The combination of umeclidinium bromide and vilanterol in the management of chronic obstructive pulmonary disease: current evidence and future prospects

Introduction

Expiratory flow limitation in patients with chronic obstructive pulmonary disease (COPD) results from progressive airway inflammation causing parenchymal destruction, mucosal edema, airway remodeling, mucoid impaction, and increased cholinergic airway smooth muscle tone [O’Donell and Lavenisiana, 2006]. Significant airflow obstruction may be present before the individual is symptomatic. Irreversible airflow limitation is caused by airway remodeling, resulting from small airway fibrosis and narrowing, and a loss of elastic recoil, a consequence of alveolar destruction [GOLD, 2013]. These changes are accompanied by increases in residual volume and air trapping, and increased hyperinflation on exertion.

The reversible component reflects ongoing airway smooth muscle contraction, airway inflammation, and mucus secretion, which also contribute to airflow limitation and hyperinflation. In many patients with COPD, short-acting bronchodilators produce an increase in forced expiratory volume in 1 second (FEV₁), consistent with an effect of a reversible component of airflow limitation. However, even in the absence of acute bronchodilation, long-acting bronchodilators may reduce hyperinflation, thereby providing symptomatic improvement [Tashkin and Kesten, 2003].

The recognition that bronchodilator therapy can be associated with clinically important improvements in desired patient-centered outcomes such as dyspnea, exercise endurance, and health status, in the presence of little or no change in FEV₁ have provided researchers and clinicians with a solid physiologic rationale for the clinical benefits of sustained pharmacologic reduction in hyperinflation in COPD patients. The goals of COPD management aim to improve symptoms, lung function, and health status and to reduce exacerbations, disease progression, and mortality [Hanania and Marciniuk, 2011]. At present, no treatment is shown to modify the rate of decline in lung function. Treatment of patients with COPD with inhaled long-acting muscarinic antagonist (LAMAs) and long-acting β2-agonist (LABAs) monotherapy has been shown to significantly improve FEV₁, resting and dynamic hyperinflation, symptoms, exercise capacity, and health status, and reduce exacerbations [O’Donnell et al. 2004; Rodrigo and Neffen, 2012].

Tiotropium, the first ultra-long-acting inhaled drug marketed, was first introduced a decade ago. Tiotropium has gained worldwide acceptance as a first-line, once-daily maintenance therapy for patients with moderate-to-severe disease. The therapeutic success of tiotropium encouraged development of other ultra-long-acting bronchodilators, with tiotropium emerging as the gold standard against which the various inhaled LAMAs and LABAs have been compared [Domingo, 2013]. Currently available LAMAs (in addition to tiotropium) are twice-daily aclidinium and once-daily glycopyrrolate.

β2-agonists constitute the other major group of bronchodilators due primarily to their ability to relax airway smooth muscle. They exert their effects via their binding to the active site of β2-adrenergic receptors. Until recently, the twice-daily β2-agonists salmeterol and formoterol and the once-daily anticholinergic tiotropium were the most widely used maintenance medications. More recently, indacaterol, a newer ultra-LABA (24 h duration of action) was approved as a monotherapy for maintenance treatment of stable COPD. Some novel once-daily β2-agonists (olodaterol, abediterol, AZD3199) are under development, mainly in combination with an inhaled corticosteroid (ICS) or a LAMA. Recently, the FDA approved a fixed-dose combination (FDC) of vilanterol (VI) and novel ICS fluticasone furoate (FF) for once-daily maintenance treatment of COPD. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether LABAs may increase the risk of asthma mortality [Cazzola et al. 2013]. The peak plasma β2-agonist concentration is able to account for only a small fraction of the decrease in airway resistance, and even very little of the inhaled dose of a β2-agonist reaches the airways; this small amount produces effective bronchodilation [Cazzola et al. 2002]. The availability of once-daily inhaled β2-agonists for the maintenance treatment of COPD marks a trend in the recent therapeutic developments in COPD, indicating a shift from multiple dosing per day to reduced dosing frequency and prolonged duration of action, including once-daily treatment [Beeh and Beier, 2009].

