Fasenra Mechanism of Action

Pharmacology: Mechanism of action: Benralizumab is an anti-eosinophil, humanised afucosylated, monoclonal antibody (IgG1, kappa). Benralizumab binds to the alpha subunit of the human interleukin-5 receptor (IL-5Rα) with high affinity (16 pM) 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 (45.5 nM) for FcγRIII receptors on immune effectors cells such as natural killer (NK) cells leading to apoptosis of eosinophils and basophils through enhanced antibody-dependent cell-mediated cytotoxicity (ADCC).
Eosinophilic inflammation is an important component in the pathogenesis of asthma. Eosinophils are a rich source of proinflammatory mediators (e.g., eicosanoids, leukotrienes, cytokines) and granule proteins (e.g. eosinophil cationic protein, eosinophil peroxidase, eosinophil neurotoxin and major basic protein). Benralizumab, by enhanced ADCC, reduces eosinophilic inflammation.
Pharmacodynamics: The pharmacodynamic response (blood eosinophil depletion) following repeat SC dosing was evaluated in asthma patients in a 12-week Phase 2 trial. Patients received 1 of 3 doses of benralizumab [25 mg (n=7), 100 mg (n=6) or 200 mg (n=6) SC] or placebo (n=6) every 4 weeks for a total of 3 doses. Median blood eosinophil levels at baseline were 400, 200, 120 and 200 cells/μL in the 25, 100, and 200 mg benralizumab and placebo groups, respectively. Blood eosinophil depletion was observed following SC administration of benralizumab at all dose levels and no depletion was observed in the placebo group. Twenty-four hours post dosing, all benralizumab dosage groups demonstrated complete or near complete depletion of median blood eosinophil levels (0, 0, and 5 cells/μL, respectively). There were no changes in median blood eosinophils in the placebo group. The effect on blood eosinophil depletion was maintained throughout the dosing period.
In a Phase 1 trial, the effect of benralizumab on eosinophils in airway mucosa was evaluated in asthmatic patients with 2.5% or more eosinophils in sputum. Patients received 100 or 200 mg SC benralizumab once every 4 weeks for 8 weeks (total benralizumab SC group n=9) or matching placebo (n=5). At the end of the 12 week treatment period, there was a median reduction from baseline in eosinophils in the airway mucosa of 96% in the total benralizumab SC group compared to a 47% reduction from baseline in the placebo group which was statistically significant (p=0.039).
In the Phase 1 trial, treatment with benralizumab was also associated with reductions in blood basophils, and in both Phase 1 and 2 trials eosinophil granule products such as serum eosinophil derived neurotoxin (EDN) and eosinophil cationic protein (ECP).
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, which corresponds to a median reduction of 100% (see Clinical efficacy as follows). This magnitude of reduction was seen at the first observed time point, 4 weeks of treatment, and was maintained throughout the treatment period. Maintenance of eosinophil depletion was observed throughout the 56 week extension phase (Trial 4) consistent with previous trials.
Immunogenicity: 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, titers 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.
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.
The two exacerbation trials SIROCCO (Trial 1) and CALIMA (Trial 2) were 48 and 56 weeks duration, respectively, and randomised a total of 2,510 patients with uncontrolled asthma. 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 forced expiratory volume in 1 second (FEV₁) below 80% in adults, and below 90% in adolescents] despite regular treatment with high dose ICS (Trial 1) or with medium or high dose ICS (Trial 2) and their current standard of care. 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.
For the oral corticosteroid-reduction trial ZONDA (Trial 3), a total of 220 asthma patients were enrolled who were being treated 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) to maintain asthma control. The trial included an 8-week run-in period during which the OCS was titrated to the minimum effective dose without losing asthma control. 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 FASENRA administered every 4 weeks for the first 3 doses, then every 8 weeks thereafter (see Dosage & Administration). (See Table 1.)

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Exacerbations: The primary endpoint for Trials 1 and 2 was the rate of clinically significant 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. 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 hospitalization. For patients on maintenance oral corticosteroids, a clinically significant 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 a clinically significant exacerbation compared to 51% on placebo. In Trial 2, 40% of patients receiving FASENRA experienced a clinically significant exacerbation compared to 51% on placebo. Compared with placebo, patients receiving FASENRA experienced significant reductions in annual exacerbation rate (Table 2). In Trial 2, there were too few events in the placebo treatment arm to draw conclusions for exacerbations requiring hospitalization or emergency room visits. (See Table 2.)

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Exacerbation results in patients with baseline blood eosinophil counts less than 300 cells/μL who were taking high-dose ICS are presented in Table 5.
The time to first exacerbation was longer for the patients receiving FASENRA compared with placebo in Trials 1 and 2 (Figure 1). (See Figure 1.)

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Lung Function: Change from baseline in mean FEV₁ was measured in both trials and is presented in Figure 2. Compared with placebo, FASENRA provided consistent improvements over time in the mean change from baseline in FEV₁. (See Figure 2.)

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Additionally, an improvement in mean change of morning and evening peak expiratory flow (PEF) from baseline was observed in patients receiving FASENRA compared to placebo at end of treatment.
Additional results from Trials 1 and 2 in patients with baseline blood eosinophil counts of greater than or equal to 300 cells/μL who were taking high-dose ICS and LABA are shown in Table 3.
Results in patients with baseline blood eosinophil counts less than 300 cells/μL who were taking high-dose ICS are presented in Table 5. (See Table 3.)

