Search

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

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

Omar S Usmani,1 Nicola Scichilone,2 Benjamin Mignot,3 Dennis Belmans,3 Cedric Van Holsbeke,3 Jan De Backer,3 Roberta De Maria,4 Erika Cuoghi,4 Eva Topole,4 George Georges4 1Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK; 2PROMISE Department of Medicine, University of Palermo, Palermo, Italy; 3FLUIDDA, Kontich, Belgium; 4Chiesi Farmaceutici, SpA, Parma, ItalyCorrespondence: George GeorgesChiesi USA Inc., 175 Regency Woods Place, Ste. 600, Cary, NC 27518, USATel +1 (919) 678 6611 x1536Email george.georges@chiesi.comIntroduction: There is a clear correlation between small airways dysfunction and poor clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), and it is therefore important that inhalation therapy (both bronchodilator and anti-inflammatory) can deposit in the small airways. Two single-inhaler triple therapy (SITT) combinations are currently approved for the maintenance treatment of COPD: extrafine formulation beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB), and non-extrafine formulation fluticasone furoate/vilanterol/umeclidinium (FluF/VI/UMEC). This study evaluated the lung deposition of the inhaled corticosteroid (ICS), long-acting β2-agonist (LABA), and long-acting muscarinic antagonist (LAMA) components of these two SITTs.Materials and Methods: Lung deposition was estimated in-silico using functional respiratory imaging, a validated technique that uses aerosol delivery performance profiles, patients’ high-resolution computed tomography (HRCT) lung scans, and patient-derived inhalation profiles to simulate aerosol lung deposition.Results: HRCT scan data from 20 patients with COPD were included in these analyses, who had post-bronchodilator forced expiratory volume in 1 second (FEV1) ranging from 19.3% to 66.0% predicted. For intrathoracic deposition (as a percentage of the emitted dose), deposition of the ICS component was higher from BDP/FF/GB than FluF/VI/UMEC; the two triple therapies had similar performance for both the LABA component and the LAMA component. Peripheral deposition of all three components was higher with BDP/FF/GB than FluF/VI/UMEC. Furthermore, the ratios of central to peripheral deposition for all three components of BDP/FF/GB were < 1, indicating greater peripheral than central deposition (0.48± 0.13, 0.48± 0.13 and 0.49± 0.13 for BDP, FF and GB, respectively; 1.96± 0.84, 0.97± 0.34 and 1.20± 0.48 for FluF, VI and UMEC, respectively).Conclusions: Peripheral (small airways) deposition of all three components (ICS, LABA, and LAMA) was higher from BDP/FF/GB than from FluF/VI/UMEC, based on profiles from patients with moderate to very severe COPD. This is consistent with the extrafine formulation of BDP/FF/GB.Keywords: tomography, X-ray computed, metered dose inhalers, dry powder inhalers, inhaled corticosteroid, long-acting beta2 agonist, long-acting muscarinic antagonist

