Expert Opinion on Drug Metabolism & Toxicology

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Pharmacokinetic/pharmacodynamic drug
evaluation of benralizumab for the treatment of
asthma

Maria Gabriella Matera, Luigino Calzetta, Barbara Rinaldi & Mario Cazzola

To cite this article: Maria Gabriella Matera, Luigino Calzetta, Barbara Rinaldi & Mario
Cazzola (2017) Pharmacokinetic/pharmacodynamic drug evaluation of benralizumab for the
treatment of asthma, Expert Opinion on Drug Metabolism & Toxicology, 13:9, 1007-1013, DOI:
10.1080/17425255.2017.1359253

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EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2017
VOL. 13, NO. 9, 1007–1013
https://doi.org/10.1080/17425255.2017.1359253

DRUG EVALUATION

Pharmacokinetic/pharmacodynamic drug evaluation of benralizumab for the

treatment of asthma
Maria Gabriella Materaa, Luigino Calzetta b
, Barbara Rinaldia and Mario Cazzola b

a
Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy; bDepartment of Systems Medicine, University of
Rome Tor Vergata, Rome, Italy

ABSTRACT ARTICLE HISTORY

Introduction: In many severe asthmatics, eosinophils cause inflammation and airways hyperrespon- Received 14 May 2017
siveness, resulting in frequent exacerbations, impaired lung function, and reduced quality of life. Accepted 20 July 2017
Interleukin-5 (IL-5) is a key cytokine for eosinophil growth, differentiation, recruitment, activation, and KEYWORDS
survival. Anti-IL-5-based therapies (mepolizumab and reslizumab are humanized monoclonal antibodies Asthma; benralizumab;
(hmAbs) that recognize free IL-5, benralizumab is a hmAb directed at the α subunit of the IL-5R) target eosinophils; humanized
the IL-5-signaling in eosinophilic asthma. monoclonal antibodies;
Areas covered: The pharmacodynamic/pharmacokinetic profile of benralizumab and how it provided interleukin-5
indications that permitted optimization of the design and timelines of the pivotal trials are described.
Expert opinion: Benralizumab has the advantage over other anti-IL-5 therapies to target the IL-5Rα
itself. Afucosylation enhances its interaction with its binding site and facilitates its pharmacological
activity. Other benefits of benralizumab are fast (within 24 h) depletion of peripheral blood eosinophils,
potent suppressive activity of bone marrow eosinophils and eosinophil precursors, tissue eosinophil
apoptosis regardless of the presence of eosinophil survival factors and even at low IL-5R densities. The
fact that benralizumab is dosed subcutaneously and is equally effective when given every eight weeks
instead than every four weeks provides patients with convenience of self-administration and make it
appealing for patients who dislike injections.

1. Overview of the market National Institute for Health and Care Excellence has not
approved mepolizumab on cost-effectiveness grounds [6].
Eosinophilic asthma is an important subtype of asthma asso-
Also benralizumab appears to be successful in its pivotal
ciated with reduced response to corticosteroid and increased
phase III studies.
risk of severe exacerbation [1]. Accumulation of eosinophils is
This article focuses on pharmacodynamic/pharmacokinetic
a well-defined feature of eosinophilic asthma where they
profile of benralizumab.
release granule-derived basic proteins, lipid mediators, cyto-
kines, and chemokines that potentiate airway inflammation
and contribute to lung tissue remodeling [2], and significantly 2. Characteristics of benralizumab
to asthma exacerbations [3].
Benralizumab is a fully humanized afucosylated IgG1κ mAb
Interleukin-5 (IL-5) is known to play a pivotal role in pro-
that binds to an epitope on IL-5Rα or CD125 (Cluster of
moting the growth, differentiation, and maturation of eosino-
Differentiation 125), which is in close proximity to the IL-5
phils in bone marrow and the recruitment, activation, and
binding site and thus inhibits IL-5R signaling, independent of
survival of this cell type in tissues [4]. Eosinophils rapidly
ligand (Box 1)[7].
undergo apoptosis in the absence of IL-5. Therefore, targeting
IL-5 was identified as a potential treatment approach to pre-
vent or blunt eosinophil-mediated inflammation [5]. 2.1. Chemistry
Different methods have been developed and trialled clini-
Benralizumab (molecular formula: C6492H10060N1724O2028S42)
cally on humans for inhibiting IL-5, including using antago-
derives from a mouse mAb that was generated using con-
nists targeting either IL-5 or the IL-5 receptor (IL-5R) [5].
ventional hybridoma technology [8]. It is produced in
Mepolizumab and reslizumab are humanized monoclonal anti-
Chinese hamster ovary cells deficient in the enzyme α-1,6-
bodies (mAbs) that recognize free IL-5, while benralizumab is a
fucosyltransferase and, consequently, is not fucosylated on
humanized mAb directed at the α subunit of the IL-5R.
the biantennary oligosaccharide core. This means that the
Mepolizumab and reslizumab have been licensed in the USA,
molecular structure of benralizumab has been engineered
Europe, and Japan for use in refractory eosinophilic asthma
without fucose sugar residue in the CH2 region of its Fc
following successful phase III studies demonstrating reduc-
domain.
tions in severe exacerbations, although in the UK, the

