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New data from the WINDWARD clinical trial program on benralizumab in severe asthma

Authors: Katrina Mountfort, Senior Medical Writer, Touch Medical Media, UK
Andrew Potter, Respiratory Account Director, Touch Medical Media, UK
Insights into the WINDWARD clinical trial program, presented and discussed at the ATS Annual Meeting, Washington DC, May 19–24, 2017

Asthma affects 315 million individuals worldwide.1 In 2014, the European Respiratory Society and American Thoracic Society (ERS/ATS) defined severe asthma as asthma that requires treatment with high-dose inhaled corticosteroids plus a second controller and/or systemic chronic oral corticosteroids (OCS).2 Up to 10% of asthma patients have severe asthma, of which 40% may be uncontrolled despite high doses of standard-of-care asthma controller medicines, and can require the use of OCS.2 Severe uncontrolled asthma is debilitating and potentially life-threatening with patients experiencing frequent exacerbations and significantly impaired lung function and quality of life. Patients with severe, uncontrolled asthma are at a particularly high risk of exacerbations, hospitalization and death, and often have severely impaired quality of life.3 Uncontrolled asthma can also lead to a dependence on OCS, and systemic steroid exposure is associated with serious and irreversible adverse effects, including weight gain, type 2 diabetes, osteoporosis, dyspeptic disease, cataracts and immunosuppression.4 Severe asthma also accounts for a high proportion of asthma health care expenditures.5

One of the barriers to successful management is the heterogeneity of asthma. Asthma is not one disease; it is a disorder that can be subdivided into a number of different phenotypes and endotypes.5 In particular, elevated eosinophil levels in the airways have been found in around half of asthma patients.6 These can cause inflammation and structural changes to the airways7 and are associated with four-times increased odds of asthma-related hospital admissions and a 53% increase in overall expenditure compared with those without elevated eosinophils.6

Benralizumab is part of a new wave of biological treatments for people with severe asthma. It is a humanized monoclonal antibody directed against the alpha subunit of the interleukin-5 (IL-5) receptor. IL-5 is a four-helix protein that promotes eosinophil production in the bone marrow and mobilization into the circulation. IL-5 is also involved in eosinophil activation and is important for cell survival.8 Benralizumab induces rapid, direct and almost complete depletion of circulating eosinophils via antibody-dependent cell-mediated cytotoxicity.9 Benralizumab is currently in clinical development in the WINDWARD program, which consists of six phase III trials in 3,068 patients and 798 sites, across 26 countries, the largest phase III development program for a biologic therapy in respiratory disease. In two phase III trials from this program, SIROCCO10 and CALIMA,11 adding benralizumab to standard-of-care treatment significantly reduced exacerbations and improved lung function and asthma symptoms in severe uncontrolled eosinophilic asthma patients. Data from two more trials in the WINDWARD program were presented at the 113th annual conference of the American Thoracic Society (ATS) in Washington, DC, USA, May 19–24, 2017.

ZONDA was a 28-week randomized, controlled trial evaluating the effects of benralizumab for patients with severe eosinophilic asthma receiving high-dosage inhaled corticosteroid/long-acting beta-2 agonist bronchodilator and OCS. Results were simultaneously published in the New England Journal of Medicine.12 Benralizumab significantly reduced the median final OCS doses from baseline by 75%, compared with a reduction of 25% in OCS doses in the placebo group (p<0.001). Patients treated with benralizumab were more than four-times as likely to reduce their OCS dose than those in the placebo group. In addition, 66% of benralizumab-treated patients reduced OCS doses by ≥50% compared with 37% receiving placebo; 37% of benralizumab-treated patients reduced OCS doses by ≥90% compared with 12% receiving placebo and 52% of benralizumab-treated patients who were eligible to discontinue OCS per the trial protocol were able to stop OCS use completely, compared with 19% receiving placebo.

Results of the GREGALE study, which assessed patient- and caregiver-reported functionality, performance, and reliability of an accessorised pre-filled syringe used to administer benralizumab subcutaneously in an at-home setting, were also presented at the ATS conference. Almost all (98%) of 116 patients and caregivers successfully administered beralizumab at home.13

Benralizumab is the latest of three monoclonal antibodies to be developed for severe asthma: reslizumab (Cinquil®, Teva)14 and mepolizumab (Nucala®, GSK)15 have already received regulatory approval for patients with severe eosinophilic asthma. However, unlike reslizumab and mepolizumab, which target the hormone that contributes to eosinophil production, benralizumab directly targets the cell. Benralizumab is easier to administer than the other agents as it is supplied in a pre-filled syringe that requires no extra preparation, and is dosed every eight weeks, as opposed to four with reslizumab and mepolizumab. Benralizumab is not yet approved but is under regulatory review in the US, EU, Japan and several other countries. In addition to WINDWARD, the ongoing phase III VOYAGER program is evaluating benralizumab in patients with severe chronic obstructive pulmonary disease (COPD).

References

1. To T, Stanojevic S, Moores G, et al., Global asthma prevalence in adults: findings from the cross-sectional world health survey, BMC Public Health, 2012;12:204.

2. Bousquet J, Khaltaev N, Cruz A, et al., International European Respiratory Society/American Thoracic Society guidelines on severe asthma, Eur Respir J, 2014;44:1377–8.

3. Peters SP, Ferguson G, Deniz Y, et al., Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment, Respir Med, 2006;100:1139–51.

4. Sweeney J, Patterson CC, Menzies-Gow A, et al., Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry, Thorax, 2016;71:339–46.

5. Lang DM, Severe asthma: epidemiology, burden of illness, and heterogeneity, Allergy Asthma Proc, 2015;36:418–24.

6. Casciano J, Krishnan JA, Small MB, et al., Burden of asthma with elevated blood eosinophil levels, BMC Pulm Med , 2016;16:100.

7. Venge P, The eosinophil and airway remodelling in asthma, Clin Respir J , 2010;4 Suppl 1:15–9.

8. Lotvall J, Pullerits T, Treating asthma with anti-IgE or anti-IL5, Curr Pharm Des , 1999;5:757–70.

9. Ghazi A, Trikha A, Calhoun WJ, Benralizumab–a humanized mAb to IL-5Ralpha with enhanced antibody-dependent cell-mediated cytotoxicity–a novel approach for the treatment of asthma, Expert Opin Biol Ther , 2012;12:113–8.

10. Bleecker ER, FitzGerald JM, Chanez P, et al., Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial, Lancet , 2016;388:2115–27.

11. FitzGerald JM, Bleecker ER, Nair P, et al., Benralizumab, an anti-interleukin-5 receptor alpha 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;388:2128–41.

12. Nair P, Wenzel S, Rabe KF, et al., Oral glucocorticoid-sparing effect of benralizumab in severe asthma,N Engl J Med, 2017;376:2448–58.

13. Ferguson GT, Mansur, A.H., Jacobs, J.S. et al, Functionality, reliability and performance of an accesoriesed pre-filled syringe with home-administered subcutaneous benralizumab for adult patients with severe asthma, Presented at the 113th annual conference of the American Thoracic Society (ATS), Washington, DC, USA, May 19–24, 2017. Abstract B32.

14. Castro M, Zangrilli J, Wechsler ME, et al., Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials, Lancet Respir Med, 2015;3:355–66.

15. Ortega HG, Liu MC, Pavord ID, et al., Mepolizumab treatment in patients with severe eosinophilic asthma, N Engl J Med, 2014;371:1198–207.

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