麻豆传媒

WASHINGTON -- The monoclonal antibody benralizumab helped patients with severe asthma reduce their need for oral glucocorticoid therapy, researchers reported here.

Two different benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75% compared with a reduction of 25% in the placebo group, Parameswaran Nair, MD, PhD, of McMaster University in Hamilton, Ontario, Canada, and colleagues found. The results were published simultaneously in the and here at the annual meeting of the American Thoracic Society.

"[Benralizumab] enabled patients to reduce their prednisone substantially compared to placebo, yet prevent exacerbations and the decline of lung function," Nair told 麻豆传媒 in an email. "The drug ... was well-tolerated, and when approved by regulators, may thus provide physicians with a useful strategy to treat patients and avoid the dreadful long-term adverse effects of systemic corticosteroids."

Need for Alternative Treatments

Among patients with asthma, 5% to 10% have a severe form that is usually managed with high-dose inhaled glucocorticoids and bronchodilators, the authors noted in their introduction. Within that severe asthma group, 32% to 45% depend on frequent or maintenance use of oral glucocorticoid therapy, which can adversely affect quality of life, raising the question of whether alternative therapies may be useful.

Eosinophilic inflammation is an important part of asthma, "and increased numbers of circulating and airway eosinophils are accompanied by more frequent asthma exacerbations and declines in lung function," they continued. Two other monoclonal antibodies -- mepolizumab and reslizumab -- have been approved to treat asthma exacerbations in patients who have severe asthma with an eosinophilic phenotype.

Benralizumab is a humanized monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor. The investigators designed a trial known as ZONDA to see whether benralizumab could reduce the dose of oral glucocorticoids needed by patients with severe asthma.

The investigators enrolled 369 patients in a a double-blind, parallel-group, placebo, controlled trial; of those, 220 were eventually randomized to either benralizumab or placebo. All participants had been treated with oral glucocorticoids for 6 months or more prior to enrollment, and were taking either oral prednisone or prednisolone at the beginning of the trial.

Inclusion criteria included a blood eosinophil count of ≥150 cells/mm³, and asthma that had been treated with medium-to-high-dose inhaled glucocorticoid and long-acting beta agonist (LABA) therapy for at least 12 months before enrollment.

Step Reductions in Steroids

During a 4-week induction phase, the oral glucocorticoid dose established during the initial run-in period was maintained; during weeks 4-24, the daily oral glucocorticoid dose was reduced every 4 weeks by 2.5 to 5.0 mg. However, if the criteria for dose reduction weren't met, the participant's oral glucocorticoid dose was returned to the previous level and stayed there until the end of the trial.

Patients in the intervention group received subcutaneous injections of benralizumab at a dose of 30 mg every 4 weeks; benralizumab at a dose of every 4 weeks for the first three doses and then every 8 weeks (with placebo at the 4-week interim visits); or placebo every 4 weeks. They continued their prescribed high-dose inhaled glucocorticoid and LABA treatments and any other asthma-controller medications. Short-acting beta agonists were allowed for rescue purposes.

Patients recorded lung-function measurements -- which were made with an electronic handheld spirometer -- and asthma symptoms in an asthma daily diary. Worsening of asthma was defined as new or increased asthma symptoms or clinical signs that were troubling to the patient or were related to an electronic diary alert. An exacerbation of asthma was defined as worsening of asthma that led to a temporary increase in the system glucocorticoid dose for at least 3 days, an emergency department visit resulting from asthma leading to treatment with a systemic glucocorticoid, or an inpatient hospitalization due to asthma.

The study's primary endpoint was the percentage reduction in oral glucocorticoid dose from baseline to the final dose at week 28. Secondary endpoints included percentage of patients who cut their average daily oral glucocorticoid dose by 25%, 50% or more, or 100%, as well as the percentage of patients with an average final oral glucocorticoid dose of 5 mg or less per day.

Overall, 24 patients (33%) who were treated with benralizumab every 4 weeks and 27 patients (37%) who received the drug every 8 weeks had a reduction of 90% or more in their final oral glucocorticoid dose, compared with nine patients (12%) on placebo. The odds of a reduction in oral glucocorticoid dose were 4.09 times as high with benralizumab given every 4 weeks and 4.12 with the drug given every 8 weeks, respectively, compared with placebo.

Steroids Stopped Entirely in Some Patients

Among the secondary endpoints, 56% of patients on the 4-week benralizumab regimen and 52% on the 8-week regimen were able to stop the oral glucocorticoids entirely, compared with 19% of those on placebo. In addition, benralizumab administered every 4 weeks resulted in an annual asthma exacerbation rate that was 55% lower than that with placebo (rate ratio 0.45, 95% CI 0.27 to 0.76, P=0.003), the researchers noted.

A total of 166 patients experienced at least one adverse event during the trial's intervention phase; the most frequently reported events included nasopharyngitis (17% of patients), worsening asthma (13%), and bronchitis (10%). Two patients in the every-8-week benralizumab group died during the trial -- one from acute cardiac failure and the other from pneumonia.

This drug seems to have a beneficial effect similar to that of omalizumab (Xolair), said Neil Schachter, MD, professor of medicine at Mount Sinai School of Medicine, in New York City, who was not involved with the study. Benralizumab, mepolizumab, and reslizumab "have an advantage over Xolair in that they seem to be effective with fewer dosings" -- with Xolair being given every 2-4 weeks versus up to 8 weeks for the other medications. In addition, "these drugs seem to be well-tolerated and have few side effects of their own over the long run."

He noted in a phone call that patients on long-term corticosteroids can develop side effects such as bone density loss, high blood pressure, and weight gain, and while this study was too short to definitively determine if those side effects would be reduced given the reduced oral glucocorticoid dose, "there is no doubt that if they reduce the amount of steroids they take over a period of time, the side effects from steroids would be less."

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