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

Figures & data

Table 1 Long-Acting Muscarinic Receptor Antagonists (LAMA) in Clinical Development

	Route of Administration	Key Preliminary Results	Latest Developments	Company Working on This Strategy
CHF 5407	Aerolized	It is an antagonist as potent and long acting as tiotropium at M3 receptors, but significantly short-acting at M2 receptors	Phase I	Chiesi Farmaceutici
Bencycloquidium	Aerolized	It shows faster onset and slower offset than that of tiotropium	Pre-clinical	Yingu Pharmaceutical
V0162/Mequitazine	DPI	It has high affinity for M3 receptors and rapid off-kinetics	Phase I/II	Pierre Fabre Medicament
QAX028	N/A	N/A	Phase II	Novartis
AZD9164	Turbohaler (DPI)	It is a potent and competitive M3 receptor antagonist, a longer duration of effect than ipratropium (12 hours)	Phase II Stopped for safety reasons	AstraZeneca Discovery and Pulmagen Therapeutics
AZD8683	Turbohaler (DPI)	It has high intrinsic metabolic clearance and human plasma protein binding (> 95%) with a t½ of 25.6 hours and 84% inhibition of bronchoconstriction at 48 hours	Phase II Stopped for safety reasons	AstraZeneca
KRP197/Imidafenacin	Oral formulation	It has a rapid onset of action and it would be the first oral formulation LAMA	Phase II	Kyorin Pharmaceutica/Ono Yakuhin
ALKS27/Trospium	AIR pulmonary delivery system (DPI)	Rapid onset of effect (15 min), maximum improvement in FEV1 at 2 h, 24-h duration of action	Phase II	Alkermes, Inc. and Indevus Pharmaceuticals, Inc
TD-4208/Revefenecin	A standard jet nebulizer connected to an air compressor.	It shows rapid onset and sustained duration of bronchodilator effect over 24 h. It is the first nebulised LAMA.	Approved FDA 2018	Theravance Biopharma and Mylan

Abbreviations: DPI, dry power inhaler; N/A, not available; MDI, metered dose inhaler.

Figure 1 Muscarinic receptor antagonists in clinical development for the treatment of COPD. Image of the QAX028ʹ molecule is not available.

Table 2 Bi-Functional (or Dual Pharmacophore) Muscarinic Antagonist/β2-Agonist (MABA) in Clinical Development

	Route of Administration	Key Preliminary Results	Latest Developments	Company Working on This Strategy
GSK-961,081/TD-5959/Batefenterol	DPI	High affinity for human M2 and M3 muscarinic receptors, but lower than tiotropium, and a β2-adrenoceptors affinity greater than albuterol	Phase III	Theravance
AZD8871/LAS191351/Navafenterol	DPI	It shows a similar profile compared to Batefenterol, but with a higher muscarinic component	Phase II	Pearl Therapeutics and Astrazenca
AZD8999/LAS190792	Nebulized solutions	Selective for the human M3 receptor and for the β2-adrenoceptor, and shows a functional potency in a similar range to BAT with a longer duration of action in isolated tissue	Phase II	Almirall and then AstraZeneca
AZD2115	MDI	N/A	Phase II	AstraZeneca and Argenta Discovery (Pulmagen Therapeutics)
CHF6366	Nebulized solutions	Good balance of the two activities, the peak effect at 5 minutes post-dose with both activities fully effective within the first 15 minutes	Phase II	Chiesi Farmaceutici
THRX200495	Nebulized solutions	A potent dual effect as anti-muscarinic and adrenoceptor agonist that persisted for over 24 h, demonstrating potent, balanced and long-lasting bronchodilation	Phase I	Theravance Incorporated

Abbreviations: DPI, dry power inhaler; N/A, not available; MDI, metered dose inhaler.

Figure 2 Muscarinic receptor antagonists in clinical development for the treatment of COPD. Image of the CHF636ʹ molecule is not available.