Summary Basis of Decision for Breo Ellipta

Clinical Pharmacology

Breo Ellipta contains both fluticasone furoate (a synthetic corticosteroid) and vilanterol (a selective long-acting beta₂-receptor agonist). Fluticasone furoate has been shown to have potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects chronic obstructive pulmonary disease (COPD) symptoms is not known. Vilanterol stimulates intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased levels of cyclic AMP cause relaxation of bronchial smooth muscle and inhibit the release of mediators of immediate hypersensitivity from cells, especially mast cells.

The comprehensive clinical pharmacology program included studies in COPD and asthma patients and healthy, hepatically impaired and renally impaired subjects.

Higher systemic exposure to fluticasone furoate was observed in East Asian populations compared to Caucasians after inhalation. In subjects with mild, moderate, and severe hepatic impairment, systemic exposure to vilanterol was not affected however, fluticasone furoate systemic exposure was higher (up to 3-fold) compared to healthy subjects. These results correlated with a 34% decrease in weighted mean serum cortisol in patients with moderate hepatic impairment. Therefore, use with caution is recommended in patients with hepatic impairment. In subjects with severe renal impairment (creatinine clearance <30 mL/min), systemic exposure to fluticasone furoate was lower and systemic exposure to vilanterol was higher compared to healthy subjects. However, the increased vilanterol systemic exposure did not result in associated pharmacodynamic effects.

The effects of fluticasone furoate/vilanterol on electrocardiogram parameters were also investigated and fluticasone furoate/vilanterol was associated with a dose-dependent increase in heart rate and QTc prolongation.

Overall, the clinical pharmacological data support the use of Breo Ellipta for the specified indication. Appropriate warnings and precautions are in place in the approved Breo Ellipta Product Monograph to address the identified safety concerns.

For further details, please refer to the Breo Ellipta Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Breo Ellipta was evaluated in four Phase III clinical studies in patients with a clinical diagnosis of COPD. Two were lung function studies and the other two were exacerbation studies. The four studies were considered pivotal studies for the COPD indication.

Lung Function Studies

Two 6-month multicentre, randomized, placebo-controlled, double-blind, parallel group studies (HZC112206, HZC112207) were designed to evaluate the efficacy of Breo Ellipta in improving lung function in patients with moderate to severe COPD. Of the 2,254 randomized patients who received at least one treatment dose, the majority were male (70%) and Caucasian (84%), and ranged in age from 40 to 85 years (mean age: 62 years). At screening, the mean post-bronchodilator percent predicted Forced Expiratory Volume in 1 second (FEV₁) was 48.1% and the mean percent reversibility was 13.8%. The mean smoking history was 44.1 pack years, and 54% of the patients were current smokers.

Study HZC112206 evaluated the efficacy of fluticasone furoate/vilanterol 50/25 µg [number of patients (n) = 206)], and Breo Ellipta 100/25 µg (n = 206) compared with fluticasone furoate 100 µg (n = 206), vilanterol 25 µg (n = 205) and placebo (n = 207), all administered once daily.

Study HZC112207 evaluated the efficacy of Breo Ellipta 100/25 µg (n = 204) and fluticasone furoate/vilanterol 200/25 µg (n = 205) compared with fluticasone furoate 100 µg (n = 204) and 200 µg (n = 203) and vilanterol 25 µg (n = 203) and placebo (n = 205), all administered once daily.

The co-primary endpoints in both studies were the weighted mean FEV₁ from 0 to 4 hours post-dose at Day 168 and change from baseline in pre-dose trough FEV₁ at the end of the study.

In Study HZC112206, for the first co-primary endpoint, Breo Ellipta 100/25 µg increased the weighted mean FEV₁ (0 4 hours) relative to placebo by 173 mL by the end of the 24-week treatment period. Similarly, an increase of 209 mL was observed in Study HZC112207. In addition, patients receiving Breo Ellipta 100/25 µg had a greater increase in weighted mean FEV₁ (0-4 hours) compared with those receiving fluticasone furoate 100 µg.

The second co-primary endpoint, change from baseline in trough FEV₁ following the final treatment day, was increased by 115 mL in Study HZC112206 and increased by 144 mL in Study HZC112207 compared with placebo. Improvement in trough FEV₁ with Breo Ellipta 100/25 µg compared with vilanterol (45 to 48 mL) did not achieve statistical significance in either study.

