AstraZeneca presents new results identifying severe asthma patients who would benefit most from benralizumab

Further analysis of the Phase III trials, SIROCCO and CALIMA, reinforces benralizumab's efficacy and identifies more frequent prior exacerbations and/or greater baseline blood eosinophil count as key predictors of an enhanced treatment effect

Findings pave the way for a personalized treatment approach to guide more precise selection of the benralizumab-responsive patient and help achieve maximum clinical benefit

MISSISSAUGA, ON, Sept. 11, 2017 /CNW/ - AstraZeneca today announced results from an integrated analysis of the SIROCCO and CALIMA Phase III trials. The results confirm benralizumab's compelling efficacy and identify key factors that predict which patients with severe, uncontrolled asthma would respond best to treatment with this potential new medicine.¹

Benralizumab is a monoclonal antibody that recruits natural killer cells, a component of the innate immune system, causing direct, rapid and near-complete depletion of eosinophils.^2,3 Eosinophils are the biological effector cells that impact airway inflammation and airway hyper-responsiveness in approximately 50% of asthma patients,^4,5,6,7 which leads to increased asthma symptoms, impaired lung function and more frequent exacerbations.⁸

In this post-hoc analysis, benralizumab demonstrated efficacy across the full range of baseline blood eosinophil counts, with an increased number of prior exacerbations and a higher baseline blood eosinophil count associated with a greater treatment effect.⁹ A combination of both higher baseline blood eosinophil count and a history of more frequent exacerbations predicted an even greater magnitude of response for patients treated with benralizumab.¹⁰ Additionally, patients on oral corticosteroids and with nasal polyposis were more likely to have an enhanced treatment response.¹¹ The results were presented at the European Respiratory Society (ERS) International Congress 2017 in Milan, Italy and were published simultaneously today in The Lancet Respiratory Medicine.

The overall safety profiles of the benralizumab and placebo arms were similar for both the SIROCCO and CALIMA trials, and the overall safety profile for benralizumab was in line with prior experiences.^12,13,14

J. Mark FitzGerald, MD, Director of the Centre for Heart and Lung Health at the Vancouver Coastal Health Research Institute and Principal Investigator of the study, said: "As a treating physician, I want to be confident that I am prescribing the right treatment that will provide maximum benefit to patients with severe, uncontrolled asthma. This important analysis shows benralizumab provides enhanced benefits for patients who experience more frequent exacerbations despite being on standard-of-care medicines and/or who present with higher baseline blood eosinophil counts. Knowing this will help us identify which patients can benefit most from benralizumab, and will ultimately help us improve the therapeutic management of severe, uncontrolled asthma."

Colin Reisner, Head of Respiratory, Global Medicines Development at AstraZeneca, said: "Severe, uncontrolled asthma affects millions of people around the world and exacerbations can be life-threatening. This new analysis of SIROCCO and CALIMA builds on robust clinical evidence supporting benralizumab for patients with severe, uncontrolled asthma, including more recent data from the Phase III ZONDA trial."

Benralizumab is under regulatory review in the US, EU, Canada, Japan and several other countries, with a US PDUFA date during the fourth quarter of 2017 and expected regulatory decisions elsewhere during H1 2018.

NOTES TO EDITORS

About Severe Asthma
Asthma affects 315 million individuals worldwide, including an estimated 3 million Canadians.¹⁵ Up to 10% of asthma patients have severe asthma,^16,17 which may be uncontrolled despite high doses of standard-of-care asthma controller medicines and can require the use of chronic oral corticosteroids (OCS).¹⁸

Severe, uncontrolled asthma is debilitating and potentially fatal with patients experiencing frequent exacerbations and significant limitations on lung function and quality of life.^19,20 Severe, uncontrolled asthma has an eight times higher risk of mortality than severe asthma.^21,22

Severe, uncontrolled asthma can lead to a dependence on OCS, with systemic steroid exposure potentially leading to serious short- and long-term adverse effects, including weight gain, diabetes, osteoporosis, glaucoma, anxiety, depression, cardiovascular disease^23,24 and immunosuppression.²⁵ There is also a significant physical and socio-economic burden of severe, uncontrolled asthma with these patients accounting for 50% of asthma-related costs.²⁶ A conservative estimate developed by the Conference Board of Canada suggests that without concerted action, the cost of asthma alone in Canada will rise to $4.2 billion by 2030.²⁷

