Regulatory Decision Summary for Bevespi Aerosphere

The Sponsor completed the clinical development program to support the registration of this product, a LABA/LAMA fixed dose combination product, in patients with COPD. Combining bronchodilators from different pharmacological classes may improve efficacy and decrease the risk of side effects compared to increasing the dose of a single bronchodilator.

The safety and efficacy of Bevespi Aerosphere (glycopyrronium/formoterol fumarate dihydrate) was evaluated in a clinical development program that included two 24-week randomized, double-blind, parallel-group, placebo-controlled lung function studies (PT003006 and PT003007), which included a 28-week extension study (PT003008) to evaluate safety over 1 year.

Studies PT003006 and PT003007 included 3699 patients aged ≥40 years and <80 years who had a clinical diagnosis of moderate to very severe COPD (with forced expiratory volume in one second / forced vital capacity ratio (FEV1/FVC) of <0.70 and post-salbutamol FEV1 <80% predicted normal value) and a history of smoking of at least 10 pack-years. Demographic characteristics were similar in both studies (PT003006 and PT003007). The majority of the 3699 patients recruited in the 24-week pivotal trials were male (56%) and Caucasian (91%), with a mean age of 63 years and an average smoking history of 51 pack-years (54% current smokers).

In both studies PT003006 and PT003007, the primary endpoint was change from baseline in morning pre-dose trough FEV1 at week 24 compared with placebo, glycopyrronium 16.6 mcg twice a day (BID) and formoterol fumarate dihydrate 11.6 mcg BID to demonstrate the bronchodilator contributions of glycopyrronium and formoterol fumarate in Bevespi Aerosphere, respectively. The secondary endpoints were change from baseline in morning pre-dose trough FEV1 over 24 weeks, peak change from baseline in FEV1 within 2 hours post-dose at week 24, change from baseline in St. Georges Respiratory Questionnaire (SGRQ) total score at week 24, change from baseline in average daily rescue use over 24 weeks and time to onset of action on Day 1.

In studies PT003006 and PT003007, Bevespi Aerosphere showed statistically significant improvements in trough FEV1 compared with placebo at 24 weeks (150 mL and 103 mL, respectively; both p<0.0001) and over 24 weeks (158 mL and 129 mL, respectively; both p<0.0001). Bevespi Aerosphere also showed statistically significant improvements in trough FEV1 compared with its individual components at 24 weeks and over 24 weeks in both studies. The magnitude of effect was consistently greater for Bevespi Aerosphere compared with placebo, glycopyrronium and formoterol fumarate through week 24 in both studies. Improvements relative to placebo were seen at the first visit assessed (Week 2).

Bevespi Aerosphere showed statistically significant improvements in peak FEV1 within 2 hours post-dose at 24 weeks relative to placebo of 291 mL (95% Confidence Interval (CI) [252, 331]) and 267 mL (95% CI [226, 308]), in PT003006 and PT003007 respectively (both p<0.0001). A 12-hour serial spirometry substudy, which evaluated the bronchodilation time-profile over 12 hours post-dose, was performed in both studies (PT003006 n = 564, PT003007 n = 585). Statistically significant adjusted mean increases from baseline in FEV1 were observed with Bevespi Aerosphere compared to placebo at all post-dose time points from 5 minutes post-dose to 12 hours post-dose on Day 1 and from 0.5 hours to 12 hours post-dose at Week 12.

Statistically significant improvements were observed in the change from baseline in average daily use of rescue medication (salbutamol) for Bevespi Aerosphere compared to placebo over 24 weeks. As well, the percentage of patients who achieved a clinically meaningful improvement from baseline in SGRQ total score (defined as a decrease of at least 4 units) was higher with Bevespi Aerosphere than with placebo.

A total of 1,036 subjects with COPD were treated with Bevespi Aerosphere twice daily at the recommended therapeutic dose during the two pivotal trials. The most common adverse events observed with a rate of 1% or greater in treated patients compared to placebo were cough, urinary tract infection, arthralgia, chest pain, muscle spasms and tooth abscess. The adverse events reported in the 28-week long term safety extension study were similar to those occurring in the 24-week placebo-controlled studies.

The potential for QTc interval prolongation was assessed in a randomized, double-blind, single-dose, placebo- and positive-controlled crossover study. A dose-dependent increase in heart rate (HR) was observed. Although statistically significant differences between treatments were noted for some HR parameters, the estimated mean changes from baseline in the mean, maximum, minimum, daytime and nighttime HR were never more than a 2 bpm decrease or a 1 bpm increase in any one treatment group, and these small changes were not deemed to be clinically meaningful.

The effect of glycopyrronium/formoterol fumarate dihydrate on cardiac rhythm in subjects with COPD was assessed using 24-hour Holter monitoring in 2-week and 24-week studies. No clinically meaningful effects on cardiac rhythm were observed.

Considering the demonstrated efficacy of the product in relation to observed adverse reactions in the intended patient population, the benefit/risk ratio of Bevespi Aerosphere is favorable for the recommended indication and the intended population of COPD patients aged 18 years and older.