Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airway diseases, ATC code: R03DX10


Mechanism of action
Benralizumab is an anti-eosinophil, humanised afucosylated, monoclonal antibody (IgG1, kappa). It specifically binds to the alpha subunit of the human interleukin-5 receptor (IL- 5Rα). The IL-5 receptor is specifically expressed on the surface of eosinophils and basophils. The absence of fucose in the Fc domain of benralizumab results in high affinity for FcɣRIII receptors on immune effector cells such as natural killer (NK) cells. This leads to apoptosis of eosinophils and basophils through enhanced antibody-dependent cell- mediated cytotoxicity (ADCC), which reduces eosinophilic inflammation.


Pharmacodynamic effects
Effect on blood eosinophils
Treatment with benralizumab results in near complete depletion of blood eosinophils within 24 hours following the first dose which is maintained throughout treatment. The depletion of blood eosinophils is accompanied by a reduction in serum eosinophil granule proteins eosinophil derived neurotoxin (EDN) and eosinophil cationic protein (ECP) and a reduction in blood basophils.


Effect on eosinophils in the airway mucosa
The effect of benralizumab on eosinophils in the airway mucosa in asthmatic patients with elevated sputum eosinophil counts (at least 2.5%) was evaluated in a 12-week, phase 1, randomised, double blind, placebo-controlled clinical study with benralizumab 100 or 200 mg SC. In this study there was a median reduction from baseline in airway mucosa eosinophils of 96% in the benralizumab treated group compared to a 47% reduction in the placebo group (p=0.039).


Clinical efficacy
The efficacy of benralizumab was evaluated in 3 randomised, double-blind, parallel- group,placebo-controlled clinical trials between 28 to 56 weeks duration, in patients aged 12 to 75 years. In these studies, benralizumab was administered at a dose of 30 mg once every 4 weeks for the first 3 doses, and then every 4 or 8 weeks thereafter as add-on to background treatment and was evaluated in comparison with placebo.


The two exacerbation trials, SIROCCO (Trial 1) and CALIMA (Trial 2), enrolled a total of 2,510 patients with severe uncontrolled asthma, 64% females, with a mean age of 49 years. Patients had a history of 2 or more asthma exacerbations requiring oral or systemic corticosteroid treatment (mean of 3) in the past 12 months, Asthma Control Questionnaire- 6 (ACQ-6) score of 1.5 or more at screening, and reduced lung function at baseline (mean predicted pre-bronchodilator forced expiratory volume in 1 second [FEV1] of 57.5%), despite regular treatment with high-dose inhaled corticosteroid (ICS) (Trial 1) or with medium or high-dose ICS (Trial 2) and a long-acting β-agonist (LABA); at least one additional controller was administered to 51% and 41% of these patients, respectively.


For the oral corticosteroid (OCS) reduction trial ZONDA (Trial 3), a total of 220 asthma patients (61% female; mean age of 51 years) were enrolled; they were treated with daily OCS (8 to 40 mg per day; median of 10 mg) in addition to regular use of high-dose ICS and LABA with at least one additional controller to maintain asthma control in 53% of the cases. The trial included an 8-week run-in period during which the OCS was titrated to the minimum effective dose without losing asthma control. Patients had blood eosinophil counts ≥150 cells/μL and a history of at least one exacerbation in the past 12 months.
While 2 dose regimens were studied in Trials 1, 2, and 3, the recommended dose regimen is benralizumab administered every 4 weeks for the first 3 doses, then every 8 weeks thereafter (see section 4.2) as no additional benefit was observed by more frequent dosing. The results summarised below are those for the recommended dose regimen.


Exacerbation trials
The primary endpoint was the annual rate of clinically significant asthma exacerbations in patients with baseline blood eosinophil counts ≥300 cells/μL who were taking high-dose ICS and LABA.
Clinically significant asthma exacerbation was defined as 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 hospitalisation. For patients on maintenance OCS, this 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 both trials, patients receiving benralizumab experienced significant reductions in annual exacerbation rates compared to placebo in patients with blood eosinophils ≥300 cells/μL.
In addition, change from baseline in mean FEV1 showed benefit as early as 4 weeks, which was maintained through to end of treatment (Table 2).