CONTACT Mario Cazzola mario.cazzola@uniroma2.it Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
© 2017 Informa UK Limited, trading as Taylor & Francis Group
1008 M. G. MATERA ET AL.
Box 1. Drug Summary
Drug name Benralizumab
Phase Phase III
Indication Treatment of asthma with an eosinophilic phenotype
Mechanism of Humanized mAb directed at the α subunit of the IL-5R
action
Route of Subcutaneous, intravenous (?)
administration
Molecular formula C6492H10060N1724O2028S42
Pivotal studies CALIMA [23], SIROCCO [24], BISE [25], ZONDA [26],
GREGALE [27]
2.2. Mechanism of action
Binding epitope mapping analyses identified the amino acid
isoleucine-61 of the segment B in domain 1 of the human IL-
5Rα as the critical residue for benralizumab binding [9]. This
epitope has previously been identified as a portion of the IL-5
binding site [10], providing an explanation for its neutralizing
activity. The binding of benralizumab with the α chain of IL-5R
results in inhibition of hetero-oligomerization of α and β sub-
units and thus no signal transduction occurs.
Afucosylation enhances the interaction of benralizumab
with its binding site. Removal of the fucose sugar residue in
the CH2 region of the oligosaccharide core of human IgG1
results in a 5- to 50-fold higher affinity to the main activating
Fcγ receptor (human FcγRIIIa) expressed on natural killer cells,
macrophages, and neutrophils. This modification amplifies
antibody-dependent cell-mediated cytotoxicity (ADCC) func-
tions of eosinophils and basophils by >1000-fold over its
fucosylated parental antibody and consequently depletes IL-
5Rα-expressing cells [9]. By acting on the IL-5R by ADCC,
benralizumab decreases blood eosinophils and basophils
close to the limit of detection and reduces eosinophil precur-
sors in the bone marrow by 80% or more.
The blockade of IL-5R signaling, independent of ligand, and
depletion of IL-5Rα-expressing cells may underlie enhanced
clinical efficacy [11].
2.3. Preclinical studies
In vitro studies demonstrated that benralizumab was capable
to prevent eosinophil and basophil degranulation and pro-
voke eosinophil and basophil apoptosis [9].
In nonhuman primates, repeat administrations of benrali-
zumab (0.1, 1, 10, or 30 mg/kg every 3 weeks, followed by an
18-day recovery period in the highest dose group) reduced
peripheral blood eosinophils to less than the limit of detection
after the first administration, indicating the desired
Table 1. Summary of pharmacokinetic parameters of benralizumab..
Dose Cmax AUC∞
0.03–3 mg/kg i.v. 1 ± 0.3–82 ± 18μg/mL 5 ± 2–775 ± 110 μg∗d/mL
25–200 mg s.c. 1.2–14 μg/mL 0.12 ± 0.071–1.2 ± 0.11 mg day/mL
Data from [12] and [13].
AUC∞: area under the curve from time 0 extrapolated to infinite time; CL: systemic clearance; Cmax: maximum concentration; T1/2: elimination half life; Vss: volume of
distribution at steady state; i.v.: intravenous; s.c.: subcutaneous.
pharmacologic effect [9]. Of particular note, benralizumab
also depleted eosinophil precursors from the cynomolgus
monkey bone marrow without affecting precursors of the
megakaryocytic, myeloid (other than eosinophilic), and ery-
throid lineages [9].
Immunohistochemical studies in the lung tissue of mild
asthmatics proved that benralizumab is able to prominently
recognize lung-tissue resident eosinophils and specifically
bind to them [9]. It stains more than 90% of eosinophils,
suggesting that IL-5R density is sufficient for benralizumab
engagement in this key location.
2.4. Pharmacokinetic and pharmacodynamic properties
Following intravenous administration in a single ascending
intravenous dose study (0.0003–3 mg/kg) in patients with
mild atopic asthma, the pharmacokinetic activity was approxi-
mately dose proportional [12]. At doses of 0.03–3 mg/kg, the
mean maximum concentration and mean area under the
curve were 1–82 and 5–775 μg/mL, respectively (Table 1).
The mean volume of distribution of benralizumab (52–
93 mL/kg) was greater than the plasma volume, suggesting
potential binding of benralizumab to IL-5Rα-expressing blood
cells and/or penetration into extravascular tissues. The mean
elimination half-life predicted was around 18 days, which is
typical for human IgG antibodies. The systemic clearance was
measured to be approximately 4 mL/kg/day. Benralizumab
was well tolerated and reduced blood eosinophil counts at
dosages of ≥0.3 mg/kg within 24 h after dosing; these eosi-
nophil count reductions lasted for at least 12 weeks.
A Phase II multiple ascending dose (25, 100, or 200 mg)
safety study using a subcutaneous formulation of benralizu-
mab in adult asthmatics resulted in pharmacokinetic/pharma-
codynamic activities similar to those observed with
intravenous dosing [13,14] (Table 1). Peripheral blood eosino-
phil levels were depleted in all active cohorts by day 7, and
this was maintained for at least 161 days with an acceptable
safety profile.
A Phase I study evaluated the effects of benralizumab on
eosinophil counts in airway mucosal/submucosal biopsies,
sputum, bone marrow, and peripheral blood in patients with
mild-to-moderate asthma and ≥2.5% sputum eosinophilia
despite inhaled corticosteroid (ICS) therapy [15]. Patients
were randomized to single intravenous placebo or benralizu-
mab 1 mg/kg (day 0) (cohort 1) and to three monthly sub-
cutaneous doses of placebo or benralizumab 100 or 200 mg
(days 0, 28, and 56) (cohort 2). Eosinophil counts were reduced
in the airway mucosa following benralizumab intravenous and
subcutaneous compared with placebo. Differences between
Parameters
CL Vss T1/2
7 ± 3–4 ± 0.6 mL/kg/day 65 ± 28–71 ± 18 mL/kg 7 ± 2–16 ± 3 days

