Triple combinations in chronic obstructive pulmonary disease – is three better than two?

Abstract

A growing body of evidence suggests that triple therapy with an antimuscarinic agent, a long-acting β₂-agonist, and an inhaled corticosteroid is efficacious in patients with more severe chronic obstructive pulmonary disease (COPD), such as those with frequent exacerbations. Moreover, this therapy is often prescribed in real-life management of COPD, even in patients who are not suffering from severe COPD. All this makes triple therapy an attractive therapeutic approach. Therefore, a variety of triple combinations are currently under development. However, there are a number of issues that need to be addressed in order to optimize the use of triple therapy in COPD because data are still too scarce and studies too short to generate a strong recommendation.

Keywords::

• bronchodilators
• chronic obstructive pulmonary disease
• combination therapy
• inhaled corticosteroids
• triple therapy

1. What guidelines suggest and healthcare practitioners do

National Institute for Health and Clinical Excellence (NICE) guidelines in the UK suggest that patients starting on long-acting antimuscarinic agents (LAMA) or a long-acting β₂-agonist (LABA) + an inhaled corticosteroid (ICS) would then progress to triple therapy (LABA+LAMA+ICS) if exacerbations or breathlessness persist [1], but Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends the combination ICS + LAMA + LABA as first choice in patients group D, those who are more severe, as it was recognized that a few patients with newly recognized very severe chronic obstructive pulmonary disease (COPD) could benefit from starting with a triple therapy [2].

Though there are these well-defined restrictions on its use, triple therapy is widely prescribed in real-life management of COPD, even in patients with mild or moderate COPD severity [3]. General practitioners are not the only ones to follow this approach. Indeed, even specialists in respiratory medicine often prefer to use the triple therapy even in patients who are not suffering from severe COPD [4] Compared to other medications, patients starting on a LAMA seem to be most likely to escalate to triple therapy in 24 months, but on the other hand, nearly one-fourth of the patients prescribed triple therapy at baseline seem to step down to LABA+ICS or LAMA within 24 months [5].

The discrepancy between what is suggested by the guidelines [1] and recommendations [2] and what healthcare practitioners prescribe [3-5] is likely due to the confidence that they have in starting a full treatment to ensure the best therapy for their patients as compared to the inadequate evidence on which this clinical practice is based. Nevertheless, a growing body of evidence suggests that triple therapy with LABAs, LAMAs, and ICS is efficacious in patients with more severe COPD, such as those with frequent exacerbations [6].

2. Evidences in favor of triple therapy

Based on published data, it is unlikely that a robust clinical case can be built in favor of triple therapy [7]. Nevertheless, we believe that meta-analyses of published data or pooled analyses of primary data generated using triple therapy in COPD could help us in understanding its real role.

In 2011, a Cochrane review was able to examine only three studies [8]. Heterogeneity and wide confidence intervals did not draw any conclusions from the outcomes except for an improvement in the quality of life scores and lung function for triple therapy versus tiotropium alone. Also a systematic literature search found 4 articles that evaluated triple therapy for the management of COPD which reported that lung function, dyspnea, and health related quality of life (HRQoL) data showed statistical significant changes with triple therapy compared to LAMA monotherapy, but the changes did not reach clinical importance and, moreover, exacerbation data were inconsistent between the trials reporting this outcome [9].

However, subsequent evaluations have provided us with different information. A systematic review assessed six studies contrasting ICS/LABA (fluticasone propionate/salmeterol or budesonide/formoterol) plus tiotropium versus tiotropium monotherapy [10]. Compared with tiotropium, ‘triple therapy’ induced a further increase in pre- and postbronchodilator FEV₁, an improvement in HRQoL, and a decrease in the rate of COPD exacerbations.

A more recent meta-analysis that has been performed to evaluate the efficacy and safety of adding fluticasone propionate/salmeterol to tiotropium in COPD patients, and has included six trials, has confirmed that the addition of fluticasone propionate/salmeterol to subjects with COPD treated with tiotropium significantly improves lung function, HRQoL, and COPD exacerbations without increasing the risk of adverse events [11].

