Mechanism Of Action
Benralizumab is a humanized afucosylated, monoclonal
antibody (IgG1, kappa) that directly binds to the alpha subunit of the human
interleukin-5 receptor (IL-5Rα) with a dissociation constant of 11 pM. The
IL-5 receptor is expressed on the surface of eosinophils and basophils. In an in
vitro setting, the absence of fucose in the Fc domain of benralizumab
facilitates binding (45.5 nM) to Fc?RIII receptors on immune effectors
cells, such as natural killer (NK) cells, leading to apoptosis of eosinophils
and basophils through antibody-dependent cell-mediated cytotoxicity (ADCC).
Inflammation is an important component in the
pathogenesis of asthma. Multiple cell types (e.g., mast cells, eosinophils,
neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine,
eicosanoids, leukotrienes, cytokines) are involved in inflammation.
Benralizumab, by binding to the IL-5Rα chain, reduces eosinophils
through ADCC; however, the mechanism of benralizumab action in asthma has not
been definitively established.
In the 52-week Phase 2 dose-ranging trial, asthma
patients received 1 of 3 doses of benralizumab [2 mg (n=81), 20 mg (n=81), or
100 mg (n=222)] or placebo (n=222). All doses were administered every 4 weeks
for the first 3 doses, followed by every 8 weeks thereafter. Median blood
eosinophil levels at baseline were 310, 280, 190 and 190 cells/μL in the
2, 20, and 100 mg benralizumab and placebo groups, respectively. Dose-dependent
reductions in blood eosinophils were observed. At the time of the last dose
(Week 40), median blood eosinophil counts were 100, 50, 40, 170 cells/μL
in the 2, 20, and 100 mg benralizumab and placebo groups, respectively.
A reduction in blood eosinophil counts was observed 24
hours post dosing in a Phase 2 trial.
In Trials 1 and 2, following SC administration of
benralizumab at the recommended dose blood eosinophils were reduced to a median
absolute blood eosinophil count of 0 cells/μL [see Clinical Studies].
This magnitude of reduction was seen at the first observed time point, 4 weeks
of treatment, and was maintained throughout the treatment period.
Treatment with benralizumab was also associated with
reductions in blood basophils, which was consistently observed across all
clinical studies. In the Phase 2 dose-ranging trial, blood basophil counts were
measured by flow cytometry. Median blood basophil counts were 45, 52, 46, and
40 cells/μL in the 2 mg, 20 mg and 100 mg benralizumab and placebo groups,
respectively. At 52 weeks (12 weeks after the last dose), median blood basophil
counts were 42, 18, 17, and 46 cells/μL in the 2 mg, 20 mg and 100 mg
benralizumab and placebo groups, respectively.
The pharmacokinetics of benralizumab was approximately
dose-proportional in patients with asthma following subcutaneous administration
over a dose range of 20 to 200 mg.
Following subcutaneous administration to patients with
asthma, the absorption half-life was approximately 3.6 days. Based on
population pharmacokinetic analysis, the estimated absolute bioavailability was
approximately 58% and there was no clinically relevant difference in relative
bioavailability in the administration to the abdomen, thigh, or arm.
Based on population pharmacokinetic analysis, central and
peripheral volume of distribution of benralizumab was 3.2 L and 2.5 L,
respectively, for a 70kg individual.
Benralizumab is a humanized IgG1 monoclonal antibody that
is degraded by proteolytic enzymes widely distributed in the body and not
restricted to hepatic tissue.
From population pharmacokinetic analysis, benralizumab
exhibited linear pharmacokinetics and no evidence of target receptor-mediated
clearance pathway. The estimated typical systemic clearance (CL) for
benralizumab was 0.29 L/d for a subject weighing 70kg. Following subcutaneous
administration, the elimination half-life was approximately 15 days.
Based on population pharmacokinetic analysis, age did not
affect benralizumab clearance.
A population pharmacokinetics analysis indicated that
there was no significant effect of gender and race on benralizumab clearance.