benralizumab and placebo in percent change in airway eosi-
nophil count were not statistically significant within cohorts,
but reached statistical significance when the two cohorts were
combined in a post hoc analysis. In the two cohorts, benrali-
zumab produced a median decrease from baseline of 61.9%
and 95.8% in airway mucosal eosinophils, 18.7% and 89.9% in
sputum, respectively. Moreover, benralizumab administration
resulted in complete suppression of bone marrow and periph-
eral blood eosinophils. Also the number of basophils, which
expressed IL-5Rα, markedly decreased.
Sera of patients enrolled in the previous two trials were
collected and compared with sera of healthy volunteers [16].
Blood eosinophils, IL-5, eosinophil-derived neurotoxin (EDN),
eosinophilic cationic protein ECP, eotaxin/chemokine (CeC
motif) 11 (CCL11), eotaxin-2/CCL24, tumour necrosis factor
(TNF), and interferon γ (IFN-γ) were measured at baseline
and post benralizumab administration. Baseline serum EDN
levels directly correlated with blood eosinophils. After treat-
ment, a significant reduction of blood eosinophils and sera
EDN and ECP were found in comparison to baseline (p < 0.05).
No changes in TNF or IFN-γ were observed, while serum IL-5,
eotaxin/CCL11, and eotaxin-2/CCL24 increased after benralizu-
mab administration vs. placebo (p < 0.05). These results sug-
gest that cytotoxic granule proteins were not released after
eosinophil reduction following treatment with benralizumab.
Two Phase I trials in Japanese healthy males confirmed the
pharmacokinetics and pharmacodynamics, safety, and tolerability
of ascending single intravenous (0.03, 0.1, 0.3, 1, or 3 mg/kg) and
subcutaneous (25, 100, or 200 mg) doses of benralizumab [17].
To characterize the pharmacokinetic and pharmacody-
namic properties of benralizumab in humans, benralizumab
pharmacokinetic and blood eosinophil count data from six
early-stage studies (two single-dose studies in healthy
volunteers in Japan and four clinical studies in adult
patients with asthma in North America) were pooled and
analyzed via a population approach [18]. The final popula-
tion pharmacokinetic model was a two-compartment model
with first-order elimination from the central compartment,
and first-order absorption from the dosing site for subcuta-
neous administered benralizumab. The estimated systemic
clearance was 0.323 L/day, which is within the range for
therapeutic mAbs [19]. The volumes of distribution of the
central and peripheral compartments were estimated to be
3.16 and 2.83 L, respectively, suggesting limited extravascu-
lar distribution of benralizumab [18]. The absorption of
benralizumab from the subcutaneous dosing site was rela-
tively slow, with an estimated absorption rate constant of
0.252/day (mean absorption time of 3.97 days) and bioavail-
ability of 52.6%. Body weight was identified as a clinically
relevant covariate affecting systemic clearance and volumes
of distribution of the central and peripheral compartments.
Race was a significant factor for the volume of distribution
of the central compartment, with Japanese healthy volun-
teers having a larger volume of distribution of the central
compartment than non-Japanese patients with asthma.
However, the racial difference in the volume of distribution
of the central compartment is not considered clinically rele-
vant [18]. Age, sex, and tobacco smoking history had no
apparent impact on the pharmacokinetic of benralizumab in
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 1009
healthy volunteers or patients with asthma. The life span of
circulating eosinophils in blood was fixed at 2.64 days, cor-
responding to a half-life of 44 h. The serum concentration
of benralizumab corresponding to half-maximal eosinophil
depletion was 82.7 ng/mL, and the maximal rate of eosino-
phil depletion by benralizumab was 18.8/day (mean eosino-
phil residence time of 0.053 days, or 1.28 h, in the presence
of excess benralizumab) [18].
Summarizing the effects of benralizumab on eosinophils,
reduction has been observed in sputum, lung tissues, and
bone marrow of patients with mild-to-moderate asthma [15],
and in blood of patients with mild [12], mild-to-moderate [15]
and moderate-to-severe asthma [20].
2.5. Clinical efficacy
The clinical efficacy of benralizumab in asthma has been
documented in several Phase II and III studies.
2.5.1. Early trials
Based on the simulated eosinophil profiles using the pharma-
cokinetic/pharmacodynamic model used by Wang et al. [18],
three benralizumab dosages (2, 20, or 100 mg) were selected
for efficacy assessment in a proof-of-concept phase IIb study
in patients with uncontrolled asthma [20]. Study drugs were
given as two subcutaneous injections every 4 weeks for the
first three doses, then every 8 weeks, for 1 year. Benralizumab
20 and 100 mg reduced the exacerbation rate in adults with
eosinophilic asthma who were on medium-dose or high-dose
ICSs with long-acting β2-agonists (LABAs) and had had two to
six exacerbations in the past year. Benralizumab did not
decrease exacerbation rates in noneosinophilic patients, but
resulted in significant improvements in FEV1 and in asthma
control in eosinophilic patients, noneosinophilic patients, and
patients with baseline blood eosinophil counts of at least 300
cells/μL.
The data from this trial were used in an exposure-response
analysis to identify the optimum benralizumab dosing regi-
mens to be studied in a Phase III study [21]. Based on this
analysis and overall risk assessment, 30 mg monthly subcuta-
neously injections, followed by every 8-week dosing appeared
to be the optimal regimen for benralizumab in adults and
adolescents with body weights ≥40 kg suffering from uncon-
trolled asthma.
It must be highlighted that also single doses (0.3 or 1.0 mg/
kg) of intravenous benralizumab are effective. In fact, when
administered 7 days after patients presented to the emer-
gency department with an asthma exacerbation, they have
decreased asthma exacerbation rates by 49% (3.59 vs. 1.82;
p = .01) and exacerbations resulting in hospitalization by 60%
(1.62 vs. 0.65; p = .02) in the combined groups over 12 weeks
irrespective of blood eosinophil counts [22].
2.5.2. Pivotal trials
The WINDWARD program in asthma is made up of six Phase III
