Jim Kling

September 10, 2014

MUNICH, Germany — The monoclonal antibody mepolizumab delivered subcutaneously is a promising treatment for patients with severe eosinophilic asthma, according to the results of 2 new studies presented here at the European Respiratory Society (ERS) International Congress 2014 and published simultaneously online in the New England Journal of Medicine.

In the Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA) trial, mepolizumab reduced asthma exacerbations and led to improvements in several measures of asthma control.

Mepolizumab has been previously shown — in the Dose Ranging Efficacy and Safety with Mepolizumab (DREAM) study — to be effective in patients with severe refractory eosinophilic asthma when delivered intravenously.

"We wanted to show similar efficacy and try to demonstrate a bridge between the IV [intravenous] and subcutaneous routes," Hector Ortega, MD, medical director at GlaxoSmithKline, told Medscape Medical News.

In the Steroid Reduction with Mepolizumab Study (SIRIUS), the antibody reduced reliance on oral glucocorticoids in patients with eosinophilic asthma.

Less than 10% of patients with asthma have severe asthma, but this population experiences much higher morbidity and mortality than other patients and represents a higher percentage of asthma healthcare costs. About one third of these patients have eosinophilic asthma, in which eosinophils promote airway inflammation as a result of recruitment from bone marrow by interleukin-5.

MENSA Trial

MENSA was a randomized, double-blind, placebo-controlled trial with 576 patients. Patients were selected according to characteristics identified in the DREAM study as being associated with better outcomes, including having blood eosinophil counts of at least 150 cells/μL in the peripheral blood at screening or at least 300 cells/μL at some time in the previous year.

Patients were receiving high doses of inhaled glucocorticoids but nevertheless had recurrent exacerbations and evidence of eosinophilic inflammation.

After a 1- to 6-week run-in period, study participants were randomly assigned to 1 of 3 groups: 75-mg intravenous dose of mepolizumab, 100-mg subcutaneous dose of mepolizumab, or a placebo. Each group received treatment every 4 weeks for 32 weeks.

The primary outcome was the number of asthma exacerbations. The difference from placebo in the rate of clinically significant exacerbations in patients receiving intravenous mepolizumab was 47% compared with 53% in patients receiving subcutaneous treatment (P < .001).

Table 1. Rate of Clinically Significant Exacerbation

Group Mean Rate per Year
Placebo (n = 191) 1.75
Intravenous (n = 191) 0.93
Subcutaneous (n = 194) 0.81

 

"In this group of patients with eosinophilic inflammation, we see an important benefit in reduction of exacerbations and important clinical endpoints like quality of life and asthma control," said Dr. Ortega.

In the SIRIUS study, researchers looked at the effect of mepolizumab on 135 patients with severe eosinophilic asthma who used oral glucocorticoids.

Mepolizumab performed very well, according to presenter Elisabeth Bel, MD, from the University of Amsterdam in the Netherlands. "Patients are amazingly happy with the drug; they can stop prednisone, and they say, 'my asthma is gone,'" Dr. Bel told Medscape Medical News.

SIRIUS

Patients received a 100-mg dose of mepolizumab or a placebo subcutaneously every 4 weeks for 20 weeks.

The results showed significant decreases in oral glucocorticoid steroid dependence in the mepolizumab group compared with placebo (odds ratio, 2.39; 95% confidence interval, 1.25 - 4.56; P = .008). The median percentage reduction from baseline in the glucocorticoid dose was 50% in the mepolizumab group compared with no reduction in the placebo group (P = .007).

Table 2. Reduction in Glucocorticoid Use With Mepolizumab

Reduction at 20 to 24 Weeks (%) Placebo (n = 66) (%) Mepolizumab (n = 69) (%)
90-100 11 23
75-90 8 17
50-75 15 13
0-50 11 10
No reduction or trial withdrawal 56 36

 

In an accompanying editorial, Parameswaran Nair, MD, writes, "The studies illustrate two new clinical observations that have important practical applications. First, the subcutaneous administration of a lower dose of the drug (100 mg) than was previously reported was shown to be efficacious. Second, characterization of the eosinophilic phenotype on the basis of a blood eosinophil count of more than 300 cells per microliter despite concurrent treatment with high doses of glucocorticoids was sufficient to select patients who were likely to have a response to this therapy."

The population of patients taking oral steroids for severe asthma is quite small, but "for them, mepolizumab is a huge advance because they're less likely to get side effects," said Peter Barnes, MD, head of respiratory medicine at Imperial College, London, United Kingdom.

"I'm a true believer," said Gertrude Möller, MD, pulmonologist and immunologist at Wilhelmina Hospital in Utrecht, the Netherlands. "It's one of the promising anti-eosinophilic drug treatments in eosinophilic asthmatics," she told Medscape Medical News.

This study was funded by GlaxoSmithKline. Dr. Ortega is an employee of GlaxoSmithKline. Dr. Bel has received grants and personal fees from GlaxoSmithKline, grant support from Chiesi, grant support and personal fees from Novartis, and personal fees from Regeneron/Sanofi and CIPLA. Dr. Möller has been on an advisory board for Novartis. Dr. Barnes conducted an early study of mepolizumab that was funded by GlaxoSmithKline.

European Respiratory Society (ERS) International Congress 2014. Abstracts 2906 and 2907. Presented September 8, 2014.

N Engl J Med. Published online September 8, 2014. MENSA abstract SIRIUS abstract Editorial

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