No formal clinical studies have been conducted to
investigate the effect of renal impairment on benralizumab. Based on population
pharmacokinetic analysis, benralizumab clearance was comparable in subjects
with creatinine clearance values between 30 and 80 mL/min and patients with
normal renal function. There are limited data available in subjects with creatinine
clearance values less than 30 mL/min; however, benralizumab is not cleared
No formal clinical studies have been conducted to
investigate the effect of hepatic impairment on benralizumab. IgG monoclonal
antibodies are not primarily cleared via hepatic pathway; change in hepatic
function is not expected to influence benralizumab clearance. Based on
population pharmacokinetic analysis, baseline hepatic function biomarkers (ALT,
AST, and bilirubin) had no clinically relevant effect on benralizumab
No formal drug-drug interaction studies have been
Cytochrome P450 enzymes, efflux pumps and protein-binding
mechanisms are not involved in the clearance of benralizumab. There is no
evidence of IL-5Rα expression on hepatocytes and eosinophil depletion does
not produce chronic systemic alterations of proinflammatory cytokines.
An effect of benralizumab on the pharmacokinetics of
co-administered medications is not expected. Based on the population analysis,
commonly co-administered medications had no effect on benralizumab clearance in
patients with asthma.
The asthma development program for FASENRA included one
52-week dose ranging exacerbation trial (NCT01238861) three confirmatory
trials, (Trial 1 [NCT01928771], Trial 2 [NCT01914757], Trial 3 [NCT02075255])
and one 12-week lung function trial (NCT02322775).
The Phase 2 randomized, double-blind, placebo-controlled,
52-week dose-ranging trial, enrolled 609 asthmatic patients 18 years of age and
older. Patients were treated with benralizumab 2 mg, 20 mg, or 100 mg or
placebo administered subcutaneously every 4 weeks for 3 doses followed by every
8 weeks. The primary endpoint was the annual exacerbation rate and forced
expiratory volume in 1 second (FEV1) and ACQ-6 were key secondary endpoints.
Patients were required to have a history of 2 or more asthma exacerbations (but
no more than 6 exacerbations) requiring systemic corticosteroid treatment in
the past 12 months, ACQ-6 score of 1.5 at least twice during screening, and
reduced morning lung function at screening [pre-bronchodilator FEV1 below 90%]
despite treatment with medium-or high-dose ICS plus LABA. Patients were
stratified by eosinophilic status. The annual exacerbation rate reduction for
patients receiving benralizumab 2 mg, 20 mg, and 100 mg were -12% (80% CI: -52,
18), 34% (80% CI: 6, 54), 29% (80% CI: 10, 44), respectively, compared to
placebo (rate 0.56).
Results from this trial and exposure-response modelling
of exacerbation rate reduction supported the evaluation of benralizumab 30 mg
in the subsequent trials [see CLINICAL PHARMACOLOGY]. FASENRA is not
approved at 2 mg, 20 mg, or 100 mg doses, and should only be administered at
the recommended dose of 30 mg [see DOSAGE AND ADMINISTRATION].
Trial 1 and Trial 2, were randomized, double-blind,
parallel-group, placebo-controlled, exacerbation trials in patients 12 years of
age and older and 48 and 56 weeks in duration, respectively. The trials
randomized a total of 2510 patients. Patients were required to have a history
of 2 or more asthma exacerbations requiring oral or systemic corticosteroid
treatment in the past 12 months, ACQ-6 score of 1.5 or more at screening, and
reduced lung function at baseline [pre-bronchodilator FEV1 below 80% in adults,
and below 90% in adolescents] despite regular treatment with high dose inhaled
corticosteroid (ICS) (Trial 1) or with medium or high dose ICS (Trial 2) plus a
long-acting beta agonist (LABA) with or without oral corticosteroids (OCS) and
additional asthma controller medications. Patients were stratified by
geography, age, and blood eosinophils count (≥300 cells/μL or
<300 cells/μL). FASENRA administered once every 4 weeks for the first 3
doses, and then every 4 or 8 weeks thereafter as add-on to background treatment
was evaluated compared to placebo.
