Injections of a potential new therapy – benralizumab – over the course of a year have reduced the frequency of asthma flare-ups in people with the most severe form of asthma, two trials suggest.

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In two trials, the progressively worsening symptoms associated with severe asthma reduced in frequency with benralizumab injections.

Asthma exacerbations (asthma attack), or flare-ups, are progressively worsening symptoms of swollen and inflamed airways, coughing, wheezing, chest tightness, and trouble breathing.

People with severe, uncontrolled asthma often have high levels of eosinophils in their blood and airways – known as eosinophilia – which is associated with frequent asthma exacerbations.

Benralizumab is a monoclonal antibody therapy that uses antibodies that are made in a lab rather than by a person’s immune system.

The antibodies recruit other parts of the immune system to rapidly clear away eosinophils – immune cells that play a role in allergies and asthma.

Cytokine interleukin-5 (IL-5) is the main driver of eosinophil proliferation, maturation, activation, and survival.

Mepolizumab and reslizumab target the IL-5 molecule directly to prevent the eosinophil maturation process, whereas benralizumab targets the IL-5 receptor, which causes eosinophil apoptosis – cell death.

“Two drugs are currently approved for the treatment of severe, uncontrolled asthma (mepolizumab and reslizumab), but both target the IL-5 molecule directly, rather than the receptor,” says Prof. Eugene Bleecker, M.D., from the Center for Genomics and Personalized Medicine Research at Wake Forest School of Medicine, in North Carolina. He is the lead author of the SIROCCO trial.

“By targeting the IL-5 receptor, benralizumab depletes eosinophils directly, and our studies show that eosinophil counts were nearly completely depleted by week 4 of treatment,” he adds.

According to the Centers for Disease Control and Prevention (CDC), there are around 17.7 million adults and 6.3 million children in the United States who have asthma. Approximately 10 percent of people with asthma worldwide have severe or uncontrolled asthma.

While severe asthma is treatable with high-dose inhaled corticosteroids (ICS) and long-acting beta agonists (LABA) in the form of inhalers, for some patients, these types of therapies are ineffective and do not control their asthma. Moreover, these patients continue to be at an increased risk of exacerbations and hospitalization.

Patients with severe, uncontrolled asthma have very few treatment options once they are already taking high-dose inhaled corticosteroids and long-acting beta agonists.”

Prof. Eugene Bleecker

Two trials, CALIMA and SIROCCO, examined the effect of benralizumab injections on 2,500 people with severe asthma compared with placebo. The participants had previously had high rates of hospitalization and had few available treatment options.

The CALIMA trial included 1,306 patients between the ages of 12-75 years with severe asthma. Patients were randomly split into categories: 30 milligrams of benralizumab every 4 weeks, 30 milligrams of benralizumab every 8 weeks (first three doses at 4 weeks apart), or placebo. Treatment was ongoing for 56 weeks.

Participants in the CALIMA trial had to have experienced two exacerbations in the previous year to qualify for the study and were already being treated with ISC and LABA.

The SIROCCO trial included 1,209 patients, split similarly into three categories, with treatment continuing for a total of 48 weeks.

The results – published in The Lancet – indicated a 28-36 percent reduction in exacerbations in the CALIMA trial and a 45-51 percent decrease in exacerbations in the SIROCCO trial, compared with placebo. Both trials noted improvements in lung function and total asthma score.

The most common adverse events across both trials included nasopharyngitis, worsening asthma, urticaria (hives), allergic granulomatous, paresthesia (pins and needles) and injection-site erythema (skin reaction).

Four patients in the CALIMA trial treated with benralizumab and five patients in the SIROCCO trial – three benralizumab-treated patients and two in the placebo group – died over the course of the trial. However, none of the deaths were connected to the treatments.

The results from both trials indicate that benralizumab treatment once every 4 or 8 weeks decreased eosinophil counts, reduced asthma exacerbations, and improved lung function for patients with severe, uncontrolled asthma with eosinophilia.”

Dr. J. Mark FitzGerald, University of British Columbia, lead author of the CALIMA trial

“Additional therapeutic options to control severe asthma are urgently needed, and our findings support the use of benralizumab as an add-on therapy for the treatment of severe asthma with persistent eosinophilia,” FitzGerald adds.

Dr. Mario Castro, from Washington University School of Medicine, adds in a linked comment:

“The CALIMA and SIROCCO studies also suggest that more frequent dosing initially followed by longer duration between treatments with an anti-interkeukin-5 monoclonal antibody should be investigated further.”

Findings from two other trials, published in The Lancet Respiratory Medicine, examine the efficacy and safety of lebrikizumab – another monoclonal antibody and an experimental immunosuppressive drug – in patients with uncontrolled asthma.

The two trials, LAVOLTA I and II, included 1,081 and 1,067 patients with severe asthma split into three categories and treated for 52 weeks. Findings were not consistent with those of benralizumab. The rates in exacerbation reductions were neither significant nor consistent.

Results from LAVOLTA I and II trials suggest that the drug, which blocks IL-13, may not provide sufficient improvements in decreasing asthma exacerbations.

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