Indication: ENERZAIR® BREEZHALER® is indicated as a maintenance treatment for asthma in adult patients not adequately controlled with a maintenance combination of a long-acting beta2-agonist and a high dose of an inhaled corticosteroid, who experienced one or more asthma exacerbations in the previous year.1
Once-daily ENERZAIR®BREEZHALER® is the first LABA/LAMA/ICS fixed-dose combination in the EU for the treatment of these patients.1–4
Two Phase III trials* have assessed the safety and efficacy of ENERZAIR® BREEZHALER® – IRIDIUM and ARGON – and their results are presented below.
3,5,6
IRIDIUM is a phase III, multicentre, randomized, double-blind, parallel-group study, designed to compare the efficacy and safety of QVM149 (ENERZAIR® BREEZHALER®) with QMF149 (ATECTURA® BREEZHALER®) (indacaterol acetate/mometasone furoate inhalation powder) in patients with asthma.
The purpose of the trial was to evaluate the efficacy and safety of two different doses of ENERZAIR® BREEZHALER® (150/50/80 µg and 150/50/160 µg) versus two respective ATECTURA® BREEZHALER® doses (150/160 µg and 150/320 µg) in patients with uncontrolled asthma, as determined by pulmonary function testing and effects on asthma control.
Primary endpoint: Demonstrate superiority in trough FEV1 of ENERZAIR® BREEZHALER® high-dose vs. ATECTURA® BREEZHALER® high-dose after 26 weeks.
Key secondary endpoint: Demonstrate superiority in ACQ-7 score with ENERZAIR® BREEZHALER® high-dose vs. ATECTURA® BREEZHALER® high-dose after 26 weeks.
4,7
ARGON (NCT03158311) is a phase IIIb, multicentre, randomized, 24-week, parallel-group, non-inferiority, open-label (blinded for the two ENERZAIR® BREEZHALER® tested doses), active-controlled study comparing the efficacy and safety of ENERZAIR® BREEZHALER®/ATECTURA® BREEZHALER® with a free combination of salmeterol xinafoate/fluticasone propionate (Sal/Flu) plus tiotropium (Tio) in patients with uncontrolled asthma.
The purpose of this trial was to demonstrate that the efficacy of two doses of the fixed-dose combination product ENERZAIR® BREEZHALER® (150/50/160 μg and 150/50/80 μg) is non-inferior to the efficacy of the free combination of Sal/Flu (50/500 μg) plus Tio (5 μg) in patients with uncontrolled asthma.
Primary endpoint: demonstrate non-inferiority of both doses of ENERZAIR® BREEZHALER® to comparator Sal/Flu plus Tio after 24 weeks of treatment based on the Asthma Quality of Life Questionnaire (AQLQ).
Secondary endpoints (secondary analyses not controlled for multiplicity; inferences based on these data cannot be made due to lack of power):
- To evaluate efficacy of both doses of ENERZAIR® BREEZHALER® compared with Sal/Flu plus Tio based on trough FEV1 after 24 weeks of treatment.
- To evaluate efficacy of both doses of ENERZAIR® BREEZHALER® compared with Sal/Flu plus Tio based on Asthma Quality of Life Questionnaire (AQLQ) over 24 weeks of treatment.
- To evaluate efficacy of both doses of ENERZAIR® BREEZHALER® compared with Sal/Flu plus Tio based on ACQ-7 over 24 weeks of treatment.
- To evaluate efficacy of both doses of ENERZAIR® BREEZHALER® compared with Sal/Flu plus Tio based on lung function over 24 weeks of treatment.
The IRIDIUM*† trial showed an improvement in lung function with high-dose ENERZAIR® BREEZHALER® vs high-dose IND/MF.5
ENERZAIR® BREEZHALER® high-dose significantly improved trough FEV1 by +65 mL (95% CI: 31, 99) at Week 26 vs. ATECTURA® BREEZHALER® high-dose, p<0.0015
Change from baseline in trough FEV1 in high dose ATECTURA® BREEZHALER® vs high dose ENERZAIR® BREEZHALER® at Week 26 and 525
Week 26
Week 525,6
LS mean change from baseline in trough FEV1 in high dose SAL/FLU vs high dose ENERZAIR® BREEZHALER® at Weeks 26 and 525,6
The ARGON* trial showed an improvement in lung function with high-dose ENERZAIR® BREEZHALER® vs high-dose SAL/FLU.7
LS mean change from baseline in trough FEV1 in high dose SAL/FLU vs high dose ENERZAIR® BREEZHALER® at Week 247
The IRIDIUM*† trial showed a fast onset of action with high dose of ENERZAIR® BREEZHALER®, with at least 50 mL improvements in FEV1 versus both doses of ATECTURA® BREEZHALER®, and at least 114 mL improvement versus FLU–SAL, observed as early as 5 min on Day 1 and sustained at all timepoints across 52 weeks.5,6
Onset of action: LS mean change from baseline in trough FEV1 in first hour post-dose (measured 5–60 minutes post-dose on Day 1)6
In the IRIDIUM trial*† , all treatment groups showed clinically relevant improvements from baseline in ACQ-7 at week 26; however, no statistically significant differences between groups were observed.5
LS mean change in ACQ-7 score from baseline to Week 265
Percentage of responders‡ achieving a minimal clinically important difference (MCID) in ACQ-7 score from Week 4 through to Week 526
The ARGON* trial showed non-inferiority in AQLQ total score with high-dose ENERZAIR® BREEZHALER® vs high dose SAL/FLU + TIO at Week 24.7