All subjects continued their background asthma therapy
throughout the duration of the trials.
Trial 3 was a randomized, double-blind, parallel-group,
OCS reduction trial in 220 asthma patients. Patients were required treatment
with daily OCS (7.5 to 40 mg per day) in addition to regular use of high-dose
ICS and LABA with or without additional controller(s). The trial included an
8-week run-in period during which the OCS was titrated to the minimum effective
dose without losing asthma control. For the purposes of the OCS dose titration,
asthma control was assessed by the investigator based on a patient's FEV1, peak
expiratory flow, nighttime awakenings, short-acting bronchodilator rescue
medication use or any other symptoms that would require an increase in OCS
dose. Baseline median OCS dose was similar across all treatment groups.
Patients were required to have blood eosinophil counts greater than or equal to
150 cells/μL and a history of at least one exacerbation in the past 12
months. The baseline median OCS dose was 10 mg (range: 8 to 40 mg) for all 3
treatment groups (placebo, FASENRA every 4 weeks, and FASENRA every 4 weeks for
the first 3 doses, and then once every 8 weeks).
While 2 dosing regimens were studied in Trials 1, 2, and
3, the recommended dosing regimen is 30 mg FASENRA administered every 4 weeks
for the first 3 doses, then every 8 weeks thereafter [see DOSAGE AND
Table 2: Demographics and Baseline Characteristics of Asthma Trials
(N = 1204)
(N = 1306)
|Mean age (yr)
|Duration of asthma, median (yr)
|Never smoked (%)
|Mean baseline FEV1 pre-bronchodilator (L)
|Mean baseline % predicted FEV1
|Mean post-SABA FEV1/FVC (%)
|Mean baseline eosinophil count (cells/^L)
|Mean number of exacerbations in previous year
The primary endpoint for Trials
1 and 2 was the rate of asthma exacerbations in patients with baseline blood
eosinophil counts of greater than or equal to 300 cells/μL who were taking
high-dose ICS and LABA. Asthma exacerbation was defined as a worsening of
asthma requiring use of oral/systemic corticosteroids for at least 3 days,
and/or emergency department visits requiring use of oral/systemic
corticosteroids and/or hospitalization. For patients on maintenance oral
corticosteroids, an asthma exacerbation requiring oral corticosteroids was
defined as a temporary increase in stable oral/systemic corticosteroids for at
least 3 days or a single depo-injectable dose of corticosteroids. In Trial 1,
35% of patients receiving FASENRA experienced an asthma exacerbation compared
to 51% on placebo. In Trial 2, 40% of patients receiving FASENRA experienced an
asthma exacerbation compared to 51% on placebo (Table 3).
Table 3: Rate of Exacerbations, Trial 1 and 2 (ITT
||Exacerbations per year
||Rate Ratio (95% CI)
||FASENRA b (n=267)
||FASENRA b (n=239)
|Exacerbations requiring hospitalization/emergency room visit
||FASENRA b (n=267)
||FASENRA b (n=239)
|Exacerbations requiring hospitalization
||FASENRA b (n=267)
||FASENRA b (n=239)
|a Baseline blood eosinophil counts of greater
than or equal to 300 cells/μL and taking high-dose ICS
b FASENRA 30mg administered every 4 weeks for the first 3 doses, and
every 8 weeks thereafter
The time to first exacerbation was longer for the
patients receiving FASENRA compared with placebo in Trial 1 (Figure 2). Similar
findings were seen in Trial 2.
Figure 2: Kaplan-Meier
Cumulative Incidence Curves for Time to First Exacerbation, Trial 1
Subgroup analyses from Trials 1
and 2 identified patients with a higher prior exacerbation history and baseline
blood eosinophil count as potential predictors of improved treatment response.
Reductions in exacerbation rates were observed irrespective of baseline
peripheral eosinophil counts; however, patients with a baseline blood
eosinophil count ≥ 300 cells/μL showed a numerically greater
response than those with counts < 300 cells/μL. In both trials patients
with a history of 3 or more exacerbations within the 12 months prior to FASENRA
randomization showed a numerically greater exacerbation response than those
with fewer prior exacerbations.