Reductions in exacerbation rates were observed irrespective of baseline eosinophil count; however, increasing baseline eosinophil counts was identified as a potential predictor of improved treatment response particularly for FEV1.


Table 2. Results of annual exacerbation rate and lung function at end of treatment of Trial 1 and 2 by eosinophil count.

Trial 1                             Trial 2

Benralizumab Placebo                Benralizumab          Placebo


Blood eosinophil count n = 267             n =267           n =239             n =248
≥300 cells/μLa
Clinically significant exacerbations

Rate                                                 0.74               1.52              0.73             1.01 
Difference                                                   -0.78                               -0.29 
Rate ratio (95% CI)                                    0.49 (0.37, 0.64)                   0.72 (0.54, 0.95)  p-value                                                     <0.001                               0.019 
Pre-bronchodilator FEV1 (L)

Mean baseline                                       1.660              1.654             1.758             1.815 
Improvement from baseline                           0.398              0.239             0.330             0.215 Difference (95% CI)                                 0.159 (0.068, 0.249)                0.116 (0.028, 0.204)  p-value                                                      0.001                               0.010 
Blood eosinophil count n =131              n =140           n =125             n =122
<300 cells/μLb

Clinically significant exacerbations
Rate                                                 1.11               1.34              0.83             1.38 
Difference                                                   -0.23                               -0.55 
Rate ratio (95% CI)                                    0.83 (0.59, 1.16)                   0.60 (0.42, 0.86) 
Pre-bronchodilator FEV1 (L)

Mean change                                         0.248              0.145             0.140             0.156 
Difference (95% CI)                                0.102 (-0.003, 0.208)               -0.015 (-0.127, 0.096) a.   Intent to treat population (patients on high-dose ICS and blood eosinophils ≥300 cells/L).
b.   Not powered to detect a treatment difference in patients with blood eosinophils <300 cells/μL.


Across Trials 1 and 2 combined, there was a numerically greater exacerbation rate reduction and greater improvements in FEV1 with increasing baseline blood eosinophils.
The rate of exacerbations requiring hospitalisation and/or emergency room visits for patients receiving benralizumab compared to placebo for Trial 1 were 0.09 versus 0.25 (rate ratio 0.37, 95% CI: 0.20, 0.67, p=<0.001) and for Trial 2 were 0.12 versus 0.10 (rate ratio 1.23, 95% CI: 0.64, 2.35, p=0.538). In Trial 2, there were too few events in the placebo treatment arm to draw conclusions for exacerbations requiring hospitalisation or emergency room visits.


In both Trials 1 and 2, patients receiving benralizumab experienced statistically significant reductions in asthma symptoms (Total Asthma Score) compared to patients receiving placebo. Similar improvement in favour of benralizumab was observed for the ACQ-6 and Standardised Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) (Table 3).


Table 3. Treatment difference in mean change from baseline in total asthma symptom score, ACQ-6 and AQLQ(s)+12 at end of treatment - Patients on high-dose ICS and blood eosinophils ≥300 cells/μL

Trial 1                                Trial 2
Benralizumab      Placebo             Benralizumab        Placebo
(na=267)          (na=267)            (na=239)            (na=248)


Total asthma symptom scoreb

Mean baseline                               2.68                2.74               2.76              2.71 Improvement from baseline                                    -1.30              -1.04               -1.40             -1.16 
Difference (95% CI)                          -0.25 (-0.45, -0.06)                    -0.23 (-0.43, -0.04) p-value                                             0.012                                  0.019 
ACQ-6
Mean baseline                               2.81                2.90               2.80              2.75 Improvement from baseline                                    -1.46              -1.17               -1.44             -1.19 Difference (95% CI)
-0.29 (-0.48, -0.10)                    -0.25 (-0.44, -0.07)

