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Pharmacology: Pharmacodynamics: Mechanism of action: Benralizumab is an anti-eosinophil, humanised afucosylated, monoclonal antibody (IgG1, kappa). It binds to the alpha subunit of the human interleukin-5 receptor (IL-5Rα) with high affinity and specificity. 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 FcγRIII 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 Fasenra 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, Fasenra 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, 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 dosing regimens were studied in Trials 1, 2, and 3, the recommended dosing regimen is Fasenra administered every 4 weeks for the first 3 doses, then every 8 weeks thereafter (see Dosage & Administration) as no additional benefit was observed by more frequent dosing. The results summarised as follows are those for the recommended dosing 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 oral corticosteroids, 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 Fasenra 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 1).
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. (See Table 1.)
Click on icon to see table/diagram/imageAcross 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 Fasenra 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 Fasenra experienced statistically significant reductions in asthma symptoms (Total Asthma Score) compared to patients receiving placebo. Similar improvement in favour of Fasenra was observed for the Asthma Control Questionnaire-6 (ACQ-6) and Standardised Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) (Table 2). (See Table 2.)
Click on icon to see table/diagram/imageSubgroup 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 3). (See Table 3.)
Click on icon to see table/diagram/imageOral corticosteroid dose reduction trial: 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. Table 4 summarizes the study results for Trial 3. (See Table 4.)
Click on icon to see table/diagram/imageLung 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.
Long-term extension trial: The long-term efficacy and safety of Fasenra 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 Fasenra 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 dosing 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 5). In patients who received Fasenra in predecessor Trials 1 and 2, 73% were exacerbation-free in the extension Trial 4. (See Table 5.)
Click on icon to see table/diagram/imageSimilar maintenance of effect was observed throughout Trial 4 in lung function, ACQ-6 and AQLQ(S)+12 (Table 6). (See Table 6.)
Click on icon to see table/diagram/imageEfficacy 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). (See figure.)
Click on icon to see table/diagram/imageImmunogenicity: Overall, treatment-emergent anti-drug antibody response developed in 107 out of 809 (13%) patients treated with Fasenra at the recommended dosing 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.
Paediatric population: There were 108 adolescents aged 12 to 17 with asthma enrolled in the phase 3 trials (Trial 1: n=53, Trial 2: n=55). Of these, 46 received placebo, 40 received Fasenra every 4 weeks for 3 doses, followed by every 8 weeks thereafter, and 22 received Fasenra every 4 weeks. In these trials, the asthma exacerbation rate in adolescent patients treated with Fasenra administered at the recommended dosing regimen was 0.70 (n=40, 95% CI: 0.42, 1.18) compared to 0.41 for placebo (n=46, 95% CI: 0.23, 0.73) [rate ratio 1.70, 95% CI: 0.78, 3.69].
Adolescent patients aged 12 to 17 (n=86) from Trials 1 and 2 continued treatment with Fasenra in Trial 4 for up to 108 weeks. Efficacy and safety were consistent with the predecessor trials.
No conclusion can be drawn regarding asthma efficacy in the paediatric population.
Pharmacokinetics: 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 patients (≥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.
Paediatric: Based on the population pharmacokinetic analysis, the pharmacokinetics of benralizumab in adolescents aged 12 to 17 years were consistent with adults. Benralizumab has not been studied in children (5 to 11 years old) (see Dosage & Administration).
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.
Drug-Drug interaction: An effect of benralizumab on the pharmacokinetics of co-administered medicinal products is not expected. 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.
Toxicology: Preclinical safety data: As benralizumab is a monoclonal antibody, no genotoxicity or carcinogenicity studies have been conducted.
Animal toxicology and/or pharmacology: Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology or repeated dose toxicity studies in monkeys. Intravenous and subcutaneous administration to cynomolgus monkeys was associated with reductions in peripheral blood and bone marrow eosinophil counts, with no toxicological findings.
Pregnancy: In a prenatal and postnatal development study in pregnant cynomolgus monkeys, there were no benralizumab-related maternal, embryo-foetal, or postnatal effects observed.
Fertility: No dedicated animal studies have been conducted. No benralizumab-related impairment was observed in reproductive parameters of male and female cynomolgus monkeys. Examination of surrogate fertility parameters (including organ weights and histopathology of reproductive tissues) in animals treated with benralizumab suggested no impairment of fertility. However, in the offspring of monkeys dosed while pregnant, there was a reduction in eosinophils.