Oral Corticosteroid Reduction
Trial 3 evaluated the effect of
FASENRA on reducing the use of maintenance oral corticosteroids. The primary
endpoint was percent reduction from baseline of the final OCS dose during Weeks
24 to 28, while maintaining asthma control (see definition of asthma control in
trial description). Compared to placebo, patients receiving FASENRA achieved
greater reductions in daily maintenance oral corticosteroid dose, while
maintaining asthma control. The median percent reduction in daily OCS dose from
baseline was 75% in patients receiving FASENRA (95% CI: 60, 88) compared to 25%
in patients receiving placebo (95% CI: 0, 33). Reductions of 50% or higher in
the OCS dose were observed in 48 (66%) patients receiving FASENRA compared to
those receiving placebo 28 (37%). The proportion of patients with a mean final
dose less than or equal to 5 mg at Weeks 24 to 28 was 59% for FASENRA and 33%
for placebo (odds ratio 2.74, 95% CI: 1.41, 5.31). Only patients with an
optimized baseline OCS dose of 12.5 mg or less were eligible to achieve a 100%
reduction in OCS dose during the study. Of those patients, 52% (22 of 42)
receiving FASENRA and 19% (8 of 42) on placebo achieved a 100% reduction in OCS
dose. Exacerbations resulting in hospitalization and/or ER visit were also
assessed as a secondary endpoint. In this 28-week trial, patients receiving
FASENRA had 1 event while those on placebo had 14 events (annualized rate 0.02
and 0.32 respectively; rate ratio of 0.07, 95% CI: 0.01, 0.63).
Change from baseline in mean
FEV1 was assessed in Trials 1, 2, and 3 as a secondary endpoint. Compared with
placebo, FASENRA provided consistent improvements over time in the mean change
from baseline in FEV1 (Figure 3 and Table 4).
Figure 3: Mean Change from Baseline in
Pre-Bronchodilator FEV1 (L), Trial 2
Table 4: Change from Baseline in Mean
Pre-Bronchodilator FEV1 (L) at End of Triala
||Difference from Placebo in Mean Change from Pre-Bronchodilator Baseline FEV1 (L)(95% CI)
||0.159 (0.068, 0.249)
||0.116 (0.028, 0.204)
||0.112 (-0.033, 0.258)
|a Week 48 in Trial 1, Week 56 in Trial 2, Week 28 in Trial 3.
Sub group analyses also showed
greater improvements in FEV1 in patients with higher baseline blood eosinophil
counts and more frequent prior exacerbation history.
The clinical development
program for FASENRA also included a 12-week, randomized, double-blind,
placebo-controlled lung function trial conducted in 211 patients with mild to
moderate asthma. Patients were treated with placebo or benralizumab 30 mg SC
every 4 weeks for 3 doses. Lung function, as measured by the change from
baseline in FEV1 at Week 12 was improved in the benralizumab treatment group
compared to placebo.
Patient Reported Outcomes
The Asthma Control
Questionnaire-6 (ACQ-6) and Standardized Asthma Quality of Life Questionnaire
for 12 Years and Older (AQLQ(S)+12) were assessed in Trials 1, 2 and 3. The
responder rate for both measures was defined as improvement in score of 0.5 or
more as threshold at the end of Trials 1, 2, and 3 (48, 56, and 28 weeks,
respectively). In Trial 1, the ACQ-6 responder rate for FASENRA was 60% vs 50%
placebo (odds ratio 1.55; 95% CI: 1.10, 2.19). In Trial 2, the ACQ-6 responder
rate for the FASENRA was 63% vs 59% placebo (odds ratio 1.16; 95% CI: 0.80,
1.68). In Trial 1, the responder rate for AQLQ(S)+12 for FASENRA was 57% vs 49%
placebo (odds ratio 1.42; 95% CI: 0.99, 2.02), and in Trial 2, 60% FASENRA vs
59% placebo (odds ratio of 1.03; 95% CI: 0.70,1.51). Similar results were seen
in Trial 3.