Change from baseline in AQLQ total score with ENERZAIR® BREEZHALER® high-dose vs. SAL/FLU high-dose + TIO at Week 247
AQLQ responders§ with ENERZAIR® BREEZHALER® high-dose vs. SAL/FLU high-dose + TIO at Week 247
Severe exacerbations reduction
Exacerbations were a secondary endpoint (not part of confirmatory testing strategy).1
The IRIDIUM*† trial showed that high-dose ENERZAIR® BREEZHALER® once daily demonstrated a reduction in the annual rate of exacerbations compared to high doses of SAL/FLU twice daily and ATECTURA® BREEZHALER® once daily.5
Annualised rate of severe exacerbations¶ between high dose ENERZAIR® BREEZHALER® vs high dose ATECTURA® BREEZHALER® and high dose SAL/FLU5
ENERZAIR® BREEZHALER® were generally well-tolerated
The ENERZAIR® BREEZHALER® device was well tolerated: AEs and SAEs were balanced and safety was comparable across treatment arms.5,7
The PLATINUM trial programme
>7,500 patients
still symptomatic on low-dose ICS up to high-dose LABA/ICS treatment were included5–8
(ENERZAIR® BREEZHALER®)1,5
- Very common AEs** during the trial included asthma exacerbation and nasopharyngitis
- Common AEs†† included upper respiratory tract infection, candidiasis, urinary tract infection, hypersensitivity, headache, tachycardia, oropharyngeal pain, cough, dysphonia, gastroenteritis, musculoskeletal pain, muscle spasms and pyrexia
- SAEs included asthma exacerbation, pneumonia, lower respiratory tract infection, cholelithiasis and pulmonary embolism
(ENERZAIR® BREEZHALER®)7
- Very common AEs** during the trial included asthma exacerbation
- Common AEs†† (affecting ≥2% in at least one treatment arm) included nasopharyngitis, bronchitis, pharyngitis, upper respiratory tract infection, headache, respiratory tract infection viral and viral upper respiratory tract infection
- SAEs included asthma exacerbation, pneumonia and atrioventricular block (second degree)
Very common AEs affect ≥1/10. Common AEs affect between ≥1/100 to <1/10.
*The doses reported within the clinical trials were contained dose rather than the delivered dose.
†None of these secondary analyses were controlled for multiplicity;5 inferences based on these data cannot be made due to lack of power.
‡ACQ-7 responder = patient achieving a minimal clinically important difference (MCID) of ≥0.5-point improvement from baseline in ACQ-7 score.5
¶A severe exacerbation was defined as an aggravation of asthma symptoms (such as shortness of breath, cough, wheezing, or chest tightness) that requires systemic corticosteroids for at least 3 consecutive days or a need for an emergency room visit, hospitalisation owing to asthma, or death due to asthma.
§AQLQ responder = patient achieving a minimal clinically important difference (MCID) of ≥0.5-point improvement from baseline in AQLQ score.4
**Very common AEs affect ≥1/10.
††Common AEs affect between ≥1/100 to <1/10.
IND/GLY/MF (ENERZAIR® BREEZHALER®) high-dose = IND/GLY/MF 150/50/160 μg (once-daily); IND/MF (ATECTURA® BREEZHALER®) medium-dose = IND/MF 150/160 μg (once-daily); IND/MF (ATECTURA® BREEZHALER®) high-dose = IND/MF 150/320 μg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 μg (twice-daily).
ACQ-7, Asthma Control Questionnaire-7; AE, adverse event; AQLQ; asthma quality of life questionnaire; CI, confidence interval; FEV1, forced expiratory lung volume; FLU, fluticasone propionate; GINA, Global Initiative for Asthma; GLY, glycopyrronium; ICS, inhaled corticosteroid; IND, indacaterol; LABA, long acting beta agonist; LAMA, long acting muscarinic antagonist; LS, least square; MCID, minimal clinically important difference; MF, mometasone furoate; SAE, serious adverse event; SAL, salmeterol xinafoate; TIO, tiotropium.
References
- ENERZAIR® BREEZHALER®. Summary of Product Characteristics. July 2020.
- Novartis Press Release. Novartis receives EC approval for Enerzair® Breezhaler®, including the first digital companion (sensor and app) that can be prescribed alongside a treatment for uncontrolled asthma in the EU. Available at: https://www.novartis.com/news/media-releases/novartis-receives-ec-approv.... Date accessed: January 2021.
- Novartis Press Release. Novartis announces positive results from Phase III IRIDIUM study of inhaled combination QVM149 in patients with uncontrolled asthma. Available at: https://www.novartis.com/news/media-releases/novartis-announces-positive.... Date accessed: January 2021.
- Novartis Press Release. Novartis Phase IIIb ARGON study meets primary endpoint in a comparison of Enerzair® Breezhaler® (QVM149) versus a free combination of two existing inhaled treatments in uncontrolled asthma. Available at: https://www.novartis.com/news/media-releases/novartis-phase-iiib-argon-s.... Date accessed: January 2021.
- Kerstjens H, et al. Lancet Respir Med 2020;8(10):1000–1012.
- Kerstjens H, et al. Lancet Respir Med 2020 supplementary appendix 1;8(10):1000–1012.
- Gessner C, et al. Respir Med 2020;170:106021 [Epub ahead of print].
- Kornmann O, et al. Respir Med 2020;161105809 [Epub ahead of print].