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Drug Evaluation
Aclidinium bromide plus formoterol for the treatment of chronic obstructive pulmonary disease
1.
Introduction
2.
Pharmacologic profiles
3.
Clinical efficacy
Chitra Lal† & Charlie Strange
4.
Regulatory affairs
†
5.
Conclusion
6.
Expert opinion
Medical University of South Carolina, Department of Pulmonary, Critical Care, Allergy and Sleep Medicine, Charleston, SC, USA
Introduction: Drugs that target dynamic hyperinflation such as long-acting b2 agonists and long-acting antimuscarinic antagonists form a cornerstone of chronic obstructive pulmonary disease (COPD) management. The idea of combining these two medications in a single formulation, which may potentially improve patient compliance, is novel and attractive. Areas covered: The pharmacologic profiles of aclidinium bromide and formoterol fumarate are discussed. However, studies to define drug interactions and alterations in the pharmacodynamics and pharmacokinetics of the fixed dose combination (FDC) of aclidinium bromide/formoterol fumarate in large populations remain unpublished. Results of Phase II and two Phase III pivotal trials, ACLIFORM/COPD and AUGMENT COPD, evaluating the FDC are discussed. Expert opinion: Initial data for the aclidinium/formoterol inhaler appears to be promising for impacting the lung function. To define if this benefit translates into improved long-term outcomes of decreased exacerbation frequency, improved quality of life and decreased disease-specific mortality are important. The introduction of this combination will likely have a significant impact on the prescribing habits of physicians across the world. Keywords: aclidinium bromide, bronchodilators, chronic obstructive pulmonary disease, formoterol fumarate, long-acting antimuscarinic antagonists, long-acting b-2 agonists Expert Opin. Pharmacother. (2015) 16(3):427-434
1.
Introduction
Chronic obstructive pulmonary disease (COPD) has been declared a global epidemic by the WHO with 64 million people affected worldwide. COPD is the third leading cause of death in the United States and the WHO predicts that COPD will become the third leading cause of death worldwide by 2030 [1,2]. It is also a leading cause of morbidity and disability as measured by impairment in activities of daily living [3]. The pathophysiology of COPD involves airway inflammation, mucus gland hyperplasia (in chronic bronchitis), and destruction of inter-alveolar septae (in emphysema) in response to noxious stimuli such as cigarette smoke. These airway changes result in limitation of expiratory flow and dynamic hyperinflation, which plays a critical role in the dyspnea perceived by COPD patients. Thus, drugs that target dynamic hyperinflation form a cornerstone of COPD management. Such medications include bronchodilators such as long-acting b2 agonists (LABA) such as salbutamol, formoterol, and salmeterol, which have been found to increase the inspiratory capacity and decrease the sensation of dyspnea [4]. Additionally, long-acting antimuscarinic antagonists (LAMA) such as tiotropium show similar improvements in inspiratory capacity [5]. The idea of combining these two medication classes in a single formulation to optimize lung 10.1517/14656566.2015.1000861 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology Route of administration Chemical structure
Aclidinium bromide/formoterol fumarate fixed dose combination (FDC) III Maintenance treatment of moderate and severe chronic obstructive pulmonary disease (COPD) Long-acting antimuscarinic agents + long-acting b-2 agonists FDC Inhalation Formoterol fumarate H
O
OH
H N
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HN
CH3
HO HO
OCH3
CH3
HN H
OCH3
N H
OH
O
Aclidinium bromide
HO +
N
Br– O
O
Pivotal trial(s)
S
ACLIFORM/COPD [27] AUGMENT COPD [28,29]
function, decrease dynamic hyperinflation and the sensation of dyspnea and potentially improve patient compliance is novel and attractive. The LABA/LAMA combinations, which have been studied, include tiotropium + formoterol, which was shown to improve the Forced Expiratory Volume in 1 sec (FEV1) and Forced Vital Capacity (FVC) more than the salmeterol + fluticasone 500 µg combination in patients with a baseline FEV1 of 55% predicted [6]. Similarly the arformoterol + tiotropium combination was shown to improve peak FEV1, peak FVC, inspiratory capacity and dyspnea more as compared to arformoterol or tiotropium alone [7]. A recent meta-analysis found that once-daily, inhaled Indacaterol/Glycopyronium fixed dose combination (FDC), showed superior efficacy (increased trough FEV1, decreased use of rescue medications, and improved percentage of patients achieving a minimal clinically important difference in the St. George’s Respiratory Questionnaire) compared with glycopyrronium and tiotropium, in patients with moderate to severe COPD [8]. Anoro Ellipta, which combines vilanterol (LABA) with umeclidinium bromide (LAMA), is the first LABA/LAMA combination approved for COPD treatment in the United States. The combination of aclidinium bromide + formoterol fumarate is the newest LAMA/LABA combination to be studied. 428
S
O
With these LABA/LAMA combinations in development, triple therapy with LABA/LAMA/inhaled corticosteroids is on the horizon. The impact of dual or triple combination therapy for COPD on patient compliance is expected to be substantial due to the ease of taking these medications in a single inhaler. Table 1 highlights the different FDC inhalers, which are either already on the market for COPD or are currently being evaluated for treatment of COPD [9]. 2.
Pharmacologic profiles
In order to understand the pharmacokinetics of the LABA/ LAMA combination, it is important to first review the pharmacologic profile of aclidinium and formoterol separately. Aclidinium bromide, marketed in the United States as Tudorza Pressair, is an anticholinergic agent with differential specificity for beneficial muscarinic receptors. In-vitro studies have shown that it has a long residence half-life at the human muscarinic M3 receptors (29.2 h) and short residence half-life at the M2 receptors (4.7 h) [10]. M3 receptors located in the airway smooth muscles mediate the bronchoconstrictor response to vagal nerve stimulation [11]. Thus aclidinium bromide is able to provide effective bronchodilation by binding to the M3 receptors in the
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Aclidinium bromide plus formoterol
Table 1. Medication combinations in COPD.
