Treatment with Novartis' Ultibro® Breezhaler® improved cardiac function in COPD patients with lung hyperinflation

• Ultibro^® Breezhaler^® provided significant improvements in cardiac and lung function in COPD patients with lung hyperinflation, compared to placebo  
   
• CLAIM is the first study to investigate the effect of dual bronchodilation on cardiac function
   
• Data published in the Lancet Respiratory Medicine

Basel, February 22, 2018 - Novartis today announced the publication of the CLAIM^* study in the Lancet Respiratory Medicine, which demonstrated that treatment once-daily Ultibro^® Breezhaler^® (indacaterol/glycopyrronium 110/50 mcg) significantly improved lung and cardiac function, when compared to placebo, in chronic obstructive pulmonary disease (COPD) patients with lung hyperinflation[1].

Many people living with COPD are at increased risk of death and disability due to comorbid cardiovascular disease[2]. Lung hyperinflation is common in people with COPD[3], and has been linked to impaired cardiac function and a worsening of COPD symptoms, especially breathlessness[4]-[6]. CLAIM is the first study to investigate the effects of dual bronchodilation on cardiac function and lung hyperinflation[1].

The CLAIM study met its primary endpoint demonstrating that treatment with Ultibro Breezhaler led to decreased lung hyperinflation and improvements in cardiac function** after 14 days of treatment[1]. This translated into clinically relevant patient benefits of improved health status and breathlessness (dyspnea), studied as exploratory endpoints[1].

"Lung hyperinflation is often associated with impaired cardiac function in patients with COPD," said Shreeram Aradhye, Chief Medical Officer and Global Head of Medical Affairs for Novartis Pharmaceuticals. "The publication of the CLAIM study is important for any COPD patient with signs of lung hyperinflation. For the first time, we demonstrated that treatment with Ultibro Breezhaler can reduce lung hyperinflation and improve cardiac function, breathlessness and health status."

In the CLAIM study Ultibro Breezhaler was well tolerated and its safety profile was comparable with placebo[1].

About the CLAIM study
The CLAIM study was a randomized, double-blinded, placebo-controlled, single-center, two period cross-over study comparing the effects of 14-day Ultibro^® Breezhaler^® therapy with placebo on cardiac and lung function in hyperinflated COPD patients[1]. It involved a total of 62 patients, of whom 57 completed both treatment periods[1]. All patients had moderate-to-very severe COPD and confirmed lung hyperinflation (residual volume >135% predicted).[1]

The primary endpoint of the study was to demonstrate the effect of 14-day once-daily Ultibro Breezhaler treatment on left ventricular end-diastolic volume (LV-EDV) as measured by MRI[1]. Secondary endpoints included effects on lung function parameters as measured by residual volume (RVol), forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC)[1].

Cardiac assessments included right ventricular end-diastolic volume (RV-EDV), left and right ventricular stroke volume (LV-SV and RV-SV), left and right ventricular end-systolic volumes (LV-ESV and RV-ESV) and cardiac index (CI)[1].

About Ultibro Breezhaler
Ultibro Breezhaler 110/50 mcg is a once-daily LABA***/LAMA**** dual bronchodilator approved in the European Union (EU) as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD[7]. Clinical trials have shown that it provides significant improvements in bronchodilation compared to treatments widely used as current standards of care, including salmeterol/fluticasone 50/500 mcg and open-label tiotropium (18 mcg)[8]^-[10]. Ultibro Breezhaler is currently approved for use in over 100 countries worldwide, including countries within the EU and Latin America, Japan, Canada, Switzerland and Australia.  

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. The Novartis COPD portfolio includes Ultibro Breezhaler (indacaterol/glycopyrronium bromide), Seebri^® Breezhaler^® (glycopyrronium bromide) and Onbrez^® Breezhaler^® (indacaterol), which are all indicated as maintenance treatments for COPD patients. Glycopyrronium bromide and certain use and formulation intellectual property were exclusively licensed to Novartis in April 2005 by Sosei and Vectura.

Novartis continues development of respiratory products for delivery via the low resistance Breezhaler inhalation device, which makes it suitable for patients with different severities of airflow limitation[11]. The Breezhaler device allows patients to hear, feel and see that they have taken the full dose correctly[7],[11].