trials, including SIROCCO, CALIMA, ZONDA, BISE, BORA, and
GREGALE (Table 2).
Data from two large pivotal Phase III registrational trials,
CALIMA [23] and SIROCCO [24], have been already published.
1010 M. G. MATERA ET AL.
Table 2. Pivotal trials with benralizumab in asthma.
Study Patients Study design
FitzGerald 1306 Patients with severe asthma Multicenter,
[23] uncontrolled by medium- tohigh- randomized,
dosage ICS plus LABA and a history of double-blind,
two or more exacerbations in the parallel-group,
previous year placebo-
controlled
Bleecker [24] 1205 Patients with a physician-based Multicenter,
diagnosis of asthma for at least 1 year randomized,
and at least two exacerbations while double-blind,
on high-dosage ICS plus LABA in the parallel-group,
previous year placebo-
controlled
Ferguson [25] 211 Patients with mild-to-moderate, Multicenter,
persistent asthma receiving either randomized,
low- to medium-dosage ICS or low- double-blind,
dosage ICS plus LABA therapy, with or parallel group,
without controller medication placebo-
controlled
Nair [26] 220 Patients with uncontrolled asthma Multicenter,
receiving high-dose ICS plus LABA randomized,
and OCS with or without additional double-blind,
asthma controller(s) parallel group,
placebo-
controlled
Ferguson [27] 116 Patients with severe asthma Multicenter, open- Benralizumab 30 mg SC injections via an Most patients and caregivers
label, 16 weeks
evaluation
FEV1: forced expiratory volume in 1 s; ICS: inhaled corticosteroid; LABA: long-acting β2-agonist; OCS: oral corticosteroid; SC: subcutaneous.
These trials evaluated the effect of two dosing regimens of
benralizumab 30 mg administered either every 4 weeks (Q4W)
or every 8 weeks with first three doses every 4 weeks (Q8W)
for 48 weeks (SIROCCO) or 56 weeks (CALIMA) as add-on
therapy to standard-of-care medicine across primary and key
secondary end points in asthmatic subjects with severe,
uncontrolled eosinophilic asthma despite the use of high-
dose ICSs and LABAs. Change in annual asthma exacerbation
rate as compared to placebo was the primary end point for
both trials. All subjects were then stratified into two groups
according to absolute blood eosinophil counts in a 2:1 ratio,
≥300 and <300 cells/μL. Subjects with absolute eosinophil
count ≥300 cells/μL show the greatest, statistically significant
benefits for the primary and secondary end points, although
subjects with eosinophil count <300 cells/μL also benefit to a
lesser but statistically significant degree.
In particular, the CALIMA trial randomized 1306 patients
and showed a 28% (Q8W) to 36% (Q4W) reduction in
exacerbations and significant increases in pre-bronchodila-
tor FEV1 compared with placebo with both dosing regimens
(125 mL with Q4W, and 116 mL with Q8W) for those with a
blood eosinophil count ≥300 cells/μL. The improvements in
pre-bronchodilator FEV1 were present within 4 weeks of
treatment start and were maintained throughout the entire
treatment period. Benralizumab also reduced blood
Therapy Key findings
Benralizumab 30 mg either every A 28% (Q8W) to 36% (Q4W) reduction
4 weeks (Q4W) or every 8 weeks in exacerbations and significant
(Q8W; first three doses every 4 weeks) increases in pre-bronchodilator FEV1
or placebo for 56 weeks as add on to compared with placebo with both
standard treatment dosing regimens for those with a
blood eosinophil count ≥300 cells/
μL. Reduction in blood eosinophils
from baseline (Q4W median 470
cells/μL; Q8W 480 cells/μL) through
week 4 (Q4W and Q8W median 0
cells/μL), and week 56 (Q4W and
Q8W median 0 cells/μL)
Benralizumab 30 mg either every Compared with placebo, both
4 weeks (Q4W) or every 8 weeks benralizumab dosing regimens
(Q8W; first three doses every 4 weeks) reduced the annual asthma
or placebo for 48 weeks as add on to exacerbation rate and significantly
standard treatment improved pre-bronchodilator FEV1
over 48 weeks. Asthma symptoms
were improved only by the Q8W
regimen
Benralizumab 30 mg or placebo SC 80 mL greater improvement from
injections every 4 weeks for 12 weeks baseline in pre-bronchodilator FEV1
with benralizumab. Reduction in
median blood eosinophil counts to 0
cells/μL with benralizumab, with 230
cells/μL in the placebo group, at
week 12
Benralizumab 30 mg either every Significant reduction in the median
4 weeks (Q4W) or every 8 weeks final OCS doses from baseline by
(Q8W; first three doses every 4 weeks) 75% vs. a reduction of 25% in the
or placebo for 28 weeks as add on to placebo group. Significant reduction
standard treatment in asthma exacerbation rate by 55%
(Q4W) and 70% (Q8W) vs. placebo
despite reduction in OCS dosages.
No significant effect on FEV1
accessorized prefilled syringe in an at- successfully administered
home setting. benralizumab
eosinophils from baseline (Q4W median 470 cells/μL; Q8W
480 cells/per μL) through week 4 (Q4W and Q8W median 0
cells/μL), and week 56 (Q4W and Q8W median 0 cells/μL).
The SIROCCO trial randomized 1205 participants and found
a 45% (Q4W) to 51% (Q8W) reduction in exacerbation rate
in the highest eosinophilic count group with both dosing
regimens compared with a 17–30% reduction in those with
a blood eosinophil count <300 cells/μL. The time to first
asthma exacerbation was longer for both benralizumab
treatment cohorts compared with placebo, with the prob-
ability of having an asthma exacerbation reduced by 37%
for the Q4W cohort and by 40% for the Q8W cohort. Lung
function was also significantly improved in the eosinophilic
group for those receiving 8-weekly injections. The difference
in least-squares mean change from baseline between the
benralizumab Q4W and placebo cohorts was 106 mL
(p = 0.0215) and between the benralizumab Q8W and pla-
cebo cohorts it was 159 mL (p = 0.0006). Asthma symptoms
were improved only by the Q8W regimen. It is noteworthy
that the reduction in exacerbation rates was greater in the
SIROCCO trial, which generally had patients with more
severe asthma, than in the CALIMA trial, which had patients
with less severe forms of asthma, but also that both studies
also demonstrated a reduction in annualized exacerbation
rates in patients whose eosinophil levels were <300 cells/μL.
 EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 1011

