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Kai Michael Beeh,1 Anne-Marie Kirsten,2 Ana-Maria Tanase,3 Alexia Richard,3 Weihua Cao,4 Bettina Hederer,3 Jutta Beier,1 Oliver Kornmann,5 Richard N van Zyl-Smit6 1Insaf Respiratory Research Institute Wiesbaden, Wiesbaden, Germany; 2Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 5IKF Pneumologie, Clinical Research Centre Respiratory Diseases, Frankfurt, Germany; 6Division of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africa Background and purpose: Fixed-dose combinations of a long-acting beta agonist and an inhaled corticosteroid are more effective than the individual components in COPD. The primary study objective was to demonstrate that the combination indacaterol acetate/mometasone furoate (IND/MF [QMF149]) was non-inferior to the twice-daily combination salmeterol xinafoate/fluticasone propionate (Sal/Flu) in terms of trough FEV1 at week 12 (day 85). Secondary objectives were to compare the efficacy of IND/MF (QMF149) vs Sal/Flu with respect to other lung function parameters, COPD exacerbations, symptoms and dyspnea, health status/health-related quality of life, and rescue medication use.Materials and methods: This was a 12-week multicenter, randomized, double-blind, double-dummy, parallel-group, Phase II study in patients with moderate-to-very-severe COPD, who were randomized (1:1) to IND/MF (QMF149) (150/160 µg once daily; n=316) or Sal/Flu (50/500 µg twice daily; n=313).Results: Over 90% of patients completed the study: 94.6% in the IND/MF (QMF149) group and 92.0% in the Sal/Flu group. The primary objective of non-inferiority of IND/MF (QMF149) to Sal/Flu for trough FEV1 at week 12 (day 85) was met: the lower limit of the CI (95% CI: 27.7, 83.3 mL) was greater than -60 mL. The analysis for superiority of IND/MF (QMF149) to Sal/Flu demonstrated superiority of IND/MF (QMF149), with a difference of 56 mL (P

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, respiratory symptoms, inflammation of the airways, and systemic manifestations of the disease. Genetic susceptibility and environmental factors are important in the development of the disease, particularly exposure to cigarette smoke which is the most notable risk factor. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are the cause of cystic fibrosis (CF), which shares several pathophysiological pulmonary features with COPD, including airway obstruction, chronic airway inflammation and bacterial colonization; in addition, both diseases also present systemic defects leading to comorbidities such as pancreatic, gastrointestinal, and bone-related diseases. In patients with COPD, systemic CFTR dysfunction can be acquired by cigarette smoking, inflammation, and infection. This dysfunction is, on average, about half of that found in CF. Herein we review the literature focusing on acquired CFTR dysfunction and the potential role in the pathogenesis of comorbidities associated with COPD and chronic bronchitis., Competing Interests: Declaration of competing interest In the past 36 months, M. Miravitlles has received consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, CSL Behring, Inhibrx, Mereo Biopharma, Verona Pharma, Spin Therapeutics, ONO Pharma, Palobiofarma SL, Takeda, Novartis, Novo Nordisk, Sanofi and Grifols, speaker fees from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Chiesi, Cipla, Janssen, Kamada, Menarini, Takeda, Speciality Therapeutics, Zambon, CSL Behring, Grifols and Novartis, support for attending meetings/travel from Novartis, Boehringer Ingelheim and Menarini, research grants from Grifols, and has participated on a data safety monitoring board for Mereo. G.J. Criner has no declarations. M.A. Mall declares editorial support from Novartis Pharma AG since the initial planning of the work, and declares grants from German Ministry for Education and Research and the German Research Foundation, consulting fees from Abbvie, Antabio, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Pieris Pharmaceuticals, Santhera, Sterna Biologicals and Vertex Paharmaceuticals, lecture fees from Arrowhead Pharmaceuticals, Boehringer Ingelheim and Vertex Pharmaceuticals, travel reimbursement from Boehringer Ingelheim and Vertex Pharmaceuticals, and personal fees for participation on advisory boards from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Enterprise Therapeutics, Antabio, Kither Biotech, Pari and Abbvie; an elected unpaid member of the ECFS board. S.M. Rowe declares grant support for clinical trials conducted through university grants/contracts from Novartis, TranslateBio, Galapagos/Abbvie, Vertex Pharmaceuticals, research grant through University grants/contracts from Synedgen/Synspira, Eloxx, Ionis and AstraZeneca, consulting fees services on the design and conduct of clinical trials from Arcturus, Cystetic