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INTRODUCTION: GINA guidelines recommend increasing the dose of inhaled corticosteroids (ICS) as a step-up option for patients with inadequately controlled asthma at GINA step 4 [inadequately controlled asthma on medium-dose ICS/long-acting beta-2 agonist (LABA)]. The aim of this study was to compare the efficacy and safety of long-acting muscarinic antagonists (LAMA) add-on to medium-dose ICS/LABA in patients at GINA 2022 step 4. METHODS: This post hoc analysis of the IRIDIUM study evaluated the change from baseline in trough forced expiratory volume (FEV1 ) in patients receiving medium-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL at Week 26. Other outcomes included improvement in lung functions [peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow between 25% and 75% of the FVC (FEF)25-75%)], asthma control [Asthma Control Questionnaire (ACQ-7)], responder analysis (≥ 0.5 unit improvement in ACQ-7), and reduction in asthma exacerbations at Weeks 26 and 52. RESULTS: A total of 1930 patients were included in this analysis. Medium-dose MF/IND/GLY improved trough FEV1 versus high-dose MF/IND (Δ 41 mL; 95% CI - 7-90) and high-dose FLU/SAL (Δ 88 mL; 95% CI 39-137) at Week 26 which were sustained until Week 52. Exacerbation rates were 16% lower with medium-dose MF/IND/GLY versus high-dose MF/IND for all (mild, moderate, and severe) exacerbations and 21-30% lower versus high-dose FLU/SAL for all (mild, moderate, and severe), moderate or severe, and severe exacerbations over 52 weeks. Further improvements in other lung functions were observed with medium-dose MF/IND/GLY. No new safety signals were identified. CONCLUSION: Medium-dose MF/IND/GLY improved lung function and reduced asthma exacerbations compared to high-dose ICS/LABA and may be an undervalued option in patients at GINA 2022 step 4. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02571777.
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A novel, once-daily (o.d.), fixed-dose combination (FDC) of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF), delivered by the inhaler Breezhaler® device, is the first long-acting beta2-adrenergic agonist/long-acting muscarinic antagonist/inhaled corticosteroid (LABA/LAMA/ICS) therapy to be approved for maintenance treatment of asthma in adults inadequately controlled on LABA/ICS. The approval of IND/GLY/MF in the European Union (EU) also included an optional electronic sensor and smartphone (or other suitable device) application, making it the first "digital companion" that can be prescribed with an asthma medication. As a result, the European Medicines Agency included this approval as one of the "outstanding contributions to public health" (for Pneumology/Allergology) in their 2020 highlights report. Alongside IND/GLY/MF, an o.d. LABA/ICS FDC, IND/MF, was also developed and approved. This review outlines the unique strategy used in the accelerated development of IND/GLY/MF that combined various approaches: (1) selecting individual components with established efficacy/safety, (2) bridging doses to optimize efficacy/safety of IND/GLY/MF and IND/MF delivered via the Breezhaler® device, (3) developing IND/GLY/MF and IND/MF in parallel, and (4) submission for regulatory approval before formal completion of the pivotal phase III studies. IND/GLY/MF and IND/MF were combined in a single-development plan (PLATINUM program), which comprised four phase III studies: QUARTZ and PALLADIUM evaluated IND/MF while IRIDIUM and ARGON evaluated IND/GLY/MF. A unique feature was the inclusion of two LABA/ICS comparators in the pivotal IRIDIUM study-IND/MF as an internal comparator, and high-dose salmeterol xinafoate/fluticasone propionate (SAL/FLU) as a marketed comparator. In the ARGON study, IND/GLY/MF was compared against o.d. tiotropium (via Respimat®) plus twice-daily (b.i.d.) high-dose SAL/FLU (via Diskus®). As a result of this development strategy, the development and approval of IND/GLY/MF was accelerated by ca. 4 years as against what would be expected from a traditional approach, novel data were generated, and a unique optional digital companion was approved in the EU. A Video Abstract by Dr Dominic Brittain, Global Drug Development, Novartis. (MP4 228293 kb).