Reports

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PRIORITY PRESS - European Respiratory Society (ERS) Annual Congress 2013

Barcelona, Spain / September 7-11, 2013

Barcelona - In the treatment algorithm for chronic obstructive pulmonary disease (COPD), the early combination of bronchodilators is expected to be moved forward in guideline-based treatment. In the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines, the combination of a long-acting beta agonist (LABA) with a long-acting muscarinic antagonist (LAMA) is already accepted as an alternative to a single bronchodilator in low-risk symptomatic patients (www.goldcopd.org). A more prominent position for this combination is expected on the basis of newly completed trials, many conducted with inhalers now in development that will combine a LABA and LAMA into a single device. The trials suggest clinical advantages relative to a single bronchodilator or a bronchodilator plus an inhaled corticosteroid (ICS). This latter combination is frequently used but specifically not recommended in GOLD guidelines for patients with mild to moderate COPD due to safety concerns.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

A LABA or a LAMA is the recommended first choice in symptomatic, low-risk COPD. These patients, designated group B in GOLD guidelines, form the largest subgroup of COPD encountered clinically. They are defined by the presence of symptomatic airflow limitation but a low rate of exacerbations (≤1 year). Data presented at the 2013 ERS suggest that the combination of a LAMA and a LABA, now a recommended alternative, improves lung function and quality of life with comparable tolerability relative to either a LABA or LAMA alone. Several experts suggested these data will change the guidelines.

“A once-daily, single-inhaler combination of two bronchodilators provided statistically significant improvements in symptoms when compared to each of the bronchodilators used separately, a different bronchodilator used separately, and the combination of a bronchodilator and an ICS,” reported Dr. Tobias Welte, Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany. Based on data drawn from three randomized trials (Welte et al. ERA 2013 Abstract 3637), Dr. Welte suggested that early use of the combination may slow progression.

Earlier Use Slowing Progression

The data from the three trials (SHINE, ILLUMINATE, and ENLIGHTEN) were part of the development program for QVA149, a bronchodilator for once-daily combined administration of the LABA indacaterol and the LAMA glycopyrronium. Together, the studies randomized 2144 patients. Although the trial designs varied, there was a significant advantage for the dual bronchodilator not only relative to placebo but to all of the active comparators for at least one symptom outcome, such as days with no daytime symptoms or days able to perform usual daily activities. 

The logical expectation that two bronchodilators with different mechanisms will be superior to a single bronchodilator for COPD is driving active development of multiple dual inhaler devices. In addition to indacaterol/glycopyrronium, single inhaler devices are also in late stages of development for vilanterol/umeclidinium, olodaterol/titropium, formoterol/aclidinium, and formoterol/glycopyrronium. As the specific LABA, LAMA, and inhaler device differ for each of these dual bronchodilators, controlled studies will be needed to determine whether they offer comparable efficacy.

Differences are anticipated. Recent and on-going expansion of options within both the LABA and LAMA therapeutic classes has been progressing in parallel with advances in inhaler design. Among LAMAs for example, the first drug in this class, tiotropium, has now been joined by glycopyrronium. Others, such as aclidinium and umeclidinium, are in trials. The LABAs salmeterol and formoterol were joined by indacaterol several years ago, but this class is also being expanded with the recently approved olodaterol. Studies leading to approval in the development program were largely placebo-controlled, but some limited data with active comparators are beginning to accumulate.

At 2013 ERS, one set of comparative data was drawn from a dual bronchodilation trial which included randomization arms to tiotropium alone or glycopyrronium alone (Wedzicha et al. ERS 2013, Abs. 180). Administered once-daily in doses of 50 μg and 18 μg, respectively, the drugs performed comparably over the 64 weeks of the trial, called SPARK, which was conducted in patients with severe-to-very-severe COPD. While both reduced rate of exacerbations and use of rescue medication from baseline, no differences between the glycopyrronium and tiotropium arms, including change in score on the St George’s Respiratory Questionnaire (SGRQ), were statistically significant.

