BACKGROUND: Long-acting muscarinic antagonists (LAMA) can be added to inhaled corticosteroid- (ICS)-long-acting ß2-agonist (LABA) therapy for inadequately controlled asthma. We aimed to evaluate the efficacy and safety of budesonide-glycopyrronium-formoterol fumarate dihydrate (BGF) versus budesonide-formoterol fumarate dihydrate using Aerosphere co-suspension delivery technology (BFFA) and the current suspension formulation (Symbicort, BFFS).
METHODS: Two multicentre, randomised, double-blind, double-dummy, phase 3 studies (KALOS and LOGOS) recruited participants aged 12-80 years with inadequately-controlled asthma despite daily medium-dose or high-dose ICS-LABA use from across 378 sites in 20 countries (KALOS), and 324 sites in 15 countries (LOGOS). Participants were randomly assigned (1:1:1:1) to BGF 320 µg, 28·8 µg, 10 µg (BGF 28·8); BGF 320 µg, 14·4 µg, 10 µg (BGF 14·4); BFFA 320 µg, 10 µg; or BFFS 320 µg, 9 µg, twice a day via pressurised metered-dose inhaler for 24-52 weeks. Primary lung function endpoints were change from baseline in FEV1 area under the curve from 0 h to 3 h (AUC0-3) and in morning pre-dose trough FEV1 from day 1 to week 24 (over 24 weeks; depending on regional health authority guidance). The primary pooled analysis across both studies was annualised severe exacerbations. The efficacy analysis set and safety set included all randomly assigned participants receiving any amount of study treatment but were analysed according to randomly assigned treatment and received treatment, respectively. The KALOS and LOGOS studies are registered with ClinicalTrials.gov (NCT04609878 and NCT04609904, respectively) and are complete.
FINDINGS: Between Dec 15, 2020, and March 21, 2025 (KALOS), and between March 1, 2021, and March 20, 2025 (LOGOS), 8820 participants were recruited and 4311 received treatment (1179 received BGF 28·8, 726 received BGF 14·4, 1210 received BFFA, and 1196 received BFFS). In each study, the pre-specified multiplicity-adjusted primary endpoints for all regulatory comparisons were met. Least squares mean differences favoured BGF 28·8 for change from baseline in trough FEV1 and FEV1 AUC0-3 across all comparisons (all p<0·05). Least squares mean differences in change from baseline in morning pre-dose trough FEV1 and in FEV1 AUC0-3 over 24 weeks for BGF 28·8 versus BFFcombined were 76 mL (95% CI 57-94; p<0·0001) and 90 mL (72-108; p<0·0001), respectively. BGF 28·8 reduced severe exacerbation rates versus BFFcombined (incidence rate ratio 0·86, 95% CI 0·76-0·97; p=0·012) and versus BFFS (0·82, 0·71-0·94; p=0·0043). Exacerbation rate ratio for BGF 28·8 versus BFFA was 0·90 (95% CI 0·78-1·03; p=0·12). 627 (53·2%) adverse events were observed with BGF 28·8, 436 (60·0%) with BGF 14·4, 666 (55·2%) with BFFA, and 698 (58·4%) with BFFS. No deaths were treatment related.
INTERPRETATION: These findings show that BGF improves lung function and reduces severe exacerbation rates in a broad population with asthma inadequately controlled despite medium-dose or high-dose ICS-LABA use. Given that these findings were observed regardless of recent exacerbation history, BGF could benefit individuals with inadequately controlled asthma without requiring a recent episode of acute deterioration on ICS-LABA before escalation.
FUNDING: AstraZeneca.
| Discipline Area | Score |
|---|---|
| Family Medicine (FM)/General Practice (GP) |  |
| General Internal Medicine-Primary Care(US) | |
| Respirology/Pulmonology | |
| Pediatrics (General) | |
| Allergy and Immunology | Coming Soon... |
This builds on the literature regarding the addition of a LAMA to patients not well controlled on ICS/LABA. This is an important addition to the literature as several studies have also demonstrated that when in poor control with exacerbation, the addition of higher dose ICS was not helpful (Tran et al. JACI IP 2026) and higher-dose ICS has been shown to have increase in side effects (Chen et al. JACI IP 20-25).
Although this work nicely demonstrates that BGF at the tested dose reduces severe exacerbations in asthma not controlled on ICS-LABA alone, I am not sure that the information will change practice noticeably. Adding a LAMA to obtain better control of asthma for individuals on ICS-LABA is already a common practice.
This pair of RCTs finds that in patients with asthma who are suboptimally controlled on ICS/LABA, triple therapy (budesonide/glycopyrrhonium/formoterol) significantly reduced exacerbations and produced a clinically meaningful increase in FEV1 compared with ICS/LABA (budesonide/formoterol). This has already been shown with different drugs within the same class, but this is the first study with this specific triple therapy combination to validate these benefits.