Mechanism Of Action
Reslizumab is an interleukin-5 antagonist (IgG4, kappa).
IL-5 is the major cytokine responsible for the growth and differentiation, recruitment,
activation, and survival of eosinophils. Reslizumab binds to IL-5 with a
dissociation constant of 81 pM, inhibiting the bioactivity of IL-5 by blocking
its binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil
surface. 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. Reslizumab, by inhibiting IL-5
signaling, reduces the production and survival of eosinophils; however, the
mechanism of reslizumab action in asthma has not been definitively established.
In clinical studies with CINQAIR 3 mg/kg, reductions in
blood eosinophil counts were observed following the first dose and maintained
through 52 weeks of treatment with no signs of tachyphylaxis. Mean eosinophil
counts were 696 cells/mcL (n=245) and 624 cells/mcL (n=244) at baseline, and
were 55 cells/mcL (92% reduction, n=212) and 496 cells /mcL (21% reduction, n=212)
at the Week 52 visit for the CINQAIR and placebo treatment groups,
respectively. Early eosinophil reduction was apparent in a subset of patients
who had blood eosinophil counts assessed at days 2-3: 220 cells/mcL and 610/mcL
for CINQAIR (n=35) and placebo (n=32), respectively. Eosinophils returned
towards baseline in those CINQAIR-treated patients who completed a 90-day
follow-up assessment (n=35, 480 cells/mcL), approximately 120 days after the
last dose of CINQAIR.
Reductions of blood eosinophils were related to
reslizumab serum levels, i.e., greater reductions of blood eosinophils were
observed in subjects with higher reslizumab serum concentrations.
Treatment-emergent anti-reslizumab antibodies did not
interfere with the blood eosinophil reduction effect by reslizumab.
The pharmacokinetics (PK) of reslizumab were
characterized in healthy adults (n=130), in patients with asthma (n=438), and
in other patient populations (n=236). The PK characteristics of reslizumab were
similar across these populations. Inter-individual variability in peak and
overall exposure was approximately 20-30%.
Peak serum concentrations were typically observed at the
end of the infusion. Serum reslizumab concentrations generally declined from
peak in a biphasic manner. Following multiple doses, serum concentrations of
reslizumab accumulated approximately 1.5 to 1.9-fold.
Systemic exposure to reslizumab appeared to be unaffected
by the presence of treatmentemergent anti-reslizumab antibodies.
Reslizumab has a volume of distribution of approximately
5 liters, suggesting minimal distribution to the extravascular tissues.
Similar to other monoclonal antibodies, reslizumab is
degraded by enzymatic proteolysis into small peptides and amino acids. As
reslizumab binds to a soluble target, it is not expected to go through a
Reslizumab clearance was approximately 7 mL/hour.
Reslizumab has a half-life of about 24 days.
Age, Race, And Gender
Population PK analyses demonstrated that there was no
significant effect of age, race, or gender on the PK of reslizumab.
No clinical studies were conducted to assess the effect
of hepatic impairment on the PK of reslizumab. The results of population PK
analyses indicated that there was no significant difference in the PK of
reslizumab between patients with normal liver function tests (total bilirubin
less than or equal to the ULN and aspartate aminotransferase [AST] less than or
equal to the ULN) and mildly increased liver function tests (total bilirubin
above the ULN and less than or equal to 1.5-times the ULN or AST greater than
ULN and total bilirubin less than or equal to the ULN).
No clinical studies have been conducted to assess the
effect of renal impairment on the PK of reslizumab. The results of population
PK analyses indicated that there was no significant difference in the PK of
reslizumab between patients with normal renal function (estimated glomerular
filtration rate [eGFR] greater than or equal to 90 mL/min/1.73 m²), mild renal impairment
(eGFR 60-89 mL/min/1.73 m²), and moderate renal impairment (eGFR 30-59 mL/min/1.73
In vitro data indicate that IL-5 and reslizumab are
unlikely to affect CYP1A2, 2B6, or 3A4 enzyme activity.
