Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis

James F Donohue, Edward Kerwin, Chris N Barnes, Edmund J Moran, Brett Haumann, Glenn D Crater, James F Donohue, Edward Kerwin, Chris N Barnes, Edmund J Moran, Brett Haumann, Glenn D Crater

Abstract

Background: Revefenacin, a once-daily, long-acting muscarinic antagonist delivered via standard jet nebulizer, increased trough forced expiratory volume in 1 s (FEV1) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in prior phase 3 trials. We evaluated the efficacy of revefenacin in patients with markers of more severe COPD.

Methods: A post hoc subgroup analysis of two replicate, randomized, phase 3 trials was conducted over 12 weeks. Endpoints included least squares change from baseline in trough FEV1, St. George's Respiratory Questionnaire (SGRQ) responders, and transition dyspnea index (TDI) responders at Day 85. This analysis included patient subgroups at high risk for COPD exacerbations and compared patients who received revefenacin 175 μg and placebo: severe and very severe airflow limitation (percent predicted FEV1 30%-< 50% and < 30%), 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) D, reversibility (≥ 12% and ≥ 200 mL increase in FEV1) to short-acting bronchodilators, concurrent use of long-acting β agonists and/or inhaled corticosteroids, older age (> 65 and > 75 years), and comorbidity risk factors.

Results: Revefenacin demonstrated significant improvements in FEV1 versus placebo at Day 85 among the intention-to-treat (ITT) population and all subgroups. Additionally, there was a greater number of SGRQ and TDI responders in the ITT population and the majority of subgroups analyzed among patients who received revefenacin versus placebo. For the SGRQ responders, the odds of response (odds ratio > 2.0) were significantly greater in the revefenacin arm versus the placebo arm among the severe airflow obstruction, very severe airflow obstruction and 2011 GOLD D subgroups. For the TDI responders, the odds of response (odds ratio > 2.0) were significantly greater among the severe airflow obstruction subgroup and patients aged > 75 years.

Conclusions: Revefenacin showed significantly greater improvements in FEV1 versus placebo in the ITT population and all subgroups. Furthermore, there were a greater number of SGRQ and TDI responders in the ITT population, and in the majority of patient subgroups among patients who received revefenacin versus placebo. Based on the data presented, revefenacin could be a therapeutic option among patients with markers of more severe COPD.

Trial registration: Clinical trials registered with www.clinicaltrials.gov (Studies 0126 [NCT02459080; prospectively registered 22 May 2015] and 0127 [NCT02512510; prospectively registered 28 July 2015]).

Keywords: COPD; Efficacy; Long-acting muscarinic antagonist; Nebulized therapy; Revefenacin.

Conflict of interest statement

JFD is a consultant and advisory committee member for Mylan Inc. and Sunovion Pharmaceuticals.

EK has participated in consulting, advisory boards, speaker panels, or received travel reimbursement for Amphastar, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mylan, Novartis, Oriel, Pearl, Sunovion, Teva and Theravance Biopharma US, Inc. He has conducted multicenter clinical research trials for approximately 40 pharmaceutical companies.

CNB was an employee of Theravance Biopharma US, Inc. at the time this study was conducted.

EJM, BH, and GDC are current employees of Theravance Biopharma US, Inc.

Figures

Fig. 1
Fig. 1
Day 85 trough FEV1 by patient subgroup. The LS mean difference for revefenacin versus placebo was statistically significant (p < 0.05) for all subgroups. CI confidence intervals; CV cardiovascular; FEV1 forced expiratory volume in 1 s; GOLD Global Initiative for Chronic Obstructive Lung Disease; LABA long-acting ß agonist; ICS inhaled corticosteroids; ITT intention-to-treat
Fig. 2
Fig. 2
Day 85 SGRQ responders by patient subgroup. The odds ratios for revefenacin versus placebo was statistically significant (p < 0.05) for the following subgroups: ITT, FEV1 30%–< 50% predicted and, 2011 GOLD category D. The subgroup, FEV1 < 30% predicted, has been excluded from the forest plot due to being out with the range of the x-axis scale. CI confidence intervals; CV cardiovascular; FEV1 forced expiratory volume in 1 s; GOLD Global Initiative for Chronic Obstructive Lung Disease; LABA long-acting ß agonist; ICS inhaled corticosteroids; ITT intention-to-treat; SGRQ St. George’s Respiratory Questionnaire
Fig. 3
Fig. 3
Day 85 TDI responders by patient subgroup. The odds ratios for revefenacin versus placebo was statistically significant (p < 0.05) for the following subgroups: FEV1 30%–< 50% predicted, and > 75 years. CI confidence intervals; CV cardiovascular; FEV1 forced expiratory volume in 1 s; GOLD Global Initiative for Chronic Obstructive Lung Disease; LABA long-acting ß agonist; ICS inhaled corticosteroids; ITT intention-to-treat; TDI transition dyspnea index

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