Robust evidence of the rapid efficacy of benralizumab
Benralizumab is a humanized anti-interleukin-5 receptor-α (IL-5Rα) antibody that depletes eosinophils by means of antibody-dependent cell-mediated cytotoxicity (ADCC) activity through natural killer (NK) cells (1). In the ADCC process, benralizumab binds to IL-5R on eosinophils, attaches NK cells to eosinophils, and causes the release of secretory lysosomes carrying lytic products, such as perforin and granzyme B, from NK cells (2). Benralizumab also induces macrophages to phagocytose or efferocytose eosinophils through its antibody-dependent cellular phagocytosis (ADCP) activity (1). Furthermore, benralizumab induces activated NK cells to release interferon-γ (IFN-γ), which increases macrophage cytotoxicity; alternatively, benralizumab promotes macrophage release of tumor necrosis factor-α (TNF-α), which binds to TNF receptor 1 (TNFR1) on eosinophils, resulting in TNFR1-dependent apoptosis (1). In general, these reactions proceed quickly in vivo, and eosinophil counts in peripheral blood and tissues rapidly decline. However, previous trials of benralizumab for acute exacerbations of asthma have failed to demonstrate the efficacy of this drug (3,4). It is noteworthy that there was no significant difference between the placebo and benralizumab in terms of the primary outcome, “number of patients who experienced exacerbation at least once in 12 weeks”, but benralizumab was found to be effective in reducing the total number of exacerbations and the incidence of hospitalization, which were secondary endpoints. Furthermore, this study reported that while prednisolone has various effects such as anti-inflammatory and immunosuppressive actions, benralizumab demonstrated superiority over steroids in terms of its strong and long-lasting direct removal of eosinophils (3). Recently, the ABRA study, in which the patient threshold eosinophil count was set 300/µL or higher and the dose of benralizumab was set at 100 mg, demonstrated the efficacy of benralizumab when used as a treatment for acute eosinophilic attacks in addition to a controller for asthma or chronic obstructive pulmonary disease (COPD) (5). Further studies are needed to determine the efficacy of benralizumab for severe exacerbations, but I believe that the results are promising and that benralizumab will provide additional treatment options for the future. The reason why benralizumab was effective for the exacerbation itself could be due to the rapid onset of the effect of benralizumab. Here, I will review this point.
The literature on the speed of eosinophil count reduction is summarized in Table 1. In a phase I study, the absolute eosinophil counts in the peripheral blood after 1 day of single intravenous doses (0.0003–3 mg/kg) of benralizumab for patients with mild atopic asthma (n=44) decreased to mean ± standard deviation of (0.01±0.00) ×103/µL (6). This pharmacokinetic study has shown that doses ranging from 0.03 to 3 mg/kg are effective. In the SIROCCO and CALIMA studies (7,8), the first forced expiratory volume in 1 s (FEV1) measurement was at week 4 after the first dose, but a pharmacokinetic (PK) study revealed that benralizumab treatment for patients with severe asthma rapidly increased the FEV1 (P<0.05 for benralizumab 30 mg every 8 weeks, first three doses 4 weeks apart versus placebo, P<0.05 for benralizumab 30 mg every 8 weeks, first three doses 4 weeks apart or benralizumab 30 mg every 4 weeks versus placebo, respectively), with a half-maximum time of 7.6 days compared with 18 days for placebo (9). These two trials also compared 4- and 8-week intervals, with 8 weeks becoming the recommended dosing interval. Reports on the morning peak expiratory flow (PEF) of patients from three clinical studies, the SIROCCO, CALIMA, and ZONDA studies (13), revealed that, compared with placebo, 30 mg of benralizumab for patients with severe asthma every 8 weeks, first three doses 4 weeks apart achieved clinically meaningful improvement in morning PEF (defined as ≥25 L/min) within the first week of treatment (within 24 hours of the first dose) (10). A sub-study of observational study for uncontrolled severe eosinophilic asthma patients to analyze the time to reach a 50% reduction in blood eosinophil count after administration of mepolizumab, benralizumab, and prednisolone revealed statistically significant changes from baseline at 2 and 4 hours in the 30 mg benralizumab administered subcutaneously group, at 4 hours in the 30 mg prednisolone administered orally. group, and at 24 hours in the 100 mg mepolizumab administered subcutaneously group (P<0.05) (11). In the ANDHI study for patients with severe eosinophilic asthma, significant improvements were observed in the 30 mg benralizumab every 8 weeks group in terms of both the prebronchodilator FEV1 and Asthma Control Questionnaire 6 (ACQ-6) scores compared with the baseline scores (P=0.0041 and P<0.0001, respectively) (12).
Table 1
| Names of studies | Findings |
|---|---|
| Brusse et al. (phase I) (6) | Peripheral blood eosinophil counts markedly decrease within 24 hours after dosing |
| SIROCCO (phase III) (7) | Prebronchodilator FEV1 significantly increased at week 4 compared with placebo in patients with peripheral blood eosinophil counts ≥300/µL (P<0.05) |
| CALIMA (phase III) (8) | Prebronchodilator FEV1 significantly increased at week 4 compared with placebo in patients with peripheral blood eosinophil counts ≥300/µL (P<0.05) |
| Chia et al. (9) | Prebronchodilator FEV1 rapidly improved on day 7.6 compared with placebo |
| Cuppu et al. (10) | Morning PEF increased within the first week of treatment (within 24 hours of the first dose) |
| Moran et al. (11) | Blood eosinophil count significantly decreased at 2 and 4 hours after dosing |
| ANDHI (phase IIIb) (12) | Prebronchodilator FEV1 and ACQ-6 score significantly improved at 2 weeks compared with baseline in patients with peripheral blood eosinophil counts ≥150/µL (P=0.0041 and P<0.0001, respectively) |
ACQ-6, Asthma Control Questionnaire-6; FEV1, forced expiratory volume in 1 s; PEF, peak expiratory flow.
As described above, benralizumab has the important feature of rapid onset through its ADCC activity. The speed of onset of the therapeutic effect (T50) will be further assessed through earlier and more frequent FEV1 measurements (days 3, 7 and 14 after the first dose) in the phase IIIb SOLANA study for patients with severe eosinophilic asthma (NCT02869438) (9). Benralizumab may be useful in emergency or critical care settings.
Acknowledgments
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Footnote
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