European Commission and Japan approve once-daily dual bronchodilator Ultibro Breezhaler (QVA149) nearly simultaneously, for COPD patients

Sep 23 2013

Novartis announced today that the European Commission approved once-daily Ultibro^® Breezhaler^® (indacaterol 85 mcg / glycopyrronium 43 mcg) as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).  In addition, the Japanese Ministry of Health, Labour and Welfare (MHLW) approved once-daily Ultibro^® Inhalation Capsules (glycopyrronium 50 mcg / indacaterol 110 mcg), delivered through the Breezhaler^® device, for relief of various symptoms due to airway obstruction in chronic obstructive pulmonary disease (COPD). Ultibro^® Breezhaler^® / Ultibro^® Inhalation Capsules were developed under the name QVA149.

“We are very pleased that the European Commission and Japan approved QVA149, nearly simultaneously, for COPD patients. This rapid approval in Japan reflects our build-up of clinical trial and regulatory capabilities in Japan,” said David Epstein, Division Head, Novartis Pharmaceuticals. “Many COPD patients will now have a better treatment option, including first-line therapy with the launch of Ultibro Breezhaler in Europe.”

Dual bronchodilation with QVA149 is expected to set a new standard of care in COPD by combining the proven efficacy benefits and safety profiles of two established Novartis COPD treatments: the LABA*, Onbrez^® Breezhaler^® (indacaterol); and the LAMA**, Seebri^® Breezhaler^® (glycopyrronium bromide). Both these components are delivered through the Breezhaler^® device, as is QVA149, and are widely available around the world.

The approvals of QVA149 in Europe and Japan were based on the comprehensive IGNITE Phase III clinical trial program, one of the largest international trial programs in COPD comprising 11 studies in total with more than 10,000 patients from 52 ^{countries1-3,6-15}. From the eight IGNITE studies which completed in 2012^1-3,6-10, data showed that QVA149 significantly improved lung function versus several current standard ^{treatments1-3,6} and showed significant symptomatic improvements versus placebo in breathlessness, exercise tolerance, rescue medication use and health-related quality of ^life1,2,6. QVA149 also demonstrated statistically significant symptomatic improvements in breathlessness, rescue medication use and health-related quality of life compared to open-label (OL) tiotropium 18 ^mcg1. The rate of all COPD exacerbations (mild, moderate and severe) was significantly improved with QVA149 compared to glycopyrronium 50 mcg and OL tiotropium 18 ^mcg3.

“Since 2007, Novartis has received approvals for 15 new treatments and 16 new indications for existing treatments in Japan,” said Timothy Wright, Global Head Development, Novartis Pharmaceuticals. “Japan plays a critical role in our global clinical research program. In the last five years, Novartis has conducted 175 clinical studies in Japan with over 14,000 patients.”

In clinical studies, QVA149 demonstrated an acceptable safety profile with no meaningful differences between the treatment groups (placebo, indacaterol 150 mcg, glycopyrronium 50 mcg, OL tiotropium 18 mcg, salmeterol / fluticasone (SFC) 50 mcg / 500 mcg) in the incidence of adverse and serious adverse ^events1-3,6. The safety profile was characterized by typical anticholinergic and beta-adrenergic effects related to the individual components of the ^{combination1-3,6-10}.

COPD is a progressive disease affecting up to 10% of adults across ^Europe4 and is projected to be the third leading cause of death by 2020.⁵ In addition, 5.3 million patients are currently living with COPD in Japan.

About the Novartis respiratory portfolio

Novartis is committed to addressing the unmet medical needs of COPD patients and improving their quality of life by providing innovative medicines and devices.

^Seebri® Breezhaler^® / Seebri^® Inhalation Capsules (glycopyrronium bromide) are a once-daily inhaled long-acting muscarinic antagonist (LAMA; also referred to as a long-acting anticholinergic) indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with ^COPD15. Glycopyrronium bromide was exclusively licensed to Novartis in April 2005 by Vectura and its co-development partner Sosei. In Phase III studies (GLOW 1, 2 and 3), once-daily glycopyrronium 50 mcg demonstrated rapid improvements in lung function after first dose on Day 1 which was sustained for 24 hours and maintained over the 52 week study period compared with ^placebo16-18. Glycopyrronium 50 mcg also significantly improved shortness of breath, health-related quality of life, exacerbation risk, and exercise endurance versus ^placebo16-18. Glycopyrronium is approved in the EU, Japan, Switzerland, Canada a number of other countries.