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Medications
LAMA/LABA Tiotropium/formoterol Tiotropium/salmeterol Tiotropium/olodaterol Vilanterol/umeclidinium bromide Aclidinium/formoterol Indacaterol/glycopyronium
Manufacturers of fixed dose combination inhalers approved and in development
Comments
Novartis and Pacira Boeringher Ingeheim Boeringher Ingeheim GlaxoSmithKline Forrest and Almirall Novartis Pharmaceuticals
Investigational Investigational Investigational LAMA/LABA US approved as Anoro Ellipta EMEA approved as Duaklir Genuair Investigational in US, approved in Europe as Xoterna Breezhaler, Ultibro Breezhaler Investigational
Glycopyrrolate/formoterol ICS/LABA Fluticasone propionate/salmeterol
GlaxoSmithKline, Elpen
Budesonide/formoterol Mometasone/formoterol
AstraZeneca Merck
Fluticasone propionate/formoterol
Mundi Pharma Napp, Skypharma Takeda Novartis Chiesi Farmaceutici S.p.A GlaxoSmithKline
Formoterol/ciclesonide Indacaterol/mometasone Carmoterol and budesonide Fluticasone furoate/vilanterol LAMA + LABA + ICS Tiotropium/salmeterol/ciclesonide Tiotropium/fluticasone/salmeterol Indacaterol/Glycopyrronium/mometasone Milveterol/darotropium/fluticasone furoate Tiotropium/formoterol/ciclesonide Aclidinium/formoterol/fluticasone or budesonide Tiotropium/formoterol/fluticasone or budesonide Glycopyronium/formoterol/mometasone Glycopyronium/formoterol/beclometasone MABA (muscarinic antagonist-b2 agonist)
Pearl Therapeutics
ICS/LABA US approved as Advair Diskus, Advair HFA ICS/LABA US approved as Symbicort ICS/LABA US approved as Dulera for asthma, investigational for chronic obstructive pulmonary disease Investigational Investigational for asthma Investigational Investigational Available in US as Breo Ellipta
NCIPD* NCIPD* NCIPD* NCIPD* Cipla NCIPD*
Investigational Investigational Investigational Investigational Approved in India as Triohale Investigational
NCIPD*
Investigational
Pearl Therapeutics Chiesi Farmaceutici S.p.A Almirall, Pfizer Argenta, Astra Zeneca Boeringer Ingelheim GlaxoSmithKline
Investigational Investigational Novel dual acting bronchodilators in a single molecule
*Not currently in public domain. ICS: Inhaled corticosteroids; LABA: Long-acting b-2 agonists; LAMA: Long-acting antimuscarinic agents.
airway smooth muscles for a longer duration, with few cardiac side effects, which are mediated by the M2 receptors [12]. In isolated guinea pig trachea, aclidinium has been shown to have comparable potency to ipratropium and tiotropium but faster onset of action than tiotropium. Aclidinium has a longer duration of action than ipratropium but shorter than tiotropium. In dogs, aclidinium has a favorable cardiac safety profile at supratherapeutic doses [10]. A study conducted in healthy human subjects found that once daily aclidinium in doses up to 800 µg per day does not prolong the QT interval [13]. The favorable cardiac safety profile of aclidinium was demonstrated in Phase III trials in COPD subjects with twice daily (b.i.d) aclidinium, 200 and 400 µg [14,15].
As compared to other anticholinergic agents on the market, aclidinium undergoes rapid hydrolysis in human plasma [16], thus indicating a low potential for any systemic side effects. Similar pharmacokinetics are seen in young (40 -- 59 years of age) and elderly subjects (‡ 70 years of age) [17]; thus no dose adjustment is needed for age. The urinary excretion of aclidinium has been found to be low in human studies [18], thus indicating that dose adjustment for renal failure is not required. Aclidinium 400 µg inhaled b.i.d is indicated for maintenance treatment of COPD. A Phase IIa study comparing aclidinium 400 µg b.i.d to tiotropium 18 µg once a day showed that whereas both drugs produced greater bronchodilation than
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placebo, significant differences between aclidinium and tiotropium, in favor of aclidinium, were seen as early as day 1 [19]. This suggests that maximal efficacy with aclidinium might be reached earlier than with tiotropium. In addition, the increased bronchodilation with aclidinium as compared to tiotropium was more pronounced in the second half of the day, suggesting greater benefit with b.i.d dosing. Subsequent larger Phase III studies (ACCORD I and ATTAIN) showed that aclidinium provided early and sustained, statistically significant improvements in peak FEV1, compared to placebo. Formoterol is a LABA, which has been on the market for some time and combines the advantages of high potency, a rapid onset of action and a long duration of action of > 12 h. The high lipophilicity of formoterol likely is responsible for long retention times in the human airway smooth muscle, as relaxant effects are resistant to repeated washings [20]. In addition, formoterol has higher potency, selectivity and affinity for the b-2 adrenoreceptor as compared to short-acting b-2 agonists [21]. Formoterol has been available as maintenance therapy for COPD for about 16 years and has been shown to produce long-term improvements in lung function, quality of life and exacerbation frequency [22,23]. The pharmacologic profile of aclidinium and formoterol makes them ideal for combination in a single inhaler [24]. Characteristics of the FDC of aclidinium bromide/formoterol fumarate are listed in the drug summary Box 1. The studies to define whether there are drug interactions, alterations in pharmacodynamics and pharmacokinetics of the FDC in large population samples remain unpublished. Use of the aclidinium bromide/formoterol fumarate combination in renally or hepatically impaired subjects also remains to be studied in large populations. Of note, the combination of umeclidinum/vilanterol showed an increase in the area under the curve of the b agonist when co-administered with the anticholinergic [25]. Similar details for the aclidinium bromide/formoterol fumarate combination remain pending at this time. 3.
