New and developing non-adrenoreceptor small molecule drugs for the treatment of asthma

ABSTRACT

Introduction: Inhaled corticosteroids (ICS) alone or in combination with an inhaled long-acting beta₂-agonist (LABA) are the preferred long-term treatment for adults and adolescents with symptomatic asthma. Additional drugs include leukotriene-receptor antagonists, slow-release theophylline and the long-acting muscarinic antagonist (LAMA) tiotropium (approved in 2015). There is a need for more effective therapies, as many patients continue to have poorly controlled asthma.

Areas covered: New and developing long-acting non-adrenoreceptor synthetic drugs for the treatment of symptomatic chronic asthma despite treatment with an ICS alone or combined with a LABA. Data was reviewed from studies published up until November 2016.

Expert opinion: Tiotropium improves lung function and has a modest effect in reducing exacerbations when added to ICS alone or ICS and LABA. The LAMAs umeclidinium and glycopyrronium are under development in fixed dose combination with ICS and LABA. Novel small molecule drugs, such as CRTH2 receptor antagonists, PDE₄ inhibitors, protein kinase inhibitors and nonsteroidal glucocorticoid receptor agonists and ‘off-label’ use of licensed drugs, such as macrolides and statins are under investigation for asthma, although their effectiveness in clinical practice is not established. To better achieve the goal of developing effective novel small molecule drugs for asthma will require greater understanding of mechanisms of disease and the different phenotypes and endotypes of asthma.

KEYWORDS:

• Asthma
• CRTH2 antagonist
• CXCR2 antagonist
• inhaled corticosteroid
• long-acting beta₂-agonist
• long-acting muscarinic antagonist
• macrolide
• phosphodiesterase inhibitor
• protein kinase inhibitor
• selective glucocorticoid receptor
• modulator
• statin
• theophylline

Article highlights

• The long-acting muscarinic antagonist (LAMA) tiotropium is the only small molecule drug approved for the maintenance treatment of adults and adolescents with asthma in recent years. Clinical trials of tiotropium in asthma report improvements in lung function and modest reductions in exacerbations in patients taking ICS alone and the combination of medium to high dose ICS and LABA.

• The LAMAs umeclidinium and glycopyrronium are under development in fixed dose combination with ICS and LABA in patients with uncontrolled severe asthma.

• Novel small molecules drugs, such as the CRTH2 receptor antagonist fevipiprant (QAW039), the PDE₄ inhibitor roflumilast, several protein kinase inhibitors and the nonsteroidal glucocorticoid receptor agonist AZD7594 are under development for asthma, although only a small number of phase III studies are registered on the clinicaltrials.gov website and none of these drugs are currently approved for use in clinical practice.

• Exploratory clinical studies of ‘off-label’ use of licensed drugs suggest that macrolides show efficacy in non-smokers with non-eosinophilic severe asthma and statins and ultralow-dose theophylline may benefit smokers with asthma, although the effectiveness of these drugs in clinical practice is not established.

• To better achieve the goal of developing effective novel small molecule drugs for asthma will require greater understanding of mechanisms of disease and the different phenotypes and endotypes of asthma.

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Declaration of interest

In the past three years, N C Thomson has participated in advisory boards and/or received consultancy/lecture fees from Bayer, Boston Scientific, Daiichi Sankyo, Novartis, Roche 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

Additional information

Funding

This paper is not funded.