There has been, and still is, a strong interest in developing once-daily bronchodilators for chronic obstructive pulmonary disease in an attempt to simplify treatment and increase adherence to the prescribed therapy
Mario Cazzola MD
Unit of Respiratory Clinical Pharmacology,
Department of Systems Medicine,
University of Romea Tor Vergata, Italy
Maria Gabriella Matera MD PhD
Centre of Excellence for Cardiovascular Diseases, Department of Experimental Medicine, Section of Pharmacology ‘L. Donatelli’, Second University of Naples, Italy
Email: [email protected]
The central role of long-acting bronchodilators in the treatment of chronic obstructive pulmonary disease (COPD) presents important marketing opportunities. Therefore, the great interest within the pharmaceutical industry in the discovery of novel bronchodilators to be used as a single agent or as part of a combination therapy for the treatment of COPD is not surprising. This review describes new long-acting bronchodilators that have recently been approved or are currently undergoing clinical development.
Bronchodilators aim to alleviate bronchial obstruction and airflow limitation. They reduce hyperinflation, and improve emptying of the lung and exercise performance. Consequently, although COPD patients often exhibit limited reversibility of airflow obstruction, bronchodilators are a key treatment of COPD.1–3
Because of this central role, there is still considerable attention in generating new bronchodilators that act via emerging targets.2,3 Unfortunately, new classes of bronchodilators have proved difficult to develop.1–3 This is the main reason for which many research groups have sought to improve the existing classes of bronchodilators. In particular, there has been, and still is, a strong interest in developing once-daily bronchodilators in an attempt to simplify the treatment and, consequently, increase adherence to the prescribed therapy.1–3 This is a crucial issue in the treatment of COPD because patients suffering from this condition with higher adherence experience fewer hospitalisations and lower healthcare costs than those with lower adherence behaviour.4
Long-acting β2-agonists (LABAs)
The need for a rapid onset of action and a long duration of the broncholytic effect is the likely reason for the development of new fast-acting LABAs, which reassures the patient of the effectiveness of the prescribed treatment, and which have true 24-hour duration of action to enhance adherence.1–3,5
Indacaterol is the archetype of once-daily LABAs and is already marketed as a maintenance therapy in patients with moderate to severe COPD.6 Several other once-daily LABAs, such as olodaterol, vilanterol and abediterol, have recently been developed.1–3,5 All have a near full agonist profile at human β2-adrenoceptors.1–3,5 All produce a dose-dependent rapid bronchodilation, which is maintained over 24 hours, with a safety and tolerability profile similar to that of placebo.1–3,5 All seem to have greater effects on most COPD symptoms and health-related quality of life (HRQoL) than formoterol or salmeterol, although differences between once-daily and twice-daily LABAs are not always statistically significant.3 Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have now approved olodaterol and vilanterol, while abediterol is in Phase III clinical development.3
Long-acting muscarinic receptor antagonists (LAMAs)
The fundamental role of tiotropium bromide, the only LAMA approved for maintenance therapy in COPD until recently, in the maintenance treatment of COPD has prompted further research to identify new LAMAs. There are number of LAMAs that are being identified but only a few have reached clinical development.7,8
Umeclidinium bromide has recently been licenced in Canada, Europe and the USA for the long-term, once-daily maintenance treatment of COPD, and is under review in several other countries.9 The data generated by the pivotal trials indicate that umeclidinium bromide delivered once-daily via the ElliptaTM inhaler, which delivers consistent doses within the respirable range over the lifetime of the product, is an effective and well-tolerated treatment for COPD.9
Glycopyrronium bromide, already on the market as a once-daily LAMA, is in clinical development in several different formulations by several pharmaceutical companies. A metered-dose inhaler (MDI) of glycopyrronium bromide (PT001), using a porous phospholipid microparticle technology that has been developed to provide respirable particles in which microcrystals of the drugs are associated with the particles, has been formulated and manufactured.7,8 SUN-101, formerly EP-101, is an inhalation solution formulation of glycopyrronium bromide optimised for administration via the investigational eFlow Nebulizer System.7,8 CHF-5259 is another inhaled formulation of glycopyrronium bromide that is delivered using a pressurised metered-dose inhaler (MDI). CHF-5259 and PT001 are likely being developed as twice-daily bronchodilators.7,8 The twice-daily dosing of bronchodilators is still considered a useful approach at least for the symptomatic treatment of COPD.2,3
There is strong clinical evidence for combining LABAs and LAMAs,10 although the nature of the clinical results obtained by the co-administration of these drugs is not entirely clear from the pharmacological point of view.11 In any case, combining a LABA and a LABA in the treatment of patients with COPD might have a rational by providing synergistic benefit on airway smooth muscle relaxation of both medium and small human airways, which, in turn, may have major implications for the use of such combinations in the clinic.12,13 Because a LAMA/LABA combination appears to play an important role in optimising bronchodilation, there is a strong interest in developing new LABA/LAMA fixed-dose combinations (FDCs).
