Investigational beta-2 adrenergic agonists for the treatment of chronic obstructive pulmonary disease

ABSTRACT

Introduction: Long-acting bronchodilators are pivotal in the therapeutic management of COPD patients with moderate-to-severe airflow obstruction. New ultra-long-acting β2-agnoists (ultra-LABAs) have been developed, some of which have been licensed for use as monotherapy and/or in combination with other bronchodilators or inhaled corticosteroids, for use in COPD patients with persistent symptoms and worsening airflow limitation. These new agents are faster in onset and have a prolonged duration of action, with a similar safety profile to the traditional twice-daily bronchodilators which may have an impact on patient concordance.

Areas covered: A number of these ultra-LABAs are still under development and bi-functional hybrid molecules containing regions functioning as β2-agonists, and as muscarinic agonists (MABAs) has been developed. This review summarizes these (excluding the licensed ultra-LABAs) with attention on phase II studies data available to-date on their pharmacological profiles, clinical efficacy and safety, and future perspectives.

Expert opinion: Despite all the new agents’ available, the challenges that persist include any differences in efficacy and safety between the various possible LAMA/LABA combinations, relative advantages of MABAs over fixed-dose LAMA/LABAs, and the impact of these new molecules in terms of long term safety, especially in certain populations in co-morbidities frequently associated with COPD.

KEYWORDS:

• COPD
• long acting beta agonists
• Bronchodilators
• COPD treatment

Article highlights

• β₂ Agonists provoke airway relaxation inducing smooth muscle contraction through cAMP activation. This effect in patients with chronic obstructive pulmonary disease (COPD) improves expiratory airflow and reduces hyperinflation. Patients treated with β₂ agonists show improving dyspnea, pulmonary function and quality of life.

• In the last decade there has been an upsurge in the research of inhalatory bronchodilators β₂ Agonists with a long acting 24-hour duration of action (Ultra-LABAs) for COPD treatment, to obtain a once-daily administration. Indacaterol, vilanterol and olodaterol are ultra LABAs approved and marketed for the treatment of COPD, favouring the advancement of numerous other ultra-LABAs in I and II investigational phases.

• Within the ultra-LABAs under investigation Abediterol seems most promising both in comparison to placebo and indacaterol in terms of lung function improvement in moderate to severe COPD patients. However large, randomized studies are needed to draw firm conclusions, including trials with direct comparisons with other ultra–LABAs.

• Ultra-LABAs and long acting once-daily anti muscarinic bronchodilators (LAMA), have been combined into single inhaler delivery devices with good safety and efficacy outcomes compared to mono-components.

• Bronchodilation using a combination of LABA and LAMA (dual bronchodilation strategy) is clearly superior to individual agents. Therefore, recently, agents have been developed with a bi-functionality, combining the action of muscarinic antagonism and β2 stimulation in a single molecule (MABA).

• Batefenterol is the most promising MABA undergoing phase II assessment. However no data are to-date disposable comparing LAMA+LABA fixed combination and MABA. The future role of MABA in the therapeutic strategies for COPD is still to define.

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Declaration of interest

M. Malerba has received sponsorship and, educational grants from various pharmaceutical companies, including: Chiesi, Menarini, Mundipharma and Pfizer. JB. Morjaria has received speaker fees and sponsorship to attend the ERS, ATS and BTS conferences, educational grants and on advisory boards from various pharmaceutical companies, including: Novartis, Boehringer Ingelheim, GlaxoSmithKline, Chiesi, MSD, Pfizer, Almirall, Teva, Napp, Astra Zeneca. 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.

Additional information

Funding

This paper was not funded.