Clinical efficacy
A few Phase II and Phase III studies have evaluated the combination of aclidinium and formoterol and are summarized here. The aclidinium bromide/formoterol fumarate combination has been developed by Almirall and Forest laboratories. Three Phase II studies evaluating this combination have been completed. A dose finding clinical trial compared three doses of formoterol (6, 12, 18 µg) combined with aclidinium bromide 200 µg, aclidinium bromide 200 µg monotherapy and formoterol 12 µg monotherapy, in stable moderate to severe COPD [26]. All the aclidinium and formoterol combinations produced greater improvements in lung function than monotherapy with either drug or placebo, except the comparison between aclidinium/formoterol 6 µg combination and formoterol 12 µg monotherapy. The bronchodilation produced by 430
the formoterol 18 µg/aclidinium 200 µg combination was similar to that produced by formoterol 12 µg/aclidinium 200 µg combination, thus suggesting that 12 µg formoterol was the optimal dose. No safety concerns were discovered. Two additional Phase II clinical trials evaluated the efficacy of the aclidinium/formoterol combination as compared to formoterol alone. Almirall and Forest laboratories announced that these studies also met their primary endpoints [24]. Positive results from these Phase II clinical trials prompted the initiation of Phase III clinical studies. ACLIFORM/ COPD(ACLIdinium/FORMoterol fumarate combination for investigative use in the treatment of moderate to severe COPD) was a 24-week randomized, double-blind trial, which compared the 400/6 mcg and 400/12 mcg FDCs of aclidinium bromide/formoterol fumarate with aclidinium bromide 400 mcg, formoterol fumarate 12 mcg and placebo administered b.i.d [27]. This was a multicenter trial conducted at 193 centers in 22 countries in patients with moderate to severe COPD. Patients were randomized to receive either aclidinium/formoterol 400/12 µg (n = 385), 400/6 µg (n = 381), aclidinium 400 µg (n = 385), formoterol 12 µg (n = 384) or placebo (n = 194) b.i.d via Genuair/Pressair. At Week 24, aclidinium/formoterol 400/12 µg and 400/6 µg lead to significant improvements from baseline in 1-h post-dose FEV1 versus aclidinium (125 ml [95% CI: 90, 160; p < 0.0001] and 69 ml [95% CI: 34, 105; p < 0.001], respectively) and trough FEV1 versus formoterol (85 ml [95% CI: 51, 119; p < 0.001] and 53 ml [95% CI: 19, 87; p < 0.01], respectively (co-primary endpoints). Both aclidinium/ formoterol 400/12 µg and 400/6 µg produced significant improvements in Transition Dyspnoea Index focal score versus placebo (1.29 units [95% CI: 0.73, 1.86; p < 0.001] and 1.16 units [95% CI: 0.59, 1.73; p < 0.001], respectively; secondary endpoint). Both aclidinium/formoterol FDC doses were found to be well tolerated with similar safety profiles to aclidinium and formoterol monotherapy. A second pivotal trial, AUGMENT COPD, was a 24-week, randomized, double-blind trial conducted in 1692 stable COPD patients with a mean prebronchodilator FEV1 of 1.36 liters [28,29]. Patients were randomized to receive aclidinium 400 µg + formoterol 12 µg (FDC 400/12), aclidinium 400 µg + formoterol 6 µg (FDC 400/6), aclidinium 400 µg, formoterol 12 µg, or placebo. Statistically significant improvements were reported in the change from baseline for the co-primary endpoints of FEV1 1-h post-dose at week 24, by the 400/12 µg combination of aclidinium/formoterol, versus 400 mcg aclidinium (108 ml, p < 0.0001) and for the morning predose trough FEV1 versus formoterol 12 µg at week 24 (45 ml, p = 0.0102). Statistically significant improvements were also seen by the 400/6 µg combination in (FEV1) 1-h post-dose versus aclidinium 400 µg (87 ml, p < 0.0001). The 400/6 µg combination did not reach significance as compared to formoterol 12 µg at week 24, for the change from baseline in morning pre-dose trough FEV1. Both combinations demonstrated statistically significant improvements
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Aclidinium bromide plus formoterol
compared to placebo in the above two endpoints. Peak FEV1 improved at 24 weeks by 285 ml with the 400/12 µg combination versus placebo (p < 0.0001) and by 259 ml with the 400/6 µg combination versus placebo (p < 0.0001). Significant results from both Phase III trials are shown in Table 2. In summary, the 400/12 µg dose of aclidinium/formoterol appears to be the optimally effective dose for moderate to severe COPD. Safety and tolerability In the AUGMENT COPD and ACLIFORM/COPD trials, both fixed-dose combination treatment arms were reported to be well tolerated. Discontinuation rates due to adverse events (AEs) were similar in all treatment groups (both FDCs aclidinium + formoterol 400/12 µg and 400/6 µg, aclidinium 400 µg, formoterol 12 µg and placebo). Serious AEs occurred with similar frequency in all treatment groups. Commonest AEs (> 5% of patients, any group) were cough (FDC 400/12, 5.1%; FDC 400/6, 3.9%; aclidinium, 2.1%; formoterol 12, 3.0%; Placebo, 3.6%) and nasopharyngitis (4.8, 5.1, 3.6, 6.6, 3.6%, respectively). A clinical trial evaluating the long-term safety and tolerability of the Aclidinium/ Formoterol FDC at 52 weeks has been completed but the results have not been published as yet (ClinicalTrials.gov identifier: NCT01437540).
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3.1
4.
Regulatory affairs
Based on these clinical trials, Almirall announced the submission of the Marketing Authorisation Application to the European Medicines Agency for the FDC of aclidinium bromide/ formoterol fumarate for the treatment of COPD, in November 2013. AstraZeneca announced on 11/24/14 that Duaklir Genuair (aclidinium bromide/formoterol fumarate 340/12 mcg) has been granted Marketing Authorisation by the European Commission to be used as a maintenance bronchodilator treatment in adult patients with COPD. In the USA, Forest Laboratories and Almirall announced in August 2013 that they would delay the planned submission of a New Drug Application (NDA) for the combination of aclidinium bromide/formoterol fumarate for COPD. This decision was based on comments provided by the US FDA at a pre-NDA meeting. It was reported that the delay is related to resolving chemistry, manufacturing and control (CMC) specifications associated with the FDC. According to an update provided by Forest Laboratories and Almirall in April, 2014, they are in discussions with the FDA to address questions related to CMC of the aclidinium bromide/formoterol fumarate FDC. 5.
Conclusion
The aclidinium/formoterol combination has been reported to produce a greater degree of bronchodilation than formoterol
or aclidinium monotherapy alone. The combination appears to be safe and well tolerated in clinical trials. The availability of the aclidinium/formoterol FDC on the market will add a novel LAMA/LABA combination for the treatment of moderate to severe COPD. 6.
