Regulatory Decision Summary for Enerzair Breezhaler

The efficacy and safety of Enerzair Breezhaler 150/50/160 micrograms (mcg) (high dose) and 150/50/80 mcg (medium dose) once-daily for the treatment of asthma in adults 18 years of age and older were evaluated in a single pivotal 52-week randomized, double-blind, double-dummy, parallel-group clinical trial. A total of 3,092 patients were randomized to 5 treatment groups. The two doses were evaluated compared to the respective high and medium dose dual combination indacaterol/mometasone furoate (MF). Both doses were also compared to another long-acting beta2-agonist (LABA)/ inhaled corticosteroid (ICS) combination, salmeterol xinafoate/fluticasone propionate.

Both doses of Enerzair Breezhaler statistically significantly (p <0.001) improved lung function as measured by trough Forced Expiratory Volume (FEV1), compared to the respective dose of the dual combination indacaterol/MF after 26 weeks of treatment. The difference was modest compared to the active comparator, indacaterol/MF (high dose, 0.065 L; medium dose 0.074 L) but, reflected the added benefit of a second bronchodilator (a long-acting muscarinic receptor antagonist, LAMA) to the active comparator of ICS/LABA. The results of other lung function endpoints were generally consistent with and support the results of the primary endpoint.

No significant or clinically relevant treatment differences were observed for the improvement in asthma control (Asthma Control Questionnaire, ACQ-7) at 26 weeks with Enerzair Breezhaler compared to the active controls. All treatment groups demonstrated comparable improvements in ACQ-7 score from baseline.

The high dose Enerzair Breezhaler demonstrated a 14% reduction in moderate to severe exacerbations and a 17% reduction in severe exacerbations compared to high dose indacaterol/MF. The medium dose demonstrated a small trend toward reduction in moderate or severe exacerbations compared to medium dose indacaterol/MF (rate ratio 0.92).

There is uncertainty regarding the efficacy of the medium dose. Enerzair Breezhaler 150/50/80 mcg did not appear to maintain the improvement in trough FEV1 from 26 weeks to 52 weeks, whereas the improvement was maintained for the high dose. In addition, the reduction in risk of asthma exacerbations for the medium dose were not considered clinically relevant and the annualized rate of asthma exacerbation was greater for medium dose Enerzair Breezhaler compared to high dose indacaterol/MF, indicating no added benefit.

The safety of Enerzair Breezhaler was demonstrated in the pivotal clinical study with no dose response for adverse events (AEs) identified. No new safety risks were identified. Overall, the incidence of AEs was comparable between treatment groups and the majority of AEs were mild or moderate in severity. Asthma was the most commonly observed AE with a lower incidence rate with Enerzair Breezhaler than the other treatment groups. The most common adverse reactions were headache, cough, dysphonia, urinary tract infection and gastroenteritis.

The benefit-risk profile of Enerzair Breezhaler 150/50/160 mcg is favourable for the recommended indication. The benefit-risk profile of the medium dose (50/50/80 mcg) is not considered favourable for the proposed indication and patient population.

The Product Monograph for the 150/50/160 mcg dose dated June 29, 2020 has been revised extensively to accurately reflect the efficacy, safety, and uncertainties identified in this New Drug Submission (NDS).