Safety and tolerability of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients

Vogelmeier, Claus; Verkindre, C.; Cheung, D.; Gáldiz, Juan B.; Güçlü, Salih Zeki; Spangenthal, Selwyn; Overend, Tim; Henley, Michael V.; Mizutani, G.; Zeldin, Robert K.

doi:10.1016/j.pupt.2010.04.005

Cited by 53 publications

(44 citation statements)

References 9 publications

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“…The combined bronchodilator approach in this study did not appear to increase the burden of AE. These results are consistent with other studies using LABA/LAMA combinations,3 6–8 10 13 and for the monocomponents, indacaterol21–23 and NVA237 18. Future long-term studies will further assess the safety and tolerability profile of QVA149.…”

Section: Discussionsupporting

confidence: 89%

QVA149 demonstrates superior bronchodilation compared with indacaterol or placebo in patients with chronic obstructive pulmonary disease

Noord

Buhl

LaForce

et al. 2010

Thorax

Self Cite

109

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Background This randomised, double-blind, placebo controlled, four-period crossover study assessed the efficacy and safety of once-daily QVA149, a dual bronchodilator consisting of the long-acting b 2 -agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237), in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Methods Patients (N¼154) were randomly assigned to receive QVA149 (indacaterol/NVA237) 300/50 mg, indacaterol 300 mg, indacaterol 600 mg, or placebo, once daily for 7 days with a 7-day washout period between each treatment. The primary endpoint was trough forced expiratory volume in 1 s (FEV 1 ) (mean of 23 h 15 min and 23 h 45 min post-dose values) on day 7. Other endpoints included trough FEV 1 on day 1, individual time point FEV 1 and monitoring and recording of all adverse events. Results A total of 135 (87.7%) patients completed the study (all randomly assigned patients: mean age 61.7 years, 61.4% male, post-bronchodilator FEV 1 52.2% predicted, FEV 1 /forced vital capacity 47.6%). The estimated treatment difference (95% CI) for trough FEV 1 on day 7 between QVA149 and placebo was 226 ml (192 to 260; p<0.001). The estimated treatment difference between QVA149 and indacaterol 300 and 600 mg was 123 ml (89 to 157; p<0.001) and 117 ml (83 to 150; p<0.001), respectively. The improvements in mean trough FEV 1 exceeded the predefined minimal clinically important differences of 100e140 ml for QVA149 versus placebo and indacaterol. Similar results were observed on day 1. All treatments were well tolerated. Conclusions QVA149 demonstrated rapid and sustained bronchodilation with significant improvements compared with indacaterol monotherapy and placebo in patients with COPD. Clinical trial registration NCT00570778.Bronchodilators are the mainstay for the treatment of chronic obstructive pulmonary disease (COPD). 1The long-acting b 2 -agonists (LABA), formoterol and salmeterol, and the long-acting muscarinic antagonist (LAMA) tiotropium are widely used as maintenance treatment for COPD. When symptoms are not adequately controlled by monotherapy, combining bronchodilators of different classes, in particular an inhaled muscarinic antagonist with a b 2 -agonist, is associated with better outcomes. 1Combining LABA with anticholinergic agents has been shown to be pharmacologically useful because b 2 -agonists decrease the release of acetylcholine, leading to consequent amplification of the bronchial smooth muscle relaxation induced by the anticholinergic agent.2 The addition of an anticholinergic agent can also reduce peripheral bronchoconstrictor effects of acetylcholine, consequently causing amplification of bronchodilation elicited by the b 2 -agonist through direct stimulation of smooth muscle b 2 -adrenoceptors. 2 The superior bronchodilation obtained by combining bronchodilators with different mechanisms of action may be attributed to complementary pharmacodynamic profiles whereby the anticholinergic causes prolonged bronchodilation and the LA...

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Section: Discussionsupporting

confidence: 89%

QVA149 demonstrates superior bronchodilation compared with indacaterol or placebo in patients with chronic obstructive pulmonary disease

Noord

Buhl

LaForce

et al. 2010

Thorax

Self Cite

109

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“…have accounted for the apparent discrepancy, our findings are consistent with the sustained lung muscarinic receptor binding effects of glycopyrronium in rats (Ogoda et al, 2011) and clinical reports on glycopyrronium wherein bronchodilation consistent with an extended duration of action was observed in patients with mild to moderate COPD (Vogelmeier et al, 2010) or asthma (Hansel et al, 2005). In dogs, the 24-hour in vivo bronchoprotective potency of TD-4208 was about 10-fold less potent than that of tiotropium.…”

Section: Pharmacology Of Lung-selective Muscarinic Antagonist Td-4208supporting

confidence: 87%

In Vivo Pharmacological Characterization of TD-4208, a Novel Lung-Selective Inhaled Muscarinic Antagonist with Sustained Bronchoprotective Effect in Experimental Animal Models

