Therapeutic Efficacy of a Neutrophil Elastase Inhibitor AZD9668 in Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible and ultimately fatal disease, characterised by scarring of the lung tissues, worsening breathlessness and progressive decline in lung function. IPF has an unknown cause and poor prognosis, with a median survival of 3-5 years after diagnosis. It is an orphan disease but its prevalence and incidence are increasing. In 2015, pirfenidone and nintedanib were approved by the FDA as the standard of care treatment for IPF. While these drugs slow disease progression and delay the decline in lung function, there is no clear mortality benefit and both drugs require close monitoring due to significant adverse effects.
Direct inhibition of neutrophil elastase (NE) activity is a potential crucial therapeutic strategy of IPF, given that NE level and activity is up-regulated in IPF. AZD9668 is a potent orally-active NE inhibitor which has superior selectivity for NE and is well-tolerated in man (having previously been trialed in other respiratory diseases). The project will explore the anti-fibrotic effect of AZD9668 in the gold standard bleomycin-induced IPF murine model.
The project will investigate the therapeutic efficacy and the prophylactic efficacy of AZD9668 in the bleomycin-induced IPF murine model with the key endpoints being i) lung histology analysis, ii) collagen and elastase measurement, ii) NE activity assessment, iv) lung function test. Additional endpoints include i) analysis of BAL fluid and blood, ii) alveolar leak measurement, iii) immunoblotting for fibrogenic signaling activities, iv) RT-PCR of relevant gene expression, v) oxidative stress and damage in lung lysates.
Principal Investigator: Assoc Prof Fred Wong Wai Shui
Institution: National University Health System
NHIC Ref: NHIC-I2D-1608135