Effect of background long-acting beta₂-agonist therapy on the efficacy and safety of a novel, nebulized glycopyrrolate in subjects with moderate-to-very-severe COPD

Abstract

BackgroundPhase III studies demonstrated efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY) in subjects with COPD. Secondary analyses were performed to examine the effect of background long-acting beta2-agonist (LABA) use on the efficacy and safety of nebulized GLY.MethodsIn two 12-week placebo-controlled studies (GOLDEN 3 and GOLDEN 4) and one 48-week, open-label active-controlled study (GOLDEN 5), a total of 2,379 subjects were stratified by background LABA use (LABA-yes: n=861; LABA-no: n=1,518) and randomized to placebo vs GLY 25 or 50 µg twice daily, or GLY 50 µg twice daily vs tiotropium (TIO) 18 µg once daily. Lung function, patient-reported outcomes, exacerbations, and safety were assessed.ResultsCompared with placebo, pooled data from the 12-week studies showed significant improvements from baseline with GLY 25 and 50 µg across LABA subgroups in trough FEV1 (LABA-yes: 0.101 and 0.110 L; LABA-no: 0.092 and 0.101 L, respectively; P<0.001) and St George’s Respiratory Questionnaire total score (SGRQ; LABA-yes: −2.957 and −3.888; LABA-no: −3.301 and −2.073, respectively; P<0.05). Incidence of treatment-emergent adverse events (TEAEs) was similar in LABA subgroups, and lower in GLY 25 µg vs placebo. In the 48-week active-controlled study, GLY and TIO both showed improvement from baseline across LABA subgroups in FEV1 (LABA-yes: 0.106 and 0.092 L; LABA-no: 0.096 and 0.096 L, respectively) and in SGRQ total score (LABA-yes: −5.190 and −3.094; LABA-no: −4.368 and −4.821, respectively). Incidence of TEAEs was similar between GLY and TIO, and across LABA subgroups. Exacerbation rates were similar across treatments and LABA subgroups, and cardiovascular events of special interest were more frequent in the LABA-no subgroup. Nebulized GLY, combined with LABA, did not generate any additional safety signals.ConclusionNebulized GLY demonstrated efficacy and was well tolerated up to 48 weeks in subjects with COPD with/without background LABA.

Improvement in Lung Function and Patient-Reported Outcomes in Patients with COPD with Comorbid Anxiety and Depression Receiving Nebulized Glycopyrrolate in the GOLDEN 3 and 4 Studies

“…5,10,25,26 A high prevalence of A/D among females and younger patients was noted in the GOLDEN 3 and 4 studies (Table 2); while these differences in baseline demographics and disease characteristics, such as background LABA use, may have contributed to the observed differences in lung function improvements between patients in the A/D (+) and A/D (-) groups, previous analyses of the results from GOLDEN 3 and 4 showed no differences in lung function improvements by gender, age, and background LABA use. [27][28][29] The higher proportion of current smokers among patients with comorbid A/D and COPD is also consistent with the literature, 5 and may be in part due to the greater difficulty of smoking cessation among patients with depression. 30 The differences in lung function improvements between patients in the A/D (+) and A/D (-) groups may have been impacted by smoking status in these patients; while there are no studies on the impact of smoking status on efficacy of treatment with nebulized GLY, a previous analysis of GLY inhalation powder delivered using a dry powder inhaler showed similar improvements among smokers and nonsmokers.…”

An overview of glycopyrrolate/eFlow® CS in COPD

“…Exacerbation rates were comparable between GLY and placebo and between GLY and TIO, respectively, albeit exacerbation rates were lower among subjects not receiving background LABA, consistent with that group having less severe disease. Incidence of AEs leading to discontinuation was similar regardless of background LABA use [51].…”

“…These results highlight the benefits from triple therapy and the important role this treatment regimen may play in patients with severe COPD. It is interesting to note that the GOLDEN phase III studies of nebulized GLY included patients receiving background LABA/ICS, making it an open triple therapy in a subset of the population [40,42,51]. Improvements in trough FEV 1 and SGRQ total scores in patients receiving this open triple therapy were similar to those in patients not receiving background LABA/ICS [51].…”

“…The impact of background LABA use on the efficacy and safety of nebulized GLY was also evaluated [51]. The design of the three phase III studies allowed for~30-40% of subjects to continue background LABA, and the majority of those were also receiving background ICS, making them more representative of the general COPD population, and indicative of more severe disease [40,42].…”

“…This would allow combinations consistent with GOLD recommendations for patients with exacerbations or more advanced symptoms to be administered using a single nebulizer. The eFlow CS nebulizer has already shown efficacy and ease of use among patients with more severe disease and/or who may be prone to exacerbations [49,51,52].…”