Optimizing management of severe eosinophilic asthma with an anti-IL5R add-on therapy
History and presentation
The patient is a 66-year-old male nonsmoker with a history of asthma since childhood and a number of well-controlled clinical conditions, including allergic rhinitis, hyperlipidaemia, severe obstructive sleep apnoea (OSA) and benign prostatic hyperplasia. He required admission to an intensive care unit during an episode of uncontrolled asthma in 2013, and has since experienced frequent asthma exacerbations (3–4 times per year) requiring treatment (ie, albuterol [4 times daily, >2 puffs each time] and oral corticosteroids [OCS]) or even hospitalization. He presented with frequent and poorly controlled asthma symptoms (Asthma Control Test [ACT] score, 10), significant allergic airway inflammation (fractional exhaled nitric oxide [FeNO] level, 184 parts per billion), and reversible airway obstruction (bronchodilator reversibility [BDR], 22 percent). Previous medical record showed high eosinophil (EOS) count (>1.71 x 109/L) and serum IgE level (93 IU/mL).
High-resolution thorax CT scan showed absence of active lung lesions and no evidence of bronchiectasis or other structural abnormalities in the lungs. Pulmonary function test showed no evidence of chronic obstructive pulmonary disease (COPD). The biomarkers, antineutrophil cytoplasmic antibodies (ANCA) and aspergillus antibody/antigen tests for assessing asthma-related disease eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome) and allergic bronchopulmonary aspergillosis, respectively, were negative, with no clinical evidence of vasculits. Ova and parasite stool test showed absence of parasitic infestation.
Treatment and response
The patient has been receiving treatment for severe asthma and allergic rhinitis on a regular basis with good compliance, with his treatment regimen including combined inhaled corticosteroid (ICS) and long-acting beta-2 agonist (LABA), tiotropium, montelukast and theophylline sustained-release tablets. However, he experienced frequent asthma exacerbations (>3 times per year) despite treatment.The anti-eosinophilic biologic benralizumab (a humanized anti-interleukin-5 receptor [IL-5R] α monoclonal antibody, 30 mg subcutaneous injection Q4W) was commenced in July 2019 as an add-on therapy. Improvements in asthma symptoms and lung function were observed after one cycle of benralizumab, with EOS count decreasing to 0 and forced expiratory volume in one second (FEV1) increasing by >400 mL. The improvements persisted over the course of treatment. (Table)
The patient did not experience any exacerbations during the 3 months (cycles) of benralizumab add-on treatment, which enabled him to reduce the use of albuterol (from 4 times to twice daily) and OCS. He tolerated benralizumab well and did not experience any commonly observed side effects, such as injection site reaction, headache and muscle pain. The patient’s quality of life (QoL) has improved and he continues to receive benralizumab as an add-on therapy.
According to the 2019 Global Initiative for Asthma (GINA) guidelines, current treatment options for severe eosinophilic asthma (Step 5 treatment strategy) include combination ICS/LABA and add-on medications such as low-dose maintenance/intermittent OCS, anti-IL4R and anti-IL5/5R agents.1 Benralizumab is an anti-IL5R biologic that decreases the production of eosinophils via induction of eosinophil apoptosis (through antibody-dependent cell-mediated cytotoxicity) and inhibiting the differentiation and maturation of eosinophils in the bone marrow.2,3
Clinical studies have demonstrated the efficacy and safety of benralizumab as add-on therapy in patients with severe, uncontrolled eosinophilic asthma.4-7 The randomized, double-blind ZONDA trial showed that benralizumab (30 mg Q4W, 28 weeks), compared with placebo, significantly reduced median final OCS doses from baseline (75 percent vs 25 percent; p<0.001) as well as annual exacerbation rate (55 percent reduction; marginal rate, 0.83 vs 1.83; p=0.003) in patients with severe asthma, without a sustained effect on FEV1.4
The randomized, phase III CALIMA study showed that extended benralizumab add-on therapy (30 mg Q4W, 56 weeks) significantly reduced annual exacerbation rates vs placebo (0.6 vs 0.93; rate ratio, 0.64; 95 percent confidence interval [CI], 0.49 to 0.85; p=0.0018) and was generally well tolerated in patients with severe, uncontrolled asthma and elevated EOS counts.5 Another randomized, phase III study, SIROCCO, also showed that benralizumab (30 mg Q4W) significantly reduced annual exacerbation rates over 48 weeks of treatment (rate ratio, 0.55 vs placebo; 95 percent CI, 0.42 to 0.71; p<0.0001) in patients with severe asthma and elevated EOS uncontrolled by high-dose combination ICS/LABA, with a similar rate of common serious adverse events vs placebo (12 percent vs 14 percent).6
The long-term safety of benralizumab was further investigated in the randomized, double-blind, phase III BORA extension trial, which involved patients who had previously participated in the CALIMA or SIROCCO study receiving a second year of benralizumab treatment.7 The results showed that the percentage of patients who had any adverse event was similar among the three studies (65–71 percent in BORA [causing treatment discontinuation in 2–3 percent of patients] vs 71–75 percent in CALIMA or SIROCCO, benralizumab group only [causing treatment discontinuation in 2 percent of patients]).7
Prior to considering benralizumab add-on therapy for patients with severe eosinophilic asthma, it is important to first control or rule out precipitating risk factors (other than eosinophilic inflammation) that may have worsened or caused the asthma symptoms (eg, allergic rhinitis, OSA, EGPA, COPD, bronchiectasis), and to ensure that the patient has demonstrated correct inhaler technique and good compliance with previous treatment.
This case illustrates that benralizumab, when given after consideration of the eosinophilic nature of asthma symptoms, absence of uncontrolled precipitating risk factors and good patient compliance, is an effective and safe add-on therapy in a patient with severe, poorly controlled asthma symptoms and frequent exacerbations. Benralizumab promptly improved symptoms and lung function and prevented exacerbations, which helped reduce the need for albuterol and OCS, and improved QoL in this patient.