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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

William A Fahy,1 Farshid Homayoun-Valiani,2 Anthony Cahn,3 Jon Robertson,4 Alison Templeton,4 Wilhelmine H Meeraus,5 Robert Wilson,3 Mike Lowings,6 Miriam Marotti,7 Sarah L West,2 Maggie Tabberer,8 Edith M Hessel9 1Discovery Medicine, GlaxoSmithKline R&D, GSK House, Brentford, UK; 2Global Clinical Operations, GlaxoSmithKline, GSK House, Brentford, UK; 3Discovery Medicine, GlaxoSmithKline, Stevenage, UK; 4Biostatistics, GlaxoSmithKline R&D, Stevenage, UK; 5Respiratory Epidemiology, Value Evidence and Outcomes, GlaxoSmithKline R&D, GSK House, Brentford, UK; 6Regulatory Affairs, GlaxoSmithKline, GSK House, Brentford, UK; 7Safety and Medical Governance, GlaxoSmithKline R&D, GSK House, Brentford, UK; 8Value Evidence and Outcomes, GlaxoSmithKline R&D, GSK House, Brentford, UK; 9Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UKCorrespondence: William A FahyDiscovery Medicine, GlaxoSmithKline R&D, GSK House, Brentford, United KingdomEmail william.a.fahy@gsk.comBackground: Management of acute exacerbations of chronic obstructive pulmonary disease (COPD) is sometimes inadequate leading to either prolonged duration and/or an increased risk of recurrent exacerbations in the period following the initial event.Objective: To evaluate the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ inhibitor, in patients experiencing an acute exacerbation of COPD.Patients and Methods: In this double-blind, placebo-controlled study, COPD patients (40– 80 years, ≥ 10 pack-year smoking history, current moderate/severe acute exacerbation of COPD requiring standard-of-care treatment) were randomized to placebo or nemiralisib 12.5 μg, 50 μg, 100 μg, 250 μg, 500 μg, or 750 μg (ratio of 3:1:1:1:1:1:3; N=938) for 12 weeks with an exploratory 12-week follow-up period. The primary endpoint was change from baseline in post-bronchodilator FEV1 at week 12. Key secondary endpoints were rate of re-exacerbations, patient-reported outcomes (Exacerbations of Chronic Pulmonary Disease Tool, COPD Assessment Test, St George’s Respiratory Questionnaire-COPD), plasma pharmacokinetics (PK) and safety/tolerability.Results: There was no difference in change from baseline FEV1 at week 12 between the nemiralisib and placebo treatment groups (posterior adjusted median difference, nemiralisib 750 μg and placebo: − 0.004L (95% CrI: − 0.051L to 0.042L)). Overall, there were also no differences between nemiralisib and placebo in secondary endpoints, including re-exacerbations. Plasma PK increased in a dose proportional manner. The most common adverse event for nemiralisib was post-inhalation cough which appeared to be dose-related.Conclusion: The addition of nemiralisib to standard-of-care treatment for 12 weeks did not improve lung function or re-exacerbations in patients with, and following an acute exacerbation of COPD. However, this study demonstrated that large clinical trials recruiting acutely exacerbating patients can successfully be conducted.Keywords: acute exacerbation, COPD, dose-ranging, nemiralisib

Anthony Cahn,1 J Nicole Hamblin,2 Jon Robertson,3 Malcolm Begg,2 Emily Jarvis,3 Robert Wilson,1 Gordon Dear,4 Claudia Leemereise,5 Yi Cui,6 Maki Mizuma,7 Mickael Montembault,8 Cedric Van Holsbeke,9 Wim Vos,9 Wilfried De Backer,10 Jan De Backer,9 Edith M Hessel2 1Discovery Medicine, GlaxoSmithKline, Stevenage, UK; 2Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK; 3Biostatistics, GlaxoSmithKline, Stevenage, UK; 4Mechanistic Safety & Disposition, GlaxoSmithKline, Ware, UK; 5Global Clinical Sciences & Delivery, GlaxoSmithKline, Amersfoort, the Netherlands; 6Pharma Safety, GlaxoSmithKline, Brentford, Middlesex, UK; 7Data Management & Strategy, GlaxoSmithKline, Tokyo, Japan; 8Global Clinical Sciences & Delivery, GlaxoSmithKline, Brentford, Middlesex, UK; 9FLUIDDA nv, Kontich, 2550, Belgium; 10Pulmonary Medicine & Pulmonary Rehabilitation, University of Antwerp, Antwerp, BelgiumCorrespondence: Anthony CahnDiscovery Medicine, GlaxoSmithKline, Stevenage, UKTel +44 1438766374Email tony.x.cahn@gsk.comPurpose: This study evaluated the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ (PI3Kδ) inhibitor, in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD).Methods: In this double-blind, placebo-controlled study, 126 patients (40– 80 years with a post-bronchodilator forced expiratory volume in 1 sec (FEV1) ≤ 80% of predicted (previously documented)) were randomized 1:1 to once daily inhaled nemiralisib (1 mg) or placebo for 84 days, added to standard of care. The primary endpoint was specific imaging airway volume (siVaw) after 28 treatment days and was analyzed using a Bayesian repeated measures model (clintrials.gov: NCT02294734).Results: A total of 126 patients were randomized to treatment; 55 on active treatment and 49 on placebo completed the study. When comparing nemiralisib and placebo-treated patients, an 18% placebo-corrected increase from baseline in distal siVaw (95% credible intervals (Cr I) (− 1%, 42%)) was observed on Day 28. The probability that the true treatment ratio was > 0% (Pr(θ> 0)) was 96%, suggestive of a real treatment effect. Improvements were observed across all lung lobes. Patients treated with nemiralisib experienced a 107.3 mL improvement in posterior median FEV1 (change from baseline, 95% Cr I (− 2.1, 215.5)) at day 84, compared with placebo. Adverse events were reported by 41 patients on placebo and 49 on nemiralisib, the most common being post-inhalation cough on nemiralisib (35%) vs placebo (3%).Conclusion: These data show that addition of nemiralisib to usual care delivers more effective recovery from an acute exacerbation and improves lung function parameters including siVaw and FEV1. Although post-inhalation cough was identified, nemiralisib was otherwise well tolerated, providing a promising novel therapy for this acutely ill patient group.Keywords: acute exacerbation, COPD, nemiralisib