In addition, Q8W dosing seemed to be more effective than 2.7. Ongoing trials
Q4W dosing.
Several trials are currently recruiting participants. The first trial
The BISE study investigated the efficacy and safety of ben-
(ClinicalTrials.gov Identifier: NCT02869438) aims to investigate
ralizumab in 211 eligible patients with mild-to-moderate, per-
the onset and maintenance of effect of benralizumab on lung
sistent asthma that received benralizumab 30 mg or placebo
function, blood eosinophils, asthma control metrics, and qual-
subcutaneously every 4 weeks for 8 weeks [25]. The primary
ity of life during 12-week treatment in patients with uncon-
end point was changed from baseline in pre-bronchodilator
trolled, severe asthma with eosinophilic inflammation. A
FEV1 at week 12. Benralizumab treatment resulted in an 80 mL
subset of patients is taking part in body plethysmography
greater improvement from baseline in pre-bronchodilator
substudy to further investigate the effect on lung function.
FEV1 than did placebo treatment. Benralizumab treatment
Also the pharmacokinetics and immunogenicity of benralizu-
reduced median blood eosinophil counts to 0 cells/μL at
mab is under evaluation.
week 12 compared with 230 cells/μL in the placebo group;
The second trial in progress (ClinicalTrials.gov Identifier:
depletion of blood eosinophils was maintained through to
NCT02821416) is a randomized, double-blind, parallel group,
week 20 in the benralizumab group.
placebo-controlled study designed to evaluate the effect of a
The ZONDA Phase III trial evaluated the oral corticosteroid
fixed 30 mg dose of benralizumab administered subcuta-
(OCS) sparing effects in 220 patients with severe asthma
neously every 4 weeks for three doses on allergen-induced
receiving high dosage ICS/LABA and OCS [26]. Benralizumab,
inflammation in subjects with mild atopic asthma challenged
at a dose of 30 mg administered subcutaneously either every
with an inhaled allergen.
4 weeks (Q4W) or every 8 weeks with the first three doses
A multicenter, double-blind, randomized, parallel group,
administered every 4 weeks (Q8W), significantly reduced the
Phase III safety extension study to evaluate the safety and
median final oral glucocorticoid doses from baseline by 75%,
tolerability of benralizumab in asthmatic adults and adoles-
as compared with a reduction of 25% in the OCS doses in the
cents on ICS plus LABA (BORA) is ongoing (ClinicalTrials.gov
placebo group. It also significantly reduced asthma exacerba-
Identifier: NCT02258542). Patients who will complete a mini-
tion rate by 55% (Q4W) and 70% (Q8W) vs. placebo despite
mum of 16 weeks, and no more than 40 weeks, in this study,
reduction in OCS dosages. No significant effect on FEV1 was
will be given the option to transition to an open-label safety
observed at the end of the trial.
extension study (MELTEMI) (ClinicalTrials.gov Identifier:
Also the GREGALE multicenter, open-label trial, which
NCT02808819); the study population will be monitored for
assessed patient- and caregiver-reported functionality, perfor-
up to 2 additional years.
mance, and reliability of an accessorized prefilled syringe used
A further trial (ClinicalTrials.gov Identifier: NCT02968914) is
to administered benralizumab 30 mg subcutaneously in an at-
an open-label, single-dose pharmacokinetic comparability
home setting, has recently been presented as an abstract [27].
study to demonstrate comparable drug exposure following
It showed that most patients and caregivers successfully admi-
subcutaneous benralizumab administration by using accessor-
nistered benralizumab in an at-home setting and the acces-
ized prefilled syringe or autoinjector devices in healthy volun-
sorized prefilled syringe was functional, reliable, and
teers stratified by weight group (55–69.9, 70–84.9, and
performed well.
85–100 kg).

