Profile of glycopyrronium for once-daily treatment of moderate-to-severe COPD

Roland Buhl, Donald Banerji, Roland Buhl, Donald Banerji

Abstract

Bronchodilators are central in the symptomatic management of chronic obstructive pulmonary disease (COPD). Long-acting muscarinic antagonists (LAMAs) and long-acting β(2)-agonists (LABAs) are the main classes of long-acting bronchodilators. To date, tiotropium is the only once-daily LAMA available for the treatment of COPD. Glycopyrronium is a novel LAMA, currently in development for COPD. Phase II studies have shown that glycopyrronium 50 μg once daily provides clinically significant 24-hour bronchodilation with a rapid onset of action, which is faster than that of tiotropium, and a favorable safety and tolerability profile. The Phase III GLycopyrronium bromide in COPD airWays (GLOW) program has now confirmed the long-term efficacy and tolerability of glycopyrronium 50 μg once daily. The three studies included in this program have further shown that the effect of glycopyrronium versus placebo is similar to that of tiotropium in reducing dyspnea and the risk of exacerbations, as well as improving lung function, exercise tolerance, and health status in patients with COPD. The safety profile of glycopyrronium is also similar to that of tiotropium in terms of overall incidence of adverse events and muscarinic side effects. Glycopyrronium could be an alternative choice to tiotropium, and like tiotropium, has the potential to be used as a monotherapy or combination therapy. Phase II studies have shown that a fixed-dose combination of glycopyrronium and the 24-hour LABA indacaterol, produces rapid and sustained bronchodilation compared with indacaterol monotherapy in patients with COPD. Phase III studies are currently ongoing to assess the long-term efficacy and safety of this combination.

Keywords: NVA237; chronic obstructive pulmonary disease; glycopyrronium; muscarinic antagonist; once daily.

Figures

Figure 1
Figure 1
GOLD 2011 pharmacologic management of COPD based on combined assessment of airflow limitation, symptoms and exacerbations. Note: Alternative choice medications can be used alone or in combination with other options in the first or second choices. Adapted from Global Initiative for Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. GOLD; 2011. Abbreviations: GOLD, Global Initiative for Obstructive Lung Disease; COPD, chronic obstructive pulmonary disease; LABA, long-acting β2-agonist; ICS, inhaled corticosteroid; LAMA, long-acting muscarinic antagonist; PDE4-inh, phosphodiesterase-4inhibitor; SABA, short-acting β2-agonist; SAMA, short-acting muscarinic antagonist; prn, pro re nata (as needed); mMRC, modified Medical Research Council; CAT, COPD Assessment Test.
Figure 2
Figure 2
Glycopyrronium induces bronchodilation by inhibiting parasympathetically mediated bronchoconstriction. Abbreviations: M, muscarinic receptor; ACh, acetylcholine.
Figure 3
Figure 3
Glycopyrronium steady-state improvement in trough FEV1 achieved on day 1 and sustained until (A) week 26 (GLOW1) and (B) week 52 (GLOW2). Adapted from D’Urzo A, Ferguson GT, van Noord JA, et al. Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respir Res. 2011;12:156 and Kerwin E, Hébert J, Korenblat P, et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with moderate-to-severe COPD over 52 weeks: The GLOW2 study. Eur Respir J. July 26, 2012. Notes: Data are LSM ± SE; *P < 0.001 versus placebo; †P = 0.007 versus tiotropium. Abbreviations: FEV1, forced expiratory volume in one second; GLOW, GLycopyrronium bromide in COPD airWays; LSM, least squares means; SE, standard error; od, once daily.
Figure 4
Figure 4
FEV1 at each time point up to 4 hours post-dose on day 1in GLOW2. Reprinted from Kerwin E, Hébert J, Korenblat P, et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with moderate-to-severe COPD over 52 weeks: The GLOW2 study. Eur Respir J. July 26, 2012. Notes: Data are LSM; P < 0.001 for glycopyrronium and tiotropium versus placebo at all time points from 5 minutes to 4 hours; P < 0.01 for glycopyrronium versus tiotropium at all time points from 5 minutes to 4 hours. Abbreviations: FEV1, forced expiratory volume in one second; GLOW, GLycopyrronium bromide in COPD airWays; LSM, least squares means.
Figure 5
Figure 5
Improvements in (A and B) dyspnea and (C and D) health-related quality of life with glycopyrronium versus placebo in GLOW1. Reprinted from D’Urzo A, Ferguson GT, van Noord JA, et al. Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respir Res. 2011;12:156. Note: Data are LSM ± SE. Abbreviations: HRQoL, health-related quality of life; GLOW, GLycopyrronium bromide in COPD airWays; LSM, least squares means; SE, standard error; TDI, Transition Dyspnea Index; MCID, minimal clinically important differences; OR, odds ratio; CI, confidence interval; SGRQ, St George’s Respiratory Questionnaire.
Figure 6
Figure 6
Improvements in (A and B) dyspnea and (C and D) health-related quality of life with glycopyrronium versus placebo in GLOW2. Reprinted from Kerwin E, Hébert J, Korenblat P, et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with moderate-to-severe COPD over 52 weeks: The GLOW2 study. Eur Respir J. July 26, 2012. Notes: Data are LSM ± 95% CI. *P < 0.05; **P < 0.01; ***P < 0.001 versus placebo. Abbreviations: HRQoL, health-related quality of life; GLOW, GLycopyrronium bromide in COPD airWays; LSM, least squares means; CI, confidence interval; TDI, Transition Dyspnea Index; od, once daily; OR, odds ratio; SGRQ, St George’s Respiratory Questionnaire.
Figure 7
Figure 7
Glycopyrronium and tiotropium prolong time to first moderate to severe COPD exacerbation compared with placebo over 52 weeks in GLOW2. Reprinted from Kerwin E, Hébert J, Korenblat P, et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with moderate-to-severe COPD over 52 weeks: The GLOW2 study. Eur Respir J. July 26, 2012. Notes: Glycopyrronium 50 μg once daily versus placebo: hazard ratio 0.66, 95% confidence interval [CI] 0.520–0.850; P = 0.001; tiotropium versus placebo 18 μg once daily: hazard ratio 0.61, 95% CI 0.456–0.821; P = 0.001. Abbreviations: COPD, chronic obstructive pulmonary disease; GLOW, GLycopyrronium bromide in COPD airWays; od, once daily.
Figure 8
Figure 8
Improvements in (A) exercise tolerance, (B) lung function during exercise, and (C) exertional dyspnea with glycopyrronium versus placebo in GLOW3. Reprinted from Beeh KM, Singh D, Di Scala L, Drollmann A. Once-daily NVA237 improves exercise tolerance from the first dose in patients with COPD: the GLOW3 trial. Int J Chron Obstruct Pulmon Dis. 2012;7:503–513. Notes: Data are LSM either ± SE or 95% CI. *P < 0.05; ***P < 0.001 versus placebo. Abbreviations: GLOW, GLycopyrronium bromide in COPD airWays; LSM, least squares means; SE, standard error; CI, confidence interval; IC, inspiratory capacity.

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