About the WINDWARD Program
The WINDWARD program in asthma is made up six Phase III trials, including SIROCCO, CALIMA, ZONDA, BISE, BORA and GREGALE. The two pivotal trials included in this analysis, SIROCCO and CALIMA, are randomized, double-blinded, parallel-group, placebo-controlled trials designed to evaluate the efficacy and safety of a regular, subcutaneous administration of benralizumab (fixed 30mg dose) for up to 56 weeks in exacerbation-prone adult and adolescent patients 12 years of age and older.^28,29

A total of 2,295 patients (1,204 in SIROCCO and 1,091 in CALIMA)³⁰ received standard-of-care medicine (including high-dosage inhaled corticosteroids and long-acting beta-2 agonists [ICS/LABA]) and were randomized globally and received either benralizumab 30mg every 4 weeks; benralizumab 30mg every 4 weeks for the first three doses followed by 30mg every 8 weeks; or placebo.^31,32 All benralizumab doses were administered via subcutaneous injection using an accessorized pre-filled syringe.^33,34

About Benralizumab
Benralizumab is a monoclonal antibody that recruits natural killer cells causing direct, rapid and near complete depletion of eosinophils. Depletion of circulating eosinophils is rapid, with an onset of action within 24 hours as confirmed in early phase I/II trials.^35,36,37 In the pivotal Phase III trials, SIROCCO and CALIMA, benralizumab demonstrated significant reduction in exacerbations and improved lung function and asthma symptoms in severe, uncontrolled eosinophilic asthma patients.^38,39 Eosinophils are the biological effector cells in approximately 50% of asthma patients, leading to frequent exacerbations, impaired lung function and asthma symptoms.^40,41,42

Benralizumab was developed by MedImmune, AstraZeneca's global biologics research and development arm and is in-licensed from BioWa, Inc., a wholly-owned subsidiary of Kyowa Hakko Kirin Co., Ltd., Japan.

About AstraZeneca Canada
AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialization of primary and specialty care medicines that transform lives. Our primary focus is on three important areas of healthcare: Cardiovascular and Metabolic disease; Oncology; and Respiratory, Inflammation and Autoimmunity. AstraZeneca operates in more than 100 countries and its innovative medicines are used by millions of patients worldwide. In Canada, we employ more than 675 employees across the country and our AstraZeneca Canada headquarters are located in Mississauga, Ontario. For more information, please visit the company's website at www.astrazeneca.ca.

REFERENCES:

