General Information

Fasenra (benralizumab) is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody (IgG1, kappa).

Fasenra is specifically indicated for the add-on maintenance treatment of patients aged 6 years and older with severe asthma, and with an eosinophilic phenotype.

Dosing/Administration

Fasenra is supplied as an injection for subcutaneous administration.

Recommended Dosage Adult and Adolescent Patients 12 Years of Age and Older:

• The recommended dosage of Fasenra is 30 mg (one injection) administered subcutaneously every 4 weeks for the first 3 doses, and then every 8 weeks thereafter.

Recommended Dosage in Pediatric Patients 6 to 11 Years of Age:

The recommended dosage of Fasenra for pediatric patients 6 to 11 years of age is based on body weight as provided below.

Mechanism of Action

Benralizumab is a humanized afucosylated, monoclonal antibody (IgG1, kappa) that directly binds to the alpha subunit of the human interleukin-5 receptor (IL-5Rα) with a dissociation constant of 11 pM. The IL-5 receptor is expressed on the surface of eosinophils and basophils. In an in vitro setting, the absence of fucose in the Fc domain of benralizumab facilitates binding (45.5 nM) to FcɣRIII receptors on immune effector cells, such as natural killer (NK) cells, leading to apoptosis of eosinophils and basophils through antibody-dependent cell-mediated cytotoxicity (ADCC).

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. Benralizumab, by binding to the IL-5Rα chain, reduces eosinophils through ADCC; however, the mechanism of benralizumab action in asthma has not been definitively established.

Side Effects

Adverse effects associated with the use of Fasenra may include, but are not limited to, the following:

• headache
• pharyngitis

Clinical Trial Results

The FDA approval of Fasenra for patients 12 years of age and older was based on the following trials:

SIROCCO AND CALIMA (Trials 1 and 2)

SIROCCO (48-week) and CALIMA (56-week) were randomized, double-blind, parallel-group, placebo-controlled, multicenter studies comparing Fasenra 30 mg SC Q4W for the first 3 doses, then Q8W thereafter; benralizumab 30 mg SC Q4W; and placebo SC. A total of 1,204 (SIROCCO) and 1,306 (CALIMA) patients aged 12-75 years old with severe asthma uncontrolled on high-dose ICS (SIROCCO) and medium- to high-dose ICS (CALIMA) plus LABA with or without additional controllers were included. Patients had a history of ≥2 exacerbations requiring systemic corticosteroids or temporary increase in usual dosing in the previous year. Patients were stratified by geography, age, and blood eosinophil counts (≥300 cells/μL and <300 cells/μL). The primary endpoint was annual exacerbation rate ratio vs placebo in patients with blood eosinophil counts of ≥300 cells/μL on high-dose ICS and LABA. Key secondary endpoints were pre-bronchodilator FEV1 and total asthma symptom score at Week 48 (SIROCCO) and Week 56 (CALIMA) in the same population.

In SIROCCO (48 weeks) and CALIMA (56 weeks), asthma exacerbation was defined as a worsening of asthma that led to use of systemic corticosteroids for ≥3 days, temporary increase in a stable OCS background dose for ≥3 days, emergency/urgent care visit because of asthma that needed systemic corticosteroids, or inpatient hospital stay of ≥24 hours because of asthma.

ZONDA (Trial 3)

A 28-week, randomized, double-blind, parallel-group, placebo-controlled, multicenter OCS reduction study comparing the efficacy and safety of Fasenra 30 mg SC Q4W for the first 3 doses, then Q8W thereafter; Fasenra (30 mg SC) Q4W; and placebo (SC) Q4W. A total of 220 adult patients aged 18 to 75 years old with severe asthma on high-dose ICS/LABA and daily OCS (7.5 to 40 mg/day), a blood eosinophil count of ≥150 cells/μL, and a history of ≥1 exacerbations in the previous year were included. The primary endpoint was the median percent reduction from baseline in the final daily OCS dose while maintaining asthma control.

In ZONDA, asthma exacerbation was defined as a worsening of asthma that led to a temporary increase in systemic corticosteroid dose for at least 3 days to treat the symptoms, an ER visit that led to treatment with a systemic corticosteroid in addition to the patient’s regular maintenance medications, or inpatient hospitalization because of asthma.

DATA

SIROCCO Trial: 51% reduction in the annual asthma exacerbation rate was observed in patients treated with Fasenra + standard of care (SOC) (n=267) vs placebo + SOC (n=267) (0.74 vs 1.52).

ZONDA Trial: 75% reduction in median final oral corticosteroid (OCS) dose was observed in OCS-dependent patients treated with FASENRA + SOC (n=73), compared to a 25% reduction with placebo + SOC (n=75) while maintaining asthma control. 

The FDA approval of Fasenra for patients 6 years of age and older was based on evidence from TATE, an open-label, multinational, non-randomized, parallel assignment Phase 3 trial, as well as adequate and well-controlled trials in adult and adolescent populations. In the TATE study, Fasenra met the primary endpoints, demonstrating pharmacokinetics (PK) and pharmacodynamics (PD) in children aged 6 to 11 years old with SEA were consistent with those seen in prior trials.