Safety and efficacy of Pur118 in the ozone challenge model

INTRODUCTION: The ozone challenge model can be used to assess the efficacy of novel anti-inflammatory compounds early during drug development. In this study we evaluated the efficacy of PUR118 in attenuating ozone-induced airway inflammation in healthy normal adult volunteers. PUR118 is a dry powder for oral inhalation that is in development as a novel anti-inflammatory drug for COPD. PUR118 is engineered in the iSPERSE dry powder delivery technology. METHODS: After screening (SC) and a baseline ozone exposure (BL, only salbutamol, n=24 subjects) 18 healthy non-smoking volunteers responding with at least a 10% increase in sputum neutrophils were included. Three doses of PUR118 were tested (L: 1.4mg, n=16; M: 5.5mg, n=18; H: 22.0mg, n=18) and each dose was inhaled 3 times (1, 13, 25h) before the ozone (O3) exposure (250ppb, 3h intermittent exercise). Each inhalation of PUR118 was preceded by 2 puffs of salbutamol. Sputum was induced 3h after the end of O3 exposure. RESULTS: All dosages of PUR118 were safe (no SAE) and no effect of PUR118 on lung function was detected. The O3 challenge resulted in a median decline in FEV1 of 0.19, 0.16, ,0,24, and 0.13 L, (3h after start of exposure at BL, L, M, H treatment), which completely resolved after 24 hours. The O3 exposure (SC vs. BL, n=24) resulted in a significant increase in the number and percentage of sputum neutrophils, sputum CD14+ cells (%), as well as in the concentration of IL-1b, IL-6, IL-8, MMP-9 and TNF-a in sputum supernatant. The mean percentage of sputum neutrophils (n=12, completed all treatments) was 64.5% at baseline and 61.5%, 70.8%, and 72.1% following treatment with the L, M, and H dose of PUR118. The H treatment group (n=16) showed a decrease in the percentage and number of sputum macrophages (p=0.04, p=0.05) as well as a decrease in blood neutrophils (p=0.04), and an increase in blood CD14+cells (p=0.04) compared to BL. CONCLUSION: The O3 challenge resulted in the expected reproducible increase of inflammatory parameters in induced sputum. Treatment with PUR118 was safe but three applications within 25 h prior to the O3 challenge had only small effects on ozone-induced airway inflammation.