These findings seem to support the use of triple therapy in patients with COPD. More recent studies seem to give further confirmation. A Scottish real-life retrospective analysis has shown that in patients exposed to ICS, concomitant use of LAMA alone as dual therapy or in combination with LABA as triple therapy was associated with reductions in all-cause mortality, while concomitant use of LABA without LAMA conferred no reduction [12]. Moreover, only triple therapy was found to confer benefits on cardiovascular mortality. Interestingly, it has also been documented that tiotropium plus fluticasone propionate/salmeterol therapy is more effective than tiotropium, salmeterol, and fluticasone propionate/salmeterol alone for reducing airway wall thickness in COPD [13].

However, a network meta-analysis of FEV₁ has reported that dual bronchodilation with indacaterol + tiotropium is expected to be comparable to triple therapies [14] and, moreover, the Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM) trial has documented that in patients with severe COPD receiving tiotropium + salmeterol, the risk of moderate or severe exacerbations was similar among those who discontinued ICSs and those who continued ICS therapy [15]. However, there was a greater decrease in lung function during the final step of ICS withdrawal. This last finding fits well with the results of a post hoc analysis from the GLOW6 study that showed that over 12 weeks, the free triple combination (glycopyrronium + indacaterol + ICS) induced significantly better improvements in lung function and dyspnoea compared to the free double combination (indacaterol + ICS) in symptomatic patients with moderate-to-severe COPD [16].

3. Triple therapies under development

The growing body of evidence suggests that triple therapy with LABAs, LAMAs, and ICS is efficacious making it an attractive combination in COPD. Therefore, a variety of triple combinations are currently under development [6].

Triohale pressurized Metered-Dose Inhaler (pMDI) has been marketed as the world’s first triple-combination inhaler to be taken only once a day (tiotropium 9 μg, formoterol fumarate 6 μg, ciclesonide 200 μg) and is already available in India. This formulation is a suspension-based product.

Budesonide, glycopyrronium, and formoterol fumarate pMDI (PT010) is a fixed-dose ICS/LAMA/LABA in Pearl Therapeutics’ cosuspension technology. A Phase I trial documented that no drug-drug interaction was evident when comparing pharmacokinetics of PT010 to glycopyrronium [17]. Systemic exposure to budesonide following administration of PT010 320/14.4/9.6 μg was slightly higher but bioequivalent to budesonide/formoterol pMDI 320/9 μg.

A new combination of beclomethasone/formoterol 100/6 µg plus glycopyrronium at dosage of 12.5 or 25 µg (CHF5993) taken twice daily is under clinical evaluation. A 52-week randomized trial is comparing the combination of beclomethasone + formoterol + glycopyrronium versus tiotropium and versus combination of beclomethasone + formoterol and tiotropium (ClinicalTrials.gov Identifier: NCT019 11364).

On the contrary, umeclidinium/vilanterol/fluticasone furoate 62.5/25/100 µg is developed once on a daily basis. A 10,000-patient trial (IMPACT study) will investigate whether the umeclidinium/vilanterol/fluticasone furoate combo, delivered through Ellipta inhaler, can reduce the annual rate of moderate and severe exacerbations compared with umeclidinium/vilanterol, and vilanterol/fluticasone furoate (ClinicalTrials.gov Identifier: NCT02164513).

It is likely that also a fixed dose combination with glycopyrronium + indacaterol + mometasone will be developed on a once-daily basis. However, to date there is still no information available regarding it.

4. Conclusion

A growing body of evidence suggests that triple therapy with LABAs, LAMAs, 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. Therefore, a variety of triple combinations are currently under development.