Current COPD guidelines recommend combination therapy with two long-acting bronchodilators with different modes of action in patients whose symptoms are not sufficiently controlled with monotherapy [GOLD, 2013]. Clinical studies combining different classes of bronchodilators, such as a LAMA and a LABA, have demonstrated greater improvements in FEV₁ in patients with COPD than monotherapy [Mahler et al. 2012; Van Noord et al. 2006]. Evidence to date indicates that there are no untoward safety issues when a LAMA is co-administered with a LABA [Van Noord et al. 2005; Mahler et al. 2012]. The rationale for combining long-acting bronchodilators with different mechanisms of action is based on the notion of additive relaxation of airway smooth muscle by direct inhibition of cholinergic activity and functional antagonism of bronchoconstriction through β2-adrenergic pathways. Cholinergic nerves exert their bronchoconstrictor and mucus secretory effects via the activation of muscarinic receptors in airway smooth muscle and submucosal glands, respectively [Belkonte, 2005]. Activation of M3 muscarinic cholinergic receptors (mAChR) increases airway tone whereas its blockade improves lung function, dyspnea, and health-related quality of life (HRQoL) in patients with COPD [Domingo, 2013]. Cholinergic mechanisms are also important in the regulation of submucosal gland secretion, which is increased in COPD. The airway smooth muscle, however, does not receive direct sympathetic innervation, but contains β2-adrenergic receptors. Airway smooth muscle relaxation (leading to bronchodilation) can be achieved either by inhibition of acetylcholine (ACh) signaling via muscarinic M3 receptors on airway smooth muscle with a muscarinic antagonist, or stimulation of the β2-adrenoreceptors with a β2-agonist [Cazzola and Molimard, 2010]. Targeting these two mechanisms of bronchoconstriction, theoretically, has the potential to maximize the bronchodilator response without increasing the dose of either component, or to help to overcome the interpatient and intrapatient variability in response to individual agents seen in COPD [Cazzola and Tashkin, 2009].

Although two long-acting controller medications with different mechanisms of action (LAMA plus LABA) are recommended for the treatment of symptomatic COPD, patients’ compliance and adherence to the treatment plans historically have been poor. Adherence rates in clinical trials are reported to be as high as 70–90%, although in clinical practice it is in the range of 10–40% [Krigsman et al. 2007]. Medication regimens for patients with COPD are particularly vulnerable to adherence problems because of the chronic nature of the disease, the use of multiple medications or polypharmacy, and the periods of symptoms remission [Bourbeau and Bartlett, 2008].

When muscarinic antagonists and β2-agonists with equivalent posologies are combined, the opportunity exists to improve patient compliance and, as a result, improve overall disease management by offering a simplified and convenient administration regimen within the same inhaler device. The purpose of this review is to discuss current evidence for FDC of umeclidinium/vilanterol (UMEC/VI) for maintenance treatment of COPD in the context of the evolving standards of care for COPD patients and future prospects.

Umeclidinium and vilanterol

In early 2013, the FDA and EMA have accepted for consideration new drug applications (NDAs) for once-daily FDC of UMEC/VI (125/25 and 62.5/25 µg doses) submitted by sponsors for maintenance treatment of COPD. In addition an NDA for once-daily UMEC 62.5 µg for monotherapy maintenance treatment of COPD has also been submitted by a sponsor to the FDA and EMA. Currently the sponsors have not marketed VI as a monotherapy.

The development program for UMEC/VI leading to its regulatory submission involved four large, 24-week pivotal trials that involved more than 4500 patients with COPD and compared the FDC of UMEC/VI, and one large 52-week safety study. The designs of the four 24-week studies are summarized in Table 1. Inclusion criteria were similar through each trial: patients were over 40 years old, with moderate-to-severe COPD and with at least a 10-pack-year smoking history. Short-acting β2-agonist (SABA) rescue medication and stable ICS doses were permitted throughout all trials. All participants were instructed to discontinue anticholinergic or LABAs during treatment.

To understand pharmacology of inhaled FDC of UMEC/VI it is necessary to address certain characteristics of its individual components that possess similar 24 h posology. UMEC shares many pharmacologic characteristics with tiotropium, including a strong affinity to M₃ receptors. UMEC is a potent anticholinergic agent that demonstrates slow functional reversibility at the human M3 mAChR and thus long duration of action [Salmon et al. 2013]. A 28-day placebo-controlled study evaluated the dose–response of once-daily UMEC in COPD patients with moderate-to-severe COPD [Decramer et al. 2013]. All doses of UMEC (125, 250, 500 µg) significantly increased through FEV₁ over placebo. UMEC doses ranging between 62.5 and 1000 µg have been well tolerated [Decramer et al. 2013]. A placebo-controlled study of once-daily treatment with UMEC (62.5 and 125 µg) administered over 12 weeks resulted in clinically significant improvements in measures of lung function, symptoms, and HRQoL in patients with COPD [Triverdi et al. 2013].

