FDA Panel Backs Mepolizumab for Severe Eosinophilic Asthma

Troy Brown, RN

June 11, 2015

The Pulmonary-Allergy Drugs Advisory Committee of the US Food and Drug Administration (FDA) has unanimously recommended mepolizumab (Nucala, GlaxoSmithKline) for add-on maintenance treatment in patients aged 18 years or older with severe eosinophilic asthma.

The panel voted 10 to 4 against recommending mepolizumab for children aged 12 to 17 years because of a lack of data in this population.

Severe eosinophilic asthma is identified by blood eosinophils greater than or equal to 150 cells/microliter at initiation of treatment or blood eosinophils greater than or equal to 300 cells/microliter in the past 12 months.

Unmet Need for Severe Asthma and Predefined Eosinophil Levels

A typical characteristic of mild asthma is airway inflammation due to eosinophils, and this inflammation is closely associated with the risk for severe asthma exacerbations. Several products are approved for long-term maintenance treatment of asthma, but there are currently no approved therapies specifically for patients with severe asthma and predefined eosinophil levels.

Long-term steroid use is required in 30% to 40% of patients and is associated with side effects including difficulty sleeping, lipodystrophy, adrenal suppression, metabolic syndrome, weight gain, and hypertension.

Mepolizumab is a humanized monoclonal antibody (IgG1, Kappa, mAb) to human interleukin 5 (IL-5). Several cytokines can affect eosinophils, but IL-5 is the primary one involved in the regulation of blood and tissue eosinophils. Mepolizumab prevents IL-5 from binding to the alpha chain of the IL-5 receptor complex that is expressed on the eosinophil cell, which inhibits IL-5 signalling, inhibiting signalling and overexpression of eosinophils in the peripheral blood and tissues.

Mepolizumab for injection is not currently marketed in any country in the world. Its approval would be the first for any monoclonal antibody to IL-5 for any indication. It is proposed to be administered at the dose of 100 mg administered subcutaneously once every 4 weeks.

"The question I ask myself is if my 16 year old daughter was a steroid dependent asthmatic, with a history of multiple exacerbations in the previous year, would I want to treat her with this compound, and the answer in my mind is a definite 'yes'," said voting member Steve N. Georas, MD, professor of medicine, division of pulmonary and critical care medicine, University of Rochester Medical Center, New York.

Clinical Studies

The panel's decision follows a discussion of data from one dose-ranging dose selection study (MEA112997; study 97) and two pivotal efficacy studies (MEA115588 and 115575; study 88 and study 75).

Study 97 was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study to evaluate the effect of mepolizumab on rates of exacerbation in patients with uncontrolled refractory asthma. The primary endpoint was the annualized rate of asthma exacerbations. Patients in this study needed to be on background maintenance therapy with high-dose inhaled corticosteroids for the prior 12 months (with or without oral corticosteroids) plus an additional controller (long-acting beta-agonist, leukotriene inhibitor, or theophylline) medication. The researchers randomly assigned patients to receive mepolizumab 75, 250, or 750 mg or placebo IV once every 4 weeks to week 48 for a treatment period or 52 weeks.

Study 88 was a 32-week exacerbation study. The study was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group study in patients aged 12 years or older with severe asthma and markers of eosinophilic inflammation. The researchers evaluated both a 75-mg intravenous (IV) and a 100-mg subcutaneous dose as well as a matching placebo.

Both study 97 and study 88 showed a statistically significant reduction in asthma exacerbations in all groups that received mepolizumab. No significant benefit was found for doses higher than 75-mg IV.

There was also no significant difference in exacerbation benefit between the 75-mg IV dose and the 100-mg subcutaneous dose of mepolizumab in study 88. The rate of hospitalizations or emergency department visits for asthma exacerbations was lower for the mepolizumab group compared with the placebo group, but the overall exacerbation rates requiring hospitalizations or emergency department visits were lower across the treatment groups.

Study 75 was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of mepolizumab adjunctive therapy to reduce steroid use in patients with severe refractory asthma. The researchers randomly assigned patients to receive either mepolizumab 100 mg subcutaneously or a matching placebo every 4 weeks. The primary endpoint was percent reduction of oral corticosteroid (OCS) dose during weeks 20-24 compared with baseline dose, while maintaining control of asthma.

In this study, mepolizumab treatment resulted in a significant reduction in OCS use. The baseline mean OCS dose was similar in the two treatment groups; 13.2 mg in the placebo group and 12.4 mg in the mepolizumab group.

"This subset of patients is at very high risk from asthma and at somewhat unknown risk from the effects of this drug, so it seems to be a question of risk-benefit ratio, so I voted 'yes' because I think the benefit is clear and the benefit is it affects a life-threatening disease and the harm is less clear," said voting committee member John E. Connett, PhD, professor, division of biostatistics, School of Public Health, University of Minnesota, Minneapolis.

Safety Issues

Local injection-site reactions were increased in the mepolizumab 100-mg subcutaneous treatment group compared with placebo. Hypersensitivity reactions (exposure adjusted values) were higher for the groups that received 250 mg and 750 mg IV compared with placebo. Hypersensitivity reactions were less frequently compared with placebo for the 100-mg subcutaneous dose, the dose that is proposed for marketing.

One potential case of anaphylaxis occurred but the patient had a prior history of sulfite allergy and exposure to sulfite.

"Long-term pharmacovigilance is important in order to make sure that with this class of drug, we're not missing anything. We all remember drugs that have been withdrawn from the market after a lengthy time of being publicly available," said voting member Kathryn Blake, PharmD, senior research scientist, Nemours Children's Clinic, Jacksonville, Florida.

None of the committee members have disclosed any relevant financial relationships.


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