Glenn Leemans,1,2 Dennis Belmans,2 Cedric Van Holsbeke,2 Vladimir Kushnarev,3 Jason Sugget,3 Kris Ides,1 Dirk Vissers,1 Wilfried De Backer4 1Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Wilrijk, Belgium; 2FLUIDDA nv, Antwerp, Kontich, Belgium; 3Trudell Medical International, London, Ontario, Canada; 4Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Wilrijk, BelgiumCorrespondence: Glenn LeemansFaculty of Medicine and Health Sciences University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, BelgiumTel +32 495 34 84 59Email glenn.leemans@uantwerpen.bePurpose: Chronic obstructive pulmonary disease (COPD) patients are prone to suffer from chronic bronchitis, which ultimately affects their quality of life and overall prognosis. Oscillating positive expiratory pressure (oPEP) devices are designed to aid in the mucus clearance by generating positive pressure pulses in the airways. The main aim of this study was to analyze the impact of a specific oPEP device – Aerobika® – on top of standard of care medication in COPD patients’ lung dynamics and drug deposition.Patients and Methods: In this single-arm pilot study, patients were assessed using standard spirometry tests and functional respiratory imaging (FRI) before and after a period of 15± 3 days of using the oPEP device twice daily (before their standard medication).Results: The utilization of the oPEP device led to a significant increase of 2.88% in specific airway volume after two weeks (1.44 (SE: 0.18) vs 1.48 (SE: 0.19); 95% CI = [0.03%,5.81%]; p=0.048). Moreover, the internal airflow distribution (IAD) was affected by the treatment: patients’ changes ranged from − 6.74% to 4.51%. Furthermore, IAD changes at the lower lobes were also directly correlated with variations in forced expiratory volume in one second and peak expiratory flow; conversely, IAD changes at the upper lobes were inversely correlated with these clinical parameters. Interestingly, this change in IAD was significantly correlated with changes in lobar drug deposition (r2=0.30, p< 0.001).Conclusion: Our results support that the Aerobika device utilization leads to an improved airflow, which in turn causes a shift in IAD and impacts the drug deposition patterns of the concomitant medication in patients with COPD.Keywords: mucus hypersecretion, airway clearance techniques, functional respiratory imaging, internal airflow distribution, drug deposition

Wilfried De Backer,1 Jan De Backer,2 Wim Vos,3 Ilse Verlinden,3 Cedric Van Holsbeke,3 Johan Clukers,1 Bita Hajian,1 Shahid Siddiqui,4 Martin Jenkins,5 Colin Reisner,4,6 Ubaldo J Martin4 1Department of Respiratory Medicine, University of Antwerp, Antwerp, Belgium; 2FLUIDDA, Los Angeles, CA, USA; 3FLUIDDA, Kontich, Belgium; 4AstraZeneca, Gaithersburg, MD, USA; 5AstraZeneca, Cambridge, UK; 6Pearl – A member of the AstraZeneca Group, Morristown, NJ, USA Background: Functional respiratory imaging (FRI) uses high-resolution computed tomography (HRCT) scans to assess changes in airway volume and resistance. Patients and methods: In this randomized, double-blind, 2-week, crossover, Phase IIIB study, patients with moderate-to-severe COPD received twice-daily glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler (GFF MDI, 18/9.6 µg) and placebo MDI, formulated using innovative co-suspension delivery technology. Co-primary endpoints included the following: specific image-based airway volume (siVaw) and specific image-based airway resistance (siRaw) at Day 15, measured using FRI. Secondary and other endpoints included the following: change from baseline in post-dose forced expiratory volume in 1 second (FEV1) and inspiratory capacity (IC; spirometry) and ratio to baseline in post-dose functional residual capacity (FRC) and residual volume (RV; body plethysmography). Results: Twenty patients (46–78 years of age) were randomized and treated; of whom 19 completed the study. GFF MDI treatment increased siVaw by 75% and reduced siRaw by 71% vs placebo MDI (both P

