Regulatory Decision Summary for Arbesda Respiclick

Pivotal studies 301 and 30017 were 12-week, multicentre, randomized, double-blind, parallel-group, placebo-controlled studies of three doses of fluticasone propionate (Fp) (55, 113, and 232 mcg) with and without a fixed dose of salmeterol (14 mcg) compared to placebo in 1,375 patients (Study 301: n = 647, about 130 per treatment arm; Study 30017: n = 728, about 145 per treatment arm) with persistent asthma. Study 301 included the low (55 mcg) and mid (113 mcg) doses of Fp and Study 30017 included the mid (113 mcg) and high (232 mcg) doses of Fp. The primary efficacy endpoints in both studies were the change from baseline in trough forced expiratory volume in one second (FEV1) at week 12 for all patients and standardized baseline-adjusted FEV1 area under the effect curve (AUEC)_0-12h at week 12 analyzed for a subset of about 300 patients who performed post-dose serial spirometry. The patients enrolled in studies 301 and 30017 were predominantly female (58%), Caucasian (80%), and never smokers (86%), with a mean age of 43 years (range 12-86). Patients had a mean FEV1 of 2.1L (66% predicted) and an FEV1/forced vital capacity (FVC) ratio of 67%. At baseline, about half of the patients were on inhaled corticosteroid (ICS) (57%) and the other half were on inhaled corticosteroid / long-acting beta2 adrenergic agonist (ICS/LABA) (43%) therapy.

For Study 301, out of the 647 patients who were randomized, 93% (n = 602) completed the study. Patients receiving FS multidose dry powder inhaler (MDPI) 55/14 mcg and FS MDPI 113/14 mcg had significantly greater improvements in trough FEV1 compared with those receiving Fp MDPI 55 mcg, Fp MDPI 113 mcg, and placebo. In addition, patients receiving Fp MDPI 55 mcg and Fp MDPI 113 mcg had significantly greater improvements in trough FEV1 compared with those receiving placebo. The analysis of the standardized baseline-adjusted FEV1 AUEC_0-12h at week 12 based on serial spirometry also showed that FS MDPI 113/14 mcg was statistically significantly superior to Fp MDPI 113 mcg, and that FS MDPI 55/14 mcg was statistically significantly superior to Fp MDPI 55 mcg.

For Study 30017, out of the 728 patients who were randomized, 89% (n = 650) completed the study. Patients receiving FS MDPI 113/14 mcg and FS MDPI 232/14 mcg had significantly greater improvements in trough FEV1 compared with those receiving Fp MDPI 113 mcg, Fp MDPI 232 mcg, and placebo. In addition, patients receiving Fp MDPI 113 mcg and Fp MDPI 232 mcg had significantly greater improvements in trough FEV1 compared with those receiving placebo. The analysis of the standardized baseline-adjusted FEV1 AUEC_0-12h based on serial spirometry for combination therapy also showed that FS MDPI 232/14 mcg was statistically significantly superior to Fp MDPI 232 mcg, and that FS MDPI 113/14 mcg was statistically significantly superior to Fp MDPI 113 mcg.

In both pivotal trials, there was supportive evidence of efficacy for FS MDPI (55/14 mcg, 113/14 mcg, and 232/14 mcg) compared with placebo for secondary efficacy endpoints over the 12 week treatment period. These include improvement in weekly average of daily through morning peak expiratory flow (AM PEF), weekly average of the total daily asthma symptom score, and weekly average of the total daily use of rescue medication, and asthma quality of life questionnaire (AQLQ).

Studies 301 and 30017 demonstrated the efficacy of three doses of Fp MDPI (55 mcg, 113 mcg, and 232 mcg) over placebo; it also demonstrated the efficacy of the combination product FS MDPI (55/14 mcg, 113 mcg/14 mcg, and 232/14 mcg) over placebo and over the individual Fp MDPI monotherapy at the same ICS strength among patients with asthma aged 12 years and older. However, efficacy of FS MDPI in pediatric patients less than 12 years of age and the efficacy on asthma exacerbation has not been studied.

The safety profile for inhaled fluticasone propionate and salmeterol in patient with asthma is well-known since they have been marketed for the treatment of asthma as Flovent Diskus (fluticasone propionate 50 mcg, 100 mcg, 250 mcg, and 500 mcg bid) and as Advair Diskus (fluticasone propionate/salmeterol 100/50 mcg, 250/50 mcg and 500/50 mcg bid). The safety assessment of FS MDPI (55/14 mcg, 113/14 mcg and 232/14 mcg bid) relies on the pooled results of the four 12-week studies (201,202, 301, and 30017) and the 26-week long-term extension study (305).

A total of 2,625 patients who were randomly assigned to treatment and received at least one dose of study drug were included in the safety assessment based on the four 12-week studies. The majority of patients in the safety population completed the study; 17% of patients overall withdrew from the study prematurely. The incidence of adverse events was reported similarly across treatment groups. The most frequent adverse events (AEs), occurring in 3% or more subjects in any treatment group were nasopharyngitis, oral candidiasis, back pain, headache, upper respiratory infection, and cough. The overall occurrence of serious adverse events (SAEs) was equally distributed across treatment groups (0% to 2%). The only SAE that occurred in more than one patient was asthma exacerbation. Asthma exacerbation was reported in 4 (1%) patients in the placebo arm and 1 (1%) patient in the FS MDPI 232/14 mcg treatment arm. Discontinuations due to AEs were balanced across treatment groups. Additionally, a total of 673 patients who were randomly assigned to treatment and received at least one dose of study drug were included in the long-term (26 weeks) safety assessment. The results of the 26-week study were consistent with the safety profile of the four 12-week studies.

Although post-marketing safety data were not available, a list of adverse drug reactions identified during post approval surveillance of other fluticasone propionate/salmeterol products was included in the PM of Arbesda Respiclick.

Safety of FS MDPI in pediatric patients less than 12 years of age has not been studied. Also some specific safety effects of FS MDPI such as regarding bone mineral density measurements, hypothalamic-pituitary-adrenal (HPA) axis, and growth have not been examined.