Effective control of severe eosoinophilic diseases with an anti–IL-5 therapy
History and presentation
A 46-year-old man with a history of severe asthma, severe chronic sinusitis and allergic rhinitis first presented in 2014. He had undergone sinus surgery in 2013, which also relieved his asthma for some time until it worsened again despite inhaled corticosteroid (ICS) treatment. The patient had no other comorbidities. A skin prick test for allergies was performed, revealing tree pollen sensitivity. A nasal steroid was added to his ongoing ICS treatment.
The patient did not return for follow-up consultation thereafter until 2019, when he presented again due to deterioration in his condition over the past 5 years. While his asthma had remained under control with twice-daily use of the ICS/long-acting β-agonist (ICS/LABA) combination inhaler, salmeterol/fluticasone propionate 50 µg/250 µg, he reported limited exercise capacity as he quickly ran out of breath upon attempting exercise. Despite regular use of the nasal steroid, he had perpetual sinus congestion, thick purulent nasal discharge, postnasal drip and constant headaches, and had completely lost his sense of smell. A repeat skin prick test was negative for tree-pollen sensitivity this time. His blood eosinophil count (BEC) was approximately 360 cells/µL.
Treatment and response
Mepolizumab 100 mg 4-weekly subcutaneous (SC) injection was added to the salmeterol/fluticasone propionate regimen in September 2019. The patient responded well to treatment, with a remarkable decrease in BEC to approximately 180 cells/µL after 2 months. His condition improved significantly over the first 3 months of mepolizumab treatment, with no more purulent nasal discharge or headaches and with nasal congestion becoming manageable. He also regained his sense of smell.
After 4 months of treatment with mepolizumab added to salmeterol/fluticasone, he reported substantial improvement in exercise tolerance and was able to play tennis singles matches on a regular basis. The ICS/LABA combination inhaler therapy was stepped down to once daily, which was sufficient to keep his asthma under good control. His lung function at rest had always been acceptable, and a lung function test was not performed in 2020 in view of the coronavirus disease 2019 (COVID-19) pandemic.
The patient tolerated mepolizumab treatment well. Last seen in August 2020, he was enjoying symptom-free, stable disease control without experiencing any adverse effects, and reported an almost complete recovery of health.
Most patients with asthma, either allergic or nonallergic, have comorbid rhinitis, and 10–40 percent of patients with allergic rhinitis have asthma. Chronic rhinosinusitis is associated with more severe asthma, especially in patients with nasal polyps. Inadequate treatment of significant comorbidities such as chronic rhinosinusitis often accounts for cases of uncontrolled or difficult-to-treat asthma.1-3
The 2020 update of the Global Initiative for Asthma (GINA) strategy for asthma management and prevention recommends biologics targeting type 2 inflammation as add-on therapy for severe asthma in the final step of asthma management, in patients with exacerbations or poor symptom control despite maximal or optimal ICS/LABA therapy who need maintenance therapy with oral corticosteroids (OCS) or have eosinophilic or allergic biomarkers, with or without type 2 comorbidities such as nasal polyposis (NP).4
Mepolizumab is a humanized IL-5 monoclonal antibody that directly inhibits IL-5, a key cytokine generated in type 2 inflammation. This reduces eosinophils in the circulation and tissue sites, thus inhibiting eosinophilic inflammation and effectively reducing exacerbations as well as the need for OCS treatment in patients with severe eosinophilic asthma (SEA).5,6
In patients with SEA treated with high-dose ICS with or without maintenance OCS, mepolizumab (100 mg SC Q4W) reduced exacerbations by 53 percent (95 percent confidence interval [CI], 36 to 65; p<0.001) and exacerbations necessitating an emergency department visit or hospitalization by 61 percent (95 percent CI, 17 to 82; p=0.02) vs placebo in the MENSA (Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma) study.5
