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

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 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: COPD exacerbations; PI3Kdelta; nemiralisib; sputum; transcriptomics.

Conflict of interest statement

MB, EJ, GB, SM, DM, ML, HW, AA, KS, RT, SA, TT and AC are employees and shareholders of GSK. JNH, RW & 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, TEVA, 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 Trudell; and personal fees from Canadian Thoracic Society, CHEST, AstraZeneca, GSK, Boehringer Ingelheim, Novartis, Grifols, Pfizer, and Trudell 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 RW is DLRC, Letchworth Garden City, UK. The current affiliation of WV is OncoRadiomics, Liège, Belgium. The current affiliation of EMH is Eligo Bioscience, Paris, France. The authors report no other conflicts of interest in this work.

© 2021 Begg et al.

Figures

Figure 1

mRNA transcriptomic alterations in induced sputum from stable COPD patients (Study A). Transcriptomic changes in induced sputum taken from stable COPD patients dosed for 14 days with nemiralisib show a partial clustering by treatment (Panel A). Unbiased pathway analysis highlighted nemiralisib-evoked alterations in neutrophil phenotype and bacterial infection response genes (Panels B and C, left), which were not observed in the samples taken 7 days apart prior to randomization (Panels B and C, right).

Figure 2

mRNA transcriptomic alterations in induced sputum from AECOPD patients (Study B). Transcriptomic changes in induced sputum taken from acutely exacerbating COPD patients. Of the predefined neutrophil-related genes a small number were altered in both the nemiralisib and placebo-treated groups (Panel A). The entire unbiased gene array output also showed a similar number of genes changing in the nemiralisib and placebo-treated groups when comparing both day 12 or day 84 to the screening time point (Panel A, SCN v D12). There was a significant overlap in the genes changing between screening and day 12 in the nemiralisib and placebo-treated groups at day 12 and day 84, with almost all genes changing in the same direction (Panel B).

Figure 3

Inflammatory biomarkers in induced sputum from AECOPD patients (Study B) Sputum and circulating biomarkers measured were also not impacted by treatment with nemiralisib. Circulating levels of CRP decreased (Panel A, left), as did neutrophil count (Panel A, right), presented as mean (95% CI) at baseline, Day 12, Day 28, Day 56, Day 84 and at follow-up. Total sputum cell count and the inflammatory cytokines IL-8, IL-6 and TNFα were also not inhibited following treatment with nemiralisib (Panel B), presented as geometric mean (95% CI) at baseline, Day 12, Day 28 and Day 84.

Figure 4

Summary of statistical analysis of FEV1 and FVC in AECOPD patients (Study B). Treatment with nemiralisib showed an improvement in FEV1 and FVC at all time points. Panel A shows adjusted median change from baseline in FEV1 (95% Cr I), and Panel B shows adjusted median change from baseline in FVC (95% Cr I) measured at clinical visits at baseline, Day 12, Day 28, Day 56 and Day 84. Data presented as adjusted median ± 95% Credible Intervals.

Figure 5

Lung transcriptomics during exacerbation recovery (Study B). Combined sputum transcriptomic data shows partial clustering by time point (Panels A and B). Unbiased overlay analysis showed a highly significant overlap with data from ECLIPSE ., The degree of overlap and gene directionality for the matching genes are displayed in (Panel C).

Figure 6

Blood transcriptomics during exacerbation recovery (Study B). Combined blood transcriptomic data shows partial clustering by time point (Panels A and B). Unbiased overlay analysis showed a highly significant overlap with data from ECLIPSE.27,30 The degree of overlap and gene directionality for the matching genes are displayed in (Panel C).