No formal clinical drug interaction studies have been
conducted with reslizumab. Population PK analyses indicate that concomitant use
of either leukotriene antagonists or corticosteroids does not affect the PK of
The asthma development program for CINQAIR 3 mg/kg
(administered once every 4 weeks) included 4 randomized, double-blind,
placebo-controlled studies (Studies I-IV) 16 to 52 weeks in duration involving
981 patients 12 years of age and older. While patients aged 12 to 17 years were
included in these trials, CINQAIR is not approved for use in this age group [see
Use In Specific Populations]. All subjects continued their background
asthma therapy throughout the duration of the studies.
Studies I And II
Studies I and II were 52-week studies in 953 patients
with asthma who were required to have a blood eosinophil count of at least
400/mcL (within 3 to 4 weeks of dosing), and at least 1 asthma exacerbation
requiring systemic corticosteroid use over the past 12 months. The majority of patients
(82%) were on medium-high dose inhaled corticosteroids plus a long-acting beta
agonist (ICS/LABA) at baseline. Maintenance oral corticosteroids (OCS) (up to
10 mg of prednisone per day or equivalent) were allowed; 106 (11%) patients
were on OCS at baseline. CINQAIR 3 mg/kg administered once every 4 weeks for a
total of 13 doses was evaluated compared with placebo.
Study III was a 16-week study in 315 patients who were
required to have a blood eosinophil count of at least 400/mcL at screening
(within 3 to 4 weeks of dosing). Maintenance OCS were not allowed. CINQAIR 3
mg/kg or 0.3 mg/kg administered once every 4 weeks for a total of 4 doses was
evaluated compared with placebo. While 2 doses of CINQAIR were studied, CINQAIR
3 mg/kg is the only recommended dose [see DOSAGE AND ADMINISTRATION].
Study IV was a 16-week study in 496 patients unselected
for baseline blood eosinophil levels (approximately 80% of patients had a
screening [within 3 to 4 weeks of dosing] blood eosinophil count of less than
400/mcL). Maintenance OCS were not allowed. CINQAIR 3 mg/kg administered once
every 4 weeks for a total of 4 doses was evaluated compared with placebo.
The demographics and baseline characteristics of these 4
studies is provided in Table 1.
Table 1: Demographics and Baseline Characteristics of
Patients in Asthma Studies
|Mean age (yr)
|Duration of asthma, mean (yr)
|Baseline Pre-bronchodilator FEV1, mean % predicteda
|Baseline Reversibility, mean % AFEV1 post-SABAa
|Baseline mean blood eosinophil count/mcLa
|Mean number of exacerbations in previous year
|a Baseline for lung function and eosinophil
count is the day of randomization.
FEV1=forced expiratory volume in 1 second; SABA=short-acting beta
All patients had to be on inhaled corticosteroid (ICS) background therapy and
could have been receiving any combination of background therapies (ICS with or
without another controller [non-ICS and/or OCS]).
The primary endpoint for Studies I and II was the
frequency of asthma exacerbations for each patient during the 52-week treatment
period. An asthma exacerbation was defined as a worsening of asthma that
required at least 1 of the following medical interventions:
- Either the use of a systemic corticosteroid, or ≥ 2-fold
an increase in the use of ICS for 3 or more days, and/or
- Asthma-related emergency treatment including at least 1
of the following: an unscheduled visit to their healthcare professional for
nebulizer treatment or other urgent treatment to prevent worsening of asthma
symptoms; a visit to the emergency room for asthma-related treatment; or an
The medical intervention had to be corroborated with at
least 1 of the following: 1) a decrease in forced expiratory volume in 1 second
(FEV1) by 20% or more from baseline, 2) a decrease in peak expiratory flow rate
(PEFR) by 30% or more from baseline on 2 consecutive days, or 3) worsening of
symptoms or other clinical signs per physician evaluation of the event.
