AstraZeneca A/S

AstraZeneca today announced results from the Phase III SYGMA trials^1,2of Symbicort Turbuhaler (budesonide/formoterol) given as an anti-inflammatory reliever ‘as needed’ versus two different treatment regimens in patients with mild asthma.The data are publishedin the New England Journal of Medicine^1,2and will be presented on Sunday 20 May at the American Thoracic Society (ATS) 2018 International Congress.^3,4

The SYGMA trials were designed to evaluate the efficacy of Symbicort Turbuhaler, taken only as needed, as an anti-inflammatory reliever versus current standard of care therapies in mild asthma:

In place of current reliever therapy, short-acting beta2-agonist (SABA) also taken as needed

As an alternative to regular maintenance controller therapy (twice-daily budesonide, an inhaled corticosteroid, ICS) plus SABA ‘as needed’

Both trials met their primary efficacy outcomes. The results of the primary and key secondary efficacy outcome measurements are:

Symbicort Turbuhaler ‘as needed’ demonstrated superior asthma-symptom control (34.4% versus 31.1%) assessed according to electronically recorded well-controlled asthma weeks (eWCAW) and a 64% reduction in exacerbations versus SABA ‘as needed’.^2,4

Symbicort Turbuhaler used as needed was non-inferior to twice-daily budesonide maintenance therapy plus SABA ‘as needed’ in reducing the risk of severe asthma exacerbations (0.11 versus 0.12),¹ achieved with 25% of the budesonide maintenance dose.^1,3

Symbicort Turbuhaler taken only as needed did not achieve non-inferiority in eWCAW versus twice-daily budesonide plus SABA.^2,4

Further details on the primary and secondary outcomes are outlined below.

Dr. Colin Reisner, Head of Respiratory, Global Medicines Development at AstraZeneca, said: “These data show the potential value of Symbicort as an anti-inflammatory reliever ‘as needed’ in mild asthma, building on the established benefits of Symbicort in moderate to severe disease.”

Paul M. O’Byrne, Dean and Vice-President, Faculty of Health Sciences at McMaster University, Canada, and the International Coordinating Investigator for SYGMA 1, said: “Asthma is an inflammatory airway disease. We know that many millions of patients around the world are over-reliant on their reliever medications, which improve symptoms but do not treat inflammation, and underuse anti-inflammatory maintenance controller treatments resulting in preventable exacerbations. The SYGMA trials provide important new data which could improve the treatment of mild asthma and inform management guidelines.”

The SYGMA trial programme comprises SYGMA 1 and 2: two, 52-week Phase III trials in more than 8,000 patients.⁵SYGMA 1 evaluated SymbicortTurbuhaler (200/6 µg^*) ‘as needed’, compared with terbutaline (0.5 mg^†) ‘as needed’ and budesonide(200 µg) twice-daily plus terbutaline (0.5 mg^†) ‘as needed’.² SYGMA 2 evaluated Symbicort Turbuhaler (200/6 µg^*) ‘as needed’, compared with budesonide(200 µg) twice-daily maintenance plus terbutaline (0.5 mg^†) ‘as needed’.¹

Safety and tolerability data for Symbicort Turbuhaler ‘as needed’ were consistent with the known profile of the medicine.^1,2 The most commonly-reported adverse events were upper respiratory tract infection (URTI), viral URTI, asthma, pharyngitis, bronchitis, headache, and allergic rhinitis.^1,2

In the US, Symbicort is approved in the pMDI device, but not the Turbuhaler device.

– ENDS –

NOTES TO EDITORS

About asthma

Asthma is a common chronic respiratory disease, and it affects the health and day-to-day lives of as many as 334 million adults and children worldwide.⁶ It is characterised by recurrent breathlessness and wheezing which varies over time, and which varies in severity and frequency from person to person.⁷

Asthma is an inflammatory disease with recurring flare-ups of inflammation (the cause) and symptoms (the consequence).^8-10 Between 50 and 75% of asthma patients have mild asthma,¹¹ and inflammation of the airways has been shown to be a distinctive feature of asthma.⁸The management of asthma should therefore be directed towards resolving this inflammatory process.⁸

About the SYGMA trial programme

The SYmbicort Given ‘as needed’ in Mild Asthma (SYGMA) trial programme is composed of two, 52-week Phase III, randomised, double-blind, multicentre, parallel-group trials in more than 8,000 patients aged 12 years and older with a clinical diagnosis of asthma for at least six months, who would qualify for treatment with regular low-dose ICS maintenance.⁵

SYGMA 1 randomised 3,849 patients to evaluate the efficacy and safety of SymbicortTurbuhaler (200/6 µg^*) ‘as needed’, compared with terbutaline (0.5 mg^†) ‘as needed’ and budesonide(200 µg) twice-daily plus terbutaline (0.5 mg^†) ‘as needed’.² The primary objective was to demonstrate that Symbicort given ‘as needed’ is superior to terbutaline ‘as needed’, as measured by electronically-recorded well-controlled asthma weeks.²

SYGMA 2 randomised 4,215 patients to evaluate the efficacy and safety of Symbicort Turbuhaler (200/6 µg^*) ‘as needed’, compared with budesonide(200 µg) twice-daily maintenance plus terbutaline (0.5 mg^†) ‘as needed’.¹ The primary objective was to demonstrate that Symbicort given ‘as needed’ is non-inferior to budesonide plus terbutaline ‘as needed’, as measured by the relative rate of annual severe asthma exacerbations^‡.¹