VI is a potent, selective, β2-adrenoreceptor agonist; in human functional cellular assays VI has a greater intrinsic efficacy than salmeterol and a greater potency than indacaterol and salbutamol [Cazzola et al. 2011; Procopiou et al. 2010]. A 24-week placebo-controlled study showed VI administered at a 25 µg dose improved lung function significantly when compared with placebo [Kerwin et al. 2013].

This review was based on four large UMEC/VI pivotal phase III COPD 24-week studies (Table 1) that enrolled 4500 patients with moderate-to-severe COPD and one large 52-week safety study. The data have been presented on three posters at the 2013 ATS congress (studies 1, 2 and 3; Table1) while the fourth is not available. Recently, UMEC/VI 62.5/25 mcg primary manuscript has also been published [Donohue et al. 2013]. The other data have not been published yet in peer-reviewed journals.

Efficacy

After 24 weeks of placebo-controlled treatment with UMEC/VI (day 169) through FEV₁ was significantly higher with both doses of UMEC/VI (62.5/25 and 125/25 µg) when compared with UMEC, VI and placebo (primary endpoint). UMEC/VI produced consistent and significant improvements in lung function at 125/25 µg dose [Celli et al. 2013] (see Figure 1) and at 62.5/25 µg [Donohue et al. 2013] (see Figure 1). When both doses of UMEC/VI were compared with tiotropium (TIO) and VI, the result was statistically significant improvement in trough FEV₁ compared with TIO and VI at day 169 and at all other visit assessments [Anzuetto et al. 2013]. Importantly, improvements in the majority of other lung function analyses were observed when comparing UMEC/VI 62.5/25 or 125/25 µg with TIO and VI treatment groups (Table 2). Although, study 4 (Table 1) is awaiting further analysis, treatment with UMEC/VI 125/25 µg resulted in a statistically significant improvement in lung function as measured by the primary endpoint, trough FEV₁ at treatment day 169 (week 24) as compared with TIO. The comparison of UMEC/VI 125/25 µg and UMEC 125 µg with respect to primary endpoint, trough FEV₁ was not statistically significant. Treatment with once-daily UMEC/VI 62.5/25 µg resulted in numerical improvements in trough FEV₁ as compared with TIO. Treatment with UMEC/VI 125/25 and 62.5/25 µg did not show statistically significant improvements in trough FEV₁ (primary endpoint) compared with treatment with UMEC 125 µg [GlaxoSmithKline, 2012b]. Additional efficacy endpoints included 0–6 h postdose weighted mean (WM) FEV₁ (measuring proportion of subjects who were responsive to UMEC/VI, UMEC or VI according to FEV₁, with responsive defined as an increase from baseline of at least 12% and 200 ml at any time over 0–6 h postdose), transition dyspnea index (TDI) focal score, St. Georges Respiratory Questionnaire (SGRQ) score, rescue albuterol use and time to first COPD exacerbation. Greater and statistically significant improvements in 0–6 h postdose WM FEV₁ were shown for UMEC/VI (62.5/25 and 125/25 µg doses) over VI and TIO.

OPEN IN VIEWER

Figure 1.

Trough FEV₁ (ITT population).

UMEC/VI and patient-centered outcomes

Safety

Common to all LABA agents are potential side effects of stimulation of the beta-adrenergic receptor. These include hypokalemia, hyperglycemia, anxiety, nervousness, tremor, palpitations, and arrhythmias (particularly supraventricular tachycardias). Dry mouth and dry cough are the most common side effects of anticholinergics. The incidence of dry mouth was low in all active treatments (≤1%). The incidence of serious adverse events (SAEs) was similar across treatment groups (3–6%). The most common SAE was COPD. No clinically meaningful treatment-related changes in vital signs, ECG, or clinical laboratory parameters were observed for active treatments compared with placebo. A 52-week safety study was also part of a NDA submission to the FDA and EMA. The sponsor has reported that the incidence of on-treatment adverse events in the 52-week multicenter safety study was 52% in the placebo group, 58% in the UMEC 125 µg group, and 53% in the UMEC/VI 125/25 µg group (DB2113359; GSK Trials Registry, 2012) The most common AEs across treatment groups were headache and nasopharyngitis. (DB2113359; GSK OTR, 2012).

In summary, the FDC of UMEC/VI at 62.5/25 and 125/25 µg doses demonstrated no untoward safety issues. In addition a 28-day UMEC/VI study using a supratherapeutic 500/25 µg dose in patients with moderate-to-very-severe COPD was not associated with any clinically significant effects relative to placebo [Feldman et al. 2012].

