Fasenra (Benralizumab)
benralizumab — afucosylated anti-IL-5Rα cytolytic monoclonal antibody
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Severe eosinophilic asthma | Adults and children ≥6 years | Add-on maintenance | FDA Approved |
| Eosinophilic granulomatosis with polyangiitis (EGPA) | Adults ≥18 years | Treatment (with background therapy) | FDA Approved (Sep 2024) |
Benralizumab is unique among anti-IL-5 pathway biologics because it targets the IL-5 receptor alpha subunit rather than the IL-5 ligand itself. Its afucosylated Fc domain enables enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), leading to near-complete depletion of eosinophils and basophils — typically reducing blood eosinophils to a median of 0 cells/μL. The EGPA indication, approved in September 2024, was based on the MANDARA trial demonstrating non-inferiority to mepolizumab. Benralizumab is not indicated for the relief of acute bronchospasm or status asthmaticus.
Hypereosinophilic syndrome (HES): Phase 3 trials (NATRON) are ongoing; open-label data show promising eosinophil depletion. Evidence quality: Moderate.
Chronic rhinosinusitis with nasal polyps (CRSwNP): The OSTRO Phase 3 trial met co-primary endpoints, but the FDA issued a complete response letter requesting additional data. A second Phase 3 trial (ORCHID) has been conducted. Not currently FDA-approved for this indication. Evidence quality: Moderate.
Eosinophilic COPD: The RESOLUTE Phase 3 trial (Sep 2025) did not achieve statistical significance on its primary endpoint despite numerical improvement. Earlier GALATHEA and TERRANOVA trials also did not meet primary endpoints. Evidence quality: Moderate (negative).
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Severe eosinophilic asthma — adults & adolescents ≥12 y | 30 mg SC q4wk ×3 | 30 mg SC q8wk | 30 mg SC q8wk | Loading phase: first 3 doses q4wk; then maintenance q8wk Self-administration via FASENRA PEN after training |
| Severe eosinophilic asthma — children 6–11 y, weight ≥35 kg | 30 mg SC q4wk ×3 | 30 mg SC q8wk | 30 mg SC q8wk | Same as adult dosing FASENRA PEN administered by caregiver or HCP only in this age group |
| Severe eosinophilic asthma — children 6–11 y, weight <35 kg | 10 mg SC q4wk ×3 | 10 mg SC q8wk | 10 mg SC q8wk | Weight-based dose; uses 10 mg/0.5 mL PFS PFS administered by HCP; similar exposure to adult 30 mg dose |
| EGPA — relapsing or refractory disease in adults | 30 mg SC q4wk | 30 mg SC q4wk | 30 mg SC q4wk | No loading/maintenance distinction; continuous q4wk dosing Single injection per dose; continue background OCS, taper under supervision |
A key prescribing distinction: benralizumab for asthma uses a loading-then-extended-interval regimen (q4wk ×3, then q8wk), while EGPA requires continuous every-4-week dosing without the extended interval. This reflects the need for sustained eosinophil suppression in active vasculitis. The asthma q8wk maintenance schedule offers patients fewer injections per year (approximately 8 per year after loading) compared to monthly biologics.
Pharmacology
Mechanism of Action
Benralizumab is a humanized, afucosylated IgG1 kappa monoclonal antibody that directly binds to the alpha subunit of the IL-5 receptor (IL-5Rα) with high affinity (dissociation constant 11 pM). Unlike mepolizumab and reslizumab, which neutralize the IL-5 ligand, benralizumab targets the receptor on the eosinophil surface, blocking IL-5 signaling while simultaneously engaging natural killer cells through its enhanced Fc-region binding. The absence of fucose in the Fc domain greatly amplifies binding to FcγRIII receptors on immune effector cells, driving potent antibody-dependent cell-mediated cytotoxicity (ADCC). This dual mechanism — receptor blockade plus direct cytolysis — achieves near-complete eosinophil depletion, with median blood counts reaching 0 cells/μL within four weeks of treatment. Basophil counts are also reduced, as basophils express IL-5Rα.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability ~59% (SC); absorption t½ ~3.5 days; no clinically relevant difference across injection sites (arm, thigh, abdomen) | Slower absorption than some mAbs; supports flexible injection site selection |
| Distribution | Vc 3.1 L; Vp 2.5 L (70 kg); distribution primarily restricted to extracellular fluid | Typical IgG distribution; body weight affects Vc proportionally |
| Metabolism | Degraded by widely distributed proteolytic enzymes; no CYP involvement; no target-mediated clearance | No dose adjustment for hepatic impairment; no CYP-mediated drug interactions |
