A year's course of benralizumab injections has led to a significant decrease in the frequency of asthma exacerbations – cutting the rate by a third to a half compared with placebo among people with the most severe form of asthma, according to two phase 3, double-blind, randomised controlled trials.
The two trials presented at the European Respiratory Society meeting in London (on 5th September), looked at the safety and efficacy of benralizumab as an add-on therapy for patients with severe, uncontrolled asthma – a group of patients who have few treatment options available and high rates of hospitalisation.
Asthma affects an estimated 315m people worldwide, approximately 10% of whom have severe or uncontrolled asthma. Patients with severe asthma require treatment with high-dose inhaled corticosteroids (ISC) and long-acting beta agonists (LABA) to control the illness – both are delivered in the form of inhalers.
However, for some patients, current treatments fail to control their asthma and they remain at high risk of exacerbations and hospitalisation.
Eosinophils are a type of white blood cell and part of the immune system controlling the mechanism associated with allergy and asthma. Many patients with severe, uncontrolled asthma have high levels of eosinophils in the blood and airways (known as eosinophilia) which is associated with frequent asthma exacerbations, high symptom burden and impaired lung function.
Cytokine interleukin-5 (IL-5) is the main driver of eosinophil proliferation, maturation, activation and survival. Two currently available drugs, mepolizumab and reslizumab, target the IL-5 molecule itself to stop the process of eosinophil maturation. Benralizumab, on the other hand, uses a different pathway by targeting the IL-5 receptor, causing eosinophil apoptosis (cell death).
In the CALIMA trial, 1,306 patients aged 12-75 with severe asthma were randomly allocated into three groups: benralizumab 30mg every 4 weeks; benralizumab 30mg every 8 weeks (first 3 doses at 4 weeks apart); or placebo. Treatment continued for 56 weeks. All patients were already being treated with ISC and LABA and had experienced at least two exacerbations in the previous year.
The aim of the trial was to measure the effect of the drug on the annual rate of exacerbations in a sub-group of 728 patients with high eosinophils counts (over 300 cells/microL) – the most severe form of asthma. Benralizumab resulted in a 28-36% reduction in exacerbation rates compared to placebo (reduction from 2.8 to 0.60 exacerbations per year for treatment every 4 weeks; 2.7 to 0.66 for treatment every 8 weeks; 2.8 to 0.93 for placebo) (table 1 & 2). Benralizumab also resulted in improved lung function (as measured via spirometry) and total asthma score (treatment every 8 weeks only).
The most common adverse events were naso-pharyngitis (169 [20%] of 866 benralizumab-treated patients vs 90 [21%] of 440 placebo-treated patients) and worsening asthma (108 [12%] vs 68 [15%]) (table 4). Four patients experienced serious adverse events which were considered related to treatment: one case of uricaria (hives) and two cases of asthma and herpes zoster in the benralizumab-treated group, and one case of non-cardiac chest pain the placebo-treated group. Seven (<1%) patients receiving benralizumab and three (<1%) receiving placebo discontinued treatment because of adverse events.
In the SIROCCO trial, 1,209 patients were similarly randomised into three groups, and underwent 48 weeks of treatment. The analysis was performed in the 809 patients with high eosinophil counts. Benralizumab resulted in a 45-51% reduction in exacerbation rates compared to placebo (reduction from 3.0 to 0.73 per year for treatment every 4 weeks; 2.8 to 0.65 for treatment every 8 weeks; 3.1 to 1.33 for placebo). Patients treated every 8 weeks also saw improvements in lung function and total asthma score.
The most common adverse events were worsening asthma (105 [13%] of 797 benralizumab-treated patients vs 78 [19%] of 407 placebo-treated patients) and nasopharyngitis (93 [12%] vs 47 [12%]). Four patients experienced serious adverse events which were considered related to treatment: one case of allergic granulomatous (an autoimmune disorder causing inflammation of blood vessels), one panic attack and one paraethisia (pins and needles) in the benralizumab-treated group, and one injection-site erythema (skin reaction) in the placebo-treated group. 18 patients (2%) receiving benralizumab and three (1%) receiving placebo discontinued treatment because of adverse events.
