Regulatory Decision Summary for Ultibro Breezhaler

 

The purpose of this Supplement to a New Drug Submission (SNDS) was to extend the currently approved clinical indication of Ultibro Breezhaler, i.e., for the long-term once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, to include "for the reduction of exacerbations".

 

Two pivotal efficacy and safety studies were submitted to support the proposed new indication.

 

In support of the proposed indication change, the sponsor submitted two studies (A2318 and A2304). Study A2318 was 52 week in duration, was multi-center, randomized, double-blind, double-dummy, parallel-group, and had an active control group. The study compared QVA 149 (indacaterol maleate/glycopyrronium bromide 110/50 mcg o.d.) to salmeterol/fluticasone (50/500 mcg b.i.d.) with regard to exacerbations (mild/moderate/severe) in patients with moderate to very severe COPD with a documented history of at least one COPD exacerbation in the previous 12 months. A total of 3,362 patients were randomized. Treatment with QVA149 demonstrated an 11% reduction in exacerbation rate for all exacerbations (mild, moderate, and severe), (3.59 vs. 4.03; rate ratio, 0.89; 95% CI, 0.83 to 0.96, p=0.003), and prolonged time to first exacerbation with a 16% reduction in risk of an exacerbation (median time: 71 days for QVA149 vs. 51 days for salmeterol/ fluticasone, p<0.001). In addition, QVA149 treatment showed a 17% reduction in moderate/severe exacerbation rate relative to salmeterol/fluticasone (0.98 vs. 1.19, rate ratio, 0.83; 95% CI, 0.75 to 0.91, p<0.001). The time to the first moderate or severe exacerbation was longer in the QVA149 treated group than that in the salmeterol/ fluticasone treated group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P<0.001).

Study A2304 was 64week in duration and was a multi-center, double-blind, parallel-group, active-controlled study designed to compare rates of reduction of COPD exacerbations between patients treated with QVA149 (indacaterol maleate/glycopyrronium bromide 110/50 mcg q.d.) and those treated with NVA237 (glycopyrronium 50 mcg q.d.). The studys primary objective was to demonstrate that QVA149 (110/50 mcg q.d.) is superior to NVA237 (50 mcg q.d.) with regard to the rate of moderate to severe COPD exacerbations during the treatment period of 64 weeks. The study population included clinically diagnosed COPD patients with severe to very severe COPD, and at least one documented COPD exacerbation requiring oral steroid treatment and/or antibiotics treatment in the preceding year. A total of 2,206 patients were randomized. Treatment with QVA149 resulted in a reduced annual rate of moderate/severe COPD exacerbations by 12% (p = 0.038) when compared with glycopyrronium (50 mcg). QVA149 also showed a 15% (0.001) reduction in the rate of all COPD exacerbations (mild, moderate and severe) when compared to glycopyrronium (50 mcg).

 

Given the efficacy results of the two pivotal clinical trials, and the fact that the active comparators in Study A2318 (i.e. salmeterol/fluticasone 50/500 mcg bid) and in Study 2304 (i.e. glycopyrronium 50 mcg q.d.) have previously shown statistically significant reduction of risk of moderate to severe COPD exacerbations when compared with placebo, the effect of QVA149 (indacaterol maleate/glycopyrronium bromide 110/50 mcg o.d.) on COPD exacerbations was considered clinically relevant. However the effect on COPD exacerbation beyond 64 weeks and among patients without a history of moderate/severe exacerbation in the past 12 months remains unknown.

 

Safety data from Study A2304 was previously reviewed and adequately described in the PM of Ultibro Breezhaler. The adverse effects (AEs) observed in Study A2318 were consistent with previous trials. The overall incidence of AEs was similar across the treatment arms. The most commonly affected primary system organ class was respiratory disorders, the frequency of AEs was less than 10% and similar between the treatment arms. The most frequently reported AE was COPD, which was reported 77.4% in the QVA149 arm compared to 81.8% in salmeterol/fluticasone arm. Other frequently reported AEs (>5% in both treatment arms) were nasopharyngitis (11.7% vs. 11.6%), viral upper respiratory tract infection (7.9% vs. 8.2%) and upper respiratory tract infection bacterial (7.4% vs. 10.0%), respectively. The number of death during the study period was comparable in each study arm (24 deaths/ arm). Adverse events suspected to be related to study drug were similar between two treatment groups. The proportion of patients experiencing a serious adverse effect (SAE) was similar across the treatment arms (18.4% and 19.9% in QVA149 and salmeterol/fluticasone arms, respectively). The incidence of overall adjudicated major adverse cardiac event and/or cardiovascular deaths was similar and balanced between the treatment arms. However, the long-term safety of QVA149 beyond 64 weeks remains unknown.

The overall benefit and risk profile of Ultibro Breezhaler for the previously approve indication and the new indication for the reduction of exacerbations of COPD in patients with a history of exacerbations is favourable.