A reduction in fertility and/or reproductive performance was identified in male rats treated with formoterol at an oral dose of 15,000 mcg/kg, (approximately 2600 times the MRHDID on an AUC basis). No such effect was seen at 3,000 mcg/kg (approximately 1500 times the MRHDID on a mcg/m2 basis). In a separate study with male rats treated with an oral dose of 15,000 mcg/kg (approximately 8000 times the MRHDID on a mcg/m2 basis), there were findings of testicular tubular atrophy and spermatic debris in the testes and oligospermia in the epididymides. No effect on fertility was detected in female rats at doses up to 15,000 mcg/kg (approximately 1400 times the MRHDID on an AUC basis).
The clinical efficacy of BREZTRI AEROSPHERE has been evaluated in two (Trial 1 and 2) randomized, double-blind, multicenter, parallel-group trials in subjects with moderate to very severe COPD who remained symptomatic while receiving 2 or more inhaled maintenance treatments for COPD for at least 6 weeks prior to screening.
Trial 1 (NCT02465567) was conducted over 52 weeks in a total of 8,588 subjects randomized (1:1:1:1) to receive BREZTRI AEROSPHERE (budesonide/glycopyrrolate/formoterol fumarate 320 mcg/18 mcg/9.6 mcg), budesonide, glycopyrrolate and formoterol fumarate [BGF MDI 160 mcg/18 mcg/9.6 mcg] (the BGF MDI 160 mcg/18 mcg/9.6 mcg dosing regimen is not approved), glycopyrrolate and formoterol fumarate [GFF MDI 18 mcg/9.6 mcg], or budesonide and formoterol fumarate [BFF MDI 320 mcg/9.6 mcg], all administered twice daily. GFF MDI and BFF MDI used the same inhaler and excipients as BREZTRI AEROSPHERE.
Trial 1 was conducted in subjects with a history of 1 or more moderate or severe exacerbations in the year prior to screening, post-bronchodilator FEV1/FVC ratio less than 0.7 and the post-bronchodilator FEV1 less than 65% predicted normal value.
The population demographics across all treatments in Trial 1 were: mean age of 65 years, 60% male, 85% Caucasian, and an average smoking history of 48 pack-years, with 41% identified as current smokers. The mean post-bronchodilator percent predicted FEV1 was 43% (range 16% to 73%). At study entry, the most common COPD medications were ICS + long-acting muscarinic antagonist (LAMA) + LABA (39%), ICS + LABA (31%), and LAMA + LABA (14%).
In Trial 1, the primary endpoint was the rate of moderate or severe COPD exacerbations for BREZTRI AEROSPHERE compared with GFF MDI and BFF MDI.
Trial 2 (NCT02497001) was conducted over 24 weeks, in a total of 1,896 subjects randomized (2:2:1:1) to receive BREZTRI AEROSPHERE (budesonide/glycopyrrolate/formoterol fumarate 320 mcg/18 mcg/9.6 mcg), glycopyrrolate and formoterol fumarate [GFF MDI 18 mcg/9.6 mcg], budesonide and formoterol fumarate [BFF MDI 320 mcg/9.6 mcg], or open-label active comparator, all administered twice daily. GFF MDI and BFF MDI used the same inhaler and excipients as BREZTRI AEROSPHERE. Trial 2 was conducted in subjects with a screening post-bronchodilator FEV1/FVC ratio less than 0.7 and post-bronchodilator FEV1 less than 80% predicted normal value. Subjects in Trial 2 were not required to have a history of moderate or severe exacerbations in the year prior to screening.
The population demographics across all treatments in Trial 2 were: mean age of 65 years, 71% male, 50% Caucasian, 45% Asian, and an average smoking history of 52 pack-years, with 40% identified as current smokers. The mean post-bronchodilator percent predicted FEV1 was 50% (range 22% to 84%). At study entry, the most common COPD medications were ICS + LAMA + LABA (27%), ICS + LABA (38%), and LAMA + LABA (20%).
In Trial 2, the primary endpoints were FEV1 area under the curve from 0-4 hours (FEV1 AUC0-4) at Week 24 for BREZTRI AEROSPHERE compared to BFF MDI and change from baseline in morning pre-dose trough FEV1 at Week 24 for BREZTRI AEROSPHERE compared to GFF MDI.
