The standard treatment strategy for COPD has so far consisted of initiating treatment with an inhaled long-acting antimuscarinic agent (LAMA), and adding combination therapy with a corticosteroid and a long-acting beta-agonist (LABA). However, the latest Global Initiative for chronic Obstructive Lung Disease (GOLD) consensus statement challenges clinicians to rethink this approach; and amongst the range of treatment options proposed is use of LAMA/LABA dual therapy as a treatment alternative for group B (high symptoms/low risk), C (low symptoms/ high risk), and D (high symptom/ high risk) patients. However, few data have been available to support the efficacy of this combination therapy over single agent bronchodilator therapy, whereas good data already exist for monotherapy with either LAMA or LABA.
The NICE clinical guideline on the management of patients with COPD published in 2010 does not address use of dual therapy with a LAMA and LABA. However it does suggest that a LAMA can be offered in addition to LABA + inhaled corticosteroid to people with COPD who remain breathless or have exacerbations despite taking LABA+ICS, irrespective of their FEV1. Glycopyrronium and indacaterol were not licensed at the time this guidance was issued.
The purpose of the randomised, double-blind 26-week SHINE study (n=2,144) was to confirm the ‘rule of combination’ – i.e. that dual bronchodilation with QVA149 (indacaterol plus glycopyrronium) will provide additional benefits compared to the individual components, as well as to tiotropium (the current gold-standard) and placebo in patients with moderate-to-severe stable COPD. The primary endpoint was trough FEV1 at week 26 and this was statistically significantly improved with QVA149 compared with indacaterol (least squares mean [LSM] difference of 0.07 L), glycopyrronium (0.09 L), tiotropium (0.08 L) and placebo (0.20 L). The authors say that the minimal clinically significant difference in this endpoint is considered to be 100mL; the difference between QVA149 and the active comparator monotherapies did not meet this.
The limitations of this study, as acknowledged by the authors, included the recruitment only of patients with moderate-to-severe disease and the short duration; they therefore were unable to provide any data on the impact of QVA149 on COPD exacerbations (this was examined in the SPARK study). The authors discuss the difficulty in evaluating spirometric endpoints when comparing active treatments and comment that the minimal clinically significant difference of 100mL is generally used for comparisons against placebo, and that the mean improvements of 70, 80 and 90 mL versus indacaterol, glycopyrronium and tiotropium, respectively, approach this threshold value.
Novartis is expecting to file for a marketing authorisation of QVA149 in the fourth quarter of 2013/first quarter 2014. Currently in the UK, the constituents of QVA149 (glycopyrronium and indacaterol) are licensed as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. Neither product is on the NICE work programme but they have been reviewed recently by NICE (glycopyrronium only) and the Drug and Therapeutics Bulletin (see links below).