Four benralizumab-treated patients died during the treatment period in the CALIMA trial, and five patients in the SIROCCO trial (three benralizumab-treated patients and two in the placebo group). None of these deaths were considered to be related to the treatments.
"Patients with severe, uncontrolled asthma have very few treatment options once they are already taking high-dose inhaled corticosteroids and long-acting beta agonists," says Professor Eugene Bleecker, Centre for Genomics and Personalised Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, lead author of the SIROCCO trial. "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. 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."
"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" adds Professor J Mark FitzGerald, The Lung Centre, Vancouver Coastal Health, University of British Columbia, Vancouver, 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."
The authors note that both trials show a strong placebo effect as rates of exacerbations decreased significantly in the placebo group who had an injection, but did not receive the drug. Patients in both trials were invited to join a two-year BORA safety extension study to provide data on longer-term use of benralizumab.
Writing in a linked Comment, Dr Mario Castro, Washington University School of Medicine, compares benralizumab to mepolizumab and reslizumab and discusses the differences in the magnitude of effect in the two trials. He adds: "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. In these studies, in the Q8W dosing regimen, benralizumab was first given Q4W for 3 months probably to deplete eosinophils more rapidly in patients with high eosinophil tissue burden. Given the efficacy of Q8W 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 Q4W dosing. Additionally, the less frequent dosing of anti-interleukin-5 might allow one to consider using these biologics earlier in the course of the disease, and in children."
Also presented at the European Respiratory Society meeting are the findings of two trials into the efficacy and safety of lebrikizumab in patients with uncontrolled asthma. These two phase 3 trials (LAVOLTA I and II) included 1081 and 1067 patients with uncontrolled asthma. In each trial, patients were randomised into three groups to receive either lebrikizumab (37.5mg or 125 mg dose) or placebo monthly for 52 weeks. The efficacy did not meet the expected reduction in the rate of exacerbations as expected from phase 2 trials. In addition, the findings did not replicate across the two studies and lebrikizumab did not consistentlyshow significant reduction of asthma exacerbations in biomarker-high patients. The findings suggest that the drug, which blocks IL-13, may not be sufficient to provide clinically meaningful improvements in reducing asthma exacerbations.
Background: Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. We aimed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts.
Methods: In this randomised, double-blind, parallel-group, placebo-controlled, phase 3 study (CALIMA) undertaken at 303 sites in 11 countries, we enrolled patients aged 12–75 years with severe asthma uncontrolled by medium-dosage to high-dosage inhaled corticosteroids plus long-acting β₂-agonists (ICS plus LABA) and a history of two or more exacerbations in the previous year. Patients were randomly assigned (1:1:1) to receive 56 weeks of benralizumab 30 mg every 4 weeks (Q4W), benralizumab 30 mg every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo (all subcutaneous injection). Patients were stratified (2:1) by baseline blood eosinophil counts 300 cells per μL or greater and less than 300 cells per μL, respectively. Patients and study centre staff were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per μL or greater (intention-to-treat analysis). Key secondary endpoints were pre-bronchodilator forced expiratory volume in 1 s (FEV1) and total asthma symptom score.
