Bronchodilation with LABAs and LAMAs plays a central role in the management of COPD. LABAs have been widely used for many years, while the first LAMA (tiotropium) became available in Europe in 2002 and in the USA and Canada in 2004 . More recently, there has been interest in new LAMAs, such as NVA237 and aclidinium, which are currently in development as long-acting bronchodilators for use in the management of COPD. These new LAMAs would be particularly valuable if they could provide bronchodilation at least equivalent to that of tiotropium, with a low incidence of troublesome adverse effects. The findings of preclinical and early clinical studies, which demonstrated a favourable efficacy and safety profile of NVA237 [6–8, 17], warranted further investigation in Phase III studies.
In the Phase III GLOW1 study, once-daily NVA237 resulted in statistically significant improvement in trough FEV1 at 12 weeks, with a treatment difference of 108 mL. A steady state for improvement in trough FEV1 versus placebo was achieved at the end of Day 1 and sustained throughout the study. NVA237 also resulted in statistically significant increases in TDI score that exceeded the 1 point difference considered clinically important  and significant improvements in SGRQ scores, with 56% patients achieving the 4-point threshold regarded as clinically significant improvement . NVA237 also significantly reduced the risk of moderate or severe COPD exacerbations and was associated with a numerical reduction in the rate of exacerbations. It should be noted that a duration of 26 weeks with the current sample size does not have adequate power to detect statistically significant differences in the rate of exacerbations. Additionally, in the population studied, a majority (> 60%) of the patients had moderate COPD and < 25% of the patients had a history of COPD exacerbations prior to screening. This accounts for the overall low rate of exacerbations observations. It also makes the improvement in the COPD exacerbations observed potentially more significant, since it may be extended to all patients with COPD and not just those with severe/very severe disease and a history of frequent exacerbations. Further, the patients with moderate-to-severe COPD who were enrolled in GLOW1 had a lower rate of exacerbations prior to enrolment (21%) than in the ECLIPSE study, in which 39% of patients with moderate COPD and 52% of those with severe COPD had one or more exacerbations during the previous year . This difference may be due to variations in the definition of exacerbations (in the GLOW1 study a pre-defined criteria needed to be met for an event to be classified as an exacerbation, while the ECLIPSE study had no such criteria), duration and timing of the assessment period (e.g. whether it includes the high-risk winter months), geographic location (since exacerbation frequency may be affected by weather, climate, and air pollution), and the frequency of follow-up .
The improvements in trough FEV1 versus placebo in the GLOW1 study are consistent with previous studies of NVA237 [6, 7] and are similar to those seen at Week 12 in randomized, double-blind studies of tiotropium [20–27]. However, such comparisons require caution due to differences between the studies (for example, patients enrolled in the tiotropium studies had more severely impaired lung function). Several studies of tiotropium have reported a similar percentage (40-60%) of patients achieving a clinically significant improvement in SGRQ scores as in the GLOW1 study [21, 22, 27–30]. Recent studies with tiotropium have also shown improvements in exacerbations, with a significant delay in time to first exacerbation and time to first hospitalization after an exacerbation [29, 31]. NVA237, in the GLOW1 study, showed similar results, with a significantly prolonged time to first moderate/severe exacerbation and severe exacerbations leading to hospitalization. In these respects, NVA237 appears to produce effects which are comparable to tiotropium. However, in other studies tiotropium has been shown to reach a steady state for trough FEV1 only by Day 7 [4, 32], compared to Day 1 with NVA237. Thus, NVA237 has a quicker time to steady state in addition to its faster onset of action . Also, tiotropium has been shown in some studies [21, 28] to result in clinically significant improvements in TDI score in a lower percentage of patients (45%) than NVA237 in the current study (62%).
Patients receiving NVA237 in GLOW1 had a numerically higher frequency of notable QTcF intervals (4.0% of patients), compared with placebo (1.1%). However, no patient in either treatment group had a QTcF interval > 500 ms and the overall results from the study indicated that NVA237 had a good safety profile, with a low frequency of cardiac AEs. Cardiovascular AEs of LAMAs result from blockade of M2 receptors, which are thought to modulate pacemaker activity, atrioventricular conduction and contraction force . The favourable cardiac safety profile of NVA237 may therefore result from its high affinity for M3 receptors and low affinity for M2 receptors, and also from its faster dissociation from the M2 receptor than from the M3 receptor [34, 35].
Hyperinflation, the main contributor to dyspnoea and reduced exercise tolerance (dynamic hyperinflation), is closely associated with IC [36, 37]. An increase in IC after bronchodilator administration signifies a reduction in hyperinflation, which may translate to a reduction in dyspnoea and improved exercise tolerance. In the current study, IC for NVA237 was higher than baseline values at all timepoints (25 min, 1 h 55 min, 3 h 55 min and 23 h 40 min post dose), and was significantly higher than placebo (p < 0.001) in the FAS. It can be hypothesized that the increase in IC with NVA237 allowed for greater expansion to tidal volume and contributed to the reduction in dyspnoea. This observation offers an opportunity to further explore the effect of NVA237 on dyspnoea and exercise capacity.