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During Trials 1 and 2, patients had an average of 68 and 88 symptom free days with FASENRA compared to 58 and 74 symptom free days with placebo, respectively.
The Asthma Control Questionnaire-6 (ACQ-6) and Standardised Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) were assessed in Trials 1 and 2. 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 and 2 (48 and 56 weeks, respectively). In Trial 1, the ACQ-6 responder rate for FASENRA was 60% vs 50% placebo (odds ratio 1.55; 95% CI: 1.09, 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).
Subgroup analyses: Subgroup analyses from Trials 1 and 2 identified patients with higher prior exacerbation history and baseline blood eosinophil count as potential predictors of improved treatment response. When considered alone or in combination, these factors may further identify patients who may achieve greater response from benralizumab treatment.
Prior Exacerbation History: In both trials, patients with a history of 3 or more exacerbations within 12 months prior to FASENRA randomization showed a numerically greater exacerbation response than those with fewer prior exacerbations. (See Table 4.)

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Patients with a prior exacerbation history of 3 or more had mean differences in FEV₁ of 0.235 L (95% CI: 0.088, 0.382) and 0.265 L (95% CI: 0.115, 0.415) at end of treatment with FASENRA, in Trials 1 and 2 respectively. Those with a prior exacerbation history of 2 had mean differences in FEV₁ of 0.113 L (95% CI: -0.002, 0.228) and 0.029 L (95% CI: -0.079, 0.137), in Trials 1 and 2 respectively.
Patients with a prior exacerbation history of 3 or more had differences from baseline in mean asthma symptom score of -0.32 (95% CI: -0.62, -0.01) and -0.41 (95% CI: -0.73, -0.09) at the end of treatment with FASENRA, in Trials 1 and 2 respectively. Those with a prior exacerbation history of 2 had differences from baseline in mean asthma symptom score of -0.22 (95% CI: -0.49, 0.04) and -0.12 (95% CI: -0.37, 0.13) at the end of treatment with FASENRA, in Trials 1 and 2 respectively.
Blood Eosinophil Count: 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 with FASENRA (see Tables 2 and 3). Table 5 presents results in patients with baseline blood eosinophil counts less than 300 cells/uL who were taking high-dose ICS. (See Table 5.)

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Across Trials 1 and 2 combined, there was a numerically greater exacerbation rate reduction with increasing baseline blood eosinophils. Analyses also showed greater improvements in FEV₁ in patients with increasing baseline blood eosinophil counts.
OCS 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. Compared to placebo, patients receiving FASENRA achieved greater reductions in daily maintenance oral corticosteroid dose, while maintaining asthma control. 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 were 59% for FASENRA and 33% for placebo (odds ratio 2.74, 95% CI: 1.41, 5.31). At the same time, patients treated with FASENRA maintained asthma control as reflected by improved lung function, reduced symptoms, and a need for rescue medication. 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, 52.4% (22 of 42) receiving FASENRA and 19% (8 of 42) on placebo achieved a 100% reduction in OCS dose. Table 6 summarizes the study results for Trial 3. Additionally, the percent reduction in exacerbations and exacerbations requiring hospitalization and/or emergency room visits for patients receiving FASENRA compared to placebo were 70% (rate 0.54 versus 1.83, rate ratio 0.30, 95% CI: 0.17, 0.53) and 93% (rates 0.02 versus 0.32, rate ratio 0.07, 95% CI: 0.01, 0.63), respectively. (See Table 6.)

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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.
Long term Extension Trial: The long-term efficacy and safety of FASENRA was evaluated in a double-blind, randomized, parallel group, Phase 3, 56-week extension trial BORA (Trial 4). The long-term safety of FASENRA was evaluated in an open-label safety extension trial MELTEMI (Trial 5) (see Adverse Reactions).
Trial 4 enrolled 2,123 adults and adolescent patients (aged 12 years and older) from Trials 1, 2 and 3 and 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 of greater than or equal to 300 cells/μL who were taking high-dose ICS) was maintained over the second year of treatment (Table 7). In patients who received FASENRA in predecessor Trials 1 and 2, 73% were exacerbation free in the extension Trial 4. (See Table 7.)

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Similar maintenance of effect was observed throughout Trial 4 in lung function, ACQ-6 and AQLQ(S)+12 (Table 8). (See Table 8.)

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Efficacy in Trial 4 was also evaluated in patients with baseline blood eosinophil counts less than 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 4 in patients enrolled from Trial 3 (Figure 3). (See Figure 3.)

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Trial 5 was designed as an open-label safety extension study, enrolling adult patients who completed at least 16 weeks in Trial 4 (see Adverse Reactions). The safety of the 2 dosing regimens studied in the predecessor studies was evaluated in 446 patients who received at least 1 dose of FASENRA. The annualised exacerbation rate in Trial 5 (0.47) was comparable to that reported in Trial 1, 2 and 4.
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. Patients were required to have a history of 2 or more asthma exacerbations requiring oral or systemic corticosteroid treatment in the past 12 months and reduced lung function at baseline (pre-bronchodilator FEV₁<90%) despite regular treatment with medium or high dose ICS and LABA with or without OCS or other controller therapy. 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]. The adverse event profile in adolescents was generally similar to the overall population in the Phase 3 studies (see Adverse Reactions).
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.
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.
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.
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 (6-11 years old) (see Dosage & Administration).
Drug-drug interaction: An effect of benralizumab on the pharmacokinetics of co-administered medications is not expected. Based on the population pharmacokinetic analysis, commonly co-administered medications had no effect on benralizumab clearance in patients with asthma.
Toxicology: Preclinical safety data: 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.
Carcinogenesis and mutagenesis: As benralizumab is a monoclonal antibody, no genotoxicity or carcinogenicity studies have been conducted.
Reproductive toxicology: In a prenatal and postnatal development study, pregnant cynomolgus monkeys there were no benralizumab-related maternal, embryo-fetal, or postnatal effects observed.
In cynomolgus monkeys, male and female fertility were unaffected.