Benralizumab Phase III trials show positive results in severe asthma

AstraZeneca's first biologic respiratory medicine met primary and key secondary endpoints in pivotal trials for severe asthma

MISSISSAUGA, ON, Sept. 6, 2016 /CNW/ - Results from pivotal Phase III trials presented at the European Respiratory Society (ERS) International Congress demonstrated that adding benralizumab to standard-of-care medicine significantly reduced exacerbations and improved lung function and asthma symptoms in severe asthma patients with an eosinophilic phenotype, as indicated by the presence of eosinophils in their blood.^{1, 2}

The SIROCCO and CALIMA trials evaluated the effect of two dosing regimens of benralizumab 30mg administered in 4-week and 8-week regimens as add-on therapy to standard-of-care medicine across primary and key secondary endpoints. Results showed:

• Reductions in the annual rate of asthma exacerbations (up to 51 per cent)³
• Improvement in lung function (change in FEV₁ of up to 159 mL), which was seen at 4 weeks after the first benralizumab dose and sustained throughout the treatment period⁴
• Improvement in asthma symptoms, such as wheeze, cough, chest tightness and shortness of breath^5,6

The outcomes were demonstrated for the 8-week dosing regimen, with no additional benefit observed with 4-week dosing, which may support less-frequent dosing.^7,8 In addition, post-hoc analysis showed greater improvements in exacerbation rate reduction, FEV₁ and total asthma symptom scores in patients with a history of more frequent asthma exacerbations (≥ 3 in the previous year).^{9, 10} Detailed results were published on September 5 in The Lancet for the Phase III SIROCCO and CALIMA trials.

"Statistics show that up to 250,000 Canadians suffer from severe asthma, and new treatment options are needed to help this patient population regain control of their disease and reduce exacerbations," said Mark FitzGerald, MD, research scientist at the Vancouver Coastal Health Research Institute, University of British Columbia, and Principal Investigator in the CALIMA trial. "This study demonstrates that the anti-eosinophil effect of benralizumab within the appropriate patient population improved outcomes for patients whose severe asthma is driven by eosinophilic inflammation."

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer, said: "Severe asthma affects the lives of millions of patients around the world and can be life threatening. The SIROCCO and CALIMA Phase III trials have shown that benralizumab can offer a meaningful treatment option for patients as evidenced by reductions in exacerbations, improvement in lung function and symptoms, with the promise of fewer doses a year. Benralizumab has a unique way of working in patients with severe asthma with an eosinophilic phenotype and reflects AstraZeneca's progress in bringing the next generation of respiratory medicines to patients."

The adverse event frequency was similar between benralizumab-treated patients versus placebo-treated patients for both SIROCCO and CALIMA (72 per cent and 74 per cent for all benralizumab treated patients vs. 76 per cent and 78 per cent for placebo-treated patients observed in SIROCCO and CALIMA, respectively).  ^11, 12 The most common (≥5 per cent) adverse events in benralizumab-treated patients observed in SIROCCO were asthma, nasopharyngitis, upper respiratory infection, headache, bronchitis, sinusitis, influenza and pharyngitis;¹³ and in CALIMA were nasopharyngitis, asthma, bronchitis, upper respiratory tract infection, headache and sinusitis.¹⁴

Severe uncontrolled asthma is a debilitating and potentially fatal form of the disease, where patients experience frequent exacerbations every year and have significant limitations on lung function and quality of life.^{15, 16} Uncontrolled asthma can lead to a dependence on oral corticosteroids (OCS), with systemic steroid exposure leading to serious and irreversible adverse effects.^{17, 18}

Benralizumab is an anti-eosinophil monoclonal antibody that induces direct, rapid and near-complete depletion of eosinophils, with an onset of action within 24 hours as confirmed in early phase I/II trials.¹⁹ Eosinophils are the biological effector cells that drive inflammation and airway hyper-responsiveness in approximately 50 per cent of asthma patients, leading to frequent exacerbations, impaired lung function and asthma symptoms.²⁰

The data from the SIROCCO and CALIMA trials will be included in regulatory submissions for benralizumab that are planned for the US and EU later in 2016.

NOTES TO EDITORS

About Severe Asthma
Asthma currently affects the health and day-to-day lifestyles of 315 million individuals worldwide,²¹ including an estimated 3 million Canadians.^{22, 23} Up to 40 per cent of asthma cases remain uncontrolled on current standard of care medicine.²⁴ A further 5 to 10 per cent of all asthma patients have severe uncontrolled asthma²⁵ that can lead to a dependence on OCS.²⁶ Systemic steroid exposure can lead to serious and irreversible adverse effects, including osteoporosis, anxiety, depression, weight gain, glaucoma and diabetes.²⁷ There is also a significant physical and socio-economic burden of severe asthma with these patients accounting for 50 per cent of asthma-related costs.²⁸ 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 2030.²⁹

About the WINDWARD Program
The WINDWARD program in asthma is made up of six Phase III trials, including SIROCCO, CALIMA, ZONDA, BISE, BORA and GREGALE. WINDWARD, the largest Phase III development program for a biologic medicine in respiratory disease, evaluated a total of 3,068 patients in 798 sites across 26 countries.