The pivotal Phase III IGNITE programme explored the effects of glycopyrronium/indacaterol 85/43μg FDC and documented a significant improvement in lung function and patient-reported outcomes including breathlessness and rescue medication use, reduced rates of COPD exacerbations and improved HRQoL compared with the current standard of care.6 It has been licenced in Europe, Japan and in several other countries and is under review by the FDA.6
Several pivotal clinical trials have documented the impact of umeclidinium bromide/vilanterol FDC on lung function and other outcome measures such as QoL, dyspnoea, rescue medication use and exercise capacity, with no clinically meaningful treatment-related changes in vital signs or clinical laboratory parameters.14 Inhaled umeclidinium bromide/vilanterol 62.5/25μg received approval in the USA, Canada, Europe and Japan.14
Two identical one-year studies have documented the efficacy and safety of once-daily tiotropium/olodaterol FDC delivered via Respimat in the maintenance therapy of patients with moderate to very severe COPD.15 The dose of 5μg for each of the two bronchodilators seems to be optimal, providing a significant improvement in all three primary endpoints (FEV1, AUC0-3, trough FEV1, and health status) and several secondary endpoints compared with tiotropium or olodaterol as monotherapy.15
Aclidinium bromide/formoterol is another investigational FDC.2,3,16 Two pivotal Phase III clinical trials have been conducted. The treatment combination was administered twice-daily to patients in the trial, which met its primary endpoints.2,3 The trial demonstrated statistically significant improvements compared to placebo. The combination was well tolerated in both studies.
PT003 is an inhaled combination of PT001 (glycopyrronium bromide) and formoterol delivered via the eFlow Nebulizer System.2,3 It is the only LAMA/LABA combination product in late-stage development in an HFA MDI dosage formulation. Phase II trials have shown that glycopyrronium/formoterol 18/9.6μg is the appropriate dose for Phase III development.
Bifunctional muscarinic β2-agonist molecules (MABAs)
MABAs constitute the real novel approach to dual bronchodilator therapy by combining muscarinic antagonism (MA) and β2-agonism (BA) in a single molecule. MABAs deliver a fixed ratio into every region of the lung. This feature has the great advantage of reducing the complexity of combination inhalers via a single pharmacokinetic profile, which enables a uniform ratio of activities at the cellular level, and a simplified clinical development programme.17 However, one limitation of MABA molecules is that the ratio of MA and BA activities cannot be adjusted as needed, which limits dosing flexibility.17 Moreover, while MABAs show promise, there is much still to be understood as to how best to use these drugs and how they will compare to existing FDC inhalers.2,3
GSK961081 will likely be the first MABA to be commercialised. It induces sustained bronchodilation similar to that of tiotropium plus salmeterol, but with a more rapid onset of action.2,3 AZD2115 is still in Phase II development by AstraZeneca and has recently gained rights to Almirall’s MABA platform in preclinical development (LAS191351, LAS194871) and Phase I (LAS190792).
The efficacy of combination therapy with a LABA plus a low dose of inhaled corticosteroids (ICS) in patients with COPD has been well documented and there is a strong interest in developing new ICS/LABA combinations, mainly on a once-daily basis, in an attempt to simplify treatment, but also to overcome the loss of patent protection.