Findings: Between Aug 21, 2013, and March 16, 2015, 2505 patients were enrolled, of whom 1306 patients were randomised; 425 patients were randomly assigned to and received benralizumab 30 mg Q4W, 441 to benralizumab 30 mg Q8W, and 440 to placebo. 728 patients were included in the primary analysis population. Benralizumab resulted in significantly lower annual exacerbation rates with the Q4W regimen (rate 0•60 [95% CI 0•48–0•74], rate ratio 0•64 [95% CI 0•49–0•85], p=0•0018, n=241) and Q8W regimen (rate 0•66 [95% CI 0•54–0•82], rate ratio 0•72 [95% CI 0•54–0•95], p=0•0188, n=239) compared with placebo (rate 0•93 [95% CI 0•77–1•12], n=248). Benralizumab also significantly improved pre-bronchodilator FEV1 (Q4W and Q8W) and total asthma symptom score (Q8W only) in these patients. The most common adverse events were nasopharyngitis (90 [21%] in the Q4W group, 79 [18%] in the Q8W group, and 92 [21%] in the placebo group) and worsening asthma (61 [14%] in the Q4W group, 47 [11%] in the Q8W group, and 68 [15%] in the group).
Interpretation: Benralizumab significantly reduced annual exacerbation rates and was generally well tolerated for patients with severe, uncontrolled asthma with blood eosinophils 300 cells per μL or greater. Our data further refine the patient population likely to receive the greatest benefit from benralizumab treatment.
J Mark FitzGerald, Eugene R Bleecker, Parameswaran Nair, Stephanie Korn, Ken Ohta, Marek Lommatzsch, Gary T Ferguson, William W Busse, Peter Barker, Stephanie Sproule, Geoffrey Gilmartin, Viktoria Werkström, Magnus Aurivillius,
Background: Eosinophilia is associated with worsening asthma severity and decreased lung function, with increased exacerbation frequency. We assessed the safety and efficacy of benralizumab, a monoclonal antibody against interleukin-5 receptor α that depletes eosinophils by antibody-dependent cell-mediated cytotoxicity, for patients with severe, uncontrolled asthma with eosinophilia.
Methods: We did a randomised, double-blind, parallel-group, placebo-controlled phase 3 study at 374 sites in 17 countries. We recruited patients (aged 12–75 years) with a physician-based diagnosis of asthma for at least 1 year and at least two exacerbations while on high-dosage inhaled corticosteroids and long-acting β2-agonists (ICS plus LABA) in the previous year. Patients were randomly assigned (1:1:1) by an interactive web-based voice response system to benralizumab 30 mg either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses every 4 weeks) or placebo Q4W for 48 weeks as add on to their standard treatment. Patients were stratified 2:1 according to blood eosinophil counts of at least 300 cells per μL and less than 300 cells per μL. All patients and investigators involved in patient treatment or clinical assessment were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo, and key secondary endpoints were prebronchodilator forced expiratory volume in 1 s (FEV1) and total asthma symptom score at week 48, for patients with blood eosinophil counts of at least 300 cells per μL. Efficacy analyses were by intention to treat (based on the full analysis set); safety analyses included patients according to study drug received.
Findings: Between Sept 19, 2013, and March 16, 2015, 2681 patients were enrolled, 1205 of whom met the study criteria and were randomly assigned: 407 to placebo, 400 to benralizumab 30 mg Q4W, and 398 to benralizumab 30 mg Q8W. 267 patients in the placebo group, 275 in the benralizumab 30 mg Q4W group, and 267 in the benralizumab 30 mg Q8W group had blood eosinophil counts at least 300 cells per μL and were included in the primary analysis population. Compared with placebo, benralizumab reduced the annual asthma exacerbation rate over 48 weeks when given Q4W (rate ratio 0•55, 95% CI 0•42–0•71; p<0•0001) or Q8W (0•49, 0•37–0•64; p<0•0001). Both benralizumab dosing regimens significantly improved prebronchodilator FEV1 in patients at week 48 compared with placebo (least-squares mean change from baseline: Q4W group 0•106 L, 95% CI 0•016–0•196; Q8W group 0•159 L, 0•068–0•249). Compared with placebo, asthma symptoms were improved by the Q8W regimen (least-squares mean difference −0•25, 95% CI −0•45 to −0•06), but not the Q4W regimen (−0•08, −0•27 to 0•12). The most common adverse events were worsening asthma (105 [13%] of 797 benralizumab-treated patients vs 78 [19%] of 407 placebo-treated patients) and nasopharyngitis (93 [12%] vs 47 [12%]).
