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LONDON -- Treatment with the monoclonal antibody benralizumab cut the annual exacerbation rate in patients with severe, uncontrolled asthma and high levels eosinophilia by up to 51%, researchers reported here.

Compared with placebo, benralizumab reduced the annual asthma exacerbation rate over 48 weeks when given every 4 weeks (0.55, 95% CI 0.42-0.71, P<0.0001) or every 8 weeks (0.49, 0.37-0.64, P<0.0001), according to , of Wake Forest School of Medicine in Winston-Salem, N.C., and colleagues.

"Patients with severe, uncontrolled asthma have very few treatment options once they are already taking high-dose inhaled corticosteroids and long-acting beta agonists," Bleecker said in a statement. "Two drugs are currently approved for the treatment of severe, uncontrolled asthma -- mepolizumab (Nucala) and reslizumab (Cinqair) -- but both target the IL-5 molecule directly, rather than the receptor. 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."

Results from another trial also showed similar effectiveness for benralizumab as add-on therapy for reducing asthma exacerbations in a population that was uncontrolled on high-dose inhaled corticosteroids and long-acting beta 2-agonists (LABA).

Benralizumab is "a humanized, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils," explained , of the University of British Columbia in Vancouver, and colleagues in the second study.

"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," FitzGerald said in a statement. "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."

Both studies were presented at the European Respiratory Society International Congress, and simultaneously reported in the Lancet.

SIROCCO

In the randomized, double-blind, placebo-controlled SIROCCO trial at 374 sites in 17 countries, 1,205 patients (ages 12-75 years) were enrolled if they had a physician-based diagnosis of asthma for at least 1 year, and at least two exacerbations while on high-dosage inhaled corticosteroids and LABA in the previous year. Patients were randomly assigned to benralizumab (30 mg either every 4 weeks or every 8 weeks; first three doses every 4 weeks) or placebo (every 4 weeks for 48 weeks) as add-on to standard treatment.

Patients were stratified according to blood eosinophil counts of at least 300 cells per μL and <300 cells per μL.

The 2013-2015 trial's primary endpoint was annual exacerbation rate ratio (RR) versus placebo, while secondary endpoints were prebronchodilator forced expiratory volume in 1 second (FEV₁) and total asthma symptom score at week 48, for patients with blood eosinophil counts of at least 300 cells per μL.

The authors reported that both benralizumab at both doses significantly improved prebronchodilator FEV₁ at week 48 compared with placebo (least-squares mean change from baseline):

• Every 4 weeks group: 0.106 L, (95% CI 0.016-0.196)
• Every 8 weeks group: 0.159 L (95% 0.068-0.249)

However, asthma symptoms were improved by the 8-week regimen (least-squares mean difference -0.25, 95% CI -0.45 to -0.06), but not the 4-week regimen (-0.08, -0.27 to 0.12) versus placebo.

The most common adverse events were worsening asthma (13% of benralizumab-treated patients versus 19% of placebo-treated patients) and nasopharyngitis (12% for treatment and placebo groups).

Benralizumab significantly reduced the annual rate of exacerbations by up to 51% after 48 weeks of treatment in patients with severe, uncontrolled asthma with eosinophilia," the authors noted, adding that the treatment resulted in "direct, rapid, and nearly complete eosinophil depletion at 4 weeks."

Study limitations included the fact that patients with blood eosinophil counts <300 cells per μL saw a smaller treatment effect, but the size of this cohort was limited because of study protocol, Bleecker's group explained.

"The threshold eosinophil count that results in significant therapeutic improvement with benralizumab treatment should be investigated in larger populations of severe or uncontrolled patients with asthma and different degrees of eosinophilia," they stated. Also, the long-term safety with benralizumab treatment could not be determined in a 1-year trial, although an extension study () will address this.

CALIMA

In the second trial, conducted at 303 sites in 11 countries, patients (ages 12-75 years) were enrolled if they had severe asthma uncontrolled by medium-dose to high-dose inhaled corticosteroids plus LABA, plus a history of two or more exacerbations in the previous year.

From 2013 to 2015, 2,505 patients were enrolled, of whom 1,306 patients were randomized to receive 56 weeks of benralizumab (30 mg every 4 weeks), or 30 g every 8 weeks (first three doses 4 weeks apart), or placebo. Patients were stratified by baseline blood eosinophil counts ≥300 cells per μL and <300 cells per μL.

The primary endpoint was annual exacerbation RR versus placebo for patients receiving high-dosage inhaled corticosteroids plus LABA with baseline blood eosinophils ≥300 cells per µL (intention-to-treat analysis). Secondary endpoints were pre-bronchodilator FEV₁) and total asthma symptom score.

Ultimately, 728 patients were included in the primary analysis which showed that benralizumab led to significantly lower annual exacerbation rates with both regimens:

• 4-week regimen: rate 0.60 (95% CI 0.48-0.74), RR 0.64 (95% CI 0.49-0.85, P=0.0018)
• 8-week regimen: rate 0.66 (95% CI 0.54-0.82), RR 0.72 (95% CI 0.54-0.95, P=0.0188)
• Placebo: rate 0.93 (95% CI 0.77-1.12)

Benralizumab also significantly improved pre-bronchodilator FEV1 at both doses, but only the 8-week regimen led to improvements in total asthma symptom score.

Common adverse events were nasopharyngitis (21% in the 4-week group; 18% in the 8-week group; 21% with placebo) and worsening asthma (14%, 11%, and 15%, respectively).

FitzGerald's group noted that the trial had some limitations, including the fact that it was not designed to compare outcomes for patients with baseline blood eosinophils ≥300 cells per µL with patients with lower blood eosinophil counts. It also was not powered to detect differences between the two benralizumab dosing regimens. Finally, the authors could not assess the efficacy of benralizumab results in patients subgroups, such as African Americans, adolescents, and atopic patients.

"The results obtained from this study, together with those obtained in SIROCCO, provide strong evidence of the clinical value of benralizumab treatment in the management of patients with severe or uncontrolled asthma and blood eosinophils 300 cells per μL or greater. Benralizumab ... represents a new mechanism of action to address the unmet needs of these patients," the authors concluded.

More Dosing Studies

In an accompanying commentary, and both at the Washington University School of Medicine in St. Louis, wrote that "The CALIMA and SIROCCO studies also suggest that more frequent dosing initially followed by longer duration between treatments with an anti-interleukin-5 monoclonal antibody should be investigated further. In these studies, in the every 8 weeks dosing regimen, benralizumab was first given every 4 weeks for 3 months probably to deplete eosinophils more rapidly in patients with high eosinophil tissue burden."

"Given the efficacy of every 8 week dosing on exacerbations, symptom scores, asthma control, and quality of life, and the economical savings of using half the amount of drug suggests a potential advantage to this dosing regimen over once monthly dosing," they noted.

They also pointed out that the less frequent dosing of anti-interleukin-5 might may make these biologics useful earlier in the course of the disease, and in children.

"Additional studies are needed using anti-interleukin-5 pathway therapies in school-age children and in patients with other eosinophilic driven diseases such as chronic rhinosinusitis, nasal polyposis, eosinophilic esophagitis, atopic dermatitis, and eosinophilic granulomatosis with polyangiitis," they said.