In Studies I and II, patients receiving CINQAIR 3 mg/kg
administered once every 4 weeks had significant reductions in the rate of all
asthma exacerbations compared to placebo (Table 2). Exacerbations requiring the
use of a systemic corticosteroid (e.g., OCS) as well as exacerbations resulting
in hospitalization or an emergency room visit were each reduced with CINQAIR 3 mg/kg.
Table 2: Frequency of Asthma Exacerbations during the
52-Week Treatment Period in Patients with Severe Asthma with an Eosinophilic
Phenotype (Studies I and II)a
||Asthma Exacerbation Rate
||Rate Ratio (95% CI)
||CINQAIR 3 mg/kg (n=245)
||CINQAIR 3 mg/kg (n=232)
|Exacerbations requiring systemic corticosteroid use
||CINQAIR 3 mg/kg (n=245)
||CINQAIR 3 mg/kg (n=232)
|Exacerbations resulting in a hospitalization AND/OR emergency room visit
||CINQAIR 3 mg/kg (n=245)
||CINQAIR 3 mg/kg (n=232)
|a Randomized patients
The proportion of patients who did not experience an
asthma exacerbation during the 52-week treatment period was higher in the
CINQAIR 3 mg/kg group (62% and 75%) compared with the placebo group (46% and
55%), in Studies I and II, respectively. The time to first asthma exacerbation
was significantly longer for the groups receiving CINQAIR 3 mg/kg compared with
placebo in both Studies I and II. A representative figure from Study I is shown
below (Figure 1). Study II showed similar results.
Figure 1: Time to First Asthma Exacerbation by
Treatment Group in Patients with Severe Asthma with an Eosinophilic Phenotype
The effect of CINQAIR 3 mg/kg administered once every 4
weeks on FEV1 over time relative to placebo was assessed in all 4 studies
(Table 3). FEV1 was the primary endpoint in the 16-week lung function studies:
Study III (Figure 2) and Study IV.
Study III also studied a lower dose, CINQAIR 0.3 mg/kg,
that produced significant but numerically smaller changes in FEV1 and blood
eosinophil reduction compared with the 3 mg/kg dose. While 2 doses of CINQAIR
were studied, CINQAIR 3 mg/kg is the only recommended dose [see DOSAGE AND
Study IV was the only study to test CINQAIR 3 mg/kg in
asthma patients unselected for blood eosinophils (measured 3 to 4 weeks prior
to dosing); association of treatment effect (i.e., difference between CINQAIR
and placebo in the change in FEV1 at Week 16) and baseline blood eosinophils was
Table 3: Mean Change (95% CI) from Baseline in FEV1 in
mL Over 16Weeks (Difference from CINQAIR and Placebo) in Patients with Severe
Asthma with an Eosinophilic Phenotype
||FEV1 Change in mL
||137 (76, 198)
||93 (30, 155)
||160 (60, 259)
|a Study IV studied asthma patients unselected
for blood eosinophils
Improvements in FEV1 were observed at 4 weeks following
the first dose of CINQAIR for Studies I and II and maintained through Week 52.
Figure 2: Mean Change from Baseline in FEV1 in
Patients with Severe Asthma with an Eosinophilic Phenotype (Study III)
The Asthma Control Questionnaire-7 (ACQ-7) and Asthma
Quality of Life Questionnaire (AQLQ) were both assessed in Studies I, II, and
III. The responder rate for both measures was defined as an improvement in
score of 0.5 or more as threshold over 16 weeks.
- For ACQ-7, the responder rate for those randomized to
CINQAIR vs. placebo was 69% vs. 65% for Study I, 70% vs. 58% for Study II, and
64% vs. 58% for Study III.
- For AQLQ, the responder rate for those randomized to
CINQAIR vs. placebo was 66% vs. 58% for Study I, 67% vs. 55% for Study II, and
64% vs. 48% for Study III.