Regulatory Decision Summary for Trelegy Ellipta

The evidence submitted in this Supplemental New Drug Submission (SNDS) supported the safety and efficacy of Trelegy Ellipta (fluticasone furoate [FF]/umeclidinium [as bromide] (UMEC)/vilanterol [as trifenatate] [VI]) 100/62.5/25 microgram (mcg) and 200/62.5/25 mcg, as a once-daily maintenance treatment of asthma, in adults 18 years of age and older who remain uncontrolled with combination medium or high dose inhaled corticosteroid (ICS)/long-acting beta2-adrenergic agonist (LABA).

The efficacy and safety of Trelegy Ellipta 100/62.5/25 mcg and 200/62.5/25 mcg for the treatment of asthma, were evaluated in a single pivotal variable duration 24 to 52-week international, multicenter, randomized, double-blind, 6-arm, parallel-group clinical trial (Study 205715). The two doses of Trelegy Ellipta were evaluated compared to the respective medium and high dose dual combination of FF/VI (100/25 and 200/25 mcg). Overall, the study was acceptable and the patient population and study duration were appropriate to evaluate added benefit of umeclidinium, a long-acting muscarinic antagonist (LAMA), to the dual combination of FF/VI for the treatment of asthma.

Both doses of Trelegy Ellipta statistically significantly (p-value <0.001) improved trough forced expiratory volume in 1 second (FEV1; primary efficacy endpoint) compared to the respective dose of the dual combination FF/VI after 24 weeks of treatment. There was uncertainty regarding the clinical relevance of the treatment differences (high dose, 110 milliliter (mL); medium dose 92 mL); however, the differences reflected the added benefit of a second bronchodilator (LAMA) to a dual combination ICS/LABA. Therefore, a greater increase may not be expected. The secondary lung function endpoint of FEV1 3 hours post-dose, showed consistent efficacy of both doses of Trelegy Ellipta compared to the respective doses of FF/VI.

The annualized rate of moderate/severe asthma exacerbations for the pooled FF dose (key secondary endpoint) did not show a statistically significant risk reduction for Trelegy Ellipta ([100 + 200]/62.5/25) compared to FF/VI ([100 + 200]/62.5/25); 13% reduction (rate ratio: 0.87). For the un-pooled analysis, there was a numerically greater treatment difference for Trelegy Ellipta 100/62.5/25 compared to FF/VI 100/25 (22%). There was no treatment difference for Trelegy Ellipta 200/62.5/25 compared to FF/VI 200/25 (3.2%). Therefore, there was uncertainty regarding the efficacy of Trelegy Ellipta for the reduction in the risk of moderate/severe asthma exacerbations. Treatment with higher doses of FF (200 mcg) resulted in lower annualized rates of asthma exacerbations in both the dual and triple combinations compared to the treatment groups with lower doses (100 mcg).

No significant or clinically relevant treatment differences were observed for the improvement in asthma control (Asthma Control Questionnaire, ACQ-7) with Trelegy Ellipta compared to the FF/VI. However, the addition of another bronchodilator (LAMA) may not be expected to have a significant effect on ACQ-7 score. The responder rates were numerically greater for both doses of Trelegy Ellipta compared to the respective doses of FF/VI.

The safety of Trelegy Ellipta was demonstrated in the pivotal clinical study with no dose response for adverse events (AEs) identified. No new safety risks were identified in the new patient population and for the higher FF 200 mcg dose. Overall, the incidence of AEs was comparable between treatment groups. Nasopharyngitis, headache, upper respiratory tract infections and bronchitis were the most commonly reported AE in all treatment groups.

A Risk Management Plan (RMP) was submitted and reviewed by the Marketed Health Products Directorate (MHPD) and included updates for the new indication for asthma.

Overall, the benefit-harm-uncertainty profile of Trelegy Ellipta 100/62.5/25 mcg and 200/62.5/25 mcg for the recommended indication and dosage was favourable.