Medicines, Galapagos/Abbvie, Ionis, Novartis, Renovion, Synedgen/Synspira, Vertex Pharmaceuticals, support for travel to attend meetings from Vertex Pharmaceuticals; co-chair of the Next Generation Steering Committee with Vertex Pharmaceuticals, research product for investigator initiated research provided from Synedgen/Synspira and Renovion, consulting services on the design and conduct of clinical trials including stock options for Synedgen/Synspira and Renovion within the past 36 months; MTAs for investigator-initiated and externally funded research efforts from Ionis, Galapagos/Abbvie and Synedgen/Synspira, all in the past 36 months; and declares six patents. C.F. Vogelmeier declares institution grants from German Ministry of Education and Science (BMBF), AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GlaxoSmithKline, Grifols and Novartis, consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Insmed, Menarini, Novartis and Nuvaira, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Insmed, Menarini and Novartis, in the past 36 months. B. Hederer was an employee of Novartis Pharma AG at the timing of writing this manuscript. M. Schoenberger is a full-time employee of Novartis Pharma AG and retains Novartis stock. P. Altman was an employee of Novartis Pharmaceutical Corporation at time of writing this manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: QMF149 is an inhaled fixed-dose combination of indacaterol acetate and mometasone furoate (MF) delivered via Breezhaler®, under development for once-daily treatment of asthma. MF delivered via Twisthaler® is approved as Asmanex® Twisthaler® for the treatment of asthma. Bridging of MF delivered via Twisthaler® to MF delivered via Breezhaler® was undertaken as part of QMF149 development to enable dose comparisons between the devices. Pharmacokinetics (PK) of MF were characterized in two studies; a single dose PK study in healthy volunteers and a pharmacokinetic/pharmacodynamic (PK/PD) study in asthma patients., Objectives: The PK study in healthy volunteers evaluated the PK of single doses of MF via Breezhaler® (50-400 μg) and compared systemic exposure of MF following administration via Breezhaler® and Twisthaler® 400 μg (2 inhalations of 200 μg). The study in patients with asthma characterized the MF PK profile following once-daily inhalation of MF via Breezhaler® and Twisthaler® devices for 4 weeks., Methods: In the open-label, single-dose, crossover study, healthy subjects sequentially received MF via Twisthaler® (400 μg, medium-dose inhaled corticosteroid [ICS]) and escalating doses via Breezhaler® (50, 100, 200, 400 μg). PK data were obtained up to 72 h post-dose. In the double-blind, double-dummy, parallel-group study, asthma patients were randomised to receive either MF 80 μg (low-dose ICS) or 320 μg (high-dose ICS) via Breezhaler®, or 200 μg (low-dose ICS) or 800 μg (2 inhalations of 400 μg; high-dose ICS) via Twisthaler® once daily for 4 weeks. PK sampling was performed on Days 1 and 28 at pre-dose and up to 24 h post-dose., Results: In the healthy volunteer PK study, 20 healthy subjects completed all treatments. Dose-normalised AUC last of MF was 1.8-1.9-fold higher when delivered via Breezhaler® versus Twisthaler®. AUC and C max of MF increased in a dose-proportional manner over the range of 50-400 μg via Breezhaler®. Results from this study guided dose selection of MF via Breezhaler® for the asthma study. In the asthma study, in a subset of 96 patients, mean systemic exposure (AUC last and C max ) for MF 80 and 320 μg via Breezhaler® was comparable with MF 200 and 800 μg via Twisthaler®, respectively, on Day 28., Conclusion: PK characterization in a healthy volunteer PK study and subsequently an asthma study enabled selection of 80 μg (low), 160 μg (medium), and 320 μg (high) delivered via Breezhaler® as MF doses comparable to the 200 μg, 400 μg and 800 μg doses delivered by Twisthaler®, respectively, as part of QMF149 formulation development., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Mometasone furoate (MF) is the inhaled corticosteroid (ICS) component in the long-acting β 2 -agonist (LABA)/ICS fixed-dose combination of indacaterol/MF, delivered via Breezhaler®, in development for asthma. MF at low (80 μg) and high (320 μg) doses delivered via Breezhaler® is expected to be comparable to MF at low (200 μg) and high (800 μg) doses respectively, delivered via Twisthaler®., Methods: This was a randomized, double-blind, double-dummy, four-week, parallel-group study of 739 adolescents and adults with persistent asthma. Eligible patients were receiving ICS treatment up to the maximum dose per day on a stable regimen for at least four weeks before screening. The study population was enriched for patients who were responsive to ICS therapy. The primary objective of the present study