AQLQ(S)+12
Mean baseline                               3.93               3.87                3.87                3.93 Improvement from baseline                                    1.56               1.26                1.56                1.31 
Difference (95% CI)                            0.30 (0.10, 0.50)                      0.24 (0.04, 0.45) a.   Number of patients (n) varies slightly due to the number of patients for whom data were available for each variable. Results shown based on last available data for each variable.
b.   Asthma symptom scale: total score from 0 (least) to 6 (most); day and night time asthma symptom scores from 0 (least) to 3 (most) symptoms. Individual day and nighttime scores were similar.


Subgroup analyses by prior exacerbation history
Subgroup analyses from Trials 1 and 2 identified patients with higher prior exacerbation history as a potential predictor of improved treatment response. When considered alone or in combination with baseline blood eosinophils count, these factors may further identify patients who may achieve greater response from benralizumab treatment (Table 4).


Table 4. Exacerbation rate and pulmonary function (FEV1) at end of treatment by number of exacerbations in the previous year - Patients on high-dose ICS and blood eosinophils ≥300 cells/μL

Trial 1                              Trial 2

Benralizumab       Placebo           Benralizumab        Placebo
(N=267)            (N=267)            (N=239)            (N=248)
Baseline of 2 exacerbations

N                                        164                 149               144                151 
Exacerbation rate                         0.57               1.04               0.63               0.62 
Difference                                         -0.47                                  0.01 
Rate ratio (95% CI)                          0.55 (0.37, 0.80)                     1.01 (0.70, 1.46) 
Pre- bronchodilator
FEV1 mean                                0.343               0.230             0.266              0.236 change

Difference (95% CI)                      0.113 (-0.002, 0.228)                 0.029 (-0.079, 0.137) Baseline of 3 or more exacerbations

N                                 103               118             95                 97 
Exacerbation rate                  0.95             2.23            0.82               1.65 
Difference                                  -1.28                           -0.84 
Rate ratio (95% CI)                  0.43 (0.29, 0.63)                0.49 (0.33, 0.74) 
Pre-bronchodilator FEV1
0.486             0.251          0.440               0.174 mean change

Difference (95% CI)                0.235 (0.088, 0.382)             0.265 (0.115, 0.415) 

Oral corticosteroid dose reduction trials
ZONDA (Trial 3), a placebo-controlled study, and PONENTE (Trial 6), a single arm, open- label study, evaluated the effect of Benralizumab on reducing the use of maintenance OCS. In Trial 3 the primary endpoint was percent reduction from baseline of the final OCS dose during Weeks 24 to 28, while maintaining asthma control. Table 5 summarises the study results for Trial 3.


Table 5. Effect of Benralizumab on OCS dose reduction, Trial 3
Benralizumab (N=73) Placebo
(N=75)
Wilcoxon rank sum test (primary analysis method)


Median % reduction in daily OCS dose from                     75 (60, 88)           25 (0, 33) baseline (95% CI)

Wilcoxon rank sum test p-value                                  <0.001 
Proportional odds model (sensitivity analysis)

Percent reduction in OCS from baseline at Week 28
≥90% reduction                                                 27 (37%)             9 (12%) 
≥75% reduction                                                 37 (51%)             15 (20%) 
≥50% reduction                                                 48 (66%)             28 (37%) 
>0% reduction                                                  58 (79%)             40 (53%) No change or no decrease in OCS                                       15 (21%)             35 (47%) 
Odds ratio (95% CI)                                               4.12 (2.22, 7.63) 
Reduction in the daily OCS dose to 0
22 (52%)              8 (19%) mg/day*

Odds ratio (95% CI)                                                  4.19 (1.58, 11.12)


Reduction in the daily OCS dose to ≤5 mg/day                         43 (59%)             25 (33%) 

Odds ratio (95% CI)                                               2.74 (1.41, 5.31) 
Exacerbation rate                                                       0.54                  1.83 
Rate ratio (95% CI)                                               0.30 (0.17, 0.53) 
Exacerbation rate requiring
0.02                  0.32 hospitalisation/emergency room visit

Rate ratio (95% CI)                                               0.07 (0.01, 0.63) * Only patients with an optimised baseline OCS dose of 12.5 mg or less were eligible to achieve a 100% reduction in OCS dose during the study.