| Elimination | t½ ~15.5 days (asthma); CL 0.29 L/day (asthma), 0.22 L/day (EGPA); not renally cleared | Lower clearance in EGPA (likely due to disease-related differences); no renal dose adjustment needed |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Headache (EGPA) | 17% | Notably higher in EGPA (MANDARA) than in asthma trials (8%); generally mild to moderate |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Headache (asthma) | 8% (vs 6% placebo) | Most common adverse reaction in asthma pivotal trials (SIROCCO, CALIMA); usually mild |
| Pharyngitis | 5% (vs 3% placebo) | Includes pharyngitis, bacterial pharyngitis, viral pharyngitis, and streptococcal pharyngitis |
| Pyrexia | 3% (vs 2% placebo) | Transient; typically resolves within 24–48 hours post-injection |
| Hypersensitivity reactions | 3% (vs 3% placebo) | Urticaria, papular urticaria, rash; not significantly different from placebo in pooled asthma data |
| Injection site reactions | 2.2% (vs 1.9% placebo) | Pain, erythema, pruritus, papule; minimal excess over placebo; generally mild |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Anaphylaxis | Rare (postmarketing) | Hours to days post-injection | Permanent discontinuation; emergency treatment; do not re-challenge |
| Angioedema | Rare (postmarketing) | Hours post-injection | Discontinue; airway management if needed |
| Helminth infection (unresolved) | Very rare (theoretical) | Any time during treatment | Screen before initiation; discontinue if infection does not respond to anti-helminth therapy |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Hypersensitivity reactions | <1% | Protocol-mandated discontinuation for anaphylaxis or severe hypersensitivity |
| Other adverse events | <2% | No single adverse event drove discontinuation at a meaningful rate |
Benralizumab has a notably clean safety profile. Injection site reactions were nearly identical to placebo (2.2% vs 1.9%), and overall adverse event rates in the pivotal asthma trials were comparable between active and placebo arms. The extended q8wk dosing interval also reduces injection burden for patients with asthma.
Drug Interactions
Benralizumab has a very low drug interaction profile. No formal drug interaction studies have been conducted. As a monoclonal antibody, it is not metabolized by CYP enzymes, efflux pumps, or protein-binding mechanisms. Population pharmacokinetic analyses showed no effect of commonly co-administered small molecule medications on benralizumab clearance. IL-5Rα is not expressed on hepatocytes, and eosinophil depletion does not produce chronic systemic alterations of proinflammatory cytokines, further supporting the absence of pharmacokinetic interactions.
Monitoring
- Blood EosinophilsBaseline, q3–6 months
RoutineConfirm eosinophilic phenotype before initiation (≥300 cells/μL is the strongest predictor of response). Near-complete depletion (median 0 cells/μL) expected by Week 4. Persistent counts suggest non-adherence or anti-drug antibody development. - Post-Injection ObservationEach administration
RoutineMonitor for hypersensitivity reactions per standard biologic practice. Reactions may be immediate or delayed by days. - Asthma ControlEvery visit
RoutineTrack exacerbation frequency, ACQ-6 scores, FEV1. Patients with higher baseline eosinophils (≥300 cells/μL) and more prior exacerbations show greatest benefit. - OCS TaperingAt each visit during taper
RoutineMonitor for adrenal insufficiency symptoms during corticosteroid reduction. In ZONDA, median OCS reduction was 75% with benralizumab vs 25% with placebo. - EGPA Disease Activityq4–12 weeks
RoutineTrack BVAS score, OCS dose, relapse frequency. Target: BVAS = 0 plus OCS ≤4 mg/day. Assess remission at Weeks 36 and 48. - Parasitic InfectionsBaseline; as clinically indicated
Trigger-basedScreen in endemic areas. Discontinue benralizumab if helminth infection does not respond to treatment. - Anti-Drug AntibodiesNot routinely tested
Trigger-basedADA developed in ~13% of asthma patients and 9% in EGPA. High-titer ADA associated with increased clearance and rising eosinophil counts. Consider ADA testing if clinical response wanes.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to benralizumab or any excipient (L-histidine, L-histidine hydrochloride monohydrate, polysorbate 20, trehalose dihydrate).
Relative Contraindications (Specialist Input Recommended)
- Active helminth infection: Treat and resolve before initiation. Discontinue benralizumab if infection does not respond to anti-helminth therapy.
- Pregnancy (3rd trimester): Monoclonal antibodies are transported across the placenta during the third trimester. Use only if potential benefit justifies potential fetal risk.
Use with Caution
- Corticosteroid-dependent patients: Do not abruptly discontinue systemic or inhaled corticosteroids. Gradual tapering under medical supervision is essential.
- Elderly patients (≥65 years): No overall differences in safety or efficacy observed, but greater sensitivity cannot be ruled out.
- Children <6 years: Safety and effectiveness have not been established.