was to show non-inferiority of these doses, i.e. the low (80 μg) and high (320 μg) doses of MF delivered via Breezhaler® once daily, compared with the corresponding low (200 μg) and high (800 μg) doses of MF delivered via Twisthaler® once daily. The primary endpoint was 24 h post-dose trough forced expiratory volume in 1 s (FEV 1 ), after four weeks of treatment in patients with asthma. A secondary objective was to evaluate the efficacy of MF 80 μg and 320 μg delivered via Breezhaler®, and MF 200 μg and 800 μg delivered via Twisthaler® in terms of Asthma Control Questionnaire-5 (ACQ-5) after one, two, three and four weeks of treatment., Results: The LS mean difference in trough FEV 1 after four weeks of treatment between MF low dose 80 μg (Breezhaler®) and MF low dose 200 μg (Twisthaler®) was 27 mL (95% CI -34, 89); for MF high dose 320 μg (Breezhaler®) and MF high dose 800 μg (Twisthaler®) the difference was 0 mL (95% CI -60, 61). These differences were neither clinically nor statistically significant. All treatment arms provided similar clinically relevant improvements in ACQ-5 after four weeks of treatment compared with baseline. Both treatments showed a similar safety profile with a low incidence of adverse events., Conclusion: The similarities in effects on lung function and ACQ after four weeks of treatment demonstrate the comparability of MF at low (80 μg) and high (320 μg) doses delivered with Breezhaler® with MF at low (200 μg) and high (800 μg) doses delivered with Twisthaler®, respectively. The study formally demonstrated that MF, delivered via Breezhaler®, is non-inferior to MF, delivered via Twisthaler® at corresponding ICS doses., Competing Interests: Declarations of competing interest RB reports grants to Mainz University and personal fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche, as well as personal fees from AstraZeneca, Chiesi, Cipla, Sanofi and Teva, all outside the submitted work. AMT, MH, ID, FP, BH and HCT are employees of Novartis Pharma AG and own Novartis Pharma AG shares. WC is an employee of Novartis Pharmaceuticals Corporation. CB and JJ are employees of Novartis Pharma AG. DZ is an employee of Novartis Pharma AG and owns Novartis Pharma AG shares. DZ has led the development of Breezhaler® dry powder inhaler and was the technical project leader for the development of the Breezhaler® mometasone drug product. FK reports personal grants or fees for scientific work, presentations and Advisory boards in the last 5 years from Mundipharma, Astra Zeneca, Novartis and TEVA. However, all of these are outside the submitted work., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Currently available long-acting inhaled bronchodilators (tiotropium, salmeterol, formoterol) have demonstrated beneficial effects on exacerbations in placebo-controlled trials. However, there have been no direct comparisons of these drugs with exacerbations as the primary outcome and consequently COPD treatment guidelines do not indicate a preference for either bronchodilator. Therefore, an international, randomized, double-blind, double-dummy, parallel-group clinical trial has been designed to investigate the comparative efficacy of 2 long-acting bronchodilators tiotropium 18 microg daily and salmeterol 50 microg bid on exacerbations. The trial will include at least 6800 randomized patients with diagnosis of COPD, >or= 10 pack-year history of smoking, post-bronchodilator FEV(1)

Aerosols delivered by Respimat Soft Mist Inhaler (SMI) are slower-moving and longer-lasting than those from pressurized metered-dose inhalers (pMDIs), improving the efficiency of pulmonary drug delivery to patients. In this four-way cross-over study, adults with chronic obstructive pulmonary disease (COPD) and with poor pMDI technique received radiolabelled Berodual (fenoterol hydrobromide 50 microg/ipratropium bromide 20 microg) via Respimat SMI or hydrofluoroalkane (HFA)-MDI (randomized order) on test days 1 and 2, with no inhaler technique training. The procedure was repeated on test days 3 and 4 after training. Deposition was measured by gamma scintigraphy. All 13 patients entered (9 males, mean age 62 years; FEV1 46% of predicted) inhaled too fast at screening (peak inspiratory flow rate [IF]: 69-161 L/min). Whole lung deposition was higher with Respimat SMI than with pMDI for untrained (37% of delivered dose vs 21% of metered dose) and trained patients (53% of delivered vs 21% of metered dose) (P(Sign-Test) = 0.15; P(ANOVA) < 0.05). Training also improved inhalation profiles (slower average and peak IF as well as longer breath-hold time). Drug delivery to the lungs with Respimat SMI is more efficient than with pMDI, even with poor inhaler technique. Teaching patients to hold their breath as well as to inhale slowly and deeply increased further lung deposition using Respimat SMI.