Interpretation: These results confirm the efficacy and safety of benralizumab for patients with severe asthma and elevated eosinophils, which are uncontrolled by high-dosage ICS plus LABA, and provide support for benralizumab to be an additional option to treat this disease in this patient population.
Eugene R Bleecker, J Mark FitzGerald, Pascal Chanez, Alberto Papi, Steven F Weinstein, Peter Barker, Stephanie Sproule, Geoffrey Gilmartin, Magnus Aurivillius, Viktoria Werkström, Mitchell Goldman
Background: In phase 2 trials, lebrikizumab, an anti-interleukin-13 monoclonal antibody, reduced exacerbation rates and improved FEV1 in patients with uncontrolled asthma, particularly in those with high concentrations of type 2 biomarkers (periostin or blood eosinophils). We undertook replicate phase 3 studies to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite inhaled corticosteroids and at least one second controller medication.
Methods: Adult patients with uncontrolled asthma, pre-bronchodilator FEV1 40–80% predicted, and stable background therapy were randomly assigned (1:1:1) with an interactive voice–web-based response system to receive lebrikizumab 37•5 mg or 125 mg, or placebo subcutaneously, once every 4 weeks. Randomisation was stratified by screening serum periostin concentration, history of asthma exacerbations within the last 12 months, baseline asthma medications, and country. The primary efficacy endpoint was the rate of asthma exacerbations over 52 weeks in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per μL), analysed with a Poisson regression model corrected for overdispersion with Pearson χ2 that included terms for treatment group, number of asthma exacerbations within the 12 months before study entry, baseline asthma medications, geographic region, screening periostin concentration, and blood eosinophil counts as covariates.
Findings: 1081 patients were treated in LAVOLTA I and 1067 patients in LAVOLTA II. Over 52 weeks, lebrikizumab reduced exacerbation rates in biomarker-high patients in the 37•5 mg dose group (rate ratio [RR] 0•49 [95% CI 0•34–0•69], p<0•0001) and in the 125 mg dose group (RR 0•70 [0•51–0•95], p=0•0232) versus placebo in LAVOLTA I. Exacerbation rates were also reduced in biomarker-high patients in both dose groups versus placebo in LAVOLTA II (37•5 mg: RR 0•74 [95% CI 0•54–1•01], p=0•0609; 125 mg: RR 0•74 [0•54–1•02], p=0•0626). Pooling both studies, the proportion of patients who experienced treatment-emergent adverse events (79% [1125 of 1432 patients] for both lebrikizumab doses vs 80% [576 of 716 patients] for placebo), serious adverse events (8% [115 patients] for both lebrikizumab doses vs 9% [65 patients] for placebo), and adverse events leading to study drug discontinuation (3% [49 patients] for both lebrikizumab doses vs 4% [31 patients] for placebo) were similar between lebrikizumab and placebo. The following serious adverse events were reported in the placebo-controlled period: one event of aplastic anaemia and five serious adverse events related to raised concentrations of eosinophils in patients treated with lebrikizumab and one event of eosinophilic pneumonia in the placebo group.
Interpretation: Lebrikizumab did not consistently show significant reduction in asthma exacerbations in biomarker-high patients. However, it blocked interleukin-13 as evidenced by the effect on interleukin-13-related pharmacodynamic biomarkers, and clinically relevant changes could not be ruled out.
Nicola A Hanania, Phillip Korenblat, Kenneth R Chapman, Eric D Bateman, Petr Kopecky, Pierluigi Paggiaro, Akihito Yokoyama, Julie Olsson, Sarah Gray, Cecile TJ Holweg, Mark Eisner, Charles Asare, Saloumeh K Fischer, Kun Peng, Wendy S Putnam, John G Matthews