Expert opinion
The easiest pathway for COPD drug approval has been for bronchodilators, as they target symptom relief. In addition, FEV1 is a universally accepted and easily measurable outcome measure for COPD, although not necessarily the most correlated with patient-reported symptoms. Other COPD outcome measures, particularly composite measures and those that encompass patient-reported outcomes, face different levels of regulatory scrutiny. Therefore, approved COPD medications to date seem to be largely redundant as the levels of bronchodilation elicited by this enlarging pharmacopeia have minimal differences. In addition, the application of short-acting bronchodilators for acute symptom relief will remain an important part of therapy that will buffer any larger differences between long-acting bronchodilators. Nevertheless, most medications achieve rapid uptake in a COPD marketplace because of the large unmet need caused by COPD-associated dyspnea. One advantage of improved numbers of similar medications on the market is that market competition might force price reductions for COPD inhalers. To date, the transition to generic medications for COPD has been slow due to the inherent linkage of the device to the medication. In the absence of generic medications, the next most effective alternative for medication cost reduction is market competition. The US cost for aclidinium bromide/formoterol fumarate remains unknown at the time of writing this manuscript. The Global initiative for Chronic Obstructive Lung Disease [30] recommends combining bronchodilator medications from different pharmacologic classes to improve efficacy and minimize side effects, as compared to increasing the dose of a single bronchodilator. The use of long-acting bronchodilators is preferable to short-acting bronchodilators because they decrease exacerbation frequency and have strong correlative trends with improved COPD and all-cause mortality. As medications that decrease exacerbation frequency likely save costs, it is hoped that an exacerbation reduction study can be done with this and other LAMA/LABA combinations. Objective studies on the refill rates of aclidinium bromide/ formoterol fumarate will be interesting once it is marketed, as the large unmet opportunity to improve medication compliance might be improved by this medication. The largest question generated by LAMA/LABA combination inhalers is whether inhaled corticosteroid medications are necessary for best outcomes in COPD. Whereas real-world studies in an older dyspneic population often contain individuals with past asthma, these individuals are often excluded in
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Table 2. Significant results from Phase III trials evaluating the aclidinium bromide/formoterol fumarate fixed dose combination at 24 weeks. Dose
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ACLIFORM-COPD
400/12 µg 400/6 µg
AUGMENT-COPD
400/12 µg 400/6 µg
Co-Primary endpoints
Secondary endpoints
1-h post-dose FEV1 versus aclidinium 400 mg
Trough FEV1 versus formoterol 12 mg
Transitional dyspnea index score versus placebo
Peak FEV1 versus placebo
125 ml (95% CI: 90, 160; p < 0.001) 69 ml (95% CI: 34, 105; p < 0.001)
85 ml (95% CI: 51, 119; p < 0.001)
ND
108 ml (p < 0.0001) 87 ml (p < 0.0001)
45 ml (p = 0.0102). Not Significant
1.29 units (95% CI: 0.73, 1.86; p < 0.001) 1.16 units (95% CI: 0.59, 1.73; p < 0.001) ND ND
259 ml (p < 0.0001)
53 ml (95% CI: 19, 87; p < 0.01)
ND
285 ml (p < 0.0001)
COPD: Chronic obstructive pulmonary disease; FEV1: Forced expiratory volume in 1 sec; ND: Not done.
licensing studies. Some physicians stratify medications containing an inhaled corticosteroid to this population; others do not. As outcomes from real-world observational studies become more important for insurers and health outcomes economists, and hospitals focus on 90 day readmission rates as an index of effective therapy, medications such as aclidinium bromide/formoterol fumarate will find their place in COPD care within a few short years. The alternatives to bronchodilator medications, with or without inhaled corticosteroids, in COPD remain elusive. Medications that are designed to alter the natural history of COPD have unclear regulatory pathways. An important concept that has been missed by many is that FEV1 in itself is a biomarker for COPD. FEV1 correlates quite poorly with many other clinical trial endpoints in a heterogeneous COPD population. Therefore, work has begun to determine if other biomarkers of COPD in addition to FEV1 might align better with the natural history of the disease. The COPD Biomarker Qualification Consortium is a collaborative effort between the FDA, academia, the COPD Foundation, the National Institutes of Health and pharmaceutical companies to accumulate evidence on the other clinically important biomarkers [31], which may show a path forward. This is especially important for a large number of COPD patients that have limited effects from bronchodilators. One of the efforts in some studies is to improve phenotyping of COPD patients, as smaller and more homogenous groups of patients may respond to medications more uniformly. Of particular importance will be studies performed in phenotypes of COPD that have a limited b2 or muscarinic component to symptoms. Only 15 -- 20% of smokers develop COPD and not all COPD patients have smoked; thus a genetic predisposition
432
clearly plays a role in development of COPD [32]. a-1 antitrypsin deficiency is one well-known genetic polymorphism, which is responsible for a small percentage of COPD cases. Understanding this mechanism of lung injury behind the genetic cause has allowed an entire class of medications to advance through clinical trials. As other genetic abnormalities in COPD are being found, the hope is that the drugs of tomorrow will be focused on medications that change the natural history of COPD, not on bronchodilators. The classes of medications that might improve the natural history of COPD would include drugs that decrease peribronchiolar fibrosis, decrease mesenchymal destruction, and improve alveolar growth. In summary, initial data from Phase III clinical trials of the aclidinium/formoterol inhaler appear to be promising for impacting lung function. We need to define if this benefit translates into improved long-term outcomes of decreased exacerbation frequency, improved quality of life and decreased disease-specific mortality. However, the introduction of this combination is a promising new development in the fight against COPD and will likely have a significant impact on the prescribing habits of physicians across the world.
Declaration of interest C Strange is a consultant and received travel monies monies from Astra Zeneca, Baxter, CSL Behring and Grifols in the past year on subjects related to COPD. He has received grants from Acelion, Alpha-1 Association, Alpha-1 Foundation, CSL Behring, Entera Health, NIH and Pearl Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Aclidinium bromide plus formoterol
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Cazzola M, Rogliani P, Segreti A, Matera MG. An update on bronchodilators in Phase I and II clinical trials. Expert Opin Investig Drugs 2012;21(10):1489-501
25.
Anoro Ellipta package insert. Available from: https://wwwgsksourcecom/gskprm/ htdocs/documents/ANORO-ELLIPTAPI-MGPDF
26.
Sliwinski P, Perng D-W, Chuchalin A, Jones PW. Efficacy and safety of oncedaily aclidinium bromide 200 µg in combination with formoterol in patients with COPD (Abstract). Thorax 2010;65:A136 A dose finding trial for the aclidinium/ formoterol fixed dose combination (FDC) in stable moderate to severe COPD.
.
27.
..
Singh D, Jones PW, Bateman ED, et al. Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study. BMC Pulm Med 2014;14(1):178 A large multicenter, Phase III clinical trial, which demonstrated the safety and efficacy of the aclidinium/
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formoterol FDC in moderate to severe COPD. 28.
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..
29.
434
D’Urzo A, Rennard S, Mergel V, et al. The AUGMENT COPD Trial: efficacy and safety of a fixed-dose combination of aclidinium bromide and formoterol fumarate in COPD patients. Chest 2014;145(3 Suppl):426A Another large Phase III 24 weeks randomized, double-blind, clinical trial, which demonstrated the efficacy and safety of the aclidinium/ formoterol FDC in COPD. D’Urzo AD, Rennard SI, Kerwin EM, et al. Efficacy and safety of fixed-dose combinations of aclidinium bromide/ formoterol fumarate: the 24-week, randomized, placebo-controlled
..
