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

*Kontaktforfatter for dette arbejde

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Abstrakt

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.

OriginalsprogEngelsk
TidsskriftInternational Journal of COPD
Vol/bind16
Sider (fra-til)1621-1636
ISSN1176-9106
DOI
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
DISKUS and ELLIPT A are owned by/licensed to the GSK group of companies. Editorial support was provided by Kate Hollingworth of Continuous Improvement Ltd, and funded by GlaxoSmithKline (GSK) R&D.

Funding Information:
This work was funded by GlaxoSmithKline (clinicaltrials. gov: NCT02130635 and NCT02522299). The sponsor/funder , as described under author contributions, was involved in the study design, data analysis, interpretation of data and writing of the manuscript.

Funding Information:
MB, EJ, GB, SM, DM, ML, HW , AA, KS, R T , SA, TT and AC are employees and shareholders of GSK. JNH, R W & EMH are former employees and shareholders of GSK. JNH, EMH and AA are named on patents related to compound GSK2269557 (nemiralisib). JNH has patents WO 2010125082 and WO 2012055846 issued. EMH has a patent WO2015055691A1 issued. AA has patents US20160263109, US20160256466, EP3057588, EP3057587, WO2015055691, and WO2015055690 issued to GSK. CVH and JDB are employees of FLUIDDA, the company responsible for FRI analysis and interpretation. WV is a former employee of FLUIDDA. WV and JDB hold FLUIDDA shares. JMF has received research funding paid directly to the University of British Columbia from AstraZeneca, GSK, Novartis, Sanofi-Regeneron, Canadian Institutes of Health Research (CIHR), NIH and AllerGen; and has received honoraria from AstraZeneca, GSK, TEV A, Sanofi for participation in Advisory Boards and speaker bureaus. JB has received grants from CIHR, Canadian Respiratory Research Network, Foundation of the McGill University Health Centre (MUHC), Aerocrine, AstraZeneca, GSK, Boehringer Ingelheim, Novartis, Grifols and T rudell; and personal fees from Canadian Thoracic Society , CHEST , AstraZeneca, GSK, Boehringer Ingelheim, Novartis, Grifols, Pfizer , and T rudell for consultancy and lectures. CP has received personal fees from GSK, Boehringer Ingelheim, Novartis, AstraZeneca and Apnee Sante. FM has received grants paid to his institution from AstraZeneca, GSK, Boehringer Ingelheim, Sanofi, Novartis and Grifols; has received personal fees from GSK, Boehringer Ingelheim, Grifols, and Novartis for serving on speaker bureaus; and is financially involved with Oxynov , a company developing an oxygen delivery system. The current affiliation of JNH is Discovery , Charles River , Chesterford Research Park, Cambridge, UK. The current affiliation of DM is Benevolent AI Ltd, London, United Kingdom. The current affiliation of R W is DLRC, Letchworth Garden City , UK. The current affiliation of WV is OncoRadiomics, Liège,

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