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Novartis AG (NVS) Cheered by COPD Trial Results  
9/4/2012 7:15:36 AM

Frimley, UK, 3 September 2012 – Further data from the Novartis once-daily chronic obstructive pulmonary disease (COPD) clinical trial programmes were presented at the European Respiratory Society (ERS) Congress. Overall, Novartis presented 14 abstracts, including data from the investigational QVA149 (fixed-dose combination of indacaterol maleate/glycopyrronium bromide) IGNITE Phase III clinical trial programme, NVA237 (glycopyrronium bromide) – an investigational long acting muscarinic antagonist (LAMA) – GLOW Phase III clinical trial programme and the indacaterol maleate (Onbrez® Breezhaler®) – a long-acting beta2-adrenergic agonist (LABA) – INERGIZE Phase III/IV clinical trial programme. The data further demonstrated the potential of the Novartis COPD portfolio to provide once-daily, innovative treatment choices for patients and clinicians.

Amongst the data presented, three new studies from the investigational QVA149 IGNITE Phase III clinical trial program (SHINE, ILLUMINATE and ENLIGHTEN) demonstrated that QVA149 significantly improved lung function compared to other COPD therapies1,2,3.

Professor of Respiratory Medicine Wisia Wedzicha, University College London, commented: “The results of the studies with the dual bronchodilator QVA149 show that dual bronchodilatation has an important place in the management of COPD with improvements noted in lung function, management of COPD symptoms and improvements in quality of life.”

About the study results

Data from the IGNITE trial programme demonstrated the efficacy of the dualbronchodilator QVA149 and showed a superior effect on lung function and patientreported outcomes versus comparators1,2,3.

ILLUMINATE compared QVA149 110/50 mcg to the twice-daily LABA/ICS salmeterol/fluticasone 50/500 mcg head-to-head over 26 weeks in patients with COPD 2.The study met its primary endpoint by demonstrating that the mean FEV1 area under the curve (AUC) for 0-12hr at Week 26 was significantly higher with QVA149 compared to salmeterol/fluticasone 50/500 mcg (+140mL; p<0.001)2. Mean FEV1 AUC0-12h was also significantly higher with QVA149 versus salmeterol/fluticasone 50/500 mcg at Day 1 (+70mL; p<0.001)2 and Week 12 (+120mL; p<0.001)2. The ILLUMINATE trial also demonstrated that QVA149, in comparison to salmeterol/fluticasone 50/500 mcg, significantly improved shortness of breath measured by transition dyspnea index or TDI (p=0.003) and reduced reliever medication use (p=0.019) over 26 weeks2.

SHINE met its primary endpoint by demonstrating that once-daily QVA149 110/50 mcg improved lung function as measured by trough FEV1 compared to once-daily indacaterol maleate 150 mcg (+70mL above indacaterol alone; p<0.001) and once-daily glycopyrronium 50 mcg (+90mL above glycopyrronium alone; p<0.001)1. QVA149 was also more effective at improving lung function compared to OL tiotropium 18 mcg (+80mL above tiotropium; p<0.001) and placebo (+200mL; p<0.001)1. Mean peak FEV1 at Week 26 was also significantly higher with QVA149 compared to placebo (+330mL, p<0.001),indacaterol 150 mcg (+120mL; p<0.001), glycopyrronium 50 mcg (+130mL; p<0.001) and OL tiotropium 18 mcg (+130mL; p<0.001)1. Mean FEV1 area under the curve (AUC) for 0- 24hr at Week 26 was significantly higher with QVA149 compared to placebo (+320mL, p<0.001), indacaterol 150 mcg (+110mL; p<0.001), glycopyrronium 50 mcg (+110mL; p<0.001) and OL tiotropium 18 mcg (+110mL; p<0.001)1.

The results also showed that QVA149 improved shortness of breath measured by TDI (p<0.001 versus placebo; p<0.05 versus OL tiotropium 18 mcg), increased health-related quality of life (HRQoL) measured by the St George’s Respiratory Questionnaire or SGRQ (p<0.01 versus placebo; p<0.05 versus OL tiotropium 18 mcg) and reduced reliever medication use (p<0.001 versus both placebo and OL tiotropium 18 mcg)1. QVA149 was superior to indacaterol 150 mcg and lycopyrronium 50 mcg at reducing use of reliever medication (p<0.05 and p<0.001 respectively) and also provided numerically higher improvements in shortness of breath and HRQoL compared to indacaterol 150 mcg and glycopyrronium 50 mcg1.

ENLIGHTEN demonstrated the efficacy of QVA149 at improving lung function over a 52-week period by showing that QVA149 increased FEV1 and forced vital capacity (FVC)versus placebo at Day 1 and Weeks 3, 6, 12, 26, 39 and 52 (p<0.001)3. At Week 52, the mean difference in FEV1 compared to placebo at 60 minutes post-dose was +257mL (p<0.001)3.

