Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials

被引：15

作者：

Begg, Malcolm ^{[1
]}

Hamblin, J. Nicole ^{[1
]}

Jarvis, Emily ^{[2
]}

Bradley, Glyn ^{[3
]}

Mark, Stephen ^{[4
]}

Michalovich, David ^{[5
]}

Lennon, Mark ^{[6
]}

Wajdner, Hannah E. ^{[5
]}

Amour, Augustin ^{[5
]}

Wilson, Robert ^{[1
]}

Saunders, Ken ^{[5
]}

Tanaka, Rikako ^{[7
]}

Arai, Saki ^{[7
]}

Tang, Teresa ^{[8
]}

Van Holsbeke, Cedric ^{[9
]}

De Backer, Jan ^{[9
]}

Vos, Wim ^{[9
]}

Titlestad, Ingrid L. ^{[10
,11
]}

FitzGerald, J. Mark ^{[12
]}

Killian, Kieran ^{[13
]}

Bourbeau, Jean ^{[14
]}

Poirier, Claude ^{[15
]}

Maltais, Francois ^{[16
]}

Cahn, Anthony ^{[1
]}

Hessel, Edith M. ^{[1
]}

机构：

[1] GlaxoSmithKline, Refractory Resp Inflammat Discovery Performance U, Stevenage, Herts, England

[2] GlaxoSmithKline R&D, Biostat, Stevenage, Herts, England

[3] GlaxoSmithKline, Computat Biol Med Sci & Technol, Stevenage, Herts, England

[4] GlaxoSmithKline, Clin Dev, Study Management, Mississauga, ON, Canada

[5] GlaxoSmithKline, Adapt Immun Res Unit, Stevenage, Herts, England

[6] GlaxoSmithKline, Nonclin & Translat Stat, Stevenage, Herts, England

[7] GlaxoSmithKline, Clin Dev, Data Management & Strategy, Tokyo, Japan

[8] GlaxoSmithKline, Clin Dev, Pharma Safety, Brentford, Middx, England

[9] FLUIDDA Nv, B-2550 Kontich, Belgium

[10] Odense Univ Hosp, Dept Resp Med, Odense, Denmark

[11] Univ Southern Denmark, Odense, Denmark

[12] Univ British Columbia, Ctr Heart & Lung Hlth, Vancouver, BC, Canada

[13] McMaster Univ, Fac Hlth Sci, Cardioresp Res Lab, Hamilton, ON, Canada

[14] McGill Univ, Dept Med, Div Expt Med, Montreal, PQ, Canada

[15] Univ Montreal, Dept Med, Resp Med Div, Montreal, PQ, Canada

[16] Univ Laval, Inst Univ Cardiol & Pneumol Quebe, Quebec City, PQ, Canada

来源：

INTERNATIONAL JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE | 2021年 / 16卷

关键词：

nemiralisib; sputum; transcriptomics; COPD exacerbations; PI3Kdelta; OBSTRUCTIVE PULMONARY-DISEASE; NEUTROPHILS; SPUTUM; INHIBITOR; RECEPTOR; GENES;

D O I：

10.2147/COPD.S309303

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

Background: Inhibition of phosphoinositide 3-kinase delta (PI3K delta) 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 PI3K delta 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(theta>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.

引用

页码：1621 / 1636

页数：16

共 40 条

[1] Acute Exacerbations of Chronic Obstructive Pulmonary Disease Identification of Biologic Clusters and Their Biomarkers [J].

Bafadhel, Mona ;

McKenna, Susan ;

Terry, Sarah ;

Mistry, Vijay ;

Reid, Carlene ;

Haldar, Pranabashis ;

McCormick, Margaret ;

Haldar, Koirobi ;

Kebadze, Tatiana ;

Duvoix, Annelyse ;

Lindblad, Kerstin ;

Patel, Hemu ;

Rugman, Paul ;

Dodson, Paul ;

Jenkins, Martin ;

Saunders, Michael ;

Newbold, Paul ;

Green, Ruth H. ;

Venge, Per ;

Lomas, David A. ;

Barer, Michael R. ;

Johnston, Sebastian L. ;

Pavord, Ian D. ;

Brightling, Christopher E. .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2011, 184 (06) :662-671

[2] Relationship between Pharmacokinetics and Pharmacodynamic Responses in Healthy Smokers Informs a Once-Daily Dosing Regimen for Nemiralisib [J].

Begg, M. ;

Wilson, R. ;

Hamblin, J. N. ;

Montembault, M. ;

Green, J. ;

Deans, A. ;

Amour, A. ;

Worsley, S. ;

Fantom, K. ;

Cui, Y. ;

Dear, G. ;

Ahmad, S. ;

Kielkowska, A. ;

Clark, J. ;

Boyce, M. ;

Cahn, A. ;

Hessel, E. M. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2019, 369 (03) :337-344

[3] C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations [J].

Butler, Christopher C. ;

Gillespie, David ;

White, Patrick ;

Bates, Janine ;

Lowe, Rachel ;

Thomas-Jones, Emma ;

Wootton, Mandy ;

Hood, Kerenza ;

Phillips, Rhiannon ;

Melbye, Hasse ;

Llor, Carl ;

Cals, Jochen W. L. ;

Naik, Gurudutt ;

Kirby, Nigel ;

Gal, Micaela ;

Riga, Evgenia ;

Francis, Nick A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2019, 381 (02) :111-120

[4] Safety, pharmacokinetics and dose-response characteristics of GSK2269557, an inhaled PI3Kδ inhibitor under development for the treatment of COPD [J].

Cahn, A. ;

Hamblin, J. N. ;

Begg, M. ;

Wilson, R. ;

Dunsire, L. ;

Sriskantharajah, S. ;

Montembault, M. ;

Leemereise, C. N. ;

Galinanes-Garcia, L. ;

Watz, H. ;

Kirsten, A. M. ;

Fuhr, R. ;

Hessel, E. M. .

PULMONARY PHARMACOLOGY & THERAPEUTICS, 2017, 46 :69-77

[5]

Cahn A, 2021, INT J CHRON OBSTRUCT

[6] MECHANISMS OF DISEASE Immunologic Aspects of Chronic Obstructive Pulmonary Disease [J].

Cosio, Manuel G. ;

Saetta, Marina ;

Agusti, Alvar .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 360 (23) :2445-2454

[7] COPD Care in the 21st Century: A Public Health Priority [J].

Criner, Rachel N. ;

Han, MeiLan K. .

RESPIRATORY CARE, 2018, 63 (05) :591-600

[8] The lung microbiome and exacerbations of COPD [J].

Dy, Rajany ;

Sethi, Sanjay .

CURRENT OPINION IN PULMONARY MEDICINE, 2016, 22 (03) :196-202

[9] Immunostimulatory sequences regulate interferon-inducible genes but not allergic airway responses [J].

Gauvreau, Gail M. ;

Hessel, Edith M. ;

Boulet, Louis-Philippe ;

Coffman, Robert L. ;

O'Byrne, Paul M. .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2006, 174 (01) :15-20

[10]

GOLD, 2020, REPORT Prevention of Chronic Obstructive Pulmonary Disease, P1141

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