About COPD
COPD affects an estimated 210 million people worldwide[12] and is the fourth leading cause of death[13]. It is progressive (usually gets worse over time) and can be a life-threatening disease[12],[14]. COPD makes it difficult to breathe, with symptoms that have a destructive impact on patients' function (i.e. activity limitation, decreased mobility) and quality of life[12],[14].

Lung hyperinflation occurs in a significant proportion of patients with COPD. It occurs as a result of air trapping, due to airway obstruction. Hyperinflation causes increased breathlessness and can affect the health status of people with COPD[6].

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political and economic conditions; safety, quality or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

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, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2017, the Group achieved net sales of USD 49.1 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 122,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.

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^*A randomized, cross-over trial to assess the effect of lung deflation with indacaterol/glycopyrronium on ventricular filling in hyperinflated COPD patients: The CLAIM study
** As measured by left ventricular end-diastolic volume (LV-EDV)
^***A long-acting beta2-adrenergic agonist
^**** A long-acting muscarinic antagonist

References
      [1]    Hohlfeld JM, Vogel-Claussen J, Biller H et al. Effect of lung deflation with indacaterol plus glycopyrronium on ventricular filling in patients with hyperinflation and COPD (CLAIM): a double-blind, randomised, crossover, placebo-controlled, single-centre trial. Lancet Respir Med 2018. Published online February 21, 2018.  http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(18)30054-7/fulltext?elsca1=tlxpr 
      [2]    Chen W, Thomas J, Sadatsafavi M. Risk of cardiovascular comorbidity in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Lancet Respir Med 2015;3:631-39
      [3]    Mayo Clinic. Hyperinflated lungs. What does it mean? Available at: https://www.mayoclinic.org/diseases-conditions/emphysema/expert-answers/hyperinflated-lungs/faq-20058169 [Accessed December 2017].
      [4]    Barr RG et al. Percent Emphysema, Airflow Obstruction, and Impaired Left Ventricular Filling. New Engl J Med. 2010;362:217-227
      [5]    Watz H et al. Decreasing Cardiac Chamber Sizes and Associated Heart Dysfunction in COPD. Chest. 2010;138:32-38
      [6]    Rossi, A., Aisanov, Z., Avdeev, S., Di Maria, G., Donner, C.F., Izquierdo, J.L., Roche, N., Similowski, T., Watz, H., Worth, H., et al. (2015). Mechanisms, assessment and therapeutic implications of lung hyperinflation in COPD. Respir. Med. 109, 785-802.
      [7]    Ultibro Breezhaler EU Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002679/WC500151255.pdf [Accessed December 2017].
      [8]    Vogelmeier C, et al. Once-daily QVA149 provides clinically meaningful improvements in lung function and clinical outcomes versus placebo, indacaterol, glycopyrronium, tiotropium and salmeterol/fluticasone in patients with COPD. [ATS abstract 40759; Session C45; Date: May 21, 2013 Time: 8:15 -10:45]. 
      [9]    Vogelmeier C, et al. Once-daily QVA149 provides clinically meaningful improvements in lung function and clinical outcomes. [ERS 2013 abstract 851178; Session 82; Date: September 8, 2013 Time: 12:50-14:40].
      [10]  Banerji D, et al. Dual bronchodilation with once-daily QVA149 improves dyspnea and health status and reduces symptoms and rescue medication use in patients with COPD: the IGNITE trials. [ERS 2013 abstract 851388; Session 346; Date: September 10, 2013 Time: 8:30-10:30].
      [11]  Pavkov R, Mueller S, Fiebich K, et al. Characteristics of a capsule based dry powder inhaler for the delivery of indacaterol. CMRO. 2010;26; 11:2527-2533.
      [12]  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 December 2017].
      [13]  World Health Organization: The top 10 causes of death fact sheet N^o 310. Available at: http://www.who.int/mediacentre/factsheets/fs310/en/ [Accessed December 2017].
      [14]  Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of COPD, 2017. Available at: http://goldcopd.org [Accessed December 2017].
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