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

Abstract

NVA237 is a novel once-daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler. This randomized, double-blind, placebo-controlled study evaluated the safety, tolerability and bronchodilator efficacy of two doses of NVA237 (100 and 200 μg), versus placebo, in patients with moderate-to-severe COPD (forced expiratory volume in 1 s [FEV₁] ≥ 30% and <80% predicted and FEV₁/forced vital capacity [FVC] < 0.7, 30 min after inhalation of 80 μg ipratropium bromide). After appropriate washout periods, patients were randomized to treatment with NVA237 100 μg (n = 92), NVA237 200 μg (n = 98) or placebo (n = 91) for 28 days. The primary objective was evaluation of safety, with efficacy measures included as secondary objectives. NVA237 was generally well tolerated and associated with a frequency and distribution of adverse events similar to placebo. Serious adverse events were uncommon and there was no evidence of adverse cardiovascular effects or unexpected events. Trough FEV₁ was significantly higher in those receiving NVA237 compared with placebo. For NVA237 100 μg the differences were 131 and 161 mL on Days 1 and 28, respectively (p < 0.05), and for NVA237 200 μg the differences were 146 and 151 mL on Days 1 and 28, respectively (p < 0.05). Peak FEV₁, FEV₁ at all timepoints up to 24 h after dosing, and FEV₁ area under the curve during 5 min–5 h post-dosing were also significantly higher in both NVA237 groups, compared with placebo. Patients receiving NVA237 required fewer daily puffs of rescue medication and had a higher percentage of days on which rescue medication was not required. Overall, the present study provides further evidence of the safety, tolerability and bronchodilator efficacy of once-daily treatment with NVA237 100 and 200 μg in patients with moderate-to-severe COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is not fully reversible [1]. Although the course of COPD varies among individuals, there is usually progressive deterioration and the condition often proves fatal. Worldwide, COPD is the fourth most frequent cause of death and results in a substantial burden of morbidity and direct and indirect healthcare costs [1].

Management of COPD requires individualized therapy to alleviate symptoms and maintain or improve quality of life [1]. Treatment with bronchodilators, either as-needed or on a long-term basis, is central to the management of COPD. Muscarinic antagonists and long-acting β₂-agonists are the principal classes of bronchodilators used in the management of COPD and are often used in combination, especially in patients with more severe disease [1]. Inhaled muscarinic antagonists such as ipratropium bromide [2], [3] and tiotropium bromide [4], [5] have been shown to improve lung function and reduce COPD symptoms, and are generally well tolerated [1].

The need for improved pharmaco-therapeutic options for COPD remains. New agents would be particularly beneficial if they could provide greater reductions in disability, improvements in quality of life and reductions in dyspnoea, while having a good safety and tolerability profile. Therapies that combine rapid and sustained efficacy with convenient dosing would be desirable.

NVA237 is a novel inhaled dry powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide, and is in development as a once-daily bronchodilator for the treatment of COPD. In early studies, NVA237 was associated with a rapid onset of action and sustained 24-h bronchodilation in patients with COPD [6], [7]. The results of a recent dose-ranging study indicate that NVA237 provides sustained bronchodilation with a faster onset of action and greater improvements in forced expiratory volume in 1 s (FEV₁) than tiotropium 18 μg. In addition, NVA237 appeared to be well tolerated at doses of up to 100 μg [8]. To expand upon these findings, we conducted a 28-day study in patients with moderate-to-severe COPD treated with the highest dose of NVA237 (100 μg) evaluated in the dose-ranging study [8] and at a two-fold higher dose (200 μg). The primary objective was to assess the safety and tolerability of 28 days of treatment with NVA237 100 and 200 μg once-daily, compared with placebo. Secondary objectives included assessment of bronchodilator efficacy and use of rescue medication.