2.6. Safety, tolerability, toxicity 2.8. Regulatory affairs

To date, the most common adverse reactions seen with ben-
ralizumab include headaches, nasopharyngitis, and nausea
[28,29]. Injection site reactions have also been reported.
Busse et al. [12] recommended an intravenous infusion rate
of at least 30 min due to mild transient acute adverse events
in four subjects dosed before this rate modification.
The adverse event frequency was similar between benrali-
zumab-treated patients vs. placebo-treated patients for both
SIROCCO and CALIMA trials (72% and 74% for all benralizu-
mab-treated patients vs. 76% and 78% for placebo-treated
patients observed in SIROCCO [24] and CALIMA [23], respec-
tively). The most common (≥5%) adverse events in benralizu-
mab-treated patients observed in SIROCCO were asthma,
nasopharyngitis, upper respiratory infection, headache, bron-
chitis, sinusitis, influenza, and pharyngitis; and in CALIMA were
nasopharyngitis, asthma, bronchitis, upper respiratory tract
infection, headache, and sinusitis. Antidrug antibodies were
detected in 15% of treated patients in CALIMA trial, but no
clinically relevant consequences were observed in those
patients.
Codeveloped by AstraZeneca and Kyowa Hakko Kirin Co.,
benralizumab may receive regulatory approval in 2017, but it
is still unclear when exactly it will happen. It has been
accepted for regulatory review in the USA, Canada, the EU,
and Japan. The European Medicines Agency (EMA) informed
that they have received an application for evaluating benrali-
zumab for centralized marketing authorization for the treat-
ment of severe asthma with an eosinophilic phenotype in
April 2017 [EMEA/H/C/004433]. The US FDA has also accepted
the autoinjector for regulatory review in the USA.
3. Conclusion
Benralizumab is a humanized mAb directed at the α subunit of
the IL-5R. Rationally designed combined preliminary pharma-
cokinetic/pharmacodynamic studies have provided an early
indication of general safety and preliminary pharmacokinetic/
pharmacodynamic parameters that have permitted optimiza-
tion of the design and timelines of the pivotal trials. Data from
the Phase III WINDWARD program have documented that
1012 M. G. MATERA ET AL.
benralizumab reduces asthma exacerbation rates, statistically
improves pre-bronchodilator FEV1, and is well tolerated.
4. Expert opinion
Eosinophils are a fundamental component (and marker) of
asthma pathophysiology in many severe asthmatics, causing
inflammation and airways hyperresponsiveness. Such effects
result in frequent exacerbations, impaired lung function, and
reduced quality of life [30]. IL-5 is a key cytokine for eosinophil
growth, differentiation, recruitment, activation, and survival
[4]. Anti-IL-5-based therapies (benralizumab, mepolizumab,
and reslizumab) target the IL-5-signaling pathway and have
been widely researched.
Single escalating doses of benralizumab result in a marked
reduction of peripheral blood eosinophil counts within 24 h
after dosing, with an acceptable safety profile [12]. It is note-
worthy that the mean volume of distribution of benralizumab
is greater than the plasma volume, suggesting potential bind-
ing of benralizumab to IL-5Rα-expressing blood cells and/or
penetration into extravascular tissues [12]. Unlike other cell
membrane receptor-targeted mAbs, benralizumab pharmaco-
kinetics is dose-proportional, and typical for IgG as a result of
rapid depletion of IL-5R-expressing eosinophils [18].
Benralizumab has the potential advantage over mepolizumab
and reslizumab, which have already been approved by both the
EMA and FDA for the treatment of asthma with an eosinophilic
phenotype, to target the IL-5Rα itself. Afucosylation enhances
the interaction of benralizumab with its binding site and allows
depletion of eosinophils and basophils through enhanced ADCC.
Benralizumab appears to be faster that other IL-5 treatments in
depleting peripheral blood eosinophils, with a peak reduction
within 24 h, and more potent in suppressing bone marrow
eosinophils and eosinophil precursors [31].
Other key benefits of benralizumab over mepolizumab and
reslizumab are its ability to cause tissue eosinophil apoptosis
regardless of the presence of eosinophil survival factors and
drive eosinophil apoptosis at low IL-5R densities because the
ADCC mechanism by which it works is relatively insensitive to
surface density of target receptors [32]. This mechanism might
explain the pronounced depletion of mucosal airway eosinophils
with benralizumab [4]. Its additional effect to deplete basophils is
also interesting, but it is still unknown whether these effects will
translate into differences in the clinical efficacy [31].
The fact that benralizumab is also dosed subcutaneously and is
equally effective when given every 8 weeks instead than every 4
weeks could provide patients with convenience of self-adminis-
tration and make it appealing for patients who dislike injections.
As suggested by Shrimanker and Pavord [4] commenting
the paper of Nowak et al. [22], benralizumab might also be
used in the treatment of acute eosinophilic asthma attacks as
an adjunct to OCSs, or even in place of them as the main
benefit from OCSs seems to be the eosinophil-depleting
effect, which is achieved rapidly with benralizumab.
However, the benefits of new biological agents, and con-
sequently also of benralizumab, to treat severe asthma clearly
depend on the selection of an appropriate patient population
[30]. Interestingly, it seems that high blood eosinophil con-
centrations and low serum dipeptidyl-peptidase and periostin
at baseline predict exacerbation rate reduction by benralizu-
mab for patients with moderate-to-severe asthma [32].
We still do not know what is the real advantage, if any,
of the intriguing pharmacokinetic/pharmacodynamic profile
of benralizumab over mepolizumab, and reslizumab. Direct
comparisons among IL-5 inhibitors for severe asthma are
not available in the literature. Two recent meta-analyses
[33,34] have explored efficacy and safety of anti-IL-5 ther-
apy in patients with asthma, but no clear superiority
appeared between benralizumab, mepolizumab, and resli-
zumab when appropriate doses were compared.
Unfortunately, both meta-analyses did not include data
from the WINDWARD program and, in any case, indirect
comparisons are difficult due to substantial differences in
study protocol designs. For this reason, we strongly agree
that further trials are necessary to determine the most
effective asthma treatment drug and studies need to be
performed that distinguish which patients will respond to
particular mAbs, both within and between classes (i.e. who
will respond to mepolizumab vs. benralizumab or reslizu-
mab vs. benralizumab) [32].
Funding
This paper was not funded.
Declaration of interest
M Cazzola and MG Matera have participated as a speaker, and advisor in
scientific meetings and courses under the sponsorship of AstraZeneca.
The authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
ORCID
Luigino Calzetta http://orcid.org/0000-0003-0456-069X
Mario Cazzola http://orcid.org/0000-0003-4895-9707
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Coumou H, Bel EH. Improving the diagnosis of eosinophilic asthma.
Expert Rev Respir Med. 2016;10(10):1093–1103.
2. Rosenberg HF, Dyer KD, Foster PS. Eosinophils: changing perspec-
tives in health and disease. Nat Rev Immunol. 2013;13(1):9–22.
3. Nissim Ben Efraim AH, Levi-Schaffer F. Tissue remodeling and
angiogenesis in asthma: the role of the eosinophil. Ther Adv
Respir Dis. 2008;2:163–171.
4. Shrimanker R, Pavord ID. Interleukin-5 inhibitors for severe asthma:
rationale and future outlook. BioDrugs. 2017;31(2):93–103.
5. Chung KF. Clinical management of severe therapy-resistant
asthma. Expert Rev Respir Med. 2017;11(5):395–402.
6. Barnes PJ. COUNTERPOINT: will new anti-eosinophilic drugs be
useful in asthma management? no. Chest. 2017;151(1):17–20.
7. Ghazi A, Trikha A, Calhoun WJ. Benralizumab - a humanized mAb
to IL-5Rα with enhanced antibody-dependent cell-mediated cyto-
toxicity - a novel approach for the treatment of asthma. Expert
Opin Biol Ther. 2012;12(1):113–118.
8. Koike M, Nakamura K, Furuya A, et al. Establishment of humanized
anti-interleukin-5 receptor alpha chain monoclonal antibodies