Wouter H van Geffen,1,2 Bita Hajian,3 Wim Vos,4 Jan De Backer,4 Anthony Cahn,5 Omar S Usmani,6 Cedric Van Holsbeke,4 Massimo Pistolesi,7 Huib AM Kerstjens,2 Wilfried De Backer3 1Department of Respiratory Medicine, Medical Centre Leeuwarden, Leeuwarden, the Netherlands; 2Department of Pulmonary Diseases, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, University of Groningen, the Netherlands; 3Department of Pulmonary Diseases, Antwerp University Hospital, Antwerp, Belgium; 4FLUIDDA nv, Kontich, Belgium; 5GlaxoSmithKline R&D, Stevenage, UK; 6Faculty of Medicine, National Heart & Lung Institute, Imperial College London, London, UK; 7Department of Experimental and Clinical Medicine, Section of Respiratory Medicine, University of Florence, Florence, Italy Background: Exacerbations of COPD are a major burden to patients, and yet little is understood about heterogeneity. It contributes to the current persistent one-size-fits-all treatment. To replace this treatment by more personalized, precision medicine, new insights are required. We assessed the heterogeneity of exacerbations by functional respiratory imaging (FRI) in 3-dimensional models of airways and lungs. Methods: The trial was designed as a multicenter trial of patients with an acute exacerbation of COPD who were assessed by FRI, pulmonary function tests, and patient-reported outcomes, both in the acute stage and during resolution. Results: Forty seven patients were assessed. FRI analyses showed significant improvements in hyperinflation (a decrease in total volume at functional residual capacity of -0.25±0.61 L, p≤0.01), airway volume at total lung capacity (+1.70±4.65 L, p=0.02), and airway resistance. As expected, these improvements correlated partially with changes in the quality of life and in conventional lung function test parameters. Patients with the same changes in pulmonary function differ in regional disease activity measured by FRI. Conclusion: FRI is a useful tool to get a better insight into exacerbations of COPD, and significant improvements in its indices can be demonstrated from the acute phase to resolution even in relatively small groups. It clearly visualizes the marked variability within and between individuals in ventilation and resistance during exacerbations and is a tool for the assessment of the heterogeneity of COPD exacerbations. Keywords: COPD exacerbations, FRI, hyperinflation, chronic obstructive pulmonary disease, symptoms, heterogeneity

Bita Hajian,1 Jan De Backer,2 Wim Vos,2 Cedric Van Holsbeke,2 Francisca Ferreira,2 Deborah A Quinn,3 Annemie Hufkens,1 Rita Claes,1 Wilfried De Backer1 1Department of Respiratory Medicine, University Hospital Antwerp, Edegem, 2FluidDA nv, Antwerp, Belgium; 3Bellerophon Therapeutics, Warren, NJ, USA Introduction: Severe chronic obstructive pulmonary disease (COPD) is often associated with secondary pulmonary hypertension (PH), which worsens prognosis. PH can be lowered by oxygen, but also by inhaled nitric oxide (NO), which has the potential to improve the health status of these patients. NO is an important mediator in vascular reactions in the pulmonary circulation. Oral compounds can act through NO-mediated pathways, but delivering pulsed inhaled NO (iNO) directly to the airways and pulmonary vasculature could equally benefit patients. Therefore, a proof-of-concept study was performed to quantify pulmonary blood vessel caliber changes after iNO administration using computed tomography (CT)-based functional respiratory imaging (FRI). Methods: Six patients with secondary PH due to COPD received “pulsed” iNO in combination with oxygen for 20 minutes via a nasal cannula. Patients underwent a high-resolution CT scan with contrast before and after iNO. Using FRI, changes in volumes of blood vessels and associated lobes were quantified. Oxygen saturation and blood pressure were monitored and patients were asked about their subjective feelings. Results: Pulmonary blood vessel volume increased by 7.06%±5.37% after iNO. A strong correlation (Ω20=0.32, P=0.002) was obtained between ventilation and observed vasodilation, suggesting that using the pulsed system, iNO is directed toward the ventilated zones, which consequently experience more vasodilation. Patients did not develop oxygen desaturation, remained normotensive, and perceived an improvement in their dyspnea sensation. Conclusion: Inhalation of pulsed NO with oxygen causes vasodilation in the pulmonary circulation of COPD patients, mainly in the well-ventilated areas. A high degree of heterogeneity was found in the level of vasodilation. Patients tend to feel better after the treatment. Chronic use trials are warranted. Keywords: pulmonary hypertension, COPD, pulsed inhaled nitric oxide, FRI