Lung function, asthma symptom score, ACQ-6 and AQLQ(S)+12 were also assessed in Trial 3 and showed results similar to those in Trials 1 and 2.


Trial 6 enrolled 598 adult patients with severe asthma (blood eosinophil count ≥150 cells/μL at entry or ≥300 cells/μL in the past 12 months if study entry count was <150 cells/μL) who were oral corticosteroid-dependent. The primary endpoints were proportion of patients who eliminated OCS while maintaining asthma control and proportion of patients who achieved a final OCS dose less than or equal to 5 mg while maintaining asthma control and taking into account adrenal function. The proportion of patients who eliminated maintenance OCS was 62.9%. The proportion of patients who achieved an OCS dose less than or equal to 5 mg (while maintaining asthma control and not limited by adrenal function) was 81.9%. Effects on OCS reduction were similar irrespective of blood eosinophil count at study entry (including patients with blood eosinophils <150 cells/μL) and maintained over an additional period of 24 to 32 weeks.
The annualised exacerbation rate in Trial 6 was comparable to that reported in previous trials.


Long-term extension trials
The long-term efficacy and safety of benralizumab was evaluated in a phase 3, 56-week extension trial BORA (Trial 4). The trial enrolled 2123 patients, 2037 adults and 86 adolescent patients (aged 12 years and older) from Trials 1, 2 and 3. Trial 4 assessed the long-term effect of benralizumab on annual exacerbation rate, lung function, ACQ-6, AQLQ(S)+12 and maintenance of OCS reduction at the 2 dosing regimens studied in the predecessor studies.


At the recommended dose regimen, the reduction in annual rate of exacerbations observed in the placebo-controlled predecessor Trials 1 and 2 (in patients with baseline blood eosinophil counts ≥300 cells/μL who were taking high-dose ICS) was maintained over the second year of treatment (Table 6). In patients who received benralizumab in predecessor Trials 1 and 2, 73% were exacerbation-free in the extension Trial 4.


Table 6. Exacerbations over an extended treatment perioda
Placebob
Benralizumab (N=318)
(N=338)
Trial 1 & 2            Trial 1 & 2             Trial 4              Trial 1, 2 & 4 c 
Rate              1.23                   0.65                 0.48                    0.56 a. Patients that entered Trial 4 from predecessor Trials 1 and 2 with baseline blood eosinophil counts ≥300 cells/μL who were taking high-dose ICS.
b. Placebo patients in Trials 1 and 2 are included up to the end of the predecessor trial (Week 48 in Trial 1, Week 56 in Trial 2).
c. Total duration of treatment: 104 - 112 weeks


Similar maintenance of effect was observed throughout Trial 4 in lung function, ACQ-6 and AQLQ(S)+12 (Table 7).


Table 7. Change from baseline for lung function, ACQ-6, and AQLQ(S)+12a Trial 1 & 2       Trial 1 & 2 EOTc Trial 4 EOTd
Baselineb
Pre-bronchodilator FEV1 (L)
 n                                                318                   305                   290 Mean baseline (SD)                        1.741 (0.621)                  --                  -- Change from baseline (SD) e                       --              0.343 (0.507)      0.404 (0.555) 
ACQ-6
 n                                                318                   315                296 
Mean baseline (SD)                        2.74 (0.90)                    --                  -- 
Change from baseline (SD) e                       --              -1.44 (1.13)       -1.47 (1.05) 
AQLQ(S)+12 n                                                307                   306                287 
Mean baseline (SD)                        3.90 (0.99)                    --                  -- 
Change from baseline (SD) e                       --              1.58 (1.23)        1.61 (1.21)  n= number of patients with data at timepoint. SD = standard deviation a. Baseline blood eosinophil counts ≥300 cells/μL and taking high-dose ICS: benralizumab administered at the recommended dosage regimen.
b. Integrated analysis of Trial 1 and 2 baseline includes adults and adolescents.
c. Integrated analysis at End of Treatment (EOT) of Trial 1(Week 48) and Trial 2 (Week 56).
d. EOT for Trial 4 was Week 48 (the last timepoint for adults and adolescent data).
e. Baseline is prior to benralizumab treatment in Trial 1 and 2.


