to produce ETI-039 in large enough quantities to test the drug’s stability under various conditions; and (4) conduct toxicology testing in rats and dogs to determine if there are any unwanted effects on organs such as the heart, lungs or central nervous system. We have designed our study as a logical series of tasks that are attentive to sample sizes, randomization, controls, males versus females, statistical significance, and appropriate dosing regimens. Our well-rounded team of scientists, including a PF researcher, pharmaceutical expert, chemist, and physicians specializing in lung diseases, will help ensure that animal experiments “translate” to human patients. Impact/Relevance: After completing this study, we aim to have sufficient evidence showing that ETI-039 is a safe and potentially
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010540
Entities
People
- Stephanie Venn-Watson
Organizations
- United States Army