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

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]).


Background
Inhaled drug delivery is the foundation of chronic obstructive pulmonary disease (COPD) pharmacological treatment [1]. The most common devices used to administer aerosolized medication in day-today respiratory practice are the pressurized metereddose inhaler (MDIs) and dry powder inhaler (DPIs) [2]. The ability to use these inhalers adequately may become problematic among patients with COPD whose disease and symptoms become more severe. For pressurized MDIs, patients need to inhale correctly and coordinate breathing and actuation to ensure effective drug delivery. For DPIs, patients may struggle to generate sufficient inspiratory capacity to overcome the internal resistance of the device to deaggregate the powdered drug into fine particles small enough for lung deposition [2,3].
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report recognize that markers (eg, symptoms and exacerbations), other than lung function impairment are associated with more severe disease [1]. Nebulized therapy may be an option in patients with more severe markers of COPD. Nebulized bronchodilators are recommended for patients with COPD who have very low inspiratory flow rates, physical, or mental impairments that preclude the use of inhalers, including elderly patients and patients with severe disease. They are also available to patients with COPD who prefer nebulized therapies [2,4,5].
Revefenacin inhalation solution is a once-daily long-acting muscarinic antagonist delivered by a standard jet nebulizer that is approved by the US Food and Drug Administration (FDA) for the maintenance treatment of patients with COPD [6]. The efficacy of revefenacin has been demonstrated in previous randomized, controlled, phase 3 trials in broad populations of patients with moderate to very severe COPD with or without concurrent long-acting ß agonist (LABA). Revefenacin significantly improved lung function (trough forced expiratory volume in 1 s [FEV 1 ] and overall treatment effect FEV 1 ) compared with placebo in two replicate 12-week studies [7]. Revefenacin treatment was shown to improve FEV 1 and respiratory health outcomes in a 52-week study with results similar to tiotropium via HandiHaler® [8]. Revefenacin was well tolerated for 52 weeks and has a safety profile that supports its long-term use in patients with COPD [9]. In addition, revefenacin was not associated with adverse cardiovascular events [10,11]. Therefore, it may provide a beneficial treatment option for patients with cardiovascular disease, one of the most common comorbidities among patients with COPD [12].
Identifying patient subgroups who are most likely to benefit from nebulized long-acting muscarinic antagonist (LAMA) treatment can help clinicians direct therapy to patients at high risk for COPD exacerbations. Here, in this post hoc subgroup analysis, we evaluated the efficacy, and health outcomes of revefenacin 175 μg versus placebo, in patients with markers of more severe COPD who participated in the replicate, placebo-controlled, 12-week phase 3 trials (0126 and 0127). Some of the methods and results of this analysis were previously reported in the form of an abstract [13].

Study design and conduct
Studies 0126 (NCT02459080) and 0127 (NCT02512510) were replicate, 12-week, randomized, double-blind, placebo-controlled, multiple-dose, parallel-group, phase 3 trials, and the design and conduct were described previously [7]. The studies were approved conducted according to the principles of the International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guideline for good clinical practice [14], and the code of ethics of the World Medical Association's Declaration of Helsinki [15]; written informed consent was obtained from all patients. The protocol was reviewed and approved by an institutional review board (Quorum Review IRB, Seattle, Washington).

Patients
Inclusion and exclusion criteria have been described previously [7]. Briefly, patients aged ≥ 40 years with moderate to very severe COPD, a smoking history ≥ 10 pack-years, post-ipratropium FEV 1 /forced vital capacity ratio < 0.7, and post-ipratropium FEV 1 < 80% of predicted normal and > 700 mL at screening were enrolled. Concomitant LABAs (with or without inhaled corticosteroids [ICS]) was permitted in up to 40% of the study population to ensure robust assessments of concurrent therapies used by patients. Once the 40% cap was reached, new patients who entered screening required a 14-day washout of any LABA-containing therapy before the ipratropium reversibility test at screening. Patients taking ICS/LABA at enrollment were switched to receive ICS monotherapy at an equivalent dose for at least 14 days, before the ipratropium reversibility visit at screening. Stable doses of ICS without concomitant LABAs were permitted, but LAMAs and short-acting muscarinic antagonists were prohibited.

Analysis population and endpoints
Endpoints of this study included the least squares (LS) change from baseline in trough FEV 1 at Day 85, St. George's Respiratory Questionnaire (SGRQ) responders, and transition dyspnea index (TDI) responders at Day 85. This analysis included the intention-to-treat (ITT) population and subgroups of patients at high risk for COPD exacerbations, and compared patients who received revefenacin 175 μg and placebo. The following subgroups of patients were analyzed: severe airflow limitation (percent predicted FEV 1 30%-< 50%), very severe airflow limitation (percent predicted FEV 1 < 30%), 2011 GOLD D, patients that are reversible (≥ 12% and ≥ 200 mL increase in FEV 1 ) to short-acting bronchodilators (ipratropium and albuterol), background ICS, background LABA and/or ICS, older age (defined as > 65 or > 75 years), and comorbidity risk factors which included history of cardiovascular disease, diabetes mellitus, and cognitive/mental impairments.

