Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials
Malcolm Begg,1 J Nicole Hamblin,1 Emily Jarvis,2 Glyn Bradley,3 Stephen Mark,4 David Michalovich,5 Mark Lennon,6 Hannah E Wajdner,5 Augustin Amour,5 Robert Wilson,1 Ken Saunders,5 Rikako Tanaka,7 Saki Arai,7 Teresa Tang,8 Cedric Van Holsbeke,9 Jan De Backer,9 Wim Vos,9 Ingrid L Titlestad,10 J Mark F...
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Dove Medical Press
2021-06-01
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Begg M Hamblin JN Jarvis E Bradley G Mark S Michalovich D Lennon M Wajdner HE Amour A Wilson R Saunders K Tanaka R Arai S Tang T Van Holsbeke C De Backer J Vos W Titlestad IL FitzGerald JM Killian K Bourbeau J Poirier C Maltais F Cahn A Hessel EM |
spellingShingle |
Begg M Hamblin JN Jarvis E Bradley G Mark S Michalovich D Lennon M Wajdner HE Amour A Wilson R Saunders K Tanaka R Arai S Tang T Van Holsbeke C De Backer J Vos W Titlestad IL FitzGerald JM Killian K Bourbeau J Poirier C Maltais F Cahn A Hessel EM Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials International Journal of COPD nemiralisib sputum transcriptomics copd exacerbations pi3kdelta |
author_facet |
Begg M Hamblin JN Jarvis E Bradley G Mark S Michalovich D Lennon M Wajdner HE Amour A Wilson R Saunders K Tanaka R Arai S Tang T Van Holsbeke C De Backer J Vos W Titlestad IL FitzGerald JM Killian K Bourbeau J Poirier C Maltais F Cahn A Hessel EM |
author_sort |
Begg M |
title |
Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials |
title_short |
Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials |
title_full |
Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials |
title_fullStr |
Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials |
title_full_unstemmed |
Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials |
title_sort |
exploring pi3kδ molecular pathways in stable copd and following an acute exacerbation, two randomized controlled trials |
publisher |
Dove Medical Press |
series |
International Journal of COPD |
issn |
1178-2005 |
publishDate |
2021-06-01 |
description |
Malcolm Begg,1 J Nicole Hamblin,1 Emily Jarvis,2 Glyn Bradley,3 Stephen Mark,4 David Michalovich,5 Mark Lennon,6 Hannah E Wajdner,5 Augustin Amour,5 Robert Wilson,1 Ken Saunders,5 Rikako Tanaka,7 Saki Arai,7 Teresa Tang,8 Cedric Van Holsbeke,9 Jan De Backer,9 Wim Vos,9 Ingrid L Titlestad,10 J Mark FitzGerald,11 Kieran Killian,12 Jean Bourbeau,13 Claude Poirier,14 François Maltais,15 Anthony Cahn,1 Edith M Hessel1 1Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK; 2Biostatistics, GlaxoSmithKline R&D, Stevenage, UK; 3Computational Biology, Medicinal Science and Technology, GlaxoSmithKline, Stevenage, UK; 4Study Management, Clinical Development, GlaxoSmithKline, Mississauga, ON, Canada; 5Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, UK; 6Nonclinical and Translational Statistics, GlaxoSmithKline, Stevenage, UK; 7Data Management & Strategy, Clinical Development, GlaxoSmithKline, Tokyo, Japan; 8Pharma Safety, Clinical Development, GlaxoSmithKline, Brentford, Middlesex, UK; 9FLUIDDA nv, Kontich, 2550, Belgium; 10Department of Respiratory Medicine, Odense University Hospital and University of Southern Denmark, Odense, Denmark; 11Centre for Heart and Lung Health, University of British Columbia, Vancouver, BC, Canada; 12Cardiorespiratory Research Laboratory, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada; 13Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada; 14Department of Medicine, Respiratory Medicine Division, University of Montreal, Montreal, QC, Canada; 15Institut Universitaire de Cardiologie et de Pneumologie de Québe, Université Laval, Quebec City, QC, CanadaCorrespondence: Malcolm BeggRefractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, Herts, UKEmail malcolm.5.begg@gsk.comBackground: 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 neutrophil 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.Keywords: nemiralisib, sputum, transcriptomics, COPD exacerbations, PI3Kdelta |
topic |
nemiralisib sputum transcriptomics copd exacerbations pi3kdelta |
url |
https://www.dovepress.com/exploring-pi3k-molecular-pathways-in-stable-copd-and-following-an-acut-peer-reviewed-fulltext-article-COPD |
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doaj-3dfbc4a83e084f59b157271439b2a0bc2021-06-08T19:41:46ZengDove Medical PressInternational Journal of COPD1178-20052021-06-01Volume 161621163665497Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled TrialsBegg MHamblin JNJarvis EBradley GMark SMichalovich DLennon MWajdner HEAmour AWilson RSaunders KTanaka RArai STang TVan Holsbeke CDe Backer JVos WTitlestad ILFitzGerald JMKillian KBourbeau JPoirier CMaltais FCahn AHessel EMMalcolm Begg,1 J Nicole Hamblin,1 Emily Jarvis,2 Glyn Bradley,3 Stephen Mark,4 David Michalovich,5 Mark Lennon,6 Hannah E Wajdner,5 Augustin Amour,5 Robert Wilson,1 Ken Saunders,5 Rikako Tanaka,7 Saki Arai,7 Teresa Tang,8 Cedric Van Holsbeke,9 Jan De Backer,9 Wim Vos,9 Ingrid L Titlestad,10 J Mark FitzGerald,11 Kieran Killian,12 Jean Bourbeau,13 Claude Poirier,14 François Maltais,15 Anthony Cahn,1 Edith M Hessel1 1Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK; 2Biostatistics, GlaxoSmithKline R&D, Stevenage, UK; 3Computational Biology, Medicinal Science and Technology, GlaxoSmithKline, Stevenage, UK; 4Study Management, Clinical Development, GlaxoSmithKline, Mississauga, ON, Canada; 5Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, UK; 6Nonclinical and Translational Statistics, GlaxoSmithKline, Stevenage, UK; 7Data Management & Strategy, Clinical Development, GlaxoSmithKline, Tokyo, Japan; 8Pharma Safety, Clinical Development, GlaxoSmithKline, Brentford, Middlesex, UK; 9FLUIDDA nv, Kontich, 2550, Belgium; 10Department of Respiratory Medicine, Odense University Hospital and University of Southern Denmark, Odense, Denmark; 11Centre for Heart and Lung Health, University of British Columbia, Vancouver, BC, Canada; 12Cardiorespiratory Research Laboratory, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada; 13Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada; 14Department of Medicine, Respiratory Medicine Division, University of Montreal, Montreal, QC, Canada; 15Institut Universitaire de Cardiologie et de Pneumologie de Québe, Université Laval, Quebec City, QC, CanadaCorrespondence: Malcolm BeggRefractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, Herts, UKEmail malcolm.5.begg@gsk.comBackground: 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 neutrophil 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.Keywords: nemiralisib, sputum, transcriptomics, COPD exacerbations, PI3Kdeltahttps://www.dovepress.com/exploring-pi3k-molecular-pathways-in-stable-copd-and-following-an-acut-peer-reviewed-fulltext-article-COPDnemiralisibsputumtranscriptomicscopd exacerbationspi3kdelta |