5. Expert opinion

Since there is now more evidence that there are subsets of patients (mainly, frequent exacerbators with predominant chronic bronchitis and those with overlap between COPD and asthma) with a favorable response to treatment with ICSs [18], triple therapy should be considered at least in the group of patients with more severe COPD who are frequent exacerbators, and also to treat patients with asthma–COPD overlap syndrome to manage both the COPD and asthma components of the disease. Interestingly, improvements in lung function can also be achieved through combining triple therapy with pulmonary rehabilitation in patients with advanced COPD [19].

However, there are a number of issues that need to be addressed in order to optimize the use of triple therapy in COPD because data are still too scarce and studies too short to generate a strong recommendation. In particular, we do not know yet whether long-lasting bronchodilators may prevent exacerbations even in the absence of an ICS in frequent exacerbators and the utility of triple therapy that includes ICS in nonfrequent exacerbators. We completely agree that further research is required to investigate the potential benefits and incremental cost-effectiveness ratio of triple therapies and whether there are phenotypes of COPD that would be more responsive to triple therapy than others [20]. The escalation and de-escalation of therapy in COPD is another important issue that we must consider when we wish to prescribe or are prescribing triple therapy. We still do not know when we should switch, step up, or step down treatments in our patient. In any case, the results of the WISDOM trial [15] seem to indicate a new paradigm: the rationale for continuing ICS therapy in patients who are also taking long-acting bronchodilators should be based on symptomatic improvement attributable to the ICS rather on the prevention of exacerbations [21].

Thinking of the triple therapy, we must also ask ourselves if it is correct to always add an ICS rather than another anti-inflammatory drug. The anti-inflammatory actions of phosphodiesterase-4 (PDE-4) inhibitors are better than those of ICSs in contrasting the pathology of COPD [22]. Moreover, they could potentially improve outcomes in combination with long-acting bronchodilators that are not evident when given alone [22]. Another potential advantage of treatment with a PDE-4 inhibitor instead of ICS is that the use of ICS increases the risk of lower respiratory tract infection in COPD [22].

GOLD recommendations insert PDE-4 inhibitors as an alternative therapy in frequent exacerbators, regardless of whether symptomatic or not, and always in combination with a long-acting bronchodilator and possibly an ICS [2]. Giembycz and Newton have presented evidence that corticosteroid, LABA, and PDE-4 inhibitor in combination can interact in a complex manner to induce a panel of genes that could act collectively to suppress inflammation and improve lung function [23]. This finding might have significant implications for COPD treatment if confirmed by a large randomized clinical trial. A trial comparing roflumilast with placebo on top of a fixed-dose LABA/ICS combination is currently ongoing [24].

In any case, we strongly believe that the development of bifunctional drugs, molecules specifically designed to have two distinct primary pharmacological actions based on distinct pharmacophores, may serve as a basis for improved triple-therapy fixed-dose combination inhalers through co-formulation that could deliver three complementary therapeutic effects for patients with COPD using only two drugs and, thus, potentially achieve better efficacy than is apparent with the current combination products that dominate the treatment of COPD [6,25]. For instance, we have recently documented that the dual PDE3/4 inhibitor RPL554 elicits synergistic activity on the relaxation of human airway smooth muscle when combined with an M3 muscarinic antagonist [26], which leads to the assumption that if this drug was combined with an anticholinergic drug, this could translate into further clinical benefit. Furthermore a trial with GSK961081, a bifunctional (or dual pharmacophore) muscarinic β₂-agonist molecule, in association with fluticasone furoate has been concluded (ClinicalTrials.gov Identifier: NCT02064504), but the results have not yet been presented.

Declaration of interest

M Cazzola has received honoraria for speaking and consulting and/or financial support for attending meetings from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Dey, GlaxoSmithKline, Guidotti, Lallemand, Malesci, Menarini Farmaceutici, Mundipharma, Novartis, Pfizer, Sigma Tau, and Takeda. MG Matera has received honoraria for speaking and consulting and/or financial support for attending meetings from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Novartis, Pfizer and Takeda. 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.