QVA149 was generally well tolerated in the SHINE, ILLUMINATE and ENLIGHTEN trials with an incidence of adverse events that was similar between respective groups1,2,3.Data were also presented on two other products from the Novartis COPD portfolio. Data from the GLOW Phase III clinical trial programme demonstrated that the investigational LAMA, glycopyrronium bromide increased lung function and improved patient outcomes compared to placebo4,5. Data from the INERGIZE Phase III/IV pooled analysis showed indacaterol 300 mcg was superior to OL tiotropium 18 mcg in improving shortness of breath6.

About the study designs

ILLUMINATE was a 26 week, multi-centre, randomised, double-blind, double dummy, parallel-group study to assess the efficacy, safety and tolerability of once-daily QVA149 compared to twice-daily fixed dose combination of salmeterol/fluticasone 50/500 mcg in patients with moderate-to-severe stable COPD2.

SHINE was a 26 week, multi-centre, randomised, double-blind, parallel-group, placebo and active controlled pivotal trial of 2,144 patients with moderate-to-severe COPD to assess efficacy in terms of trough FEV1 1. Patients were randomised to receive QVA149, indacaterol maleate 150 mcg, glycopyrronium 50 mcg, OL tiotropium 18 mcg or placebo.

ENLIGHTEN was a 52 week, multi-centre, randomised, double-blind, parallel-group, placebo controlled pivotal trial of 339 patients with moderate-to-severe COPD to assess the safety and tolerability of QVA1493.

GLOW1 and GLOW2 were multi-centre, randomised, double-blind, placebo controlled, parallel group studies in patients with moderate-to-severe COPD. GLOW1 was a 26 week study with patients randomised to receive once-daily glycopyrronium 50 mcg or placebo. GLOW2 was a 52 week study with patients randomised to receive once-daily glycopyrronium 50 mcg or placebo, and included an exploratory arm to compare the effects of once-daily OL tiotropium 18 mcg versus placebo4,5

The first pooled analysis assessed the efficacy of once-daily glycopyrronium 50 mcg versus placebo and once-daily OL tiotropium 18 mcg over 26 to 52 weeks in 1,888 patients with moderate-to-severe COPD from clinical trials (GLOW1 and GLOW2)4. The second pooled analysis assessed the efficacy of once-daily glycopyrronium 50 mcg versus placebo and once-daily OL tiotropium 18 mcg at reducing COPD acerbations, symptoms and improving health status over 26 to 52 weeks in 1,854 patients from clinical trials (GLOW1 and GLOW2)5.

INERGIZE data analysis compared data from three randomised studies (INVOLVE,INHANCE and INLIGHT2) in the clinical trial programme which included 3,176 patients with moderate-to-severe COPD6. The analysis assessed patients randomised to receive once-daily indacaterol maleate 150 mcg, once-daily indacaterol maleate 300 mcg, placebo or once-daily OL tiotropium 18 mcg for six months6.

About the Novartis COPD 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. Onbrez® Breezhaler® (indacaterol maleate) is a long-acting beta2-adrenergic agonist (LABA) that is currently the only COPD treatment on the market to offer clinically relevant 24-hour bronchodilation combined with a rapid onset of action at first dose, as demonstrated in the INERGIZE Phase III/IV trial program7-10. Onbrez® Breezhaler® is approved in more than 85 countries around the world. It was first launched in the EU (150 mcg and 300 mcg once-daily doses) and has since received approvals in markets worldwide including Japan (Onbrez® Inhalation Capsules 150 mcg once-daily) and US (ArcaptaTM NeohalerTM 75 mcg once-daily).

Glycopyrronium bromide is an investigational LAMA developed as a once-daily inhaled maintenance therapy for the treatment of COPD. Phase III data from the GLOW 1, 2 and 3 studies demonstrated that glycopyrronium increased patients' lung function over a 24-hour period ompared to placebo with a fast onset of action at first dose, and improved exercise endurance versus placebo11-13. Glycopyrronium bromide was licensed to Novartis in April 2005 by Vectura and its co-development partner Sosei. In June 2012, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for the approval of glycopyrronium bromide in Europe under the brand name Seebri® Breezhaler®.

QVA149 is an investigational inhaled, once-daily, fixed-dose combination of indacaterol maleate and glycopyrronium bromide. QVA149 is being 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 10 studies in total with more than 7,000 patients across 42 countries1-3,14-20. The first five studies (ILLUMINATE, SHINE, BRIGHT, ENLIGHTEN, SPARK) have already completed in 2012 with three additional studies (BLAZE, ARISE, BEACON) expected to complete by the end of the year. The studies are designed to investigate efficacy, safety and tolerability, lung function, exercise endurance, exacerbations, shortness of breath and quality of life. Initial filings for regulatory approval are expected in Q4 2012 for Europe and Japan. US filing is expected at the end of 2014.