The results of the primary and key secondary efficacy outcome measurements are:

SYGMA 1: versus SABA ‘as needed’

Symbicort Turbuhaler used as needed provided superior asthma-symptom control to SABA used as needed, assessed according to electronically recorded well-controlled asthma weeks (eWCAW) (34.4% versus 31.1%), the primary efficacy outcome.²

Symbicort Turbuhaler used as needed resulted in a 64% lower annual severe exacerbation rate than SABA used as needed (0.07 versus 0.20).²

SYGMA 1: versus twice-daily budesonide plus SABA ‘as needed’

Symbicort Turbuhaler used as needed was inferior to twice-daily budesonide maintenance therapy plus SABA ‘as needed’, as measured by eWCAWs (34.4% versus 44.4%).²

The rates of severe exacerbations in the Symbicort group and the budesonide maintenance group did not differ significantly (0.07 versus 0.09); this was achieved at a substantially lower steroid dose (17% of the budesonide maintenance dose).²

SYGMA 2: versus twice-daily budesonide plus SABA ‘as needed’

Symbicort Turbuhaler used as needed was non-inferior to twice-daily budesonide maintenance therapy plus SABA ‘as needed’ in reducing the risk of severe asthma exacerbations (0.11 versus 0.12), the primary efficacy outcome.¹ This was achieved at a substantially lower steroid dose (25% of the budesonide maintenance dose).¹

Symbicort Turbuhaler provided less symptom control than twice-daily budesonide maintenance therapy plus SABA ‘as needed’ as measured by the Asthma Control Questionnaire-5 (mean difference of 0.11 units).¹

About Symbicort

Symbicort is a combination formulation containing budesonide, an ICS that treats underlying inflammation, and formoterol, a long-acting beta2-agonist bronchodilator (LABA) with a fast onset of action, in a single inhaler. Symbicort is approved as a treatment regimen for patients with moderate to severe disease. Symbicort was launched in 2000 and is approved in approximately 120 countries to treat asthma and/or COPD either as Symbicort Turbuhaler or Symbicort pMDI (pressurised metered-dose inhaler).

About AstraZeneca in Respiratory Disease

Respiratory disease is one of AstraZeneca’s main therapy areas, and the Company has a growing portfolio of medicines that reached more than 18 million patients in 2017. AstraZeneca’s aim is to transform asthma and COPD treatment through inhaled combinations at the core of care, biologics for the unmet needs of specific patient populations, and scientific advancements in disease modification.

The Company is building on a 40-year heritage in respiratory disease and AstraZeneca’s capability in inhalation technology spans pressurised metered-dose inhalers and dry powder inhalers, as well as the Aerosphere Delivery Technology. The company also has a growing portfolio of respiratory biologics. AstraZeneca’s research is focused on addressing underlying disease drivers focusing on the lung epithelium, lung immunity and lung regeneration.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

For more information, please visit www.astrazeneca.com and follow us on Twitter @AstraZeneca.

Media contact, Petra Eurenius, External Communications Director, AstraZeneca Nordic-Baltic. Mobile: +46 709 186562

* Corresponds to a delivered dose of budesonide/formoterol of 160/4.5 µg

^†Corresponds to a 0.4 mg delivered dose of terbutaline, delivered by a Turbuhaler

^‡Severe exacerbations defined as worsening asthma requiring use of systemic corticosteroids for ≥3 days, inpatient hospitalisation, or emergency department visit requiring systemic corticosteroids

References

1.Bateman ED, Reddel HK, O’Byrne PM, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med. 2018; 378: 1877-1887.

2.O’Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med. 2018; 378: 1865-1876.

3.Bateman ED, Reddel HK, O’Byrne PM, et al. Severe exacerbations and inhaled corticosteroid load with as-needed budesonide/formoterol vs maintenance budesonide in mild asthma. American Thoracic Society 2018 International Congress. Abstract Number: A7654 / P917.

4.O’Byrne PM, FitzGerald JM, Bateman ED, et al. Efficacy and safety of as-needed budesonide/formoterol in mild asthma. American Thoracic Society 2018 International Congress. Abstract Number: A7655 / P918.

5.O’Byrne PM, FitzGerald JM, Zhong N, et al. The SYGMA programme of phase 3 trials to evaluate the efficacy and safety of budesonide/formoterol given “as needed” in mild asthma: study protocols for two randomised controlled trials. Trials. 2017; 18: 12.

6.The Global Asthma Network. The Global Asthma Report 2014. [Online]. Available at: http://www.globalasthmanetwork.org/publications/Global_Asthma_Report_2014.pdf [Last accessed 16 May 2018].

7.From: Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Asthma Education and Prevention Program, Third Expert Panel on the Diagnosis and Management of Asthma. Bethesda (MD): National Heart, Lung, and Blood Institute (US), 2007.

8.Beasley R, Burgess C, Crane J, et al. Pathology of asthma and its clinical implications. J Allergy Clin Immunol. 1993; 92: 148–154.

9.Busse WW, Lemanske RF. Asthma. N Engl J Med. 2001; 344: 350–362.

10.Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2018. Available from: www.ginasthma.org [last accessed 16 May 2018].

11.Dusser D, Montani D, Chanez P, et al. Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations. Allergy. 2007; 62(6): 591–604.