Development of Inhaled PPI for Treatment of Pulmonary Fibrosis

Altitude Pharma, Inc., San Diego CA

Investigators

Abstract

? DESCRIPTION (provided by applicant): Altitude Pharma, Inc. is developing a novel inhaled form of a generic drug (proton pump inhibitor; PPI) for the treatment of idiopathic pulmonary fibrosis (IPF) and/or radiation-induced lung fibrosis (RILF); orphan indications with severely limited treatment options. In both forms, accumulation of fibrous tissue in the lung parenchyma induces a restrictive physiology that impairs respiration, and leads to death within 3-4 years from the time of diagnosis. Although the etiology of IPF is not known, RILF is sequelae of exposure to ionizing radiation and/or chemotherapy used to treat thoracic malignancies. For IPF, the prevalence and incidence in the US is reported to be 494.5 cases per 100,000 and 93.7 cases per 100,000 respectively. Recently, a number of retrospective or prospective case series studies that reviewed interstitial lung disease (ILD) databases have reported that IPF patients placed on anti-acid therapy (mainly on PPIs) appear to have improved outcomes in measures of lung function and overall health including longer period of lung transplant-free survival, reduced baseline fibrotic score on High Resolution Computed Tomography (HRCT) evaluation, reduced hospitalization for pulmonary-related illnesses and significantly reduced episodes of acute exacerbations. Intriguingly, the 2015 Official Clinical Practice Guideline, endorsed by all major Thoracic Societies (ATS/ERS/JRS/ALAT), recommended the use of PPIs for the treatment of IPF. However, there is no prospective study evaluating the use of PPIs in IPF. In addition, the potential mechanism by which the PPIs improve measures of lung function and/or transplant-free survival in IPF has not been elucidated. Recently, we demonstrated that a prototype PPI, esomeprazole, possesses potent anti-inflammatory, antioxidant and antifibrotic properties and directly regulates processes involved in the development and progression of inflammation and tissue remodeling. We demonstrate the pleiotropic effect of esomeprazole using in vitro studies of primary lung cells exposed to bleomycin or ionizing radiation. Remarkably, our recent data also shows that esomeprazole when administered orally, showed robust efficacy in mitigating the inflammatory and fibrotic responses in a rodent model of chemotherapy (bleomycin)-induced lung injury. Accordingly, the major goal of this project is to determine if PPIs might be reformulated to treat lung fibrosis. This strategy is anticipated to deliver sufficient amount of drug directly to the lungs in order to improve overall lung function and avoid PPI-related systemic side effects. Accordingly, we aim to: 1) complete the formulation of an inhalable PPI that provides optimal biophysical/biological properties for localized delivery; 2) conduct safety and tolerability studies including comprehensive drug profiling and 3) conduct efficacy studies in two mouse models of experimentally-induced lung injury (i.e. bleomycin and ionizing radiation). This Phase I SBIR grant will allow Altitude to rapidly execute essential studies in order to launch Good Laboratory Practice (GLP) activities and pre-IND meetings with the FDA.