Single-Inhaler Extrafine Triple Therapy of Inhaled Corticosteroid, Long-Acting B2-Agonist and Long-Acting Muscarinic Antagonist Therapy Improves Lung Function and Reduces Asthma Exacerbations(1)

• Data from two randomized, double-blind, parallel-group, active-controlled studies on the efficacy and safety of single-inhaler triple therapy in adult patients with uncontrolled asthma is published in The Lancet for the first time.
• TRIMARAN and TRIGGER compared the single-inhaler triple therapy consisting of extrafine beclometasone dipropionate (inhaled corticosteroid; BDP), formoterol fumarate (long-acting β2-agonist; FF), and glycopyrronium (long-acting muscarinic antagonist; G), versus fixed combination BDP/FF.
• Lung function, defined as pre-dose morning FEV₁ (Forced Expiratory Volume in 1 second), increased by up to 73mL (p=0.0025) after 26 weeks of treatment with BDP/FF/G versus BDP/FF.
• Rate of severe asthma exacerbations was reduced by 23% (p=0.0076) after 52 weeks of treatment with BDP/FF/G versus BDP/FF.

PARMA, Italy, Oct. 01, 2019 (GLOBE NEWSWIRE) -- Today, Chiesi Farmaceutici, an international research-focused healthcare group (Chiesi Group), announced the results of two studies published in The Lancet concluding that a single-inhaler triple therapy with extrafine beclometasone dipropionate (inhaled corticosteroid; BDP), formoterol fumarate (long-acting β2-agonist; FF), and glycopyrronium (long-acting muscarinic antagonist; G) improves lung function and reduces exacerbations in adult patients with asthma uncontrolled on ICS/LABA therapy with a history of one or more exacerbation in the previous year. These are the first studies to evaluate the relative efficacy and safety of single-inhaler triple therapy with those of inhaled corticosteroid plus a long-acting β2-agonist in adults with asthma.

The two Phase III, 52-week studies, TRIMARAN (N=1,155) and TRIGGER (N=1,437), compared the efficacy and safety of medium-ICS dose BDP/FF/G 100/6/10 micron (μg) versus BDP/FF 100/6μg (TRIMARAN) and high-ICS dose BDP/FF/G 200/6/10μg versus BDP/FF 200/6μg and BDP/FF 200/6μg plus tiotropium 2.5μg (TRIGGER) in adult patients with asthma uncontrolled on medium or high-dose ICS plus long-acting β2-agonist therapy (ICS/LABA). Study authors concluded that by week 26, BDP/FF/G improved pre-dose FEV₁ by 57mL (95% CI 15–99; p=0.0080) and 73mL (26–120; p=0.0025) versus BDP/FF in TRIMARAN and TRIGGER, respectively, with 15% (rate ratio 0.846 [0.725–0.987]; p=0.0331) and 12% (0.880 [0.751–1.030]; p=0.1102) reductions in moderate-to-severe exacerbation rate over 52 weeks. Furthermore, in the pre-specified pooled analysis, BDP/FF/G reduced the rate of severe exacerbations versus BDP/FF by 23% (p=0.0076), reduced the rate of moderate exacerbations by 12% (p=0.0427), and reduced the rate of combined moderate and severe exacerbations by 14% (p=0.0083).

Prof. Johann Christian Virchow, one of the principal investigators of the TRIMARAN and TRIGGER studies, from Rostock, Germany, said, “Some patients with uncontrolled asthma are required to use two different inhalers, of different design and with different instructions for use – and often with different dosing regimens. This is not only inconvenient for patients and healthcare providers who provide instruction on correct inhaler use, but can also negatively impact treatment adherence and persistence, leading to poor disease control. So, these findings are exciting for patients and healthcare providers alike because they provide first-time evidence of the benefits of a single-inhaler triple combination of BDP/FF/G for those with uncontrolled asthma.”

Alessandro Chiesi, Region Europe Head, Chiesi Group, said, “Today’s publication in The Lancet highlights Chiesi’s commitment to providing efficacious, well-tolerated and convenient treatment options for a disease that affects 8% of adults across Europe.² We are proud to be supporting these innovative studies, which provide us with key evidence on the benefits of single-inhaler triple therapy over other combination inhaler therapies. We look forward to continuing to showcase the benefits that our triple therapy in a single inhaler can bring to adult patients with asthma uncontrolled on ICS/LABA therapy.”

Adverse events were reported by 410–431 (72–75%) patients with BDP/FF/G, 443–455 (77–79%) with BDP/FF and 210 (73%) with BDP/FF plus tiotropium. The majority of events were mild or moderate in severity, and few were considered related to treatment. The most common adverse event in all groups was asthma exacerbation, the occurrence of which was lower with triple therapy than with BDP/FF.