Future prospects

Long-acting bronchodilators play a central role in maintenance management of symptomatic COPD. Published UMEC/VI evidence demonstrate greater improvement in lung function in patients with moderate-to-severe COPD when compared to monotherapy (UMEC, VI or TIO). However, FEV₁ alone may not adequately reflect the overall health status of the patient [Van Der Molen and Cazzola, 2012].

In addition to improvements in lung function consistently observed across both UMEC/VI doses submitted for approval versus UMEC, VI and TIO monotherapy, there were a number of added benefits of UMEC/VI combination (both 125/25 and 62.5/25 µg doses) in maximizing bronchodilation and improving many of patient-centered outcomes such as dyspnea, HRQoL and rescue medication use. An important finding in several phase III studies is that treatment with UMEC/VI showed in disease control since sustained bronchodilator effect of UMEC/VI was associated with significant increase in rescue-free days compared with placebo. However, the large interpatient and interstudy variability in FEV₁ with bronchodilators makes determination of optimum dose difficult.

COPD is a heterogeneous disease affecting individual patients in different ways. Therefore, management of COPD should be individualized according to the symptoms and impairments that patients are experiencing, which may change over the course of the disease [GOLD, 2013]. In recent years many types of guidelines have been formulated to help prescribers choose appropriate therapy for specific conditions, with some success, although there is evidence that guidelines are ineffective unless they are accompanied by either education or financial incentives [Bourbeau and Bartlett, 2008].

Both β2-agonists and anticholinergic agents have been shown to exert anti-inflammatory effects in vitro. However, the clinical relevance of these effects is not clear, which does not prevent them from being effective at improving respiratory mechanics, relieving dyspnea, increasing exercise tolerance, preventing exacerbations and HRQoL [Rodrigo and Neffen, 2012; Tashkin et al. 2008].

Patients with COPD are often prescribed aerosolized medications to use from two to six times daily plus concurrent therapy for other comorbidities that may include diabetes, hypertension, and coronary artery disease [Krigsman et al. 2007]. Although standard treatment regimens for both asthma and COPD often require patients to use several daily inhaled medications, COPD and its therapies differ markedly from asthma and its therapies in a number of ways. COPD, as opposed to asthma, is a progressive, debilitating, and often fatal disease, with treatment options that can improve HRQoL and reduce exacerbation, but cannot fully reverse or control disease symptoms [Restrepo et al. 2008]. The nature of the disease, the treatment, and the patients’ beliefs and expectations about therapy all combined to influence patient adherence to therapy. Not surprisingly, a large retrospective study reported that patients’ adherence was strongly correlated with dosing frequency [Toy et al. 2011]. COPD patients who initiated treatment with once-daily dosing had significantly higher adherence than other daily dosing frequency. The future availability of LAMA/LABA FDCs (such as UMEC/VI) should make this therapeutic option more convenient than separate administration by two inhalers, currently the only option [Tashkin and Ferguson, 2013].

Exacerbations of COPD indicate clinical instability and progression of the disease and are associated with reduced health status, physical and physiologic deterioration, and an increased risk of morbidity and mortality [Anzueto et al. 2007]. The prevention or reduction of exacerbations thus constitutes a major treatment goal. The results of several important trials designed to evaluate the effectiveness of currently available medications on exacerbations provide clinicians with evidence that pharmacotherapy is effective. However, the choice of the best therapy is unclear.

Symptomatic COPD patients do not complain about their rate of decline of FEV₁ but are worried by disease exacerbations and the impact of COPD on their general well-being. New GOLD guidelines published in 2011 included a fundamental change: symptoms and not just airflow limitation now have to be taken into account to guide the management of COPD. The rationale behind this change is that airflow limitation, which is linked to the frequency of exacerbations and measure future risks, has poor correlation with the daily impact of the disease upon the individual patient, and therefore serves little practical use on its own [Mousseau, 2011].

The persistent increase in airflow obstruction that characterizes COPD is best addressed by improving lung function throughout the 24 h day. In this setting, even modest improvements spirometrically often indicate larger functionally important changes. Future studies assessing the impact of LAMA/LABA combination therapies on COPD exacerbations may enhance our ability to prevent the incidence of COPD exacerbations, delay disease progression and to improve HRQoL of patients with COPD.

In summary, the UMEC/VI combination appears to offer substantial therapeutic benefits over either LABA or LAMA (tiotropium) monotherapy for the treatment of moderate-to-severe COPD. More research is needed to delineate possible UMEC/VI role in preventing COPD exacerbations. Triple therapy with a LAMA plus a LABA and an ICS may offer further clinical benefits to those with severe COPD [Short et al. 2009; Welte et al. 2009] and clinicians will be eagerly awaiting future studies.