Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials.
Int J Chron Obstruct Pulmon Dis
; 16: 1621-1636, 2021.
Article
en En
| MEDLINE
| ID: mdl-34113094
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 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 31) or B) AECOPD (N=44, randomized 11) 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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fosfatidilinositol 3-Quinasas
/
Enfermedad Pulmonar Obstructiva Crónica
Tipo de estudio:
Clinical_trials
/
Diagnostic_studies
Límite:
Humans
Idioma:
En
Revista:
Int J Chron Obstruct Pulmon Dis
Año:
2021
Tipo del documento:
Article
País de afiliación:
Reino Unido