^Onbrez® Breezhaler^® / Onbrez^® Inhalation Capsules (indacaterol) are a once-daily inhaled long-acting _beta2-adrenergic agonist (LABA) that offer clinically relevant 24 hour bronchodilation combined with a rapid onset of action within five minutes at first dose, as demonstrated in the INERGIZE Phase III trial ^program19-33. Indacaterol 150 mcg provided greater clinical benefit in terms of reduced shortness of breath, lower use of rescue medication and improved health status, compared with blinded tiotropium bromide 18 ^mcg30. Indacaterol was first approved and launched in the EU (150 mcg and 300 mcg once-daily doses) for maintenance bronchodilator treatment of airflow obstruction in adult patients with ^COPD34. It has now received approvals in more than 100 countries around the world including Japan (as Onbrez^® Inhalation Capsules 150 mcg once-daily) and USA (as ^{ArcaptaTM NeohalerTM} 75 mcg once-daily).

^Ultibro® Breezhaler^® / Ultibro^® Inhalation Capsules (QVA149) are an inhaled, once-daily, fixed-dose combination of glycopyrronium bromide and indacaterol maleate. QVA149 was investigated for the treatment of COPD in the Phase III IGNITE clinical trial program. IGNITE is one of the largest international clinical trial programs in COPD comprising 11 studies in total (ILLUMINATE, SHINE, BRIGHT, ENLIGHTEN, SPARK, BLAZE, ARISE, BEACON, RADIATE, LANTERN, FLAME) with more than 10,000* patients across 52 ^{countries1-3,5-14}. The first eight studies (ILLUMINATE, SHINE, BRIGHT, ENLIGHTEN, SPARK, BLAZE, ARISE, BEACON) completed in 2012^1-3,5-9. The studies were designed to investigate efficacy (lung function, exercise endurance, exacerbations, shortness of breath and quality of life), safety and tolerability of patients treated with ^{QVA1491-3,5-12}.

*Total refers to all 11 IGNITE studies.

Results from the Phase III IGNITE trials have demonstrated statistically significant improvements in bronchodilation with QVA149 versus several ^{treatments1-3,5} widely used as current standards of care. Data showed that QVA149 significantly improved lung function compared to OL tiotropium 18 mcg, fixed dose combination SFC 50 mcg / 500 mcg, indacaterol maleate 150 mcg, glycopyrronium 50 mcg and placebo providing a rapid onset of action within five minutes, and sustained bronchodilation during a 24 hour period which was maintained for up to 26 ^weeks2,5. In the IGNITE phase III trial program, QVA149 also showed symptomatic improvements versus placebo in COPD ^{patients1,2,5}. These symptomatic improvements included breathlessness, exercise tolerance, rescue medication use and health-related quality of ^life1,2,5. QVA149 also significantly improved the rate of all COPD exacerbations (mild, moderate and severe) compared to glycopyrronium 50 mcg and OL tiotropium 18 ^mcg3.

Novartis continues development of respiratory products for delivery via the Breezhaler^® device. This is a single-dose dry powder inhaler (SDDPI), which has low air flow resistance, making it suitable for patients with different severity of airflow ^limitation36. The Breezhaler^® device allows patients to hear, feel and see that they have taken the full dose ^correctly32.

About COPD

COPD is a progressive life-threatening disease that makes it hard to breathe, with symptoms that have a destructive impact on patients’ function and quality of ^life37. It affects an estimated 210 million people ^worldwide5 and is projected to be the third leading cause of death by 2020³⁷. COPD is often considered to be a disease of later years, but estimates suggest that 50% of those with COPD are now less than 65 years old, resulting in increases in absenteeism, premature ^retirement38 and reductions in workforce ^{participation38,39}.