Statistical analyses
The full analysis set included all randomized patients who received at least one dose of study drug and had at least one recorded post-baseline FEV 1 assessment. Pooled analyses were conducted using a repeated statement of subject ID nested within study instead of a random statement to ensure convergence. Changes from baseline in FEV 1 were analyzed using a mixed model for repeated measures.
Trough FEV 1 at Day 85 is defined as the mean of the 23.25-and 23.75-h spirometry assessments post the Day 84 dose. Trough FEV 1 at Days 15, 29, 57, and 84 is defined as the mean of the − 45 min and − 15 min pre-dose spirometry assessments. SGRQ and TDI responders were the proportions of patients with a reduction in SGRQ total score ≥ 4 units, or an increase in TDI score ≥ 1 unit (ie, minimum clinically important differences [MCID]), respectively [16,17].

Patient demographics and baseline characteristics
Data from 812 patients were pooled for analysis, with 395 patients receiving revefenacin 175 μg, and 417 patients receiving placebo (Table 1). Across both treatment groups, approximately 45% of patients were > 65 years, 10% were > 75 years, and 37% were on background LABA and/or ICS. In addition, approximately 31% of patients had severe airflow limitation (percent predicted FEV 1 30%-< 50%), and 34% met 2011 GOLD D criteria. For comorbidities, approximately 47%, 20%, and 15% of patients had a history of cardiovascular disease, diabetes mellitus, and cognitive/mental impairments, respectively. Overall, patient demographics and baseline characteristics from the pooled analysis indicated that revefenacin and placebo groups were well balanced across all variables (Table 1).

SGRQ responders
In the ITT population, a higher proportion of patients in the revefenacin 175 μg arm (46.9%) met the MCID criteria of SGRQ responder than placebo (36.2%) ( Fig. 2 and Table 3), with the odds of response significantly greater in the revefenacin 175 μg arm than in the placebo arm (p = 0.0116). In general, the majority of subgroup analyses showed a higher rate of responders for revefenacin than for placebo, with the odds of response (odds ratio > 2.0) significantly greater in the revefenacin arm than in the placebo arm, among the severe (p = 0.037) and very severe (p < 0.001) airflow limitations, and 2011 GOLD D (p = 0.004) subgroups. In addition, the cardiovascular disease subgroup showed a non-significant trend, with the odds of response exceeding 2.0; odds ratio 2.3 (95% confidence intervals 0.68-7.83, p = 0.1822) ( Fig. 2 and Table 3).

TDI responders
In the ITT population, a higher proportion of patients in the revefenacin arm (55.0%) met the MCID criteria of TDI responder than placebo (47.2%), with the odds of response greater in the revefenacin arm than in the placebo arm ( Fig. 3 and Table 4).
Overall, the majority of subgroup analyses showed a higher rate of responders for revefenacin than for placebo, with the odds of response significantly greater among the severe airflow obstruction subgroup, odds ratio 2.37 (95% confidence intervals 1.10-5.08, p = 0.027), and a tendency towards  3 and Table 4).