Pulido‐Rios¹,

McNamara²,

Obedencio³

et al. 2013

J Pharmacol Exp Ther

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Tiotropium is currently the only once-daily, long-acting muscarinic antagonist (LAMA) approved in the United States and other countries for the treatment of chronic obstructive pulmonary disease (COPD). Glycopyrronium has shown promise as a LAMA and was recently approved for once-daily maintenance treatment of COPD in the European Union. Here, we describe the in vivo preclinical efficacy and lung selectivity of a novel inhaled muscarinic antagonist, TD-4208 (biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester) and compare its profile to tiotropium and glycopyrronium. In anesthetized dogs, TD-4208, along with tiotropium and glycopyrronium, produced sustained inhibition of acetylcholine-induced bronchoconstriction for up to 24 hours. In anesthetized rats, inhaled TD-4208 exhibited dosedependent 24-hour bronchoprotection against methacholineinduced bronchoconstriction. The estimated 24-hour potency (expressed as concentration of dosing solution) was 45.0 mg/ml. The bronchoprotective potencies of TD-4208 and tiotropium were maintained after 7 days of once-daily dosing, whereas glycopyrronium showed a 6-fold loss in potency after repeat dosing. To assess systemic functional activity using a clinically relevant readout, the antisialagogue effect of compounds was also evaluated. The calculated lung selectivity index (i.e., ratio of antisialagogue and bronchoprotective potency) of TD-4208 was superior to glycopyrronium after both single and repeat dosing regimens and was superior to tiotropium after repeat dosing. In conclusion, the in vivo preclinical profile suggests that TD-4208 has the potential to be a long-acting bronchodilator for once-daily treatment of respiratory diseases. Its greater functional selectivity for the lung in preclinical models may translate to an improved tolerability profile compared with marketed muscarinic receptor antagonists.

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“…3-[(cyclopentylhydroxyphenylacetyl oxy]-1,1-dimethylpyrrolidinium bromide (NVA237) is a novel once-daily dry powder formulation of the LAMA glycopyrronium bromide, which is in development for the treatment of COPD. It has a rapid onset and long duration of action (Ͼ24 h) with an acceptable safety and tolerability profile Vogelmeier et al, 2010;D'Urzo et al, 2011;Fogarty et al, 2011). A rapid onset of action is a desirable feature of bronchodilators; rapid relief from symptoms provides reassurance of effect and may help improve compliance with the medication (Breekveldt-Postma et al, 2007;Bourbeau and Bartlett, 2008).…”

Section: Introductionmentioning

confidence: 99%

The Influence of Receptor Kinetics on the Onset and Duration of Action and the Therapeutic Index of NVA237 and Tiotropium

Sykes

Dowling

Leighton-Davies

et al. 2012

J Pharmacol Exp Ther

113

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Studies under nonphysiological conditions suggest that long receptor residency time is responsible for the 24-h duration of action of the long-acting muscarinic antagonist (LAMA) tiotropium. Our aim was to determine how clinically relevant dissociation rates under more physiological conditions influence the differences in onset of action between tiotropium and 3-[(cyclopentylhydroxyphenylacetyl oxy]-1,1-dimethyl-pyrrolidinium bromide (NVA237), a once-daily dry-powder formulation of the LAMA glycopyrronium bromide in development for chronic obstructive pulmonary disease. In addition, we have investigated kinetic selectivity at each of the muscarinic receptor subtypes to determine whether the improved cardiovascular therapeutic index obtained with NVA237 in animal models is attributable to differences in kinetic rate constants. The binding of radioligand [ 3 H]N-methyl-scopolamine was measured in the presence/absence of several concentrations of unlabeled competitors, and data were analyzed using a competition kinetic model to provide on/off rates for the competitor. We found shorter dissociation half-lives for NVA237 and tiotropium under physiological (11.4 and 46.2 min, respectively) versus nonphysiological conditions (173 and 462 min, respectively). NVA237 had a more rapid onset of action (3-4.8 times) versus tiotropium, determined in an vitro calcium and rat tracheal strip assay. Simulations suggested that the more rapid onset of NVA237 action could be explained by differences in kinetic parameters. NVA237 had greater equilibrium binding and kinetic selectivity for muscarinic type 3 (M 3 ) versus muscarinic type 2 (M 2 ) receptors, with a faster off rate from M 2 versus M 3 receptors than tiotropium, potentially affording it a more favorable therapeutic index. This study suggests that the 24-h duration of action of NVA237 and tiotropium is not solely the result of their slow dissociation from the M 3 receptor and highlights the importance of conducting in vitro experiments in conditions reflecting those in vivo.

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Safety and tolerability of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients

Cited by 53 publications

References 9 publications

QVA149 demonstrates superior bronchodilation compared with indacaterol or placebo in patients with chronic obstructive pulmonary disease

QVA149 demonstrates superior bronchodilation compared with indacaterol or placebo in patients with chronic obstructive pulmonary disease

In Vivo Pharmacological Characterization of TD-4208, a Novel Lung-Selective Inhaled Muscarinic Antagonist with Sustained Bronchoprotective Effect in Experimental Animal Models

The Influence of Receptor Kinetics on the Onset and Duration of Action and the Therapeutic Index of NVA237 and Tiotropium

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