Effect of the S-nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma.

Abstract

<h4>Rationale</h4>Patients with asthma demonstrate depletion of the endogenous bronchodilator GSNO and upregulation of GSNOR.<h4>Objectives</h4>An exploratory proof of concept clinical study of N6022 in mild asthma to determine the potential bronchoprotective effects of GSNOR inhibition. Mechanistic studies aimed to provide translational evidence of effect.<h4>Methods</h4>Fourteen mild asthma patients were treated with intravenous N6022 (5 mg) or placebo and observed for 7 days, with repeated assessments of the provocative dose of methacholine causing a 20% fall in FEV1 (methacholine PC₂₀ FEV1), followed by a washout period and crossover treatment and observation. In vitro studies in isolated eosinophils investigated the effect of GSNO and N6022 on apoptosis.<h4>Measurements and main results</h4>This was a negative trial as it failed to reach its primary endpoint, which was change from baseline in methacholine PC₂₀ FEV1 at 24 h. However, our exploratory analysis demonstrated significantly more two dose-doubling increases in PC₂₀ FEV1 for N6022 compared with placebo (21% vs 6%, P < 0.05) over the 7-day observation period. Furthermore, a significant treatment effect was observed in the change in PC₂₀ FEV1 from baseline averaged over the 7-day observation period (mean change: +0.82 mg/ml [N6022] from 1.34 mg/ml [baseline] vs -0.18 mg/ml [placebo] from 1.16 mg/ml [baseline], P = 0.023). N6022 was well tolerated in mild asthmatics. In vitro studies demonstrated enhanced eosinophilic apoptosis with N6022.<h4>Conclusions</h4>In this early phase exploratory proof of concept trial in asthma, N6022 did not significantly alter methacholine PC₂₀ FEV1 at 24 h, but did have a treatment effect at 7 days compared to baseline. Further investigation of the efficacy of S-nitrosoglutathione reductase inhibition in a patient population with eosinophilic asthma is warranted.