1. Bateman ED, Ferguson GT, Barnes N, et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. European Respiratory Journal [Published on May 30 2013]. doi: http://dx.doi.org/10.1183/09031936.00200212. [Accessed 12 September 2013].
2. Vogelmeier C et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol/fluticasone in patients with COPD (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respiratory Medicine. 2013;1(1): 51-60.
3. Wedzicha JA et al. Analysis of Chronic Obstructive Pulmonary Disease Exacerbations with the Dual Bronchodilator QVA149 Compared with Glycopyrronium and Tiotropium (SPARK): a Randomized, Double-blind, Parallel-group Study. Lancet Respiratory Medicine 2013;1(3): 199-209.
4. European Federation of Allergy and Airways Diseases Patients Associations. Chronic Obstructive Pulmonary Disease. Available at: http://www.efanet.org/wp-content/uploads/2012/07/EFACOPDBook.pdf. [Accessed 18 September 2013].
5. Global Alliance Against Chronic Respiratory Diseases (GARD). Global surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach. Available at: http://www.who.int/gard/publications/GARD_Manual/en/. [Accessed 18 September 2013].
6. Beeh K et al. QVA149 once daily improves exercise tolerance and lung function in patients with COPD: the BRIGHT study. Thorax. 2012;67(2) A147.
7. Dahl R et al. Safety and efficacy of dual bronchodilation with QVA149 in COPD patients: the ENLIGHTEN study. Respiratory Medicine Journal 2013;107:1558-1567.
8. Mahler D et al. Superior lung function with once-daily QVA149 translates into improvements in patient reported breathlessness compared with placebo and tiotropium in COPD patients: the BLAZE study. [ATS abstract 45308; Session C20; Date: May 21, 2013 Time: 8:15-10:45].
9. ClinicalTrials.gov, n.d. Long Term Safety and Tolerability of QVA149 Versus Tiotropium in Japanese Patients With Chronic Obstructive Pulmonary Disease (COPD) (ARISE). [Online] Available at: http://www.clinicaltrials.gov/ct2/show/NCT01285492?term=%28ARISE%29&rank=4. [Accessed 18 September 2013].
10. ClinicalTrials.gov, n.d. Comparison of Safety and Efficacy of the Combination Product QVA149A Against the Concurrent Administration of the Individual Components, QAB149 and NVA237, in Patients With Chronic Obstructive Pulmonary Disease (COPD) (BEACON). [Online]
    Available at: www.clinicaltrials.gov/ct2/show/NCT01529632?term=BEACON&rank=6. [Accessed 18 September 2013].
11. ClinicalTrials.gov, n.d. Comparison of Long-term Safety of the Combination Product QVA149A Against Placebo and Standard of Care Treatment in Chronic Obstructive Pulmonary Disease Patients With Moderate to Severe Airflow Limitation (RADIATE). [Online] Available at: www.clinicaltrials.gov/ct2/show/NCT01610037?term=GLISTEN&rank=1. [Accessed 18 September 2013].
12. ClinicalTrials.gov, n.d. A 26-week Treatment Randomized, Double-blind, Double Dummy, Parallel-group Study to Assess the Efficacy, Safety and Tolerability of QVA149 (Indacaterol / Glycopyrronium Bromide) Compared to Fluticasone/Salmeterol in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease. (LANTERN) [Online]. Available at: www.clinicaltrials.gov/ct2/show/NCT01709903?id=01709903&rank=1. [Accessed 18 September 2013].  
13. ClinicalTrial.gov, n.d. A 52-week Treatment, Multi-center, Randomized, Double-blind, Double Dummy, Parallel-group, Active Controlled Study to Compare the Effect of QVA149 (Indacaterol Maleate / Glycopyrronium Bromide) With Salmeterol/Futicasone on the Rate of Exacerbations in Subjects With Moderate to Very Severe COPD (FLAME). [Online] Available at: http://clinicaltrials.gov/ct2/show/NCT01782326?term=COPD+novartis+52&rank=2. [Accessed 18 September 2013].
14. FDA Access Data, n.d.Spiriva Medical Review Part 2. [Online]
    Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-395_Spiriva.cfm. [Accessed 18 September 2013].
15. FDA Access Data, 2003.Advair Medical Review. [Online]
