Exploring PI3Kδ molecular pathways in stable COPD and following an acute exacerbation, two randomized controlled trials

Malcolm Begg*, J. Nicole Hamblin, Emily Jarvis, Glyn Bradley, Stephen Mark, David Michalovich, Mark Lennon, Hannah E. Wajdner, Augustin Amour, Robert Wilson, Ken Saunders, Rikako Tanaka, Saki Arai, Teresa Tang, Cedric Van Holsbeke, Jan De Backer, Wim Vos, Ingrid L. Titlestad, J. Mark FitzGerald, Kieran KillianJean Bourbeau, Claude Poirier, François Maltais, Anthony Cahn, Edith M. Hessel

*Corresponding author for this work

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Abstract

Background: Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) exerts corrective effects on the dysregulated migration characteristics of neutrophils isolated from patients with chronic obstructive pulmonary disease (COPD). Objective: To develop novel, induced sputum endpoints to demonstrate changes in neu- trophil phenotype in the lung by administering nemiralisib, a potent and selective inhaled PI3Kδ inhibitor, to patients with stable COPD or patients with acute exacerbation (AE) of COPD. Methods: In two randomized, double-blind, placebo-controlled clinical trials patients with A) stable COPD (N=28, randomized 3:1) or B) AECOPD (N=44, randomized 1:1) received treatment with inhaled nemiralisib (1mg). Endpoints included induced sputum at various time points before and during treatment for the measurement of transcriptomics (primary endpoint), inflammatory mediators, functional respiratory imaging (FRI), and spirometry. Results: In stable COPD patients, the use of nemiralisib was associated with alterations in sputum neutrophil transcriptomics suggestive of an improvement in migration phenotype; however, the same nemiralisib-evoked effects were not observed in AECOPD. Inhibition of sputum inflammatory mediators was also observed in stable but not AECOPD patients. In contrast, a placebo-corrected improvement in forced expiratory volume in 1 sec of 136 mL (95% Credible Intervals -46, 315mL) with a probability that the true treatment ratio was >0% (Pr(θ>0)) of 93% was observed in AECOPD. However, FRI endpoints remained unchanged. Conclusion: We provide evidence for nemiralisib-evoked changes in neutrophil migration phenotype in stable COPD but not AECOPD, despite improving lung function in the latter group. We conclude that induced sputum can be used for measuring evidence of alteration of neutrophil phenotype in stable patients, and our study provides a data set of the sputum transcriptomic changes during recovery from AECOPD.

Original languageEnglish
JournalInternational Journal of Chronic Obstructive Pulmonary Disease
Volume16
Pages (from-to)1621-1636
ISSN1178-2005
DOIs
Publication statusPublished - 2021

Bibliographical note

Publisher Copyright:
© 2021 Begg et al.

Keywords

  • COPD exacerbations
  • Nemiralisib
  • PI3Kdelta
  • Sputum
  • Transcriptomics

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