Duvelisib, a PI3K-δ,γ inhibitor, in subjects with mild asthma

Abstract

<b>Background:</b> Duvelisib (IPI-145), an oral phosphoinositide-3-kinase (PI3K)-δ,γ inhibitor, has shown activity in preclinical models of inflammation, including lung inflammation. Based on these findings, Study IPI-145-03 (ClinicalTrials.gov NCT01653756) was initiated in patients (pts) with asthma. <b>Objective:</b> To investigate the clinical activity and safety of duvelisib in pts with mild asthma undergoing allergen challenge. <b>Methods:</b> This was a randomized, double-blind, placebo-controlled, 2-way cross-over study evaluating 3 doses of duvelisib (1 mg, 5 mg, and 25 mg BID) administered over 5-14 days. The primary efficacy assessment was the maximum decrease in FEV₁ following allergen challenge, assessed as early asthmatic response (EAR) and late asthmatic response (LAR). Key secondary endpoints included AUC of FEV₁, provocative concentration of methacholine inducing a 20% fall in FEV₁ (PC20), and exhaled nitric oxide (NO) concentration following allergen challenge. Exploratory endpoints included changes in selected chemokines and cytokines. Safety was assessed through monitoring of adverse events (AEs) and safety laboratory findings. <b>Results:</b> The primary endpoint was not met at any dose examined. However, clinical improvement in LAR was observed at 25 mg (p=0.052) as well as statistically significant improvements for the secondary endpoints of AUC of FEV₁ (p=0.0096) and methacholine PC20 (p=0.0362). A treatment effect was observed associated with serum levels of key mediators of airway inflammation. All doses of duvelisib were well tolerated. <b>Conclusions:</b> Duvelisib, an oral PI3K-δ,γ inhibitor, demonstrated evidence of activity in pts with mild asthma in an allergen challenge model and was well tolerated at all doses evaluated.