AUGMENT COPD study. Respir Res 2014;15(1):123 Large Phase III 24 weeks randomized, double-blind, clinical trial, which demonstrated the efficacy and safety of the aclidinium/formoterol FDC in COPD.
30.
Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187(4):347-65
31.
Casaburi R, Celli B, Crapo J, et al. The COPD Biomarker Qualification Consortium (CBQC). COPD 2013;10(3):367-77
32.
Pelaia G, Vatrella A, Gallelli L, et al. Biological targets for therapeutic
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interventions in COPD: clinical potential. Int J Chron Obstruct Pulmon Dis 2006;1(3):321-34
Affiliation
Chitra Lal†1 MD & Charlie Strange2 MD † Author for correspondence 1 Assistant Professor of Medicine, Medical University of South Carolina, Allergy and Sleep Medicine, Department of Pulmonary, Critical Care, 96 Jonathan Lucas Street, CSB 812, Msc 630, Charleston, SC 29425, USA Tel: +1 843 792 7776; Fax: +1 843 876 2057; E-mail: [email protected] 2 Professor of Medicine, Medical University of South Carolina, Department of Pulmonary, Critical Care, Allergy and Sleep Medicine, 96 Jonathan Lucas Street, CSB 812, Msc 630,Charleston, SC 29425, USA
Drug Evaluation
Aclidinium bromide plus formoterol for the treatment of chronic obstructive pulmonary disease
1.
Introduction
2.
Pharmacologic profiles
3.
Clinical efficacy
Chitra Lal† & Charlie Strange
4.
Regulatory affairs
†
5.
Conclusion
6.
Expert opinion
Medical University of South Carolina, Department of Pulmonary, Critical Care, Allergy and Sleep Medicine, Charleston, SC, USA
Introduction: Drugs that target dynamic hyperinflation such as long-acting b2 agonists and long-acting antimuscarinic antagonists form a cornerstone of chronic obstructive pulmonary disease (COPD) management. The idea of combining these two medications in a single formulation, which may potentially improve patient compliance, is novel and attractive. Areas covered: The pharmacologic profiles of aclidinium bromide and formoterol fumarate are discussed. However, studies to define drug interactions and alterations in the pharmacodynamics and pharmacokinetics of the fixed dose combination (FDC) of aclidinium bromide/formoterol fumarate in large populations remain unpublished. Results of Phase II and two Phase III pivotal trials, ACLIFORM/COPD and AUGMENT COPD, evaluating the FDC are discussed. Expert opinion: Initial data for the aclidinium/formoterol inhaler appears to be promising for impacting the lung function. To define if this benefit translates into improved long-term outcomes of decreased exacerbation frequency, improved quality of life and decreased disease-specific mortality are important. The introduction of this combination will likely have a significant impact on the prescribing habits of physicians across the world. Keywords: aclidinium bromide, bronchodilators, chronic obstructive pulmonary disease, formoterol fumarate, long-acting antimuscarinic antagonists, long-acting b-2 agonists Expert Opin. Pharmacother. (2015) 16(3):427-434
1.
Introduction
Chronic obstructive pulmonary disease (COPD) has been declared a global epidemic by the WHO with 64 million people affected worldwide. COPD is the third leading cause of death in the United States and the WHO predicts that COPD will become the third leading cause of death worldwide by 2030 [1,2]. It is also a leading cause of morbidity and disability as measured by impairment in activities of daily living [3]. The pathophysiology of COPD involves airway inflammation, mucus gland hyperplasia (in chronic bronchitis), and destruction of inter-alveolar septae (in emphysema) in response to noxious stimuli such as cigarette smoke. These airway changes result in limitation of expiratory flow and dynamic hyperinflation, which plays a critical role in the dyspnea perceived by COPD patients. Thus, drugs that target dynamic hyperinflation form a cornerstone of COPD management. Such medications include bronchodilators such as long-acting b2 agonists (LABA) such as salbutamol, formoterol, and salmeterol, which have been found to increase the inspiratory capacity and decrease the sensation of dyspnea [4]. Additionally, long-acting antimuscarinic antagonists (LAMA) such as tiotropium show similar improvements in inspiratory capacity [5]. The idea of combining these two medication classes in a single formulation to optimize lung 10.1517/14656566.2015.1000861 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology Route of administration Chemical structure
Aclidinium bromide/formoterol fumarate fixed dose combination (FDC) III Maintenance treatment of moderate and severe chronic obstructive pulmonary disease (COPD) Long-acting antimuscarinic agents + long-acting b-2 agonists FDC Inhalation Formoterol fumarate H
O
OH
H N
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HN
CH3
HO HO
OCH3
CH3
HN H
OCH3
N H
OH
O
Aclidinium bromide
HO +
N
Br– O
O
Pivotal trial(s)
S
ACLIFORM/COPD [27] AUGMENT COPD [28,29]
function, decrease dynamic hyperinflation and the sensation of dyspnea and potentially improve patient compliance is novel and attractive. The LABA/LAMA combinations, which have been studied, include tiotropium + formoterol, which was shown to improve the Forced Expiratory Volume in 1 sec (FEV1) and Forced Vital Capacity (FVC) more than the salmeterol + fluticasone 500 µg combination in patients with a baseline FEV1 of 55% predicted [6]. Similarly the arformoterol + tiotropium combination was shown to improve peak FEV1, peak FVC, inspiratory capacity and dyspnea more as compared to arformoterol or tiotropium alone [7]. A recent meta-analysis found that once-daily, inhaled Indacaterol/Glycopyronium fixed dose combination (FDC), showed superior efficacy (increased trough FEV1, decreased use of rescue medications, and improved percentage of patients achieving a minimal clinically important difference in the St. George’s Respiratory Questionnaire) compared with glycopyrronium and tiotropium, in patients with moderate to severe COPD [8]. Anoro Ellipta, which combines vilanterol (LABA) with umeclidinium bromide (LAMA), is the first LABA/LAMA combination approved for COPD treatment in the United States. The combination of aclidinium bromide + formoterol fumarate is the newest LAMA/LABA combination to be studied. 428
S
O
With these LABA/LAMA combinations in development, triple therapy with LABA/LAMA/inhaled corticosteroids is on the horizon. The impact of dual or triple combination therapy for COPD on patient compliance is expected to be substantial due to the ease of taking these medications in a single inhaler. Table 1 highlights the different FDC inhalers, which are either already on the market for COPD or are currently being evaluated for treatment of COPD [9]. 2.
