Prescribing information

 

       

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

Graphic showing 65 ml improvement in trough FEV1

 

Change from baseline in trough FEV1 in high dose ATECTURA® BREEZHALER® vs high dose ENERZAIR® BREEZHALER® at Week 26 and 525

Week 26

Graph showing 65 ml improvement in trough FEV1 with high dose Enerzair Breezhaler versus high dose Atectura Breezhaler to week 26

 

Week 525,6

Graph showing 86 ml improvement in trough FEV1 with high dose Enerzair Breezhaler versus high dose Atectura Breezhaler to week 52

 

LS mean change from baseline in trough FEV1 in high dose SAL/FLU vs high dose ENERZAIR® BREEZHALER® at Weeks 26 and 525,6

 

Graphs showing significantly higher LS mean trough FEV1 scores in high dose Enerzair Breezhaler versus high dose SAL/FLU at week 26 and week 52

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

 

Graph showing significantly higher LS mean trough FEV1 scores in high dose Enerzair Breezhaler versus high dose SAL/FLU at week 24

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

Graph showing a faster onset of action in the first hour post-dose for high dose Enerzair Breezhaler versus high and medium dose Atectura Breezhaler, and high dose SAL/FLU

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

 

Graph comparing the LS mean change in ACQ-7 scores between Enerzair Breezhaler versus high dose Atectura Breezhaler

 

 

Percentage of responders achieving a minimal clinically important difference (MCID) in ACQ-7 score from Week 4 through to Week 526

 

Graph comparing the percentage of responders achieving minimal clinically important difference in ACQ-7 between Enerzair Breezhaler, Atectura Breezhaler and SAL/FLU at weeks 4, 12, 26 and 52

 

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

 

Graph comparing the change in AQLQ score between Enerzair Breezhaler and SAL/FLU at week 24

 

AQLQ responders§ with ENERZAIR® BREEZHALER® high-dose vs. SAL/FLU high-dose + TIO at Week 247

 

Graph comparing the number of AQLQ responders between Enerzair Breezhaler and SAL/FLU at week 24

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

 

Graph showing significantly lower annualised rate of severe exacerbations in high dose Enerzair Breezhaler versus high dose Atectura Breezhaler, and versus high dose SAL/FLU

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

Table listing the adverse and serious adverse events across each of the three treatment arms (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

Table listing the adverse and serious adverse events across each of the three treatment arms (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

  1. ENERZAIR® BREEZHALER®. Summary of Product Characteristics. July 2020.
  2. 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.
  3. 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.
  4. 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.
  5. Kerstjens H, et al. Lancet Respir Med 2020;8(10):1000–1012.
  6. Kerstjens H, et al. Lancet Respir Med 2020 supplementary appendix 1;8(10):1000–1012.
  7. Gessner C, et al. Respir Med 2020;170:106021 [Epub ahead of print].
  8. Kornmann O, et al. Respir Med 2020;161105809 [Epub ahead of print].
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UK | February 2021 | 103403
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Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Novartis via [email protected] or online through the pharmacovigilance intake (PVI) tool at www.report.novartis.com
If you have a question about the product, please contact Medical Information on 01276 698370 or by email at [email protected]