Fluticasone furoate/vilanterol is a novel ICS/LABA FDC that, by simplifying the dosing schedule, allows for the first time a shift from twice-daily to once-daily treatment, with an acceptable safety and tolerability profile that is consistent with the ICS/LABA class.18 Contribution of vilanterol to fluticasone furoate/vilanterol in COPD patients has been demonstrated on 0–4 hour weighted mean FEV1, whereas contribution of fluticasone furoate to fluticasone furoate/vilanterol has been shown by reductions in annual rate of moderate and severe exacerbations.18 The FDA has approved fluticasone furoate/vilanterol dry powder inhaler (DPI) for the long-term, once-daily maintenance treatment of airflow limitation in COPD patients, including chronic bronchitis and/or emphysema and to reduce exacerbations of COPD in patients with a history of exacerbations, whereas the EMA has recommended the granting of a marketing authorisation for fluticasone furoate/vilanterol DPI for the symptomatic treatment of adults with COPD with a FEV1<70% predicted normal (post-bronchodilator) with an exacerbation history despite regular bronchodilator therapy.
A combination of mometasone furoate and formoterol administered on a twice-daily basis has already been approved in US for asthma in two different doses of the mometasone component and Phase III trials in COPD have also been completed, although the FDA has not yet approved it for a COPD indication.19 In view of the fact that mometasone is also effective when it is administered once-daily, a mometasone/indacaterol FDC (QMF149) is being evaluated in patients with COPD administered via the Breezhaler device, but apparently its clinical development is still in Phase II.3
LAMA/LABA/ICS triple therapy
A growing body of evidence suggests that triple therapy with LAMAs, LABAs and ICS is efficacious in patients with more severe COPD, such as those with frequent exacerbations. This makes triple therapy an attractive combination in COPD, although it has still inadequate scientific support. Even so, a variety of triple combinations are currently under development.20
The first triple inhaler containing tiotropium 9μg, formoterol fumarate 6μg and ciclesonide 200μg, to be taken once-daily is already available in India.20 This formulation is a suspension-based product and is the only pMDI to contain three therapeutics in one device. The three drugs are suspended in HFA 227, with apparently no other additives.
Umeclidinium/vilanterol/fluticasone furoate 62.5/25/100µg is under development on a once-daily basis.20 A 10,000-patient trial (IMPACT study) will investigate whether the umeclidinium/vilanterol/fluticasone furoate combination, delivered through Ellipta inhaler, can reduce the annual rate of moderate and severe exacerbations compared with umeclidinium/vilanterol, and vilanterol/fluticasone furoate.20
Other triple combinations, glycopyrronium/formoterol/budesonide pMDI (PT010) and beclomethasone/formoterol 100/6µg plus glycopyrronium at dosage of 12.5 or 25µg (CHF5993) are under clinical evaluation on a twice-daily basis.20 In any case, there is documentation that systemic exposure to budesonide following administration of PT010 320/14.4/9.6μg was slightly higher but bioequivalent to budesonide/formoterol pMDI 320/9μg.20 It is likely that glycopyrronium/indacaterol/mometasone FDC is under development on a once-daily basis, but detailed status has not yet been disclosed.20
In any case, we presume that the MABA approach will provide the best opportunity to develop triple combinations because only two drugs need to be co-formulated, rather than three.2 A combination of GSK961081 and fluticasone furoate is in an early phase of clinical development.
Because there is a well-established belief that the only limits set for the development of a long-lasting bronchodilator with a new product profile are medical needs and marketing opportunities, many research groups have sought to improve the existing classes of bronchodilators.3 For this reason, there is currently the launch of many, perhaps too many, new long-acting bronchodilators that can be administered alone or in combination with another bronchodilator or an ICS.
Despite differences in the pharmacological properties between these bronchodilators, data from randomised controlled trials (RCTs) suggest that they perform similarly under RCT conditions, and this generates the spontaneous question whether we really need all these new bronchodilators.