Pharmacologic profiles
In order to understand the pharmacokinetics of the LABA/ LAMA combination, it is important to first review the pharmacologic profile of aclidinium and formoterol separately. Aclidinium bromide, marketed in the United States as Tudorza Pressair, is an anticholinergic agent with differential specificity for beneficial muscarinic receptors. In-vitro studies have shown that it has a long residence half-life at the human muscarinic M3 receptors (29.2 h) and short residence half-life at the M2 receptors (4.7 h) [10]. M3 receptors located in the airway smooth muscles mediate the bronchoconstrictor response to vagal nerve stimulation [11]. Thus aclidinium bromide is able to provide effective bronchodilation by binding to the M3 receptors in the
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Table 1. Medication combinations in COPD.
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Medications
LAMA/LABA Tiotropium/formoterol Tiotropium/salmeterol Tiotropium/olodaterol Vilanterol/umeclidinium bromide Aclidinium/formoterol Indacaterol/glycopyronium
Manufacturers of fixed dose combination inhalers approved and in development
Comments
Novartis and Pacira Boeringher Ingeheim Boeringher Ingeheim GlaxoSmithKline Forrest and Almirall Novartis Pharmaceuticals
Investigational Investigational Investigational LAMA/LABA US approved as Anoro Ellipta EMEA approved as Duaklir Genuair Investigational in US, approved in Europe as Xoterna Breezhaler, Ultibro Breezhaler Investigational
Glycopyrrolate/formoterol ICS/LABA Fluticasone propionate/salmeterol
GlaxoSmithKline, Elpen
Budesonide/formoterol Mometasone/formoterol
AstraZeneca Merck
Fluticasone propionate/formoterol
Mundi Pharma Napp, Skypharma Takeda Novartis Chiesi Farmaceutici S.p.A GlaxoSmithKline
Formoterol/ciclesonide Indacaterol/mometasone Carmoterol and budesonide Fluticasone furoate/vilanterol LAMA + LABA + ICS Tiotropium/salmeterol/ciclesonide Tiotropium/fluticasone/salmeterol Indacaterol/Glycopyrronium/mometasone Milveterol/darotropium/fluticasone furoate Tiotropium/formoterol/ciclesonide Aclidinium/formoterol/fluticasone or budesonide Tiotropium/formoterol/fluticasone or budesonide Glycopyronium/formoterol/mometasone Glycopyronium/formoterol/beclometasone MABA (muscarinic antagonist-b2 agonist)
Pearl Therapeutics
ICS/LABA US approved as Advair Diskus, Advair HFA ICS/LABA US approved as Symbicort ICS/LABA US approved as Dulera for asthma, investigational for chronic obstructive pulmonary disease Investigational Investigational for asthma Investigational Investigational Available in US as Breo Ellipta
NCIPD* NCIPD* NCIPD* NCIPD* Cipla NCIPD*
Investigational Investigational Investigational Investigational Approved in India as Triohale Investigational
NCIPD*
Investigational
Pearl Therapeutics Chiesi Farmaceutici S.p.A Almirall, Pfizer Argenta, Astra Zeneca Boeringer Ingelheim GlaxoSmithKline
Investigational Investigational Novel dual acting bronchodilators in a single molecule
*Not currently in public domain. ICS: Inhaled corticosteroids; LABA: Long-acting b-2 agonists; LAMA: Long-acting antimuscarinic agents.
airway smooth muscles for a longer duration, with few cardiac side effects, which are mediated by the M2 receptors [12]. In isolated guinea pig trachea, aclidinium has been shown to have comparable potency to ipratropium and tiotropium but faster onset of action than tiotropium. Aclidinium has a longer duration of action than ipratropium but shorter than tiotropium. In dogs, aclidinium has a favorable cardiac safety profile at supratherapeutic doses [10]. A study conducted in healthy human subjects found that once daily aclidinium in doses up to 800 µg per day does not prolong the QT interval [13]. The favorable cardiac safety profile of aclidinium was demonstrated in Phase III trials in COPD subjects with twice daily (b.i.d) aclidinium, 200 and 400 µg [14,15].
As compared to other anticholinergic agents on the market, aclidinium undergoes rapid hydrolysis in human plasma [16], thus indicating a low potential for any systemic side effects. Similar pharmacokinetics are seen in young (40 -- 59 years of age) and elderly subjects (‡ 70 years of age) [17]; thus no dose adjustment is needed for age. The urinary excretion of aclidinium has been found to be low in human studies [18], thus indicating that dose adjustment for renal failure is not required. Aclidinium 400 µg inhaled b.i.d is indicated for maintenance treatment of COPD. A Phase IIa study comparing aclidinium 400 µg b.i.d to tiotropium 18 µg once a day showed that whereas both drugs produced greater bronchodilation than
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placebo, significant differences between aclidinium and tiotropium, in favor of aclidinium, were seen as early as day 1 [19]. This suggests that maximal efficacy with aclidinium might be reached earlier than with tiotropium. In addition, the increased bronchodilation with aclidinium as compared to tiotropium was more pronounced in the second half of the day, suggesting greater benefit with b.i.d dosing. Subsequent larger Phase III studies (ACCORD I and ATTAIN) showed that aclidinium provided early and sustained, statistically significant improvements in peak FEV1, compared to placebo. Formoterol is a LABA, which has been on the market for some time and combines the advantages of high potency, a rapid onset of action and a long duration of action of > 12 h. The high lipophilicity of formoterol likely is responsible for long retention times in the human airway smooth muscle, as relaxant effects are resistant to repeated washings [20]. In addition, formoterol has higher potency, selectivity and affinity for the b-2 adrenoreceptor as compared to short-acting b-2 agonists [21]. Formoterol has been available as maintenance therapy for COPD for about 16 years and has been shown to produce long-term improvements in lung function, quality of life and exacerbation frequency [22,23]. The pharmacologic profile of aclidinium and formoterol makes them ideal for combination in a single inhaler [24]. Characteristics of the FDC of aclidinium bromide/formoterol fumarate are listed in the drug summary Box 1. The studies to define whether there are drug interactions, alterations in pharmacodynamics and pharmacokinetics of the FDC in large population samples remain unpublished. Use of the aclidinium bromide/formoterol fumarate combination in renally or hepatically impaired subjects also remains to be studied in large populations. Of note, the combination of umeclidinum/vilanterol showed an increase in the area under the curve of the b agonist when co-administered with the anticholinergic [25]. Similar details for the aclidinium bromide/formoterol fumarate combination remain pending at this time. 3.
