Budesonide Glycopyrronium Formoterol Improved Lung Function in Phase 3 Asthma Trials

Key Takeaways

• Multiplicity-adjusted primary lung-function endpoints were met in both studies, and lung function favored budesonide-glycopyrronium-formoterol 320/28.8/10 mcg across comparisons.
• Pooled severe exacerbation rates were lower versus the combined budesonide-formoterol comparators and versus BFFS, while the BFFA comparison was not statistically significant.
• Adverse-event frequencies were reported across treatment groups, and no deaths were considered treatment related.

In the KALOS and LOGOS phase 3 trials, budesonide-glycopyrronium-formoterol 320/28.8/10 mcg was associated with a 76 mL advantage in morning pre-dose trough FEV1 over 24 weeks versus the combined budesonide-formoterol comparators. The studies enrolled adolescents and adults with asthma that remained inadequately controlled despite daily medium-dose or high-dose ICS-LABA use and compared triple therapy with budesonide-formoterol regimens. Pooled analyses also showed lower severe exacerbation rates with the higher-dose triple regimen than with the combined budesonide-formoterol comparators.

KALOS and LOGOS were multicentre, randomized, double-blind, double-dummy phase 3 studies in patients aged 12-80 years whose asthma remained inadequately controlled despite daily medium-dose or high-dose ICS-LABA use. Participants were assigned 1:1:1:1 to budesonide-glycopyrronium-formoterol 320/28.8/10 mcg, BGF 320/14.4/10 mcg, BFFA 320/10 mcg (budesonide-formoterol fumarate dihydrate using Aerosphere co-suspension delivery technology), or BFFS 320/9 mcg (the current suspension formulation [Symbicort]). Treatment was delivered twice daily by pressurised metered-dose inhaler for 24-52 weeks. A total of 8820 participants were recruited, and 4311 received treatment. Of those treated, 1179 received BGF 28.8 mcg, 726 received BGF 14.4 mcg, 1210 received BFFA, and 1196 received BFFS. The primary lung-function endpoints were change from baseline in FEV1 AUC0-3 and morning pre-dose trough FEV1, and the primary pooled analysis across both studies was annualized severe exacerbations.

In each study, all prespecified multiplicity-adjusted primary endpoints for regulatory comparisons were met. Against the combined budesonide-formoterol comparators, BGF 28.8 mcg produced a 76 mL least-squares mean advantage in trough FEV1 over 24 weeks. The corresponding 95% CI was 57-94, with p<0.0001. For FEV1 AUC0-3, the least-squares mean difference was 90 mL, with a 95% CI of 72-108 and p<0.0001. BGF 28.8 mcg also favored trough FEV1 and FEV1 AUC0-3 across all comparisons in both trials.

In pooled analyses, annualized severe exacerbation rates were lower with BGF 28.8 mcg than with the combined budesonide-formoterol comparators, with an incidence rate ratio of 0.86. The 95% CI was 0.76-0.97, with p=0.012, and the rate ratio versus BFFS was 0.82 with a 95% CI of 0.71-0.94 and p=0.0043. The BFFA comparison was not statistically significant, with an incidence rate ratio of 0.90, a 95% CI of 0.78-1.03, and p=0.12. Adverse events occurred in 53.2% with BGF 28.8 mcg, 60.0% with BGF 14.4 mcg, 55.2% with BFFA, and 58.4% with BFFS. No deaths were treatment related. The authors interpreted the findings as showing improved lung function and lower severe exacerbation rates in a broad population, regardless of recent exacerbation history.