Muscarinic antagonists in early stage clinical development for the treatment of asthma

ABSTRACT

Introduction: Parasympathetic neurons utilize the neurotransmitter acetylcholine to modulate and constrict airway smooth muscles at the muscarinic acetylcholine receptor. Inhaled agents that antagonize the muscarinic (M) acetylcholine receptor, particularly airway M3 receptors, have increasing data supporting use in persistent asthma.

Areas covered: Use of inhaled long-acting muscarinic antagonists (LAMA) in asthma is explored. The LAMA tiotropium is approved for maintenance in symptomatic asthma patients despite the use of inhaled corticosteroids (ICS), leukotriene receptor antagonists (LTRA) and/or long-acting beta₂ agonists (LABA). LAMA agents currently approved for chronic obstructive pulmonary disease (COPD) include tiotropium, glycopyrrolate/glycopyrronium, umeclidinium and aclidinium. These agents are reviewed for their pharmacological differences and clinical trials in asthma.

Expert opinion: Current guidelines place inhaled LAMAs as adjunctive maintenance therapy in symptomatic asthma not controlled by an ICS and/or a LTRA. LAMA agents will play an increasing role in moderate to severe symptomatic asthma patients. Additional LAMA agents are likely to seek a maintenance indication perhaps as a combined inhaler with an ICS or with an ICS and a LABA. These fixed-dose combination inhalers are being tested in COPD and asthma patients. Once-a-day dosing of inhaled LAMA agents in severe asthma patients will likely become the future standard.

KEYWORDS:

• Asthma
• long-acting muscarinic antagonist (LAMA)
• tiotropium
• glycopyrrolate
• umeclidinium
• aclidinium

Article highlights

• Tiotropium, an inhaled long-acting muscarinic antagonist (LAMA) has already been FDA approved for maintenance treatment of asthma

• Several large high-quality clinical trials have been done that supported application of tiotropium for the asthma indication

• Despite reducing the dose of inhaled corticosteroids (ICS) in half, adding tiotropium improved spirometry in asthmatics

• Two other inhaled LAMA agents (glycopyrrolate and umeclidium) approved for COPD have published and unpublished clinical trials evaluating their potential efficacy in asthma treatments

• Combining an inhaled LAMA with an ICS, a long-acting beta2 agonists (LABA) or both given once a day appears to be a likely strategy for new products for asthma as well as chronic obstructive pulmonary disease (COPD)

• The other inhaled LAMA agent, Aclidinium, currently approved for COPD, does not yet have published or available unpublished studies in asthma patients and must be given twice a day

• Currently, asthma guidelines recognize the usefulness of inhaled short-acting muscarinic antagonists (SAMA) in the treatment of acute exacerbations of asthma but do recommend the chronic use of inhaled SAMAs

• International asthma guidelines suggest the use of inhaled LAMA agents for adjunctive maintenance therapy in patients who continue to be symptomatic despite ICS or other maintenance drug use

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Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.