Wim Vos,1 Bita Hajian,2 Jan De Backer,1 Cedric Van Holsbeke,1 Samir Vinchurkar,1 Rita Claes,2 Annemie Hufkens,2 Paul M Parizel,3 Lieven Bedert,4 Wilfried De Backer2 1FLUIDDA nv, Groeningenlei, Kontich, 2Department of Respiratory Medicine, 3Department of Radiology, University Hospital Antwerp, Wilrijkstraat, Edegem, 4Department of Respiratory Medicine, ZNA Middelheim Hospital, Antwerp, Belgium Background: Patients with COPD show a significant reduction of the lobar hyperinflation at the functional residual capacity level in the patients who improved >120 mL in forced expiratory volume in 1 second (FEV1) after 6 months of treatment with roflumilast in addition to inhaled corticosteroids (ICSs)/long-acting beta-2 agonists (LABAs)/long-acting muscarinic antagonists (LAMAs).Methods: Functional respiratory imaging was used to quantify lobar hyperinflation, blood vessel density, ventilation, aerosol deposition, and bronchodilation. To investigate the exact mode of action of roflumilast, correlations between lobar and global measures have been tested using a mixed-model approach with nested random factors and Pearson correlation, respectively.Results: The reduction in lobar hyperinflation appears to be associated with a larger blood vessel density in the respective lobes (t=−2.154, P=0.040); lobes with a higher percentage of blood vessels reduce more in hyperinflation in the responder group. Subsequently, it can be observed that lobes that reduce in hyperinflation after treatment are better ventilated (t=−5.368, P

Jan De Backer,1 Wim Vos,1 Cedric Van Holsbeke,1 Samir Vinchurkar,1 Rita Claes,2 Paul M Parizel,3 Wilfried De Backer2 1FluidDA nv, Kontich, Belgium; 2Department Respiratory Medicine, University Hospital, Antwerp, Belgium; 3Department Radiology, University Hospital, Antwerp, Belgium Background: Previous studies have demonstrated the potential beneficial effect of N-acetylcysteine (NAC) in chronic obstructive pulmonary disease (COPD). However, the required dose and responder phenotype remain unclear. The current study investigated the effect of high-dose NAC on airway geometry, inflammation, and oxidative stress in COPD patients. Novel functional respiratory imaging methods combining multislice computed tomography images and computer-based flow simulations were used with high sensitivity for detecting changes induced by the therapy. Methods: Twelve patients with Global Initiative for Chronic Obstructive Lung Disease stage II COPD were randomized to receive NAC 1800 mg or placebo daily for 3 months and were then crossed over to the alternative treatment for a further 3 months. Results: Significant correlations were found between image-based resistance values and glutathione levels after treatment with NAC (P = 0.011) and glutathione peroxidase at baseline (P = 0.036). Image-based resistance values appeared to be a good predictor for glutathione peroxidase levels after NAC (P = 0.02), changes in glutathione peroxidase levels (P = 0.035), and reduction in lobar functional residual capacity levels (P = 0.00084). In the limited set of responders to NAC therapy, the changes in airway resistance were in the same order as changes induced by budesonide/formoterol. Conclusion: A combination of glutathione, glutathione peroxidase, and imaging parameters could potentially be used to phenotype COPD patients who would benefit from addition of NAC to their current therapy. The findings of this small pilot study need to be confirmed in a larger pivotal trial. Keywords: functional respiratory imaging, computational fluid dynamics, computed tomography, chronic obstructive pulmonary disease, N-acetylcysteine

This article discusses a study that introduces a deep learning-based framework called ADNEX-AI for the automated detection of ovarian cancer using ultrasound scans. The study compares the performance of ADNEX-AI with traditional clinical practice in diagnosing ovarian cancer. The results show that ADNEX-AI achieves a high level of accuracy in distinguishing between benign and malignant ovarian tumors. However, the study suggests that the difference in performance between ADNEX-AI and traditional methods may be due to the clinician's ability to examine the tumor from different angles. Overall, ADNEX-AI demonstrates comparable performance to traditional methods when considering the constraints of tumor visibility. [Extracted from the article]