    Available at: www.accessdata.fda.gov/drugsatfda_docs/nda/2003/021077_S003_ADVAIR_DISKUS.pdf. [Accessed 18 September 2013].
16. Vogelmeier C et al. Indacaterol provides 24-hour bronchodilation in COPD: a placebo-controlled blinded comparison with tiotropium. Respir Res 2010;11:135.
17. Balint B et al. Onset of action of indacaterol in patients with COPD: comparison with salbutamol and salmeterol- fluticasone. Int J Chron Obstruct Pulmon Dis 2010;5:311-8.
18. La Force C et al. Sustained 24-hour efficacy of once-daily indacaterol (300 μg) in patients with chronic obstructive pulmonary disease: a randomized, crossover study. Pulm Pharmacol Ther 2011;24:162-8.
19. Beeh KM, Wagner F, Khindri S, Drollmann AF. Effect of indacaterol on dynamic lung hyperinflation and breathlessness in hyperinflated patients with COPD. COPD 2011;8(5):340–5).
20. O’ Donnell DE et al. Effect of indacaterol on exercise endurance and lung hyperinflation in COPD.  Respir Med 2011; 105(7):1030-6.
21. Magnussen H et al. Indacaterol once-daily is equally effective dosed in the evening or morning in COPD.  Respir Med 2010;104:1869-76.
22. Feldman G et al. Efficacy and safety of indacaterol 150 µg once-daily in COPD: a double-blind, randomised, 12-week study. BMC Pulm Med 2010;10:11.
23. Barnes PJ et al. Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design. Pulm Pharmacol Ther 2010;23:165–71.
24. Donohue JF et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med 2010;182:155–62.
25. Kornmann O et al. Once-daily indacaterol vs twice-daily salmeterol for COPD: a placebo-controlled comparison. Eur Respir J 2011;37:273-279.
26. Dahl R et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist, indacaterol, versus twice-daily formoterol in COPD. Thorax 2010;65:473–9.
27. Buhl R et al. Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD. Eur Respir J 2011; 38:797-803.
28. Chapman KR et al. Long-term safety and efficacy of indacaterol, a novel long-acting _β2-agonist, in subjects with COPD: a randomized, placebo-controlled study. Chest 2011;140;68-75.
29. Korn S et al. Indacaterol once-daily provides superior efficacy to salmeterol twice-daily in COPD: a 12-week study. Respir Med 2011;105:719-26.
30. Mahler DA et al. Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised double-blind comparison. Thorax 2012. Doi:10.1136/thorax8jnl-2011-201140.
31. EMA, 2012. Onbrez^® Breezhaler^® (indacaterol) EU Summary of Product Characteristics. [Online] July 26, 2012 Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001114/WC500053732.pdf. [Accessed 18 September 2013].
32. EMA. 2012. Seebri Breezhaler EU Summary of Product Characteristics. [Online] 17 October 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002430/WC500133769.pdf. [Accessed 18 September 2013].
33. D'Urzo A et al. Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respiratory Research 2011;12:156.
34. Kerwin E et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: The GLOW2 study. Eur Resp J 2012;40(5):1106-1114.
35. Beeh K et al. Once-daily NVA237 improves exercise endurance from first dose in patients with COPD: the GLOW3 trial. Int J Chron Obstruct Pulmon Dis 2012;7:503-513.
36. Pavkov et al. Characteristics of a capsule based dry powder inhaler for the delivery of indacaterol. CMRO 2010; 26; 11:2527–2533. doi:10.1185/03007995.2010.518916.
37. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2013. http://www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html. [Accessed 18 September 2013].
38. Fletcher MJ et al. COPD Uncovered: An International survey on the impact of chronic obstructive pulmonary disease (COPD) on a working age population. BMC Public Health 2011;11:612.
39. daCosta M et al. The burden of chronic obstructive pulmonary disease among employed adults. Int J Chron Obstruct Pulmon Dis 2012;7:211-219. Published online 2012 March doi: 10.2147/COPD.S29280. [Accessed 18 September 2013].