By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Medical Director, Pharmacy, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a parenteral, humanized, monoclonal antibody directed at interleukin-5 for the treatment of severe asthma. Mepolizumab is produced by recombinant DNA technology in Chinese hamster ovary cells and is marketed by GlaxoSmithKline as Nucala.
INDICATIONS
Mepolizumab is indicated for add-on maintenance treatment of adult patients ≥ 12 years of age with severe asthma and with an eosinophilic phenotype.1
DOSAGE
The recommended dose is 100 mg given subcutaneously (SC) once every 4 weeks.1 Mepolizumab is available as 100 mg single-dose vials.
POTENTIAL ADVANTAGES
Mepolizumab has been reported to reduce oral glucocorticoid requirement and improve clinical outcomes (symptoms and exacerbation).1,2
POTENTIAL DISADVANTAGES
Mepolizumab did not significantly improve FEV1 from baseline. Six percent of subjects treated with mepolizumab developed anti-mepolizumab antibodies.1 The clinical relevance of these antibodies is not known. Most common adverse events were headache and injection site reaction. Immediate and delayed hypersensitivity reactions have been reported. Long-term effects of the inhibition of eosinophils is not known, as these are involved in immunological responses to some infections. Herpes zoster infections have been reported. Consider varicella vaccination prior to starting treatment if medically appropriate. Mepolizumab is not indicated for the treatment of acute symptoms. Reduction in corticosteroid dose may unmask conditions previously controlled or may lead to withdrawal symptoms.1
COMMENTS
Interleukin-5 plays an important role in the pathogenesis of eosinophilic disorders.3 Eosinophilic asthma is a specific phenotype that is associated with thickening of the basement membrane and appears to be responsive to glucocorticoids.2 Mepolizumab binds to interleukin-5, which results in reduced production and survival of eosinophils. As a result, there is reduced peripheral blood eosinophils, airway eosinophils, and percent of airway eosinophils.1,3 Safety and efficacy was evaluated in three double-blind, randomized, placebo-controlled trials.1,2 Subjects had eosinophilic asthma, which was inadequately controlled on high-dose inhaled steroids, plus an additional controller(s) with or without oral corticosteroids. Trials 1 and 2 included subjects with a history of two or more exacerbations in the previous year (mean 3.6). Trial 1 was a 52-week study comparing IV mepolizumab 75 mg, 200 mg, and 250 mg vs placebo every 4 weeks (n = 616). Trial 2 was a 32-week study comparing mepolizumab 75 mg vs 100 mg (SC), or placebo (n = 576). In both trials, mepolizumab was added on to background therapy. Trial 3 was a 24-week study comparing SC mepolizumab vs placebo. The geometric mean eosinophil counts ranged from 240-290 counts/mcL. The primary endpoint for trials 1 and 2 was the frequency of exacerbations defined as worsening of asthma requiring use of oral/systemic corticosteroids and/or hospitalization and/or emergency department (ED) visits. Mepolizumab (75 mg IV or 100 mg SC) reduced all exacerbations by about 50%. Exacerbations requiring hospitalization and/or ED visits and exacerbations requiring only hospitalization were also reduced. The time to first exacerbation was longer with mepolizumab compared to placebo. Trial 3 assessed the reduction in use of maintenance oral corticosteroid during weeks 20 to 24.2 Those randomized to mepolizumab had a 2.39 times greater likelihood of reduction of glucocorticoid dose stratum. Forty percent of mepolizumab patients had ≥ 75% reduction compared to 20% for placebo.
CLINICAL IMPLICATIONS
Asthma is a common chronic inflammatory lung disease affecting 5-10% of the population with approximately 10% with severe disease. Severe asthma is defined as uncontrolled asthma despite high-dose therapy.5 It is a heterogeneous condition and has been divided into different phenotypes based on various clinical, molecular, morphological, and functional characteristics.5 Eosinophilic asthma is one of the phenotypes characterized by high T-helper types 2 driven inflammation.4,5 This phenotype has higher IgE and peripheral blood and sputum eosinophil counts and recurrent exacerbations. Interleukin-5 plays an important role in the production, maturation, differentiation, survival, and activation of eosinophils.6 Mepolizumab is a new targeted therapy for patients with eosinophilic asthma.5 The wholesale cost for mepolizumab is $2500 for a single 4-week injection.
REFERENCES
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Nucala Prescribing Information. GlaxoSmithKline. November 2015.
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Bel EH, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014;371:1189-1197.
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Menzella F, et al. Profile of anti-IL-5 mAb mepolizumab in the treatment of severe refractory asthma and hypereosinophilic diseases. J Asthma Allergy 2015:8:105-114.
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Woodruff PC, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respor Crit Care Med 2009;180:388-395.
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Chung KF, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Resp J 2014:43:343-373.
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Patterson MF, et al. The past, present, and future of monoclonal antibodies to IL-5 and eosinophilic asthma: A review. J Asthma Allergy 2015;8:125-134.