All Novartis COPD portfolio products are being developed for delivery via the Breezhaler® device, a single-dose dry powder inhaler (SDDPI), which has low air flow resistance, making it suitable for patients with airflow limitation, such as COPD patients. The Breezhaler® device allows patients to hear, feel and see that they have taken the drug correctly18.

About COPD

COPD is a progressive disease associated mainly with tobacco smoking, air pollution or occupational exposure, which can cause obstruction of airflow in the lungs resulting in debilitating shortness of breath. It affects an estimated 3.7 million people in the UK21 and is predicted to be the third leading cause of death by 202022. Although COPD is often thought of as a disease of the elderly, 50% of patients are estimated to be under the age of 65, which means that half of the COPD population is likely to be affected at the peak of their earning power and family responsibilities23.

About Novartis

Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2011, the Group’s continuing operations achieved net sales of USD 58.6 billion,while approximately USD 9.6 billion (USD 9.2 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Novartis Group companies employ approximately 126,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

References

1. Bateman E et al. Benefits of dual bronchodilation with QVA149 once daily versus placebo, indacaterol, NVA237 and tiotropium in patients with COPD: the SHINE study. [ERS abstract 700179; Session 306; Monday September 3, 2012; 14:45:–16:45].

2. Vogelmeier C et al. Once-daily QVA149 significantly improves lung function and symptoms compared to twice-daily fluticasone/salmeterol in COPD patients: The ILLUMINATE study. [ERS abstract 70045; Session 52; Sunday September 2, 2012; 08:30-10:30].

3. Dahl R et al. QVA149 administered once daily provides significant improvements in lung function over 1 year in patients with COPD: the ENLIGHTEN study. [ERS abstract 853405; Session 315; Date: September 03, 2012 Time: 14:45-16:45.

4. Banerji D et al. Once-daily NVA237 improves lung function in COPD patients: pooled results of the GLOW1 and GLOW2 studies. [ERS abstract 853239; Session 245; Date: September 03, 2012 Time: 12:50-14:40.

5. Banerji D et al. Once-daily NVA237 reduces exacerbations and improves symptoms in COPD patients: a pooled analysis, of the GLOW1 and GLOW2 studies. [ERS abstract 853213; Session 314; Date: September 03, 2012 Time: 14:45-16:45.

6. Mahler D et al. Effectiveness of indacaterol and tiotropium in patients with severe dyspnoea. [ERS abstract 850630; Session 245; Date: September 03, 2012 Time: 12:50-14:40.

7. Donohue JF et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: Indacaterol versus tiotropium. Am J Respir Crit Care Med 2010;182:155-162.

8. Dahl R, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twicedaily formoterol in COPD. Thorax 2010;65(6):473-9.

9. Kornmann O, et al. Once-daily indacaterol vs twice-daily salmeterol for COPD: a placebo-controlled comparison. Eur Respir J 2011;37:273-279.

10. 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;5:311-318.

11. 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 (7 December 2011).

12. Kerwin E, et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with moderateto- severe COPD over 52 weeks: The GLOW2 study. Eur Resp J 2012. Published on July 26, 2012

(doi:10.1183/09031936.00040712). 13. Beeh KM, et al A . Int J Chron Obstruct Pulmon Dis. 2012;7:503-513.

14. QVA149 2305 (BRIGHT). Data on file, Novartis Pharma AG. ClinicalTrials.gov identifier: NCT01294787.

15. QVA149 2322 (BLAZE). Data on file, Novartis Pharma AG. ClinicalTrials.gov identifier: NCT01490125.

16. QVA149 1301 (ARISE). Data on file, Novartis Pharma AG. ClinicalTrials.gov identifier: NCT01285492.

17. QVA 149 A2304 (SPARK). Data on file, Novartis Pharma AG. ClinicalTrials.gov identifier.NCT01120691.

18. Onbrez® Breezhaler® (indacaterol) EU Summary of Product Characteristics May 31, 2011 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001114/human_med _001219.jsp&mid=WC0b01ac058001d124. Last accessed 20 June 2012.

19. FDA Access Data. Spiriva® HandiHaler® Medical Review Part 2, pages 37- 38.http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-395_Spiriva.cfm. Last accessed 28 March 2012. 20. FDA Access Data. Advair Medical Review Nov. 17, 2003, Page 133. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/021077_S003_ADVAIR_DISKUS.pdf Last accessed 30 March 2012.

21. British Lung Foundation, 2007. Invisible Lives Chronic Obstructive Pulmonary Disease (COPD): Finding the Missing Millions. Available at: http://www.lunguk.org/. Last accessed 16 May 2012.

22. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated December 2011. http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_Feb21.pdf Last accessed 30 August 2012.

23. 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.

For more information:

http://www.novartis.com.


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