____________________
¹ FitzGerald JM, Bleecker ER, Menzies-Gow A, Zangrilli JG, Hirsch I, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med. 2017.
² Pham TH, Damera G, Newbold P, Ranade K. Reductions in eosinophil biomarkers by benralizumab in patients with asthma. Respir Med. 2016 Feb; 111:21-9.
³ Kolbeck R, Kozhich A, Koike M, et al. MEDI-563, a humanized anti–IL-5 receptor a mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010 Jun;125(6):1344-1353.e2.
⁴ Pham TH, Damera G, Newbold P, Ranade K. Reductions in eosinophil biomarkers by benralizumab in patients with asthma. Respir Med. 2016 Feb; 111:21-9.
⁵ Kolbeck R, Kozhich A, Koike M, et al. MEDI-563, a humanized anti–IL-5 receptor a mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010 Jun;125(6):1344-1353.e2.
⁶ Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002 Nov 30;360(9347):1715-21.
⁷ Possa SS, Leick EA, Prado CM, Martins MA, et al. Eosinophilic Inflammation in Allergic Asthma. Front Pharmacol. 2013 Apr; 4:46.
⁸ De Groot JC, ten Brinke A, Bel EHD. Management of the patient with eosinophilic asthma: a new era begins. ERJ Open Res, 2015; 1: 00024–2015.
⁹ FitzGerald JM, Bleecker ER, Menzies-Gow A, Zangrilli JG, Hirsch I, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med. 2017. 
¹⁰ Ibid.
¹¹ Ibid.   
¹² Ibid.  
¹³ Bleecker ER, Fitzgerald MJ, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016. Volume 388, Issue 10056, 2115 – 2127.
¹⁴ FitzGerald MJ, Bleecker E, Parameswaran N, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016. Volume 388, Issue 10056, 2128 – 2141.
¹⁵ Asthma Society of Canada. Asthma Facts & Stats. Available at: http://www.asthma.ca/corp/newsroom/pdf/asthmastats.pdf.
¹⁶ Fernandes AG, Souza-Machado C, Coelho RC et al. Risk factors for death in patients with severe asthma. J Bras Pneumol. 2014; 40(4): 364-372.
¹⁷ Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43: 343–73.
¹⁸ Peters SP, Ferguson G, Deniz Y, Reisner C. Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment. Respir Med. 2006: 100(7):1139-51.
¹⁹ Price D, Fletcher M, van der Molen T. Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med. 2014; 12; 24:14009.
²⁰ Peters SP, Ferguson G, Deniz Y, Reisner C. Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment. Respir Med. 2006: 100(7):1139-51.
²¹ Fernandes AG, Souza-Machado C, Coelho RC et al. Risk factors for death in patients with severe asthma. J Bras Pneumol. 2014; 40(4): 364-372.
²² Price D, Fletcher M, van der Molen T. Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med. 2014; 12; 24:14009.
²³ Hyland ME, Whalley B, Jones RC, Masoli M. A qualitative study of the impact of severe asthma and its treatment showing that treatment burden is neglected in existing asthma assessment scales. Qual Life Res. 2015 Mar;24(3):631-9. doi: 10.1007/s11136-014-0801-x. Epub 2014 Sep 9.
²⁴ Global Initiative for Asthma (GINA). Online appendix. Global strategy for asthma management and prevention. Updated 2017. Available from: http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention/. Last accessed May 2017.
²⁵ Zazzali JL, Broder MS, Omachi TA, Chang E, Sun GH, Raimundo K. Risk of corticosteroid-related adverse events in asthma patients with high oral corticosteroid use. Allergy Asthma Proc. 2015 Jul-Aug;36(4):268-74. doi: 10.2500/aap.2015.36.3863.
²⁶ Papathanassiou E, Loukides S, Bakakos P. Severe asthma: antiIgE or antiIL5? Eur Clin Respir J. 2016; 3: 10.3402/ecrj.v3.31813.
²⁷ Hermus G., et al. Cost Risk Analysis for Chronic Lung Disease in Canada." The Conference Board of Canada. 2012.
²⁸ FitzGerald MJ, Bleecker E, Parameswaran N, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016. Volume 388, Issue 10056, 2128 – 2141.
²⁹ Bleecker ER, Fitzgerald MJ, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016. Volume 388, Issue 10056, 2115 – 2127.
³⁰ FitzGerald JM, Bleecker ER, Menzies-Gow A, Zangrilli JG, Hirsch I, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med. 2017. 
³¹ Ibid.
³² Bleecker ER, Fitzgerald MJ, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016. Volume 388, Issue 10056, 2115 – 2127.
³³ FitzGerald MJ, Bleecker E, Parameswaran N, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016. Volume 388, Issue 10056, 2128 – 2141.
³⁴ Bleecker ER, Fitzgerald MJ, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016. Volume 388, Issue 10056, 2115 – 2127.
³⁵ Pham TH, Damera G, Newbold P, Ranade K. Reductions in eosinophil biomarkers by benralizumab in patients with asthma. Respir Med. 2016 Feb; 111:21-9.
³⁶ Kolbeck R, Kozhich A, Koike M, et al. MEDI-563, a humanized anti–IL-5 receptor a mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010 Jun;125(6):1344-1353.e2.
³⁷ Laviolette M, Gossage DL, Gauvreau G, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013 Nov; 132(5): 1086 - 1096.e5.
³⁸ FitzGerald MJ, Bleecker E, Parameswaran N, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016. Volume 388, Issue 10056, 2128 – 2141.
³⁹ Bleecker ER, Fitzgerald MJ, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016. Volume 388, Issue 10056, 2115 – 2127.
⁴⁰ Zhang JY, Wenzel SE. Tissue and BAL Based Biomarkers in Asthma. Immunol Allergy Clin N Am. 27 (2007) 623-632.
⁴¹ Talini D, Novelli F, Bacci E, et al. Sputum eosinophilia is a determinant of FEV1 decline in occupational asthma: results of an observational study. BMJ Open 2015; 5: e005748.
⁴² De Groot JC, ten Brinke A, Bel EHD. Management of the patient with eosinophilic asthma: a new era begins. ERJ Open Res, 2015; 1: 00024–2015.

SOURCE AstraZeneca Canada Inc.

Mary-Anne Cedrone, AstraZeneca Canada, Tel: [phone], E-mail: [email protected]; Courtney McNamara, Edelman, Tel: [phone], E-mail: [email protected]