The two pivotal trials, SIROCCO and CALIMA, are randomized, double-blind, 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.

A total of 2,511 patients (1,205 in SIROCCO and 1,306 in CALIMA) currently receiving standard of care medicine (including high-dosage inhaled corticosteroids and long-acting beta 2 agonists [ICS/LABA]) 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. All benralizumab doses were administered via subcutaneous injection using an accessorized pre-filled syringe.

In addition to WINDWARD, the Phase III VOYAGER program is currently underway, which is evaluating the efficacy and safety of benralizumab in patients with severe chronic obstructive pulmonary disease (COPD).

About Benralizumab
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.

About AstraZeneca in Respiratory Disease
Respiratory disease is one of AstraZeneca's main therapy areas, and we have a growing portfolio of medicines that reached more than 17 million patients in 2015. Our 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. We are building on a 40-year heritage in respiratory disease, and our capability in inhalation technology spans both pressurized metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs), as well as our unique Co-Suspension^TM Delivery Technology. Our research is focused on three key biological pathways: eosinophilic disease, Th2-driven disease and epithelial-driven pathobiology.

About AstraZeneca
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, 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. The Lancet. September 5, 2016.

² Bleeker ER, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β_²-agonists (SIROCCO): a randomised, multicentre, placebo controlled phase 3 trial. The Lancet. September 5, 2016.

³ FitzGerald JM, 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. The Lancet. September 5, 2016.

⁴ Bleeker ER, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β_²-agonists (SIROCCO): a randomised, multicentre, placebo controlled phase 3 trial. The Lancet. September 5, 2016.

⁵ Bleeker ER, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β_²-agonists (SIROCCO): a randomised, multicentre, placebo controlled phase 3 trial. The Lancet. September 5, 2016.

⁶ FitzGerald JM, 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. The Lancet. September 5, 2016.

⁷ FitzGerald JM, 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. The Lancet. September 5, 2016.

⁸ Bleeker ER, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β_²-agonists (SIROCCO): a randomised, multicentre, placebo controlled phase 3 trial. The Lancet. September 5, 2016.

⁹ FitzGerald JM, 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. The Lancet. September 5, 2016.

¹⁰ Bleeker ER, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β_²-agonists (SIROCCO): a randomised, multicentre, placebo controlled phase 3 trial. The Lancet. September 5, 2016.

¹¹ Bleeker ER, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β_²-agonists (SIROCCO): a randomised, multicentre, placebo controlled phase 3 trial. The Lancet. September 5, 2016.

¹² FitzGerald JM, 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. The Lancet. September 5, 2016.

¹³ Bleeker ER, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β_²-agonists (SIROCCO): a randomised, multicentre, placebo controlled phase 3 trial. The Lancet. September 5, 2016.

¹⁴ FitzGerald JM, 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. The Lancet. September 5, 2016.

¹⁵ Gaga M, Zervas E, Chanez P. Update on severe asthma: what we know and what we need. Eur Respir Rev. 2009;18(112):58-65.

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¹⁷ de Groot JC, Ten Brinke A, Bel E. Management of the patient with eosinophilic asthma: a new era begins. ERJ Open Research. May 2015.

¹⁸ Hyland ME, et al. 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 24.3 (2014): 631-639. Web. 1 Sept. 2016.

¹⁹ Pham TH, Damera G, Newbold P, Ranade K. Reductions in eosinophil biomarkers by benralizumab in patients with asthma. Respir Med. 2016;111:21-9.

²⁰ Schleich et al. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation BMC Pulmonary Medicine 2013, 13:11

²¹ FitzGerald JM, 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. The Lancet. September 5, 2016.

²² Statistics Canada. Asthma, by sex, provinces and territories (Number of persons). Available at http://www.statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/health50a-eng.htm. Accessed August 29, 2016.

²³ Public Health Agency of Canada. Life and Breath: Respiratory Disease in Canada. 2007.

²⁴ Adelphi Real World Respiratory Disease Specific Program. 2012–2014. [Asthma patient data file], Bollington, UK. Unpublished raw data, cited with permission.

²⁵ Fernandes AG, et al. Risk factors for death in patients with severe asthma. J Bras Pneumol. 2014;40(4):364-72.

²⁶ de Groot JC, Ten Brinke A, Bel E. Management of the patient with eosinophilic asthma: a new era begins. ERJ Open Research. May 2015

²⁷ Hyland ME, et al. 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 24.3 (2014): 631-639. Web. 1 Sept. 2016.

²⁸ Blaiss M. Economic Analysis of the Cost of Treatments for Severe Asthma. World Allergy Organization. Available at: http://www.worldallergy.org/educational_programs/world_allergy_forum/anaheim2005/blaiss.php. Accessed September 1, 2016.

²⁹ Hermus G., et al. Cost Risk Analysis for Chronic Lung Disease in Canada." The Conference Board of Canada. 2012.

SOURCE AstraZeneca Canada Inc.

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