having a potent neutralizing activity. Hum Antibodies. 2009;18(1–
2):17–27.
9. Kolbeck R, Kozhich A, Koike M, et al. MEDI-563, a humanized anti-
IL-5 receptor α mAb with enhanced antibody-dependent cell
mediated cytotoxicity function. J Allergy Clin Immunol. 2010;125
(6):1344–1353.e2.
10. Ishino T, Pasut G, Scibek J, et al. Kinetic interaction analysis of
human interleukin 5 receptor alpha mutants reveals a unique
binding topology and charge distribution for cytokine recognition.
J Biol Chem. 2004;279(10):9547–9556.
11. Tan LD, Bratt JM, Godor D, et al. Benralizumab: a unique IL-5
inhibitor for severe asthma. J Asthma Allergy. 2016;9:71–81.
12. Busse WW, Katial R, Gossage D, et al. Safety profile, pharmacoki-
netics, and biologic activity of MEDI-563, an anti-IL-5 receptor anti-
body, in a phase I study of subjects with mild asthma. J Allergy Clin
Immunol. 2010;125(6):1237–1244. DOI:10.1016/j.jaci.2010.04.005.
• An important Phase I study of subjects with mild asthma
documenting that single escalating doses of benralizumab
had an acceptable safety profile and resulted in marked reduc-
tion of blood eosinophil counts within 24 h after dosing.
13. Jin F, White W, Gossage D, et al. Multiple ascending subcutaneous
(SC) dose study of MEDI-563: pharmacokinetics and immune
response in adult asthmatics [abstract]. European Respiratory
Society – 20th Annual Congress, Barcelona, Sept 18-22, 2010,
P4553
14. Gossage D, Geba G, Gillen A, et al. A multiple ascending subcuta-
neous (SC) dose study of MEDI-563, a humanized anti-IL5Ra mono-
clonal antibody, in adult asthmatics [abstract]. European
Respiratory Society – 20th Annual Congress, Barcelona, Sept
18-22, 2010, P1177
15. Laviolette M, Gossage DL, Gauvreau G, et al. Effects of benralizu-
mab on airway eosinophils in asthmatic patients with sputum
eosinophilia. J Allergy Clin Immunol. 2013;132:1086–1096.
16. Pham T, Damera G, Newbold P, et al. Reductions in eosinophil
biomarkers by benralizumab in patients with asthma. Respir Med.
2016;111:21–29.
17. Saito H, Yuji W, Kawai H, et al. Ascending single intravenous and
subcutaneous dose studies of benralizumab in Japanese healthy
male volunteers: safety, tolerability, pharmacokinetics and pharma-
codynamics [abstract]. Am J Respir Crit Care Med. 2015;191:A4270.
18. Wang B, Yan L, Yao Z, et al. Population pharmacokinetics and
pharmacodynamics of benralizumab in healthy volunteers and
patients with asthma. PT Pharmacometrics Syst Pharmacol. 2017;6
(4):249–257. DOI:10.1002/psp4.12160.
• An interesting article that describes a population approach that
has characterized the pharmacokinetic/pharmacodynamic
properties of benralizumab with data from six early-stage
clinical studies in healthy volunteers and patients with asthma.
19. Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic
monoclonal antibodies. Clin Pharmacokinet. 2010;49:633–659.
20. Castro M, Wenzel SE, Bleecker ER, et al. Benralizumab, an anti-
interleukin 5 receptor alpha monoclonal antibody, versus placebo
for uncontrolled eosinophilic asthma: a phase 2b randomised dose-
ranging study. Lancet Respir Med. 2014;2(11):879–890.
DOI:10.1016/S2213-2600(14)70201-2.
• A phase IIb trial documenting that benralizumab at 20 and 100
mg doses seemed to reduce asthma exacerbations in adults
with uncontrolled eosinophilic asthma and baseline blood
eosinophils of at least 300 cells/μL. The data from this trial
have been used in an exposure-response analysis to identify
the optimum benralizumab dosing regimens to be studied in a
Phase III study.
21. Wang B, Yan L, Hutmaker M, et al. Exposure-response analysis for
determination of benralizumab optimal dosing regimen in adults
with asthma [abstract]. Am J Respir Crit Care Med. 2014;189:A1324.
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 1013