Efficacy in Trial 4 was also evaluated in patients with baseline blood eosinophil counts <300 cells/μl and was consistent with Trials 1 and 2. Maintenance of the reduction in daily OCS dose was also observed over the extension trial in patients enrolled from Trial 3 (Figure 1).


Figure 1. Median percent reductions in daily OCS over time (Trial 3 and 4)a aPredecessor   Trial 3 patients who continued benralizumab treatment into Trial 4. Patients were permitted to enter a second extension trial after a minimum of 8 weeks in Trial 4 without completing the 56-week extension period.


In Trial 5, a second long-term safety extension study (see section 4.8), the annualised exacerbation rate (0.47) in patients receiving the approved dose regimen was comparable to that reported in the predecessor Trials 1, 2 (0.65) and 4 (0.48).


Immunogenicity
Overall, treatment-emergent anti-drug antibody response developed in 107 out of 809 (13%) patients treated with benralizumab at the recommended dose regimen during the 48 to 56 week treatment period of the phase 3 placebo-controlled exacerbation trials. Most antibodies were neutralising and persistent. Anti-benralizumab antibodies were associated with increased clearance of benralizumab and increased blood eosinophil levels in patients with high anti-drug antibody titres compared to antibody negative patients; in rare cases, blood eosinophil levels returned to pre-treatment levels. Based on current patient follow- up, no evidence of an association of anti-drug antibodies with efficacy or safety was observed.


Following a second year of treatment of these patients from the phase 3 placebo- controlled trials, an additional 18 out of 510 (4%) had newly developed treatment- emergent antibodies. Overall, in patients who were anti-drug antibody positive in the predecessor trials, titres remained stable or declined in the second year of treatment. No evidence of an association of anti-drug antibodies with efficacy or safety was observed.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
The pharmacokinetics of benralizumab were dose-proportional in patients with asthma following subcutaneous administration over a dose range of 2 to 200 mg.


Absorption
Following subcutaneous administration to patients with asthma, the absorption half-life was 3.5 days. Based on population pharmacokinetic analysis, the estimated absolute bioavailability was approximately 59% and there was no clinically relevant difference in relative bioavailability in the administration to the abdomen, thigh, or upper arm.


Distribution
Based on population pharmacokinetic analysis, central and peripheral volume of distribution of benralizumab was 3.1 L and 2.5 L, respectively, for a 70 kg individual.


Biotransformation
Benralizumab is a humanised IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body and not restricted to hepatic tissue.


Elimination
From population pharmacokinetic analysis, benralizumab exhibited linear pharmacokinetics and no evidence of target receptor-mediated clearance pathway. The estimated systemic clearance (CL) for benralizumab was at 0.29 L/d. Following subcutaneous administration, the elimination half-life was approximately 15.5 days.


Special populations
Elderly (≥65 years old)
Based on population pharmacokinetic analysis, age did not affect benralizumab clearance.
However, no data are available in patients over 75 years of age.

Gender, race
A population pharmacokinetics analysis indicated that there was no significant effect of gender and race on benralizumab clearance.


Renal impairment
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 renally.


Hepatic impairment
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 clearance.


Interaction
Based on the population pharmacokinetic analysis, commonly co-administered medicinal products (montelukast, paracetamol, proton pump inhibitors, macrolides and theophylline/aminophylline) had no effect on benralizumab clearance in patients with asthma.