Discussion
This post hoc subgroup analysis of two replicate, randomized, double-blind, placebo-controlled, parallelgroup, 12-week phase 3 trials (0126 and 0127) provides evidence for the efficacy of revefenacin delivered by a standard jet nebulizer in patients with COPD that had markers of severe disease. This analysis of pooled data from Studies 0126 and 0127 in all subgroups of patients with COPD that had markers of severe disease, showed that revefenacin was associated with significant improvements in lung function (range, 102-176 mL), which was comparable with the ITT population (148 mL). In addition, revefenacin demonstrated improvements in health-related quality of life (as measured by SGRQ responders) and dyspnea (as measured by TDI responders) in the majority of patient subgroups versus placebo; these improvements were also comparable to those observed in the ITT population. The odds of being a SGRQ responder were significantly greater among patients with severe airflow obstruction (percent predicted FEV 1 30%-< 50%), very severe airflow obstruction (percent predicted FEV 1 < 30%), and those classified as 2011 GOLD D. Among patients with comorbidities, the odds of response in the revefenacin group with a history of cardiovascular disease showed a non-significant trend (odds ratio > 2.0) compared with placebo. It is likely significance was not met due to the relatively small patient numbers. The odds of being a TDI responder were significantly greater among patients with severe airflow obstruction (percent predicted FEV 1 30%-< 50%), and those aged > 75 years, and there was a tendency towards significance in the 2011 GOLD D subgroup.
Results of this analysis are consistent with other studies that evaluated the efficacy of patients taking revefenacin and a concomitant LABA or LABA/ICS, or combining other LAMAs with LABA or LABA/ICS. Revefenacin 175 μg demonstrated improvements in FEV 1 in concomitant LABA patients in a 52 week study [8]. The efficacy of combined LAMA/LABA treatments has been shown to improve lung function and health outcomes [18][19][20]. In a systematic review and metaanalysis, it was reported that combining LAMA with LABA and ICS in patients with advanced COPD have better lung function and health-related quality of life and lower rates of moderate/severe COPD exacerbations than dual therapy or monotherapy [21]. In this analysis, revefenacin resulted in significant improvements in lung function, SGRQ and TDI among patients with severe airflow obstruction (percent predicted FEV 1 30%-< 50%) and classified as GOLD D in this study, which is consistent with previous studies. Nebulized glycopyrrolate was shown to improve FEV 1 , SGRQ, and TDI in patients with moderate to very severe COPD [22]. Furthermore, tiotropium demonstrated higher efficacy versus salmeterol in prolonging time to first COPD exacerbation and reducing number of exacerbations in patients both at high exacerbation risk [18]. In addition, aclidinium 400 μg significantly improved respiratory symptoms among patients who were classified as GOLD D at baseline [23]. Patients with COPD frequently have comorbid conditions, which can influence mortality and hospitalizations [1]. In this study, revefenacin demonstrated significant improvements in FEV 1 and health outcomes among patient subgroups with cardiovascular disease, and diabetes mellitus compared with patients who received placebo. Similarly, nebulized glycopyrrolate improved FEV 1 , and patient-reported outcomes in patients with COPD, irrespective of cardiovascular risk status [24]. In previous studies of patients with COPD and comorbid type 2 diabetes, ICS therapy may have a negative impact on diabetes control, and patients prescribed higher doses may be at greater risk of diabetes progression [25,26]. In the GOLD report, combination ICS/ LABA or LAMA/LABA or LAMA monotherapy are recommended for GOLD D patients [1]. However, in patients with comorbid diabetes, it may be more appropriate to limit the use of ICS to the minority of patients with COPD who might benefit.
There were no safety issues identified with the use of revefenacin in patients with cardiac risk factors [7,9]. In a preclinical study, revefenacin was shown to be a highaffinity competitive antagonist at human recombinant muscarinic acetylcholine receptors with kinetic functional selectivity for M 3 over M 2 muscarinic acetylcholine receptors [27]. In addition, revefenacin is a metabolically labile primary amide "soft-drug" site that allows rapid systemic clearance of the parent drug, thus potentially minimizing systemically mediated adverse events [27,28].
Results of this analysis also demonstrated significant improvements in FEV 1 in patients who received revefenacin among subgroups aged > 65 years and > 75 years, and cognitive/mental impairments, versus those who received placebo. Similarly, a retrospective analysis demonstrated the efficacy and safety of tiotropium among elderly patients with COPD (< 70 years, 70-79 years, and ≥ 80 years) [29]. Previous studies have suggested that nebulized therapy may be an appropriate option in patients with COPD and arthritis, impaired manual dexterity, chronic muscle weakness, or mental health or confusion disorders, or who are in hospitals, tertiary care centers, and assisted care settings as they may prefer nebulized therapy that is easy to use and does not require special training [2,30].
Several limitations should be noted for this study. The treatment period was only three months, which does not allow for conclusions on long-term treatment. Due to small sample sizes in the subgroups and post hoc nature of this study, results should be interpreted with caution. The populations assessed in this study had stable COPD and did not include patients that had recent hospitalizations or respiratory infections. Peak inspiratory flow rate was not assessed at baseline, and therefore, patients with a suboptimal peak inspiratory flow rate could not be assessed as a potential population with markers of more severe COPD.

Conclusions
In summary, in this post hoc subgroup analysis of data from Studies 0126 and 0127 among patients with markers of more severe COPD, revefenacin treatment showed significant improvements in lung function. In addition, there was a greater number of SGRQ and TDI responders in the ITT population and 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. Availability of data and materials Theravance Biopharma (and its affiliates) will not be sharing individual deidentified participant data or other relevant study documents. Theravance Biopharma reviews the appropriateness of public disclosure of de-identified study data on a regular basis; however, at this time, has determined that public disclosure is not appropriate for advancing the knowledge around COPD treatment.

Ethics approval and consent to participate
This study was conducted in accordance with the protocol, the principles of the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline for Good Clinical Practice, the United States Code of Federal Regulations, the principles of the World Medical Association Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects, and all applicable regulatory requirements. The protocol was reviewed and approved by an institutional review board (Quorum Review IRB, Seattle, Washington). Written informed consent was obtained from all patients.

Consent for publication Not applicable.
Competing interests 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.