Switching of biologic treatment to an anti-IL-5Rα agent in a patient with severe eosinophilic asthma
History, presentation and initial treatment
A 42-year-old female office worker first presented in mid-2018 with chest tightness and wheezing. Other than a past medical history of depression, she had no other comorbidities.
Two months prior to presentation to the clinic, the patient experienced respiratory symptoms and was hospitalized for pneumonia. Chest X-ray showed air space disease of her right lung compatible with pneumonia. Although the pneumonia resolved with a course of antibiotics, her respiratory symptoms and wheezing persisted after discharge from hospital. She was prescribed other medications without a definitive diagnosis to explain her persistent symptoms.
At presentation, the patient reported chest tightness on physical exertion and some limitations in exercise tolerance. She also had multiple episodes of nighttime awakening per week as a result of chest tightness. Physical examination showed bilateral expiratory wheezes in her chest. The peak expiratory flow rate (PEFR) was 230 L/min. She was diagnosed with adult-onset asthma and started on a short course of oral corticosteroids (OCS), along with inhaled long-acting beta agonist (LABA) and inhaled corticosteroids (ICS). Improvements in shortness of breath and wheezing were noted following treatment, and her PEFR increased to 400 L/min.
Over the following year, the patient continued to have several episodes of exacerbations despite guideline recommended treatment. She was given 4–5 short courses of OCS as rescue therapy within a few months. The ICS dosage was gradually uptitrated to 1,000 μg/day, and add-on therapies including a leukotriene receptor antagonist were initiated. Although the patient responded to each course of OCS, the response was short-lived, lasting for only a few weeks. She also received multiple courses of oral antibiotics from GPs for frequent flu-like symptoms and upper respiratory tract infections. Despite the use of high-dose OCS and ICS, her asthma control remained suboptimal, and she continued to have frequent exacerbations that required medical attention, hospitalization or sickness absence. Her quality of life (QoL) and mental health deteriorated.
Omalizumab, an anti–immunoglobulin E (IgE) biologic, was added to the patient’s ongoing treatment in June 2019 following consultation with a specialist in allergy and immunology. At the start of omalizumab treatment, the patient’s IgE level remained stable, while her eosinophil (EOS) count was 0.2–0.4 x 109/L in serial blood tests. Omalizumab therapy led to reduced exacerbations, increased PEFR (480–500 L/min), reduced chest tightness and nighttime awakening, as well as improved QoL and exercise tolerance in daily living. However, attempts at ICS dose reduction resulted in further chest tightness and exacerbations, and high-dose ICS maintenance was required. The patient also reported further symptoms of chest tightness around 20–25 days after the last dose of omalizumab and requested earlier administration of omalizumab a few days ahead of the scheduled 28-day cycle.
Switch to an anti-IL-5Rα agent and response
Due to inadequate control of symptoms after 12 doses of omalizumab and inability to reduce the dosages of ICS and other medications, the patient’s add-on therapy was switched to the anti-eosinophilic, humanized anti-interleukin-5 receptor α (IL-5Rα) monoclonal antibody, benralizumab (30 mg subcutaneous injection, Q4W for first 3 doses, Q8W afterwards), in November 2020. She fulfilled the criteria of having an eosinophilic phenotype with her EOS count rising up to 0.6 x 109/L once recorded a few months prior to the switch of add-on therapy.
Within the first month upon initiation of benralizumab treatment, the patient no longer experienced pre-dosing chest tightness and her PEFR improved further to 550 L/min. Her EOS count dropped rapidly to undetectable levels in May 2021, and remained undetectable thereafter. Apart from one episode of exacerbation 7 days after receiving the second dose of the mRNA coronavirus disease 2019 (COVID-19) vaccine, there were no further instances that required additional OCS use. Her benralizumab treatment schedule was unaffected by the vaccination as the first and second vaccine doses were administered in between the scheduled Q8W interval of benralizumab dosing.
The patient tolerated benralizumab treatment well without any adverse effects. Her asthma symptoms had almost completely resolved. She had been managing well with PEFR self-monitoring to ensure that daily PEFR would not drop by >10 percent below her usual range, in which case she would seek medical attention. With good asthma control maintained for 6 months, step-down of ICS dosage would commence as part of her asthma management plan once she is stabilized following COVID-19 vaccination.
Our patient with OCS-dependent, poorly controlled, severe eosinophilic asthma (SEA) benefitted from Global Initiative for Asthma (GINA) guideline recommended treatment. GINA guidelines recommend biologics targeting type 2 inflammation as add-on therapy for severe asthma in the final step (Step 5) of management, in patients with exacerbations or poor symptom control despite maximal or optimal ICS/LABA therapy or add-on tiotropium, who need OCS maintenance or have eosinophilic or allergic biomarkers, with or without type 2 comorbidities.1
GINA guidelines also recommend monitoring patients’ response to and satisfaction with an initial trial of add-on type 2 targeted therapy, and to consider switching to a different type 2 targeted therapy if needed.1 Due to suboptimal results with the initial anti-IgE therapy, our patient was switched to benralizumab, given her elevated EOS levels.
Benralizumab induces direct, rapid and nearly complete depletion of EOS via antibody-dependent cell-mediated cytotoxicity, thus inhibiting eosinophilic inflammation and effectively reducing exacerbations regardless of baseline EOS count, allowing for corticosteroid-sparing treatment in SEA.2
Benralizumab add-on therapy significantly reduced asthma exacerbations and improved lung function and disease control vs placebo in patients with severe, uncontrolled asthma and elevated EOS count in the phase III SIROCCO and CALIMA trials, while its long-term safety and efficacy was demonstrated in BORA, the 2-year extension trial of SIROCCO and CALIMA.3,4 Results of BORA reaffirmed that treatment with benralizumab Q8W potently decreases EOS counts, and that long-term EOS depletion by benralizumab did not lead to any unexpected adverse consequences.5
GINA guidelines also recommend stepping down ICS therapy in patients who respond well to type 2 targeted therapy.1 Our case illustrates the efficacy of benralizumab in maintaining asthma control in SEA, without OCS use, with a possibility of ICS dose reduction, as demonstrated in the randomized, double-blind, phase III ZONDA trial.6 ZONDA showed that in patients with severe asthma on medium- to high-dose ICS/LABA and long-term OCS, with EOS count ≥150 cells/μL and a history of ≥1 exacerbations in the past 12 months, benralizumab (30 mg Q8W, for 28 weeks) therapy led to significant reductions in final OCS doses from baseline (75 per-cent vs 25 percent; p<0.001) as well as annualized asthma exacerbation rate (70 percent reduction; marginal rate, 0.54 vs 1.83; p<0.001) vs placebo.6 (Figure)
Building on ZONDA and other OCS-sparing studies, the phase IIIb, single-arm PONENTE trial showed that irrespective of EOS count, 62.2 percent and 80.6 percent of OCS-dependent asthmatics treated with benralizumab achieved OCS elimination and maximal possible OCS reduction (where adrenal insufficiency prevented further reduction), respectively. Additionally, fewer patients had exacerbations during the OCS reduction phase than in the previous year (25.8 percent vs 84.4 percent).7,8
Many SEA patients remain inadequately treated with long-term corticosteroids. With biologics emerging as new treatment options for severe asthma, physicians should keep abreast with the latest developments on the use of diagnostic tests and biomarkers, such as EOS count or IgE levels, and adopt such tests to help identify patients who may benefit from biologic treatments.