Effects of Asm‐024, A Modulator of Acetylcholine Receptor Function, On Airway Responsiveness and Allergen‐Induced Responses in Patients with Mild Asthma

Abstract

OBJECTIVES: To evaluate the safety, tolerability and clinical activity of ASM-024, a new cholinergic compound with dual nicotinic and muscarinic activity, in mild allergic asthma.METHODS: The present study involved 24 stable, mild allergic asthmatic subjects. In a cross-over design, ASM-024 (50 mg or 200 mg) or placebo were administered once daily by nebulization over three periods of nine consecutive days separated by a three-week washout. The effect of each treatment on the forced expiratory volume in 1 s (FEV1), provocative concentration of methacholine causing a 20% decline in FEV1 (PC20), early and late asthmatic responses, and allergen-induced inflammation were measured.RESULTS: Seventeen subjects completed the study. During treatment with ASM-024 at 50 mg or 200 mg, the PC20 value increased respectively from a mean (± SD) 2.56±3.86 mg/mL to 4.11 mg/mL (P=0.007), and from 3.12±4.37 mg/mL to 5.23 mg/mL (P=0.005) (no change with placebo). On day 7 (day preceding allergen challenge), postdosing FEV1 increased by 2.0% with 50 mg (P=0.005) and 1.9% with 200 mg (P=0.008) (placebo −1.1%). ASM-24 had no inhibitory effect on early and late asthmatic responses, nor on sputum eosinophil or neutrophil levels. ASM-024 induced no serious adverse events, but caused cough in 22% and 48% of the subjects with 50 mg and 200 mg, respectively, compared with 10% who were on placebo.CONCLUSIONS: ASM-024 did not inhibit allergen-induced asthmatic response and related airway inflammation, but reduced methacholine airway responsiveness and slightly improved lung function. The mechanism by which ASM-024 improves these outcomes requires further study.

Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators

“…The clinical results showed that although this compound was well tolerated at different doses, it improved neither the primary target engagement (P50) nor cognitive outcomes in schizophrenia, indicating lack of efficacy for AVL-3288. ASM-024 has completed phase II trials for the treatment of chronic obstructive pulmonary disease, mild allergic asthma, and asthma, respectively [ 88 ]. The results indicated that this PAM improves bronchial airway hyperreactivity and asthma induced by methacholine but not induced by allergens.…”

Therapeutic Targeting of α7 Nicotinic Acetylcholine Receptors

“…Therapeutic Targeting of a7 nAChR channel, they do induce D s and D i unlike the classic competitive antagonist methyllycaconitine (MLA). Signal-transduction studies in non-neuronal cells (Thomsen and Mikkelsen, 2012a; Boulet et al, 2015;Papke et al, 2015a;Yue et al, 2015;Zanetti et al, 2016;King et al, 2017b;Maldifassi et al, 2018) have implicated silent agonists and the D s and/or D i states of the receptor as likely to mediate channel-independent signaling. Developing specific therapeutics for the treatment of inflammatory diseases and pain may therefore come from defining the structural features of drugs that predict silent agonism.…”

Allergen bronchoprovocation test: an important research tool supporting precision medicine

“…With respect to testing of investigational therapies, allergen inhalation test was initially used to assess the first monoclonal antibody, omalizumab, directed at IgE, in the treatment of allergic asthma [61,62]. This study was followed by several others using inhaled allergen challenge as a proof of concept to evaluate small molecule inhibitors [63][64][65][66][67][68][69], novel corticosteroids, oligonucleotides and monoclonal antibodies [70][71][72][73][74][75][76][77].…”