Exacerbation Studies

Two 12-month studies (HZC102970, HZC102871) were designed to evaluate the efficacy of Breo Ellipta in reducing COPD exacerbations in COPD patients with a history of exacerbations.

Studies HZC102970 and HZC102871 were 12-month, multicentre, randomized, double-blind, parallel-group studies comparing the effect of fluticasone furoate/vilanterol 200/25 µg, Breo Ellipta 100/25 µg, fluticasone furoate/vilanterol 50/25 µg and vilanterol 25 µg, all administered once daily (OD), on the annual rate of moderate/severe exacerbations in patients with COPD. The intent-to-treat population included 3,255 patients with an established history of COPD and a history of exacerbations (but no other significant respiratory disorders) and a smoking history of a mean of 46.2 pack years. The majority of the patients were male (57%) and Caucasian (85%), and ranged in age from 40 to 90 (mean age: 64 years) and had moderate to very severe airflow obstruction.

The primary endpoint was the annual rate of moderate and severe exacerbations. Moderate/severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalization. Both studies had a 4-week run-in period during which all patients received open-label fluticasone propionate/salmeterol 250/50 µg twice daily to standardize COPD pharmacotherapy and stabilize disease prior to randomization to blinded study medication for 52 weeks. Prior to run-in, patients discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta₂-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta₂-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Patients used salbutamol on an as-needed basis throughout the studies.

The results of both studies showed that treatment with Breo Ellipta 100/25 µg OD resulted in a lower annual rate of moderate/severe COPD exacerbations compared with vilanterol. Both of the 12-month exacerbation studies (HZC102970 and HZC102871) demonstrated that all three strengths of fluticasone furoate/vilanterol OD were more efficacious than vilanterol 25 µg OD alone in reducing the annual rate of moderate and severe COPD exacerbations Treatment with all three strengths of fluticasone furoate/vilanterol decreased the annual rate of moderate and severe exacerbations by between 13% and 34% compared with treatment with VI 25 OD alone across the two studies. In particular, compared with vilanterol 25 µg OD alone, treatment with Breo Ellipta 100/25 µg consistently reduced the annual rate of moderate and severe COPD exacerbations, with reductions of 34% and 21%. In Study HZC102970, Breo Ellipta 100/25 µg significantly lowered the risk for time to first moderate or severe exacerbation at any time point compared to treatment with vilanterol 25 µg alone [hazard ratio 0.8, 95% confidence interval (CI): 0.66, 0.99]. In Study HZC102871, the risk for time to first moderate or severe exacerbation at any time point was numerically lower for Breo Ellipta 100/25 µg compared to vilanterol 25 µg alone (hazard ratio of 0.72; 95% CI: 0.59, 0.89). In Study HZC102970, Breo Ellipta 100/25 µg significantly reduced the annual rate of COPD exacerbations requiring systemic/oral corticosteroids compared to treatment with vilanterol 25 µg alone (hazard ratio of 0.77; 95% CI 0.60, 0.99). In Study HZC102871, the annual rate of COPD exacerbations requiring systemic/oral corticosteroids was numerically lower for Breo Ellipta 100/25 µg compared to vilanterol 25 µg alone (ratio of 0.62; 95% CI 0.49, 0.78).

Efficacy Conclusion

Three doses of the fluticasone furoate/vilanterol combination were taken to Phase III: fluticasone furoate/vilanterol 50/25 µg; fluticasone furoate/vilanterol 100/25 µg, and fluticasone furoate/vilanterol 200/25 µg. The totality of the data supports the dose of fluticasone furoate/vilanterol 100/25 µg OD, in the morning or in the evening, as the most appropriate dose for the specified indication. While the dose of fluticasone furoate/vilanterol 50/25 µg was sub-optimal, the dose of fluticasone furoate/vilanterol 200/25 µg did not provide any added benefits, while at the same time increased the risks.