Lung Function
In Trial 1, a subset of subjects were included in a spirometric sub-study with primary endpoints of FEV1 AUC0-4 at Week 24 (mL) and change from baseline in morning pre-dose trough FEV1 at Week 24 (mL). BREZTRI AEROSPHERE demonstrated an increase in on-treatment FEV1 AUC0-4 and trough FEV1 at Week 24 relative to BFF MDI and GFF MDI (Table 2). The effects on lung function (mean change from baseline in on-treatment morning pre-dose trough FEV1) of BREZTRI AEROSPHERE compared with GFF MDI and BFF MDI were observed at all timepoints over the course of the study (Figure 1).
In Trial 2, BREZTRI AEROSPHERE demonstrated an increase in on-treatment FEV1 AUC0-4 at Week 24 relative to BFF MDI and an increase in mean change from baseline in morning pre-dose trough FEV1 at Week 24 compared with GFF MDI (Table 2). The comparison of BREZTRI AEROSPHERE with GFF MDI in mean change from baseline in morning pre-dose trough FEV1 at Week 24 was not statistically significant.
In both trials, there were consistent improvements in lung function in patient subgroups classified by age, sex, degree of airflow limitation (moderate, severe, and very severe), and previous ICS use.
Figure 1: Adjusted Mean Change from Baseline in Trough FEV1 Over Time (Trial 1)1
1The analysis excluded spirometry data collected after discontinuation of study treatment.
In Trial 2, the median time to onset on Day 1, defined as a 100 mL increase from baseline in FEV1, was within 5 minutes in subjects receiving BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg. In Trial 1, subjects treated with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg on average used less daily rescue medication over 24 weeks compared to subjects treated with GFF MDI 18 mcg/9.6 mcg and BFF MDI 320 mcg/9.6 mcg.
Exacerbations
In Trial 1, the primary endpoint was the rate of on-treatment moderate or severe COPD exacerbations in subjects treated with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg compared with GFF MDI and BFF MDI.
Exacerbations were defined as worsening of 2 or more major symptoms (dyspnea, sputum volume, and sputum color) or worsening of any 1 major symptom together with any 1 of the following minor symptoms: cough, wheeze, sore throat, colds (nasal discharge and/or nasal congestion), and fever without other cause for at least 2 consecutive days. Exacerbations were considered to be moderate severity if treatment with systemic corticosteroids and/or antibiotics was required and were considered to be severe if they resulted in hospitalization or death.
In Trial 1, treatment with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg demonstrated a reduction in the rate of on-treatment moderate or severe COPD exacerbations over 52 weeks compared with GFF MDI and BFF MDI (see Table 3).
In Trial 2, treatment with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg reduced the annual rate of on-treatment moderate or severe COPD exacerbations compared with GFF MDI 18 mcg/9.6 mcg (rate ratio [95% CI]: 0.48 [0.37, 0.64]), and compared with BFF MDI 320 mcg/9.6 mcg (rate ratio [95% CI]: 0.82 [0.58, 1.17]). The comparison of BREZTRI AEROSPHERE with GFF MDI was not statistically significant due to failure higher in the analysis hierarchy.
Health-Related Quality of Life
In both trials, health-related quality of life was assessed using the St. George's Respiratory Questionnaire (SGRQ) responder analysis which was defined as an improvement in SGRQ score from baseline of 4 or more.
In Trial 1, the on-treatment percentage of SGRQ responders at Week 24 was greater for subjects treated with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg (50%) compared with both GFF MDI 18 mcg/9.6 mcg (43%; odds ratio 1.4; 95% CI: 1.2, 1.5) and BFF MDI 320 mcg/9.6 mcg (45%; odds ratio 1.2; 95% CI: 1.1, 1.4). Similar differences between treatments were observed at Week 52.
In Trial 2, the on-treatment percentage of SGRQ responders at Week 24 was greater for subjects treated with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg (50%) compared with both GFF MDI 18 mcg/9.6 mcg (44%; odds ratio 1.3; 95% CI: 1.0, 1.6) and BFF MDI 320 mcg/9.6 mcg (43%; odds ratio 1.3; 95% CI: 1.0, 1.7).