Clinical efficacy
A few Phase II and Phase III studies have evaluated the combination of aclidinium and formoterol and are summarized here. The aclidinium bromide/formoterol fumarate combination has been developed by Almirall and Forest laboratories. Three Phase II studies evaluating this combination have been completed. A dose finding clinical trial compared three doses of formoterol (6, 12, 18 µg) combined with aclidinium bromide 200 µg, aclidinium bromide 200 µg monotherapy and formoterol 12 µg monotherapy, in stable moderate to severe COPD [26]. All the aclidinium and formoterol combinations produced greater improvements in lung function than monotherapy with either drug or placebo, except the comparison between aclidinium/formoterol 6 µg combination and formoterol 12 µg monotherapy. The bronchodilation produced by 430
the formoterol 18 µg/aclidinium 200 µg combination was similar to that produced by formoterol 12 µg/aclidinium 200 µg combination, thus suggesting that 12 µg formoterol was the optimal dose. No safety concerns were discovered. Two additional Phase II clinical trials evaluated the efficacy of the aclidinium/formoterol combination as compared to formoterol alone. Almirall and Forest laboratories announced that these studies also met their primary endpoints [24]. Positive results from these Phase II clinical trials prompted the initiation of Phase III clinical studies. ACLIFORM/ COPD(ACLIdinium/FORMoterol fumarate combination for investigative use in the treatment of moderate to severe COPD) was a 24-week randomized, double-blind trial, which compared the 400/6 mcg and 400/12 mcg FDCs of aclidinium bromide/formoterol fumarate with aclidinium bromide 400 mcg, formoterol fumarate 12 mcg and placebo administered b.i.d [27]. This was a multicenter trial conducted at 193 centers in 22 countries in patients with moderate to severe COPD. Patients were randomized to receive either aclidinium/formoterol 400/12 µg (n = 385), 400/6 µg (n = 381), aclidinium 400 µg (n = 385), formoterol 12 µg (n = 384) or placebo (n = 194) b.i.d via Genuair/Pressair. At Week 24, aclidinium/formoterol 400/12 µg and 400/6 µg lead to significant improvements from baseline in 1-h post-dose FEV1 versus aclidinium (125 ml [95% CI: 90, 160; p < 0.0001] and 69 ml [95% CI: 34, 105; p < 0.001], respectively) and trough FEV1 versus formoterol (85 ml [95% CI: 51, 119; p < 0.001] and 53 ml [95% CI: 19, 87; p < 0.01], respectively (co-primary endpoints). Both aclidinium/ formoterol 400/12 µg and 400/6 µg produced significant improvements in Transition Dyspnoea Index focal score versus placebo (1.29 units [95% CI: 0.73, 1.86; p < 0.001] and 1.16 units [95% CI: 0.59, 1.73; p < 0.001], respectively; secondary endpoint). Both aclidinium/formoterol FDC doses were found to be well tolerated with similar safety profiles to aclidinium and formoterol monotherapy. A second pivotal trial, AUGMENT COPD, was a 24-week, randomized, double-blind trial conducted in 1692 stable COPD patients with a mean prebronchodilator FEV1 of 1.36 liters [28,29]. Patients were randomized to receive aclidinium 400 µg + formoterol 12 µg (FDC 400/12), aclidinium 400 µg + formoterol 6 µg (FDC 400/6), aclidinium 400 µg, formoterol 12 µg, or placebo. Statistically significant improvements were reported in the change from baseline for the co-primary endpoints of FEV1 1-h post-dose at week 24, by the 400/12 µg combination of aclidinium/formoterol, versus 400 mcg aclidinium (108 ml, p < 0.0001) and for the morning predose trough FEV1 versus formoterol 12 µg at week 24 (45 ml, p = 0.0102). Statistically significant improvements were also seen by the 400/6 µg combination in (FEV1) 1-h post-dose versus aclidinium 400 µg (87 ml, p < 0.0001). The 400/6 µg combination did not reach significance as compared to formoterol 12 µg at week 24, for the change from baseline in morning pre-dose trough FEV1. Both combinations demonstrated statistically significant improvements
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compared to placebo in the above two endpoints. Peak FEV1 improved at 24 weeks by 285 ml with the 400/12 µg combination versus placebo (p < 0.0001) and by 259 ml with the 400/6 µg combination versus placebo (p < 0.0001). Significant results from both Phase III trials are shown in Table 2. In summary, the 400/12 µg dose of aclidinium/formoterol appears to be the optimally effective dose for moderate to severe COPD. Safety and tolerability In the AUGMENT COPD and ACLIFORM/COPD trials, both fixed-dose combination treatment arms were reported to be well tolerated. Discontinuation rates due to adverse events (AEs) were similar in all treatment groups (both FDCs aclidinium + formoterol 400/12 µg and 400/6 µg, aclidinium 400 µg, formoterol 12 µg and placebo). Serious AEs occurred with similar frequency in all treatment groups. Commonest AEs (> 5% of patients, any group) were cough (FDC 400/12, 5.1%; FDC 400/6, 3.9%; aclidinium, 2.1%; formoterol 12, 3.0%; Placebo, 3.6%) and nasopharyngitis (4.8, 5.1, 3.6, 6.6, 3.6%, respectively). A clinical trial evaluating the long-term safety and tolerability of the Aclidinium/ Formoterol FDC at 52 weeks has been completed but the results have not been published as yet (ClinicalTrials.gov identifier: NCT01437540).
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3.1
4.
Regulatory affairs
Based on these clinical trials, Almirall announced the submission of the Marketing Authorisation Application to the European Medicines Agency for the FDC of aclidinium bromide/ formoterol fumarate for the treatment of COPD, in November 2013. AstraZeneca announced on 11/24/14 that Duaklir Genuair (aclidinium bromide/formoterol fumarate 340/12 mcg) has been granted Marketing Authorisation by the European Commission to be used as a maintenance bronchodilator treatment in adult patients with COPD. In the USA, Forest Laboratories and Almirall announced in August 2013 that they would delay the planned submission of a New Drug Application (NDA) for the combination of aclidinium bromide/formoterol fumarate for COPD. This decision was based on comments provided by the US FDA at a pre-NDA meeting. It was reported that the delay is related to resolving chemistry, manufacturing and control (CMC) specifications associated with the FDC. According to an update provided by Forest Laboratories and Almirall in April, 2014, they are in discussions with the FDA to address questions related to CMC of the aclidinium bromide/formoterol fumarate FDC. 5.
Conclusion
The aclidinium/formoterol combination has been reported to produce a greater degree of bronchodilation than formoterol
or aclidinium monotherapy alone. The combination appears to be safe and well tolerated in clinical trials. The availability of the aclidinium/formoterol FDC on the market will add a novel LAMA/LABA combination for the treatment of moderate to severe COPD. 6.