“The data from this study suggest glycopyrronium and tiotropium offer similar efficacy and similar tolerability,” reported Dr. Jadwiga A. Wedzicha, Centre for Respiratory Medicine, University College, London, UK. Despite experimental data that suggest glycopyrronium has a faster onset of action than tiotropium (Sykes et al. J Pharmacol Exp Ther 2012;343:520-8), Dr. Wedzicha reported that single-agent performance over the relatively long-term of the SPARK trial was of the same order of magnitude.

The goals of dual bronchodilation are ambitious. While the data so far suggest improvement in symptom control, there is also a strong potential for dual bronchodilation to slow lung deterioration, according to Dr. Marc Decramer, Respiratory Division, University Hospitals, Leuven, Belgium. First author of clinical studies with vilanterol/umeclidinium (Decramer et al. ERS 2013 Abs 3640) and indacaterol/glycopyrronium (Decramer et al ERS 2013, Abs 756), Dr. Decramer suggested data from each provide support for early use of dual bronchodilation.

In the study of vilanterol/umeclidinium, the delivery of these two bronchodilators in a single inhaler provided improvements in lung function as measured with FEV1 over 24 hours relative to both umeclidinium alone and tiotropium alone, although the advantage was only statistically significant relative to tiotropium. In the data he presented on indacaterol/glycopyrronium, which was a substudy of SPARK, there was a reduction in the rate of COPD exacerbations compared with glycopyrronium alone or tiotropium alone.

“The data suggest that controlling exacerbations may lead to concomitant improvements in health status as reflected by improved SGRQ total score,” reported Dr. Decramer who cited data from the UPLIFT tiotropium trial suggesting that exacerbations are correlated with a decline in lung function (Tashkin et al. N Engl J Med 2008;359:1543-1554).

If protection against exacerbations with dual bronchodilation can be shown in early disease, Dr. Decramer suggested that this therapy may alter the natural history of the disease. The same concept was proposed by Dr. Wedzicha, who suggested that combining LABAs and LAMAs may have more than additive effects. Specifically, while LABAs appear to provide a greater impact on the symptoms of COPD, such as dyspnea, Dr. Wedzicha cited recent data suggesting that LAMAs have an anti-inflammatory effect that provides greater protection from the pathology that drives progression, such as sputum production (Holowinia et al. Adv Exp Med Biol 2013;756:9-14).

Delivery Systems

In achieving these benefits, one of the most important variables may be the relative ability of the inhaler device to deliver active drug to lung tissue. In a study comparing delivered dose (DD) and lung deposition (LD) or four trademarked inhalers that may be used for the delivery of dual bronchodilators, substantial variability was observed (Gjaltema et al. ERS 2013 Abs 3384). Although this was an in vitro study, the first author of the study, Dr. Doetie Gjaltema, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands, said past in vitro to in vivo correlations “predict different inhalation systems will have significantly different lung depositions.”

Bronchodilators are identified as the cornerstone of COPD management, but data presented at the ERS 2013 suggest opportunities to ensure better outcome with these agents may be improving. While this includes an expansion in the number of LAMAs and LABAs available for clinical use, the movement toward relatively early use of dual bronchodilators may change the trajectory of the disease if this strategy leads to preservation of lung function, reduction in exacerbations, and a reduction in disease progression.

“On the basis of the evidence of benefit from early use of dual bronchodilators, we may be able to convince physicians to end the overuse of ICS in COPD patients with mild to moderate disease,” reported Jørgen Vestbo, MD, Respiratory Research Group, Manchester Academic Health Sciences Centre, Manchester, UK. Co-author of the on-going FLAME study (Wedzicha et al. ERS 2013. Abs 696), which is randomizing patients to a dual bronchodilator or a bronchodilator plus an ICS with exacerbations as the primary end point, Dr. Vestbo said that even a non-inferiority result would favor dual bronchodilation based on the well-documented association of ICS with increased risk of pneumonia and other safety issues.

Conclusion

There is evidence that earlier use of a LAMA and LABA in combination, now an alternative treatment option for patients with mild to moderate COPD in GOLD guidelines, will be given a more prominent role when guidelines are revised next year. This is based on evidence that dual bronchodilation with both a LABA and a LAMA improves symptom control and may slow disease progression. Inhaler devices now in development that are capable of delivering a LAMA and LABA simultaneously may accelerate the adoption of this treatment strategy.