Long-Acting Muscarinic Antagonists Under Investigational to Treat Chronic Obstructive Pulmonary Disease

Abstract

Introduction

Bronchodilators are the cornerstone of chronic obstructive pulmonary disease (COPD) therapy and long-acting muscarinic antagonists (LAMAs) as a mono or combination treatment play a pivotal role. Several LAMAs are already available on the market in different formulations, but developing a new compound with a higher M3 receptor selectivity and a lower affinity to M2 receptors to increase the therapeutic effect and minimize the adverse effects is still a goal. Moreover, new formulations could improve adherence to therapy.

Areas Covered

This systematic review assesses investigational long-acting muscarinic antagonist in Phase I and II clinical trials over the last decade. It offers insights on whether LAMAs and/or their new formulations in clinical development can become effective treatments for COPD in the future.

Expert Opinion

Research on LAMA seems to have come to a standstill, the few new molecules under study do not show distinctive characteristics compared to the previous ones. Muscarinic antagonist/β2-agonist (MABAs) appear to be the major innovation currently under investigation, and they could theoretically open new research frontiers on the effect between adrenergic and muscarinic interaction in the same cell.

Keywords:

• long-acting muscarinic antagonist
• MABA
• LAMA
• Phase I
• Phase II
• efficacy
• safety
• COPD treatment
• investigational drugs
• chronic obstructive pulmonary disease

Abbreviations

Ach, acetylcholine; AE, adverse effect; ASM, airway smooth muscles; AZD/LAS, AZD8999/LAS190,792; BAT, GSK-961,081/TD-5959/Batefenterol; BCQB, bencycloquidium bromide; C_max, peak plasma concentrations; COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; FDA, Food and Drug Administration; FEV₁, forced expiratory volume in 1 second; FF, fluticasone furoate; FORM, formoterol; FP, fluticasone propionate; GLY, glycopyrronium bromide; ICS, inhaled corticosteroid; IPRA, ipratropium bromide; LABA, long-acting β2 adrenoceptor agonist; LAMA, long-acting muscarinic antagonists; MABA, muscarinic antagonist/β2-agonist; mAChR, postjunctional muscarinic receptors; NAV, AZD8871/LAS191351/Navafenterol; PK, pharmacokinetics; REV, Revefenacin/TD-4208; TIO, tiotropium bromide; UMEC, umeclidinium bromide; VI, vilanterol.

Article Highlights

• Currently, just a few LAMA molecules are under study while many of them were stopped about five years ago.

• Revefenacin is the last LAMA approved by the FDA and it offers the advantage of being the first once-daily LAMA for nebulization in patients with COPD, plus it can be used in hospitalised or ventilated COPD patients.

• Imidafenacin is an M3-selective LAMA, already used for overactive bladder, currently under investigation for COPD. It would be the first available oral LAMA on the market, although its effect on improving FEV1 is modest.

• MABA is a new class of bronchodilators, which combine long-acting muscarinic antagonism with β2-agonist activity.

• The main issue on MABAs is formulating a balanced compound with similar antimuscarinic and β-adrenergic activities.

• New in vitro ed ex vivo models are necessary to improve and make the development of new drugs more efficient.

Authorship

All authors (JO, AC, MC, LC, PR):

• Made a significant contribution to the work reported.

• Have drafted, written, and revised the article.

• Have agreed on the journal to which the article was submitted.

• Reviewed and agreed on all versions of the article before submission, during revision, the final version accepted for publication, and any significant changes introduced at the proofing stage.

• Agree to take responsibility and be accountable for the contents of the article.

Disclosure

JO participated as a speaker in scientific meetings and courses under the sponsorship of AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Novartis, Zambon. AC participated as a speaker in scientific meetings and courses under the sponsorship of AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, and Zambon. MC reports personal fees from AstraZeneca, GlaxoSmithKline, and Cipla, and grants and personal fees from Novartis, during the conduct of the study; and grants and personal fees from Almirall, Boehringer Ingelheim, Novartis, and Zambon, and personal fees from ABC Farmaceutici, AstraZeneca, Biofutura, Chiesi Farmaceutici, Cipla, Edmond Pharma, GlaxoSmithKline, Lallemand, Menarini, Mundipharma, Ockham Biotech, Pfizer, Sanofi, and Verona Pharma, outside the submitted work. LC has participated as advisor in scientific meetings under the sponsorship of Boehringer Ingelheim and Novartis, received non-financial support by AstraZeneca, received a research grant partially funded by Boehringer Ingelheim, Novartis and Almirall, and is or has been a consultant to Edmond Pharma, Zambon and Verona Pharma. His department was funded by Almirall, Boehringer Ingelheim, Novartis, and Zambon. PR participated as a lecturer, speaker, and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Mundipharma, and Novartis. Her department was funded by Almirall, Boehringer Ingelheim, Novartis, and Zambon. The authors report no other potential conflicts of interest for this work.

Additional information

Funding

There is no funding to report.