In patients with SEA requiring daily OCS therapy to maintain asthma control, the SIRIUS (Steroid Reduction with Mepolizumab Study) found that mepolizumab had a significant glucocorticoid-sparing effect vs placebo (overall odds ratio for reduction in OCS dose, 2.39; 95 percent confidence interval [CI], 1.25 to 4.56; p=0.008) (median reduction from baseline in daily OCS dose, 50 percent vs no reduction; p=0.007). Despite the OCS reduction, patients in the mepolizumab group had a 32 percent relative reduction in annualized rate of exacerbations (p=0.04) as well as significantly improved control of asthma symptoms (p=0.004) vs those in the placebo group.6
In a matching-adjusted indirect comparison of mepolizumab and benralizumab (an IL-5 receptor inhibitor recommended by GINA) at their approved doses, both treatments significantly reduced the rate of clinically significant exacerbations and improved asthma control vs placebo in patients with SEA, regardless of BEC. Mepolizumab, however, was associated with significantly greater improvements in clinically significant exacerbations compared with benralizumab in patients with similar BECs (rate ratio [RR] for BEC >400 cells/µL: 0.55; 95 percent CI, 0.35 to 0.87) (RR for BEC >300 cells/µL: 0.61; 95 percent CI, 0.37 to 0.99) (RR for BEC >150 cells/µL: 0.66; 95 percent CI, 0.49 to 0.89) (all p<0.05).4,7
Our case illustrates the efficacy of mepolizumab in severe eosinophilic disease. Besides being effective in SEA, mepolizumab has also demonstrated efficacy in the subgroup of asthma patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma. Considering the patient’s history and elevated BEC, the use of mepolizumab was supported by positive results from the SYNAPSE (Effect of Mepolizumab in Severe Bilateral Nasal Polyps) study, which found that adding mepolizumab (vs placebo) to standard of care (SoC) significantly reduced nasal polyp size and obstruction in adults with CRSwNP.8
The phase III, double-blind, randomized, parallel-group SYNAPSE study included 407 adults with severe chronic rhinosinusitis already on SoC treatment who had prior nasal polyp surgery. Results showed that adding mepolizumab (100 mg SC Q4W) to SoC treatment significantly reduced nasal polyp size vs placebo, as measured by total endoscopic nasal polyp score from baseline to week 52 (median difference, -0.73; 95 percent CI, -1.11 to -0.34; p<0.001). By week 52, significantly fewer patients in the mepolizumab vs placebo arm were deemed to be in need of nasal surgery (9.0 percent vs 23.0 percent; hazard ratio, 0.43, 95 percent CI, 0.25 to 0.76; p=0.003).8
The use of mepolizumab in SEA patients with comorbidities is further supported by the results of a meta-analysis of the MUSCA (Mepolizumab Adjunctive Therapy in Subjects with Severe Eosinophilic Asthma) and MENSA studies (combined n=936 included, of which 18 percent had NP at baseline screening), which demonstrated the significant and clinically meaningful benefits of mepolizumab add-on therapy vs placebo in improving asthma control and health-related quality of life.5,9,10 Of note, patients with the clinical phenotype of SEA plus NP may obtain greater benefit from mepolizumab treatment due to their higher baseline BEC than patients without comorbid NP (440 cells/µL vs 290 cells/µL). Mepolizumab reduced the annual rate of clinically significant exacerbations vs placebo in patients with SEA regardless of NP status, but to a greater extent in patients with NP (80 percent) than those without (49 percent).10 (Figure 1)
The long-term safety and durability of mepolizumab response have been demonstrated in the COLUMBA (Open-label Long Term Extension Safety Study of Mepolizumab in Asthmatic Subjects) study, which included 347 patients monitored over an average of 3.5 years (maximum, 4.5 years; total exposure, 1,201 patient-years). Results showed that after long-term use in patients with SEA, mepolizumab maintained clinical efficacy and continued to demonstrate a favourable safety profile, with no evidence of inducing neutralizing antibodies.11 (Figure 2)
Our patient tolerated mepolizumab well without experiencing side effects. Other than injection site reactions and immunosuppressive side effects, such as parasitic infections associated with biologic treatments, there are no major contraindications to the use of mepolizumab in patients with severe eosinophilic disease.