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An anti–IL-5R biologic as a beneficial alternative to long-term OCS in severe uncontrolled eosinophilic asthma

Dr. Angus Lo
Specialist in Respiratory and Critical Care Medicine
Private practice, Hong Kong
6 days ago

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.

Discussion

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)

385md

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.

 

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