Hypersensitivity reactions including anaphylaxis, angioedema, urticaria, and rash have been reported following administration of benralizumab both in clinical trials and in postmarketing experience. These reactions generally occur within hours of administration but may have delayed onset over several days. Benralizumab should be permanently discontinued in the event of a hypersensitivity reaction. Healthcare providers should be prepared to manage anaphylaxis when administering benralizumab.
Patient Counselling
Purpose of Therapy
Benralizumab works by directly targeting and eliminating eosinophils, a type of white blood cell that drives inflammation in severe asthma and EGPA. Unlike some similar medications that block the chemical signal (IL-5), benralizumab binds to the receptor on the eosinophil surface and triggers the body’s own immune cells to destroy them. This leads to a rapid and near-complete reduction in eosinophil counts, which helps prevent asthma attacks and, in EGPA, supports disease remission and steroid tapering.
How to Take
Benralizumab is given as a single injection under the skin. For asthma, the first three doses are given every four weeks, then every eight weeks thereafter. For EGPA, injections continue every four weeks indefinitely. The injection can be given by a healthcare provider using a prefilled syringe, or patients/caregivers can self-inject at home using the FASENRA PEN autoinjector after proper training. The device should be brought to room temperature for about 30 minutes before use. Injections can be given in the thigh, abdomen, or upper arm (by caregiver only).
Sources
- FASENRA (benralizumab) injection, for subcutaneous use. Full Prescribing Information. AstraZeneca Pharmaceuticals LP. Revised 09/2024. accessdata.fda.govPrimary source for all dosing, indications, adverse events, PK parameters, and contraindications in this monograph.
- Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO). Lancet. 2016;388(10056):2115-2127. doi:10.1016/S0140-6736(16)31324-148-week pivotal exacerbation-reduction trial showing 51% reduction in exacerbations with benralizumab q8wk vs placebo.
- FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA). Lancet. 2016;388(10056):2128-2141. doi:10.1016/S0140-6736(16)31322-856-week confirmatory exacerbation trial demonstrating 28% reduction in exacerbations in patients with BEC ≥300 cells/μL on high-dose ICS.
- Nair P, Wenzel S, Rabe KF, et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma (ZONDA). N Engl J Med. 2017;376(25):2448-2458. doi:10.1056/NEJMoa170350128-week OCS-reduction trial showing 75% median reduction in daily OCS dose with benralizumab vs 25% with placebo.
- Wechsler ME, Nair P, Engel B, et al. Benralizumab versus mepolizumab for eosinophilic granulomatosis with polyangiitis (MANDARA). N Engl J Med. 2024;390(10):911-921. doi:10.1056/NEJMoa231115552-week head-to-head non-inferiority trial vs mepolizumab; 59% remission with benralizumab vs 57% mepolizumab; basis for EGPA approval.
- FitzGerald JM, Bleecker ER, Menzies-Gow A, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med. 2018;6(1):51-64. doi:10.1016/S2213-2600(17)30344-2Pooled analysis identifying higher baseline eosinophils and prior exacerbation history as key predictors of treatment response.
- Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, 2025. ginasthma.orgLists benralizumab as a Step 5 add-on biologic option for severe eosinophilic asthma in patients ≥6 years.
- Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation guideline for the management of ANCA-associated vasculitis. Arthritis Rheumatol. 2021;73(8):1366-1383. doi:10.1002/art.41773Guideline covering vasculitis management including EGPA; published before benralizumab EGPA approval but provides treatment framework.
- Kolbeck R, Kozhich A, Koike M, et al. MEDI-563, a humanized anti-IL-5 receptor α mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010;125(6):1344-1353.e2. doi:10.1016/j.jaci.2010.04.004Preclinical characterization of the afucosylated Fc domain and ADCC-mediated eosinophil depletion mechanism.
- Yan L, Wang B, Chia YL, Roskos LK. Population pharmacokinetic modeling of benralizumab in adult and adolescent patients with asthma. Clin Pharmacokinet. 2019;58(7):943-958. doi:10.1007/s40262-019-00738-4Comprehensive population PK analysis establishing the two-compartment model parameters used in this monograph (F1 59%, CL 0.29 L/day, t½ 15.5 days).
- Wang B, Yan L, Yao Z, Roskos LK. Population pharmacokinetics and pharmacodynamics of benralizumab in healthy volunteers and patients with asthma. CPT Pharmacometrics Syst Pharmacol. 2017;6(4):249-257. doi:10.1002/psp4.12160Earlier PK/PD modeling study establishing benralizumab dose-proportional PK and eosinophil depletion transit model.
- Chia YL, Yan L, Yu B, et al. Relationship between benralizumab exposure and efficacy for patients with severe eosinophilic asthma. Clin Pharmacol Ther. 2019;106(2):383-390. doi:10.1002/cpt.1371Exposure-response analysis supporting the 30 mg q8wk dosing regimen for asthma.