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

Effect of the S-nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma.
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Que LG, Yang Z, Lugogo NL, Katial RK, Shoemaker SA, Troha JM, Rodman DM, Tighe RM, Kraft M,


Que LG, Yang Z, Lugogo NL, Katial RK, Shoemaker SA, Troha JM, Rodman DM, Tighe RM, Kraft M, (click to view)

Que LG, Yang Z, Lugogo NL, Katial RK, Shoemaker SA, Troha JM, Rodman DM, Tighe RM, Kraft M,

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Immunity, inflammation and disease 2018 04 11() doi 10.1002/iid3.220
Abstract
RATIONALE
Patients with asthma demonstrate depletion of the endogenous bronchodilator GSNO and upregulation of GSNOR.

OBJECTIVES
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.

METHODS
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 PC 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.

MEASUREMENTS AND MAIN RESULTS
This was a negative trial as it failed to reach its primary endpoint, which was change from baseline in methacholine PC FEV1 at 24 h. However, our exploratory analysis demonstrated significantly more two dose-doubling increases in PC 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 PC 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. CONCLUSIONS
In this early phase exploratory proof of concept trial in asthma, N6022 did not significantly alter methacholine PC 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.

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