Overall, the contribution of the vilanterol component to the combination product, Breo Ellipta (fluticasone furoate/vilanterol 100/25 µg), has been shown based on the totality of the data, including an analysis of both co-primary endpoints from the lung function studies, as well as the 24-hour spirometric time curve from the preliminary dose-ranging study. The results were both statistically significant and clinically meaningful, demonstrating the contribution of the vilanterol component to the combination.

The benefit that fluticasone furoate provides to the combination product was demonstrated in the exacerbation studies with support drawn from the trough FEV1 results obtained in the four pivotal Phase III studies. Since the contribution of an inhaled corticosteroid (ICS) in a combination product on lung function (trough FEV1) is relatively small, the major contribution of fluticasone furoate to the combination was evaluated in the 1-year, exacerbation studies by measuring the effect of the combination on the annual rate of moderate and severe COPD exacerbations. Treatment with Breo Ellipta 100/25 µg once daily resulted in a lower annual rate of moderate/severe COPD exacerbations compared with vilanterol thus showing the contribution of fluticasone furoate to the combination.

In conclusion, the efficacy results from the pivotal Phase III studies are considered positive. The totality of the data provided by the sponsor supports the specified indication of Breo Ellipta for the long-term once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema, and to reduce exacerbations of COPD in patients with a history of exacerbations.

For more information, refer to the Breo Ellipta Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The primary COPD safety database for Breo Ellipta included data from the four pivotal Phase III COPD studies described in the Clinical Efficacy section. A total of 2,257 patients were included in the 6-month lung function studies, and 3,255 patients in the 12-month exacerbation studies. Additional safety results were obtained from 2,342 patients in various other COPD studies. Overall, the safety database was considered large and adequate.

The safety analyses included evaluation of adverse events (AEs), serious adverse events (SAEs), and deaths. Adverse events of special interest, usually associated with ICS use, such as pneumonia, bone disorders and fractures, adrenal function; or associated with long acting beta₂-agonist (LABA) use, such as cardiovascular effects (electrocardiograms, Holter monitoring, thorough QT study), tremors, hypokalemia, and hyperglycemia were also assessed.

The most common AEs were nasopharyngitis, headaches, upper respiratory tract infection (URTI), and oral and oropharyngeal candidiasis. In the two 6-month studies, these AEs had the following incidence rate for Breo Ellipta versus (vs.) placebo: nasopharyngitis 9% vs. 8%; headache 7% vs. 5%; URTI 7% vs. 3%; and oral and oropharyngeal candidiasis 5% vs. 2%; respectively.

A total of 43 on-treatment deaths were reported in the 12-month exacerbation studies and 8 on-treatment deaths were reported in the 6-month lung function studies. Common causes of deaths included COPD exacerbation, respiratory failure, and myocardial infarction, which are well known causes of death in older COPD patients. The number of deaths, AEs, and SAEs did not raise any safety concerns.

Two safety findings of interest were pneumonia and bone fractures. Pneumonia was observed in the fluticasone furoate treatment arms, more prominently in the 12-month exacerbation studies that were conducted in COPD patients whose condition was worse. However, pneumonia is a known risk of high-dose inhaled steroids in patients with COPD and has been seen with other ICS/LABA combination products. An increased risk of fractures was also seen with Breo Ellipta compared to vilanterol. Similar to pneumonia, a decrease in bone mineral density and increased fractures are also known risk factors for inhaled corticosteroids and have been seen in previous ICS/LABA combination product development programs for COPD.

Other safety assessments, such as assessments of cardiovascular function and adrenal axis did not show any safety signals. Analysis of common AEs, laboratory parameters, and vital signs also did not show any specific findings of concern.

The limitations of the safety database have been discussed in the Risk Management Plan (RMP) and risk minimization activities, including routine pharmacovigilance practices, as well as action beyond routine pharmacovigilance (post-market cardiovascular safety assessments) plans have been included in the RMP.

Overall, the submitted data support the safety of Breo Ellipta for use as maintenance treatment of airflow obstruction and reducing exacerbations in patients with COPD. Appropriate warnings and precautions are in place in the approved Breo Ellipta Product Monograph to address the identified safety concerns. A Black Box Warning is used to warn prescribers and users that Breo Ellipta is not indicated for the treatment of asthma. Long-acting beta₂-adrenergic agonists, including vilanterol (an active ingredient in Breo Ellipta), are associated with an increased risk of asthma-related death.