An anti–IL-5R biologic as a beneficial alternative to long-term OCS in severe uncontrolled eosinophilic asthma
History and presentation
The patient is an 85-year-old man, who is overweight (body mass index [BMI], 28.6 kg/m2) with a history of diabetes, hypertension, chronic hepatitis B infection and persistent cough. He presented in January 2019 with common cold and respiratory symptoms, including wheezing, dyspnoea and worsening cough, and was diagnosed with asthma.
Treatment and response
The patient received an oral corticosteroid (OCS), prednisone (30 mg QD for 1 week), with the combined inhaled corticosteroid (ICS) and long-acting beta-2 agonist (LABA) medication fluticasone/salmeterol (500/50 mcg per inhalation, 1 inhalation BID). Asthma symptoms were stabilized after a week of treatment, but he developed hyperglycaemia and deranged liver function with a mildly elevated hepatitis B virus DNA level, requiring antiviral therapy.
The patient experienced two asthma exacerbations in March and July 2019, and received prednisone (20 mg QD for 1 week) for each episode. Phenotype testing showed elevated total serum immunoglobulin E (IgE) level (approximately 150 IU/mL), normal eosinophil (EOS) count (0.2 x 109 /L), and absence of specific allergens. Lung function tests showed obstructive lung disease with a forced expiratory volume in 1 second (FEV1) of approximately 67 percent predicted.
At that time, the patient was on fluticasone furoate/vilanterol (200/ 25 mcg per inhalation, QD), tiotropium (2.5 mcg per inhalation, 2 inhalations daily) and montelukast (10 mg tablet, nocte). Despite optimal inhaler technique and medication compliance, the patient experienced two additional exacerbation episodes, the last of which occurred in August 2019 when he developed dyspnoea and hypoxia, requiring hospitalization and oxygen therapy. Tests showed normal chest X-ray, elevated white blood cell count (approximately 20 x 109/L) with neutrophilia, and elevated EOS count (0.6 x 109/L).
The anti-eosinophilic biologic benralizumab (a humanized anti–interleukin-5 receptor [IL-5R] α monoclonal antibody, 30 mg subcutaneous injection, Q4W for first 3 doses, Q8W afterwards) was commenced in early September 2019 as an add-on therapy to fluticasone furoate/vilanterol (200/ 25 mcg per inhalation, QD). The patient’s EOS count dropped to 0 a few days after the first dose of benralizumab.
As of March 2020, the patient has remained free of asthma exacerbations. He continues to receive benralizumab add-on therapy, and has treatment with OCS, montelukast and tiotropium. No adverse effects have been reported with benralizumab apart from mild discomfort in the throat after the first injection.
A majority of respiratory and family physicians in Hong Kong follow the Global Initiative for Asthma (GINA) guidelines for asthma management. Approximately 33,000 patients in Hong Kong suffer from severe asthma (half of them likely have an eosinophilic phenotype) and are eligible for biologic treatment. Prior to biologic prescription, it is important to ascertain the diagnosis of severe asthma and to distinguish it from uncontrolled asthma, which could be caused by comorbidities and complicating conditions including rhinosinusitis, obesity, gastroesophageal reflux disease, aspirin-exacerbated respiratory disease, eosinophilic granulomatosis with polyangiitis and allergic bronchopulmonary aspergillosis, in addition to poor inhaler technique and suboptimal medication compliance.1
The anti–IL-5R biologic benralizumab is a GINA-recommended Step 5 add-on treatment option for adult patients with severe eosinophilic asthma uncontrolled by Step 4 or 5 treatment.1
One of the key benefits of benralizumab compared with other biologics is a reduced number of required injections, which minimizes the number of clinic visits and helps improve patient acceptance and compliance. In terms of efficacy and safety, the randomized, phase III CALIMA study showed that extended benralizumab add-on therapy (30 mg Q4W, for 56 weeks) significantly reduced annual exacerbation rates by more than one-third 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 (baseline count ≥0.3 x 109/L).2
Another randomized, phase III study, SIROCCO, showed that benralizumab (30 mg Q4W/Q8W) significantly reduced annual exacerbation rates by around 50 percent over 48 weeks (Q4W rate ratio, 0.55 vs placebo; 95 percent CI, 0.42 to 0.71; p<0.0001) (Q8W rate ratio, 0.49 vs placebo; 95 percent CI, 0.37 to 0.64; p<0.0001) in patients with severe asthma and elevated EOS (baseline count ≥0.3 x 109/L) uncontrolled by high-dose ICS/ LABA combination therapy, with a similar rate of serious adverse events (AEs) vs placebo (Q4W, 12 percent; Q8W, 13 percent; placebo, 14 percent).3
The long-term safety of benralizumab was investigated in the BORA study, a randomized, phase III extension trial, which involved patients from the CALIMA or SIROCCO studies receiving benralizumab for the second year.4 The results showed that the percentage of patients who experienced any AE was similar between the three studies (65–71 percent in BORA vs 71–75 percent in CALIMA or SIROCCO, benralizumab group only), with similar rates of treatment discontinuation (2–3 percent in BORA vs 2 percent in SIROCCO and CALIMA).4
Another randomized, double-blind trial, ZONDA, showed that benralizumab (30 mg Q4W/Q8W, for 28 weeks) significantly reduced the median final OCS doses from baseline (75 percent vs 25 percent in the placebo group; p<0.001) and the annual exacerbation rate (Q4W: by 55 percent; p=0.003) (Q8W: 70 percent; p<0.001) vs placebo in patients with severe eosinophilic asthma dependent on OCS, without a significant effect on FEV1.5
The study also found that at least one-third of the patients receiving benralizumab had a reduction of ≥90 percent from baseline in their final OCS dose, with significantly higher odds of OCS discontinuation observed among patients receiving benralizumab vs placebo.5 (Table)
The emergence of biologics, particularly anti–IL-5R monoclonal antibodies such as benralizumab, has substantially improved the clinical outcome of patients with severe asthma, whose main treatment option in the past was long-term OCS that often resulted in significant AEs. Better patient education can help resolve skepticism over the role of injection as an effective means of asthma medication delivery. This, together with improved affordability of biologics (the main concern for most patients), would help increase its acceptance among patients and enable more of them to benefit from this new class of asthma medication.
This case illustrates the efficacy and safety of benralizumab as an add-on therapy for severe eosinophilic asthma in an elderly, overweight patient with poor perception of his asthma severity as a result of being accustomed to uncontrolled symptoms and frequent exacerbations despite repeated OCS treatment. He opted for benralizumab add-on therapy over other biologics due to its favourable injection frequency, which promptly prevented exacerbations, enabled cessation of OCS treatment, and helped stabilize his asthma symptoms with a negligible side effect.