However, because patients enrolled in RCTs represent only people selected for their specific characteristics that match the requirements of the trial and do not correspond to the general population, it is likely that in real life there are substantial differences between bronchodilators in terms of clinical and healthcare outcomes in patients with COPD from which we can take advantage to improve the treatment of each individual patient.
- Long-acting bronchodilators are central in the treatment of COPD.
- New once-daily fast-acting LABAs enhance adherence of COPD patients to prescribed treatment.
- Combining a LAMA and a LABA in the treatment of COPD provides synergistic benefit on airway smooth muscle relaxation.
- The interest in developing new ICS/LABA combinations is likely due to the need to overcome the loss of patent protection.
- Triple therapy is an attractive combination in COPD, but it still has inadequate scientific support.
- Cazzola M et al. Pharmacology and therapeutics of bronchodilators. Pharmacol Rev 2012;64(3):450–504.
- Cazzola M, Matera MG. Bronchodilators: current and future. Clin Chest Med 2014;35(1):191–201.
- Cazzola M, Page CP. Long-acting bronchodilators in COPD: where are we now and where are we going? Breathe 2014;10(2):110–20.
- Simoni-Wastila L et al. Association of chronic obstructive pulmonary disease maintenance medication adherence with all-cause hospitalization and spending in a Medicare population. Am J Geriatr Pharmacother 2012;10(3):201–10.
- Cazzola M et al. β2-agonist therapy in lung disease. Am J Respir Crit Care Med 2013;187(7):690–6.
- Matera MG, Rogliani P, Cazzola M. Indacaterol for the treatment of chronic obstructive pulmonary disease. Expert Opin Pharmacother 2015;16(1):107–15.
- Cazzola M, Page C, Matera MG. Long-acting muscarinic receptor antagonists for the treatment of respiratory disease. Pulm Pharmacol Ther 2013;26(3):307–17.
- Matera MG, Rogliani P, Cazzola M. Muscarinic receptor antagonists for the treatment of chronic obstructive pulmonary disease. Expert Opin Pharmacother 2014;15(7):961–77.
- Segreti A et al. Umeclidinium for the treatment of chronic obstructive pulmonary disease. Expert Rev Respir Med 2014;8(6):665–71.
- van der Molen T, Cazzola M. Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes. Prim Care Respir J 2012;21(1):101–18.
- Cazzola M, Molimard M. The scientific rationale for combining long-acting β2-agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther 2010;23(4):257–67.
- Cazzola M et al. Pharmacological characterization of the interaction between aclidinium bromide and formoterol fumarate on human isolated bronchi. Eur J Pharmacol 2014;745:135–43.
- Cazzola M et al. Translational study searching for synergy between glycopyrronium and indacaterol. COPD 2015;12(2):175–81.
- Matera MG et al. Umeclidinium bromide + vilanterol for the treatment of chronic obstructive pulmonary disease. Expert Rev Clin Pharmacol 2015;8(1):35–41.
- Buhl R et al. Once-daily tiotropium and olodaterol fixed-dose combination via the Respimat® improves outcomes vs mono-components in COPD in two 1-year studies. European Respiratory Society Annual Congress, Munich, Germany, 6–10 September, 2014: abstr OP1895.
- Cazzola M, Rogliani P, Matera MG. Aclidinium bromide/formoterol fumarate fixed-dose combination for the treatment of chronic obstructive pulmonary disease. Expert Opin Pharmacother 2013;14(6):775–81.
- Cazzola M, Lopez-Campos JL, Puente-Maestu L. The MABA approach: a new option to improve bronchodilator therapy. Eur Respir J 2013;42(4):885–7.
- Matera MG, Capuano A, Cazzola M. Fluticasone furoate and vilanterol inhalation powder for the treatment of COPD. Expert Rev Respir Med 2014;DOI: 10.1586/17476348.2015.986468.
- Cazzola M et al. Inhaled corticosteroids for chronic obstructive pulmonary disease. Expert Opin Pharmacother 2013;14(18):2489–99.
- Cazzola M, Matera MG. Triple combinations in chronic obstructive pulmonary disease – is three better than two? Expert Opin Pharmacother 2014;15(17):2475–8.