Regulatory Decision Summary for Atectura Breezhaler

The efficacy and safety of Atectura Breezhaler (150/320 mcg, 150/160 mcg, and150/80 mcg) in adults and adolescent patients (≥ 12 years of age and older) with asthma was evaluated in two pivotal phase 3 clinical trials (B2301 and B2303).

Study B2301 was a 52-week treatment, multicenter, randomized, double-blind, triple-dummy, parallel-group study that evaluated two doses of Atectura Breezhaler 150/160 mcg once daily (n = 439) and 150/320 mcg once-daily (n = 445) via Breezhaler over mometasone furoate (MF) 400 mcg (n = 444) and 800 mcg (n = 442) via Twisthaler, respectively. A third active control arm included patients treated with salmeterol xinafoate /fluticasone propionate (SAL/FP) 50/500 mcg twice daily (n = 446). The primary purpose of the study was to demonstrate superiority of either Atectura Breezhaler 150/160 mcg once daily to MF 400 mcg daily or Atectura Breezhaler 150/320 mcg once daily to MF 800 mcg daily. The primary efficacy endpoint was trough Forced Expiratory Volume in the first second (FEV1) at week 26, the key secondary endpoint was asthma control questionnaire (ACQ-7) after 26 weeks of treatment, and asthma exacerbation at week 52 was captured as one of secondary efficacy endpoints. Patients 12 years of age and older with a documented diagnosis of asthma and a pre-bronchodilator FEV1 ≥ 50% and <85% of the predicted normal were eligible for the study. A total of 2,216 patients met the inclusion and exclusion criteria and were randomized to treatment groups.

Study B2303 was a 12-week treatment, multicenter, randomized, double-blind, double-dummy, parallel-group study that evaluated Atectura Breezhaler 150/80 mcg once daily (n = 398) via Breezhaler over MF 200 mcg once daily (n = 404) via Twisthaler. The primary purpose of the study was to demonstrate superiority of Atectura Breezhaler 150/80 mcg once daily to MF 200 mcg once daily via Twisthaler. The primary efficacy endpoint was trough FEV1 at week 12, the key secondary endpoint was asthma control questionnaire (ACQ-7) after 12 weeks of treatment. Patients 12 years of age and older with a documented diagnosis of asthma and a pre-bronchodilator FEV1 ≥ 60% and <90% of the predicted normal were eligible for the study. A total of 802 patients met the inclusion and exclusion criteria and were randomized to treatment groups.

Key Benefit
In Study B2301, almost all patients (2,207 out of 2,216) completed at least 26 weeks treatment, and 1,368 (61.7%) patients completed 52 weeks of treatment. Atectura Breezhaler 150/160 mcg and 150/320 mcg once daily demonstrated statistically significant improvements in trough FEV1 and ACQ-7 score at week 26 compared to MF 400 and 800 mcg daily,respectively. After 26 weeks of treatment, the estimated treatment differences in trough FEV1 were 130 mL (95% confidence interval [CI]: 86 to 173 mL) (p <0.001) for Atectura Breezhaler 150/320 mcg vs MF 800 mcg, and 211 mL (95% CI: 167 to 255 mL) (p <0.001) for Atectura Breezhaler 150/160 mcg vs MF 400 mcg. The improvements in trough FEV1 in adolescents (12-17 years old) (n = 106) were consistent with that observed in the overall population (12-75 years of age). After 26 weeks of treatment, the Least Squares ( LS) mean treatment difference in ACQ-7 score for both doses of Atectura Breezhaler combined versus both doses of MF combined improved (decreased) by -0.209 (95% CI: -0.270, -0.148; p <0.001. The proportion of patients with asthma exacerbation at week 52 was lower (40-51% lower rate) in Atectura Breezhaler treatment groups than in the corresponding MF treatment groups. Atectura Breezhaler 150/320 mcg once daily showed a similar reduction in the annual rate of moderate or severe exacerbation when compared with salmeterol/fluticasone 50/500 mcg twice daily (b.i.d.).

In Study B2303, almost all patients (794 out of 802) completed this 12-week study. Atectura Breezhaler 150/80 mcg once daily demonstrated a statistically significant improvement in baseline trough FEV1 and ACQ-7 score at week 12 compared to MF 200 mcg once daily. After 12 weeks of treatment, the estimated treatment difference in trough FEV1 was 182 mL (95% CI: 148 to 217 mL) (p <0.001). The improvements in trough FEV1 in adolescents (12-17 years old) (n = 64) were consistent with that observed in the overall population (12-75 years of age). At week 12, The LS mean treatment difference in ACQ-7 score was statistically significant (-0.218, 95% CI: -0.293, -0.143) (p <0.001). A greater percentage of subjects were ACQ-7 responders for Atectura Breezhaler 150/80 mcg (74.7%) compared to MF 200 mcg (64.9%).

Key Harm
In the 52-week study (Study B2301), the most common adverse drug reactions (ADRs) related to Atectura Breezhaler were headache, musculoskeletal pain, oropharyngeal pain, dysphonia, oral candidiasis, and hypersensitivity. Asthma exacerbation was the most frequently reported serious adverse event (SAE) with a slightly higher incidence in the MF 400 mcg group. Pneumonia was reported in 11 patients in this study (5 were on MF 800 mcg). Myocardial infarction was reported in 3 patients (2 were on Atectura Breezhaler 150/320 mcg). One death (0.2%) due to asthma exacerbation was reported in an adolescent patient 18 years of age who was taking low dose MF 400 mcg on Day 314 of the study. Hypersensitivity was the most frequently reported adverse event (AE) of special interest, with the highest rate in the MF 400 mcg group (79.1%). Immunosuppression was the second most frequently reported AE of special interest, with the highest rate in MF 800 mcg group (10%). Rates of other AEs of special interest such as bone fracture, reduced bone mineral density, cardiac arrhythmia, cerebrovascular events, ischaemic heart disease and myocardial infarction, cataract, diabetes mellitus, and liver toxicity, were low and comparable across 5 treatment groups. The safety profile of adolescents (12-17 years old) were similar to that of the overall population (12-75 years of age). Overall, no new safety signals associated with the treatment of Atectura Breezhaler were observed in pivotal clinical trials.

Key Uncertainties
Uncertainties of Benefit: Although Atectura Breezhaler significantly improved the lung function measured by trough FEV1 at 26 weeks in patients 12 years of age and older with asthma, the long-term effect of on lung function beyond 26 weeks remains unknown. Efficacy in asthma patients under 12 years of age and pregnant women has not been evaluated in pivotal trials. Moderate to severe asthma exacerbation is an important clinical endpoint; asthma exacerbation was captured as a secondary efficacy endpoint in the 52-week pivotal study and the results were considered as descriptive in nature. Therefore, the effect of Atectura Breezhaler on asthma exacerbation is not well established.

Uncertainties of Harm: An increased risk of pneumonia and cardiovascular adverse events were not observed in pivotal trials, post-marketing surveillance systems are important to continue monitoring these risks in patients treated with Atectura Breezhaler.

The totality of evidence submitted in this New Drug Submission (NDS) supports the safety and efficacy of Atectura Breezhaler (indacaterol/mometasone furoate) for the indication as a once-daily maintenance treatment of asthma in adults and adolescents 12 years of age and older with reversible obstructive airways disease. The benefit-risk profile of Atectura Breezhaler (indacaterol/mometasone furoate) for the recommended indication and dosage is favourable.

The Product Monograph of Atectura Breezhaler accurately reflects the efficacy, safety, and uncertainties identified in this NDS.