22. Nowak RM, Parker JM, Silverman RA, et al. A randomized trial of
benralizumab, an antiinterleukin 5 receptor α monoclonal anti-
body, after acute asthma. Am J Emerg Med. 2015;33(1):14–20.
DOI:10.1016/j.ajem.2014.09.036.
• An interesting paper showing that when added to usual care, a
single intravenous dose (0.3 or 1.0 mg/kg) of benralizumab
reduced the rate and severity of exacerbations experienced
over 12 weeks by subjects who presented to the emergency
department with acute asthma.
23. FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-inter-
leukin-5 receptor α monoclonal antibody, as add-on treatment for
patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a
randomised, double-blind, placebo-controlled phase 3 trial. Lancet.
2016;388(10056):2128–2141. DOI:10.1016/S0140-6736(16)31322-8.
•• A fundamental pivotal trial that documented that benralizu-
mab significantly reduced annual exacerbation rates and was
generally well tolerated for patients with severe, uncontrolled
asthma with blood eosinophils 300 cells/μL or greater. This
study helps to identify the patient population likely to receive
the greatest benefit from benralizumab treatment.
24. Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of
benralizumab for patients with severe asthma uncontrolled with
high-dosage inhaled corticosteroids and long-acting β2-agonists
(SIROCCO): a randomised, multicentre, placebo-controlled phase 3
trial. Lancet. 2016;388(10056):2115–2127. DOI:10.1016/S0140-6736(16)
31324-1.
•• Another fundamental pivotal trial that confirms the efficacy
and safety of benralizumab for patients with severe asthma
and elevated eosinophils, which are uncontrolled by high-
dosage ICS plus LABA, and provides support for benralizumab
to be an additional option to treat this disease in this patient
population.
25. Ferguson GT, FitzGerald JM, Bleecker ER, et al. Benralizumab for
patients with mild to moderate, persistent asthma (BISE): a rando-
mised, double-blind, placebo-controlled, phase 3 trial. Lancet
Respir Med. 2017;5(7):568–576.
26. Nair P, Wenzel S, Rabe KF, et al. Oral glucocorticoid-sparing effect
of benralizumab in severe asthma. N Engl J Med. 2017;376
(25):2448–2458.
27. Ferguson GT, Mansur AH, Jacobs JS, et al. Functionality, reliability, and
performance of an accessorized pre-filled syringe with home-admi-
nistered subcutaneous benralizumab for adult patients with severe
asthma [abstract]. Am J Respir Crit Care Med. 2017;195:A3194.
28. Patel SV, Khan DA. Adverse reactions to biologic therapy. Immunol
Allergy Clin North Am. 2017;37(2):397–412.
29. Bagnasco D, Ferrando M, Caminati M, et al. Targeting interleukin-5 or
interleukin-5Ra: safety considerations. Drug Saf. 2017;40:559–570.
30. Low K, Bardin PG. Targeted therapy for severe asthma: identifying
the right patients. Mol Diagn Ther. 2017;21(3):235–247.
31. Nixon J, Newbold P, Mustelin T, et al. Monoclonal antibody therapy
for the treatment of asthma and chronic obstructive pulmonary
disease with eosinophilic inflammation. Pharmacol Ther.
2017;169:57–77.
32. Newbold P, Wu Y, Shih V, et al. High blood eosinophil concentrations
and serum biomarkers of low IL-13 pathway activation at baseline
predict exacerbation rate reduction by benralizumab for patients with
moderate to severe asthma [abstract]. Am J Respir Crit Care Med.
2016;193:A4351.
33. Wang FP, Liu T, Lan Z, et al. Efficacy and safety of anti-interleukin-5
therapy in patients with asthma: a systematic review and meta-
analysis. PLoS One. 2016;11(11):e0166833.
34. Cabon Y, Molinari N, Marin G, et al. Comparison of anti-interleukin-
5 therapies in patients with severe asthma: global and indirect
meta-analyses of randomized placebo-controlled trials. Clin Exp
Allergy. 2017;47(1):129–138.