Expert opinion
The easiest pathway for COPD drug approval has been for bronchodilators, as they target symptom relief. In addition, FEV1 is a universally accepted and easily measurable outcome measure for COPD, although not necessarily the most correlated with patient-reported symptoms. Other COPD outcome measures, particularly composite measures and those that encompass patient-reported outcomes, face different levels of regulatory scrutiny. Therefore, approved COPD medications to date seem to be largely redundant as the levels of bronchodilation elicited by this enlarging pharmacopeia have minimal differences. In addition, the application of short-acting bronchodilators for acute symptom relief will remain an important part of therapy that will buffer any larger differences between long-acting bronchodilators. Nevertheless, most medications achieve rapid uptake in a COPD marketplace because of the large unmet need caused by COPD-associated dyspnea. One advantage of improved numbers of similar medications on the market is that market competition might force price reductions for COPD inhalers. To date, the transition to generic medications for COPD has been slow due to the inherent linkage of the device to the medication. In the absence of generic medications, the next most effective alternative for medication cost reduction is market competition. The US cost for aclidinium bromide/formoterol fumarate remains unknown at the time of writing this manuscript. The Global initiative for Chronic Obstructive Lung Disease [30] recommends combining bronchodilator medications from different pharmacologic classes to improve efficacy and minimize side effects, as compared to increasing the dose of a single bronchodilator. The use of long-acting bronchodilators is preferable to short-acting bronchodilators because they decrease exacerbation frequency and have strong correlative trends with improved COPD and all-cause mortality. As medications that decrease exacerbation frequency likely save costs, it is hoped that an exacerbation reduction study can be done with this and other LAMA/LABA combinations. Objective studies on the refill rates of aclidinium bromide/ formoterol fumarate will be interesting once it is marketed, as the large unmet opportunity to improve medication compliance might be improved by this medication. The largest question generated by LAMA/LABA combination inhalers is whether inhaled corticosteroid medications are necessary for best outcomes in COPD. Whereas real-world studies in an older dyspneic population often contain individuals with past asthma, these individuals are often excluded in
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Table 2. Significant results from Phase III trials evaluating the aclidinium bromide/formoterol fumarate fixed dose combination at 24 weeks. Dose
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ACLIFORM-COPD
400/12 µg 400/6 µg
AUGMENT-COPD
400/12 µg 400/6 µg
Co-Primary endpoints
Secondary endpoints
1-h post-dose FEV1 versus aclidinium 400 mg
Trough FEV1 versus formoterol 12 mg
Transitional dyspnea index score versus placebo
Peak FEV1 versus placebo
125 ml (95% CI: 90, 160; p < 0.001) 69 ml (95% CI: 34, 105; p < 0.001)
85 ml (95% CI: 51, 119; p < 0.001)
ND
108 ml (p < 0.0001) 87 ml (p < 0.0001)
45 ml (p = 0.0102). Not Significant
1.29 units (95% CI: 0.73, 1.86; p < 0.001) 1.16 units (95% CI: 0.59, 1.73; p < 0.001) ND ND
259 ml (p < 0.0001)
53 ml (95% CI: 19, 87; p < 0.01)
ND
285 ml (p < 0.0001)
COPD: Chronic obstructive pulmonary disease; FEV1: Forced expiratory volume in 1 sec; ND: Not done.
licensing studies. Some physicians stratify medications containing an inhaled corticosteroid to this population; others do not. As outcomes from real-world observational studies become more important for insurers and health outcomes economists, and hospitals focus on 90 day readmission rates as an index of effective therapy, medications such as aclidinium bromide/formoterol fumarate will find their place in COPD care within a few short years. The alternatives to bronchodilator medications, with or without inhaled corticosteroids, in COPD remain elusive. Medications that are designed to alter the natural history of COPD have unclear regulatory pathways. An important concept that has been missed by many is that FEV1 in itself is a biomarker for COPD. FEV1 correlates quite poorly with many other clinical trial endpoints in a heterogeneous COPD population. Therefore, work has begun to determine if other biomarkers of COPD in addition to FEV1 might align better with the natural history of the disease. The COPD Biomarker Qualification Consortium is a collaborative effort between the FDA, academia, the COPD Foundation, the National Institutes of Health and pharmaceutical companies to accumulate evidence on the other clinically important biomarkers [31], which may show a path forward. This is especially important for a large number of COPD patients that have limited effects from bronchodilators. One of the efforts in some studies is to improve phenotyping of COPD patients, as smaller and more homogenous groups of patients may respond to medications more uniformly. Of particular importance will be studies performed in phenotypes of COPD that have a limited b2 or muscarinic component to symptoms. Only 15 -- 20% of smokers develop COPD and not all COPD patients have smoked; thus a genetic predisposition
432
clearly plays a role in development of COPD [32]. a-1 antitrypsin deficiency is one well-known genetic polymorphism, which is responsible for a small percentage of COPD cases. Understanding this mechanism of lung injury behind the genetic cause has allowed an entire class of medications to advance through clinical trials. As other genetic abnormalities in COPD are being found, the hope is that the drugs of tomorrow will be focused on medications that change the natural history of COPD, not on bronchodilators. The classes of medications that might improve the natural history of COPD would include drugs that decrease peribronchiolar fibrosis, decrease mesenchymal destruction, and improve alveolar growth. In summary, initial data from Phase III clinical trials of the aclidinium/formoterol inhaler appear to be promising for impacting lung function. We need to define if this benefit translates into improved long-term outcomes of decreased exacerbation frequency, improved quality of life and decreased disease-specific mortality. However, the introduction of this combination is a promising new development in the fight against COPD and will likely have a significant impact on the prescribing habits of physicians across the world.
Declaration of interest C Strange is a consultant and received travel monies monies from Astra Zeneca, Baxter, CSL Behring and Grifols in the past year on subjects related to COPD. He has received grants from Acelion, Alpha-1 Association, Alpha-1 Foundation, CSL Behring, Entera Health, NIH and Pearl Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Affiliation
Chitra Lal†1 MD & Charlie Strange2 MD † Author for correspondence 1 Assistant Professor of Medicine, Medical University of South Carolina, Allergy and Sleep Medicine, Department of Pulmonary, Critical Care, 96 Jonathan Lucas Street, CSB 812, Msc 630, Charleston, SC 29425, USA Tel: +1 843 792 7776; Fax: +1 843 876 2057; E-mail: [email protected] 2 Professor of Medicine, Medical University of South Carolina, Department of Pulmonary, Critical Care, Allergy and Sleep Medicine, 96 Jonathan Lucas Street, CSB 812, Msc 630,Charleston, SC 29425, USA
