Regulatory Decision Summary for Trelegy Ellipta

The safety and efficacy of the components of Trelegy Ellipta, fluticasone Furoate (FF) 100 µg, Umeclidinium (UMEC) 62.5 µg and Vilanterol (VI) 25 µg have been previously evaluated in the clinical programs for monotherapy with UMEC 62.5 µg, and dual combinations of FF/VI 100/25 and UMEC/VI 62.5/25 and were all found to have a favorable risk benefit profile. The benefit/risk for use of FF/UMEC/VI in COPD is based on efficacy and safety data from the pivotal study CTT116853 and supporting studies 200109/200110.

Study CTT116853 was a 24-week evaluation with 54-week extension study in patients with COPD who were symptomatic and at risk of exacerbations, the fixed triple combination of FF/UMEC/VI was compared with a benchmark ICS/LABA combination, budesonide/formoterol (BUD/FOR 400/12). In the intention-to-treat (ITT) Population up to 24 weeks, FF/UMEC/VI demonstrated statistically significant and clinically meaningful efficacy in improving airflow obstruction compared with an established ICS/LABA as assessed by the primary end-point, change in trough forced expiratory volume in one second (FEV1) from baseline to Week 24. The co-primary endpoint of St. Georges Respiratory Questionnaire (SGRQ) achieved statistical significance but was not clinically meaningful. Secondary outcomes such as other lung function parameters, COPD exacerbations, COPD symptoms, responder analyses, annual rate of exacerbations, Transitional Dyspnoea Index (TDI), COPD Assessment Test (CAT), and rescue medication use demonstrated consistent benefit for FF/UMEC/VI compared with BUD/FOR. The efficacy profile at 52 weeks was consistent with the efficacy profile observed in the ITT Population up to 24 weeks. The supportive studies, 200109 and 200110, compared the effects of adding UMEC (62.5 µg or 125 µg) to a fixed-dose combination of FF/VI 100/25 using separate inhalers. The outcome for the primary efficacy endpoint, change from baseline in trough FEV1 at Day 85, was statistically significantly superior for UMEC + FF/VI compared with FF/VI. Furthermore, the secondary and other efficacy end-points also provided evidence of the beneficial effects of adding UMEC to FF/VI. Since, as per GOLD 2018 guidance, triple therapy should not be used as initial therapy for COPD and should be reserved for patients who require additional treatment because of ongoing symptoms and or exacerbations while on dual therapies, the Sponsors proposed indication was restricted to patients who are not adequately treated by a dual therapy of an ICS/LABA.

The overall safety profile of FF/UMEC/VI in CTT116853 was consistent with the pharmacologic class of each component and with the safety profiles of the previously approved dual combinations FF/VI and UMEC/VI. No new safety signals emerged in the ITT Population up to 24 weeks or in the extended (EXT) Population up to 52 weeks. In the ITT Population up to 24 weeks in study CTT116853, there were no major differences between the treatment groups comparing Adverse events (AEs), Serious AEs, fatal AEs and AEs leading to permanent discontinuation of study drug and/or withdrawal from the study. However, there was a higher incidence of pneumonia in the FF/UMEC/VI group in the ITT Population compared with the BUD/FOR group. Pneumonia events (including pneumonias resulting in hospitalisation) are common with the use of ICS in the COPD population. In addition, this imbalance in the pneumonia incidence was not observed in the EXT Population up to 52 weeks. The Sponsor has implemented pharmacovigilance and risk minimisation activities aimed at minimizing the risk of pneumonia in patients with COPD using FF/UMEC/VI. In the pivotal trial, the incidence of cardiovascular adverse events was similar between FF/UMEC/VI and BUD/FOR in the ITT Population up to 24 weeks and the EXT Population up to 52 weeks. Despite two thirds of subjects having cardiovascular (CV) risk factors other than smoking at baseline, there was a low incidence of events in the pre-specified MACE analysis. The overall incidence of fatal events was low, and the events were in line with what would be expected in patients with advanced COPD with multiple underlying co-morbidities. No emerging safety signals were identified on review of ECG, Holter, vital signs, or laboratory data. The numerical differences observed between treatment groups in the incidence of AEs based on gender, age, race, body mass index (BMI) category, CV risk, exacerbation history, pneumonia history, eosinophil level category, geographical region, or smoking status were not considered to impact the overall benefit/risk profile. The supportive studies did not show any safety concerns.

Overall, the benefit-risk balance for Trelegy Ellipta is considered to be positive in patients with moderate to severe COPD who are not adequately treated by a combination of an ICS/LABA.