Regulatory Decision Summary for Breztri Aerosphere

The efficacy and safety of Breztri Aerosphere 182/8.2/5.8 microgram (mcg) for the treatment of chronic obstructive pulmonary disease (COPD) were evaluated in two pivotal international, multicenter, randomized, double-blind, parallel-group clinical studies (Study PT010005 and Study PT010006). In both studies, Breztri Aerosphere was evaluated compared to the dual combinations of budesonide/formoterol fumarate dihydrate metered dose inhaler (BFF MDI) and glycopyrronium/formoterol fumarate dihydrate (GFF MDI). Subjects had moderate to very severe COPD and were symptomatic with at least dual combination inhalation therapy (i.e., inhaled corticosteroid (ICS)/ long-acting beta2-adrenergic agonist (LABA) or long-acting muscarinic antagonist (LAMA)/LABA). In study PT010005, patients were to have a history of moderate or severe COPD exacerbations, whereas in study PT010006, a history of exacerbations was not an inclusion criterion and only 26% of subjects had a history of exacerbations in the year prior to study entry.

In study PT010005 (number of subjects (n) = 8,573), treatment with Breztri Aerosphere for 52 weeks demonstrated a statistically significant (p-value [p] <0.001) reduction in the rate of moderate or severe COPD exacerbations by 24% (rate ratio 0.76; p<0.001) compared to GFF MDI and by 13% (rate ratio 0.87; p = 0.0027) compared with BFF MDI. In a subset of 3,088 subjects, treatment with Breztri Aerosphere demonstrated a statistically significant improvement in morning pre-dose trough Forced Expiratory Volume in 1 second (FEV₁) over 24 weeks compared with GFF MDI (43 millilitre (mL); p<0.0001) and a nominally statistically significant improvement compared to BFF MDI (76 mL; p<0.0001).

In study PT010006 (n = 1899 subjects), treatment with Breztri Aerosphere resulted in a statistically significant improvement in change from baseline in morning pre-dose trough FEV₁ over 24 weeks (primary endpoint) compared with GFF MDI (Least Squares (LS) mean treatment difference 22 mL; p = 0.0139). However, this difference is not considered clinically relevant. A greater treatment difference was observed compared to BFF MDI (74 mL; p<0.0001). A statistically significant improvement in FEV₁ area under the curve from 0 to 4 (AUC_0-4) over 24 weeks (co-primary endpoint) was observed for Breztri Aerosphere compared to BFF MDI (104 mL; p<0.0001). In a subset of 3,088 subjects in study PT010005, treatment with Breztri Aerosphere resulted in a statistically significant improvement in morning pre-dose trough FEV₁ over 24 weeks compared with GFF MDI (43 mL; p<0.0001) and a nominally significant improvement compared with BFF MDI (76 mL; p<0.0001).

Statistically significant improvements with Breztri Aerosphere compared to BFF MDI and GFF MDI were reported for some secondary endpoints including the rate of moderate or severe COPD exacerbations (Study PT010006), dyspnea (Study PT010005) and improvements in quality of life (Study PT010005 and Study PT010006). However, there is uncertainty regarding the clinical relevance of the treatment differences for the dyspnea and quality of life endpoints, which were below the established minimal clinical important differences (MCID).

The safety of Breztri Aerosphere was evaluated in the pivotal clinical studies in which 639 subjects were treated with Breztri Aerosphere for up to 24 weeks in study PT010006 with 159 subjects treated for an additional 24 weeks in the safety extension study PT010008. In study PT010005, 2144 subjects were treated with Breztri Aerosphere for up to 52 weeks. In general, the frequency and pattern of adverse events were similar across treatment groups, and the most common adverse reactions across both studies were pneumonia, oral candidiasis, muscle spasms and cough.

Overall, the safety data for Breztri Aerosphere showed evidence of known adverse effects associated with inhaled corticosteroid treatment. There was no evidence of an increase in adverse effects associated with the LAMA or LABA and there was no evidence of an additive effect of the three medicinal ingredients administered together as a fixed dose combination.

The non-clinical studies and published literature reviewed suggest that the risk of the budesonide, glycopyrronium and formoterol combination is consistent with known risks of the mono-components.

The Product Monograph for Breztri Aerosphere was revised to accurately reflect the efficacy, safety, and uncertainties identified.

A Risk Management Plan was submitted and reviewed by the Marketed Health Products Directorate. Safety issues are identified in the Product Monograph.

Overall, the benefit-harm-uncertainty profile of Breztri Aerosphere 182/8.5/5.8 mcg for the recommended indication and dosage is favourable.