For severe eosinophilic asthma, the novel monoclonal antibody mepolizumab cut exacerbations whether given as an injection or infusion and reduced steroid use in patients dependent on them, two trials showed.
The drug, which targets interleukin-5 (IL-5) to inhibit eosinophilic inflammation,cut exacerbations by 47% with intravenous dosing and by 53% with subcutaneous dosing when compared with placebo (0.93 and 0.81 versus 1.75 per year, both P<0.001), Hector G. Ortega, MD, ScD, of GlaxoSmithKline, found in the MENSA trial.
Mepolizumab injections more than doubled the likelihood of glucocorticoid dose strata reduction compared with placebo, with a median 50% dose reduction from baseline versus none with placebo (P=0.007), Elisabeth H. Bel, MD, PhD, of the University of Amsterdam, and colleagues found in a second study, dubbed SIRIUS. Investigators in both trials said that safety issues with the drug were no different from placebo.
Both trials were reported online in the New England Journal of Medicine in conjunction with presentation at the European Respiratory Society meeting in Munich.
Three prior trials had already shown that anti-IL-5 drugs helped in asthma cases targeted by sputum eosinophil levels, Parameswaran Nair, MD, PhD, of McMaster University in Hamilton, Ontario, noted in an accompanying editorial.
The two new trials provided some clinical observations with “important practical applications,” though, he wrote.
“First, the subcutaneous administration of a lower dose of the drug (100 mg) than was previously reported was shown to be efficacious,” he noted.
“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.
“Both these observations make it potentially simple and easy for practitioners to identify patients who are likely to benefit and administer the drug to them.”
Some previous studies that had tried to identify candidates for treatment based on clinical characteristics alone had failed.
Sputum eosinophil counts have been used since, but their greater sensitivity to change than blood eosinophil levels comes at a cost in convenience.
“Although persistent blood eosinophilia may be sufficient to identify patients who are likely to have a response to this treatment, whether this biomarker is sufficient or is as effective as airway eosinophilia in monitoring the response to treatment remains to be seen,” Nair pointed out.
The Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA) trial included 576 patients with recurrent asthma exacerbations and eosinophilic inflammation (at least 150 eosinophil cells/microliter in the peripheral blood at screening or at least 300 per microliter at some time in the prior year) despite high doses of inhaled glucocorticoids (at least the equivalent of 880 mcg of fluticasone propionate per day).
Patients were randomly assigned to double-blind treatment atop their pre-existing asthma therapy regimen with placebo or mepolizumab as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, every 4 weeks for 32 weeks.
Among the secondary outcomes, IV mepolizumab reduced exacerbations necessitating an emergency department visit or hospitalization by 32%, while the subcutaneous route reduced that rate by 61% compared with placebo.
Lung function at week 32 showed 100 mL greater mean increase from baseline in forced expiratory volume in 1 sec (FEV1) on IV mepolizumab and 98 mL greater mean increase on subcutaneous mepolizumab than with placebo (P=0.02 and P=0.03, respectively).
Quality of life improvements were fairly similar between IV and subcutaneous mepolizumab groups, at 6.4 and 7.0 points over placebo group on the St. George’s Respiratory Questionnaire score, both exceeding the minimal clinically important change threshold of 4 points and statistical significance at P<0.001.
The improvements in the five-item Asthma Control Questionnaire (ACQ-5) score were similar at 0.42 points and 0.44 points greater, respectively, than placebo, which met statistical significance but not the clinically important threshold of 0.5 points.
Nair cautioned, though, that the findings could have been an artifact of participating in a clinical trial. Specifically, he suggested that the high baseline exacerbation rate (mean 3.6 per year) might have meant doses of inhaled glucocorticoids and long-acting bronchodilators were not optimized prior to enrollment.
“Although the magnitudes of the reductions in exacerbations with the two routes of administration … were similar and greater than the reduction achieved with placebo, it is remarkable that the patients receiving placebo had a 50% reduction, as compared with their baseline rate,” he wrote.
Lack of adherence is the top reason for poor asthma control even in well characterized populations, he pointed out.
Standard therapies, judiciously used, and as guided by sputum cell counts have been shown to cut exacerbations to a degree clinically equivalent to biologic therapies “and are likely to be more cost-effective,” Nair wrote.
“This finding would suggest that most patients in this clinical trial might have had improvement in symptoms without mepolizumab simply by the institution of good clinical practice, as recommended by current international guidelines.”
But the severe asthma population truly dependent on systemic glucocorticoids for control do desperately need better therapies, he acknowledged.
The Steroid Reduction with Mepolizumab Study (SIRIUS) trial included 135 patients with severe eosinophilic asthma randomized to 100 mg subcutaneous mepolizumab or placebo, every 4 weeks for 20 weeks.
After first establishing the lowest dose of maintenance oral glucocorticoids associated with acceptable asthma control, those doses were reduced by 1.25 to 10 mg per day every 4 weeks during weeks four to 20 on the basis of asthma control and symptoms of adrenal insufficiency.
The odds of a drop in the glucocorticoid dose strata — 90% to 100%, 75% to less than 90%, 50% to less than 75%, or more than 0% to less than 50% reduction versus no decrease, uncontrolled asthma in the last 4 weeks, or withdrawal — was 2.39-fold higher with mepolizumab (95% CI 1.25-4.56).
But despite that reduced glucocorticoid dose, mepolizumab reduced the annualized rate of exacerbations by a relative 32% (1.44 versus 2.12, P=0.04).
The monoclonal antibody also cut asthma symptoms by a clinically-important 0.52 points on the ACQ-5 versus placebo (P=0.004).
However, “the mean percentage reduction in the dose of glucocorticoids (50%) and the proportion of patients who had this reduction (54%) were lower than reductions that have been reported for higher doses of the drug (750 mg) administered intravenously in patients with sputum eosinophilia (87% dose reduction and 100% of patients, respectively),” Nair pointed out.
“However, these studies do not suggest that all patients with uncontrolled asthma who have peripheral blood eosinophilia will require an expensive anti-IL-5 therapy for clinical benefit,” Nair wrote.
Still, he called it reasonable to consider such a biologic for patients with severe asthma with elevated eosinophil count in sputum or blood despite high doses of systemic glucocorticoids, regardless of their atopic status.
When top-line results from the two trials were released by drugmaker GlaxoSmithKline in March, the company said it hoped to file for approval of mepolizumab by the end of 2014.
Whether mepolizumab dose adjustment by airway eosinophils level would have been better, and what is the most effective dose, route, and frequency of administration still need to be determined, Nair noted.