Single-inhaler triple therapy consisting of an extrafine formulation (i.e., with mass median aerodynamic diameter <2μm) of BDP/FF/G delivered via a pressurised metered-dose inhaler (pMDI) is in development for patients with asthma. Studies suggest that extrafine formulations result in improved deposition in the small airways, which is potentially important given that asthma patients with significant small airways dysfunction tend to have poorer asthma control and quality of life and are at increased exacerbation risk.^3,4

Notes to Editors

Media Contacts:
Valentina Biagini
Senior Group Communication Manager
Tel: +39 348 7693 623
Email: v.biagini@chiesi.com

Rita Martins
M&F Health
Tel: +44 20 7492 1788
Email: rita.martins@mandfhealth.com

For Journalists: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32215-9/fulltext

About the TRIMARAN and TRIGGER studies
TRIMARAN and TRIGGER are two randomised, parallel-group, double-blind, active-controlled studies. Eligible patients were adults with uncontrolled asthma, history of ≥1 exacerbation, and previously treated with inhaled corticosteroid (TRIMARAN, medium-dose; TRIGGER, high-dose) plus long-acting β2-agonist. After two weeks receiving BDP/FF (TRIMARAN, 100/6μg; TRIGGER, 200/6μg), patients were randomised to 52 weeks with BDP/FF/G 100/6/10μg or BDP/FF 100/6μg, two inhalations twice-daily in TRIMARAN; and BDP/FF/G 200/6/10μg or BDP/FF 200/6μg, or open-label BDP/FF 200/6μg two inhalations twice-daily plus tiotropium 2.5μg two inhalations once-daily in TRIGGER.

Between February 2016 and May 2018, 1,155 patients in TRIMARAN received BDP/FF/G (N=579) or BDP/FF (N=576); between April 2016 and May 2018, 1,437 patients in TRIGGER received BDP/FF/G (N=573), BDP/FF (N=576) or BDP/FF plus tiotropium (N=288).

Co-primary endpoints (BDP/FF/G vs BDP/FF) were: pre-dose FEV₁ at week 26; rate of moderate-to-severe exacerbations over 52 weeks. Key secondary endpoints included severe exacerbation rate over 52 weeks (using pooled data).

About Asthma
Asthma is a common long-term condition that can affect people of all ages and causes inflammation in the airways.⁵ The prevalence of asthma in the European Union (EU) is 8.2% in adults and 9.4% in children.² Difficult-to-treat or severe asthma occurs in 24% of patients.⁶ The direct and indirect costs of asthma to societies are substantial.⁷ Recent calculations estimate direct costs within the EU to be nearly €20 billion, indirect costs to be €14 billion and a monetized value of DALYs lost to be €38 billion, which totals €72 billion.⁸

About Chiesi Group
Based in Parma, Italy, Chiesi Farmaceutici is an international research-focused Healthcare Group, with over 80 years of experience in the pharmaceutical industry, and with presence in 28 countries. Chiesi researches, develops and markets innovative drugs in the respiratory therapeutics, specialist medicine and rare disease areas. Its R&D organization is headquartered in Parma (Italy), and integrated with 4 other key R&D groups in France, the USA, the UK and Sweden to advance Chiesi's pre-clinical, clinical and registration programs. Chiesi employs over 5,600 people. Chiesi Group is a Certified Benefit Corporation. For more information, please visit www.chiesi.com.

References
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¹ Virchow J C et al. Single inhaler extrafine triple therapy in uncontrolled asthma: two randomised, double-blind, parallel group, controlled trials (TRIMARAN and TRIGGER). Lancet 2019
² Selroos O et al. National and regional asthma programmes in Europe. Eur Respir Rev 2015; 24: 474–483
³ Lipworth B, Manoharan A, Anderson W. Unlocking the quiet zone: the small airway asthma phenotype. Lancet Respir Med 2014; 2: 497–506
⁴ Postma DS, Brightling C, Baldi S, et al. Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study. Lancet Respir Med 2019; 7: 402–16
⁵ European Lung Foundation - ELF. Adult asthma. [online] Available at: https://www.europeanlung.org/en/lung-disease-and-information/lung-diseas... Last accessed September 2019
⁶ Global Strategy for Asthma Management and Prevention. Difficult to treat and severe asthma in adolescents and adult patients. April 2019 [online] Available at: https://ginasthma.org/wp-content/uploads/2019/04/GINA-Severe-asthma-Pock.... Last accessed September 2019
⁷ Bahadori K, Doyle-Waters MM, Marra C, et al. Economic burden of asthma: a systematic review. BMC Pulm Med 2009; 9: 24
⁸ Gibson J, Loddenkemper R, Sibille Y, et al., eds. Lung Health in Europe. Facts and Figures. Sheffield, European Respiratory Society/European Lung Foundation, 2013