Benralizumab (Fasenra)

Number: 0925

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Brand Selection for Medically Necessary Indications for Commercial Medical Plans

According to Aetna commercial benefit plans, health care services are considered not medically necessary if they are more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that member’s illness, injury or disease. Aetna commercial plans may require a trial of a lower-cost drug (preferred medication) that is at least as likely to produce equivalent therapeutic results before approving coverage for a higher-cost drug within the same therapeutic class. For a list of preferred drugs, refer to the Aetna Commercial Clinical Program Summary.

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses benralizumab (Fasenra) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of benralizumab (Fasenra) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of benralizumab call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: For commercial plans, Site of Care Utilization Management Policy applies for benralizumab (Fasenra). For information on site of service, see Utilization Management on Site of Care for Specialty Drug Infusions.

1. Prescribing Specialties

   For the indication of asthma: This medication must be prescribed by or in consultation with an allergist/immunologist or pulmonologist.

2. Criteria for Initial Approval

   Aetna considers benralizumab (Fasenra) medically necessary for the treatment of the following indications when criteria are met:

   1. Asthma

      1. For members 6 years of age or older who have previously received a biologic drug (e.g., Dupixent, Nucala) indicated for asthma in the past year; or
      2. For treatment of severe asthma when all of the following criteria are met:
         
         
         1. Member is 6 years of age or older; and
         2. Member meets either of the following criteria:
            
            
            1. Member has a baseline blood eosinophil count of at least 150 cells per microliter; or
            2. Member is dependent on systemic corticosteroids; and

         3. Member has uncontrolled asthma as demonstrated by experiencing at least one of the following within the past year:

            1. Two or more asthma exacerbations requiring oral or injectable corticosteroid treatment; or
            2. One or more asthma exacerbation resulting in hospitalization or emergency medical care visit; or
            3. Poor symptom control (frequent symptoms or reliever use, activity limited by asthma, night waking due to asthma); and

         4. Member has inadequate asthma control despite current treatment with both of the following medications at optimized doses:

            1. High-dose inhaled corticosteroid; and
            2. Additional controller (i.e., long acting beta2-agonist, long acting muscarinic antagonist, leukotriene modifier, or sustained-release theophylline); and
               

         5. Member will continue to use maintenance asthma treatments (e.g., inhaled corticosteroid, additional controller) in combination with the requested medication; 

   2. Eosinophilic granulomatosis with polyangiitis (EGPA)

      For treatment of EGPA when all of the following criteria are met:
      

      1. Member is 18 years of age or older; and
      2. Member has a history or the presence of a blood eosinophil count of more than 1000 cells per microliter or a blood eosinophil level of greater than 10%; and
      3. Member is currently taking oral corticosteroids, unless contraindicated or not tolerated; and
      4. Member has at least two of the following disease characteristics of EGPA:
         
         
         1. Biopsy showing histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation
         2. Neuropathy, mono or poly (motor deficit or nerve conduction abnormality)
         3. Pulmonary infiltrates, non-fixed
         4. Sino-nasal abnormality
         5. Cardiomyopathy (established by echocardiography or magnetic resonance imaging)
         6. Glomerulonephritis (hematuria, red cell casts, proteinuria)
         7. Alveolar hemorrhage (by bronchoalveolar lavage)
         8. Palpable purpura
         9. Anti-neutrophil cytoplasmic anti-body (ANCA) positive (Myeloperoxidase or proteinase 3); and

      5. Member has had at least one relapse (i.e., requiring increase in oral corticosteroid dose, initiation/increased dose of immunosuppressive therapy or hospitalization) within 2 years prior to starting treatment with the requested medication or has a refractory disease.

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

   Aetna considers continuation of benralizumab (Fasenra) therapy medically necessary for the following indications when criteria are met:
   

   1. Asthma

      For treatment of severe asthma when all of the following criteria are met:

      1. Member is 6 years of age or older; and
      2. Asthma control has improved on the requested medication as demonstrated by at least one of the following:
         
         
         1. A reduction in the frequency and/or severity of symptoms and exacerbations; or
         2. A reduction in the daily maintenance oral corticosteroid dose; and

      3. Member will continue to use maintenance asthma treatments (e.g., inhaled corticosteroid, additional controller) in combination with the requested medication;

   2. Eosinophilic granulomatosis with polyangiitis (EGPA)

      For continuation of treatment of EGPA when all of the following criteria are met:
      

      1. Member is 18 years of age or older; and
      2. Member has a beneficial response to treatment with the requested medication as demonstrated by any of the following:
         
         
         1. A reduction in the frequency of relapses; or
         2. A reduction or discontinuation of daily oral corticosteroid dose; or
         3. No active vasculitis.

4. Other

   For all indications: Member cannot use the requested medication concomitantly with any other biologic drug or targeted synthetic drug for the same indication.

   Note: If the member is a current smoker or vaper, they should be counseled on the harmful effects of smoking and vaping on pulmonary conditions and available smoking and vaping cessation options.

5. Related Policies

   1. CPB 0670 - Omalizumab (Xolair)
   2. CPB 0897 - Mepolizumab (Nucala)
   3. CPB 0907 - Reslizumab (Cinqair)
   4. CPB 1003 - Tezepelumab-ekko (Tezspire)

Dosage and Administration

Benralizumab is available as Fasenra and supplied for subcutaneous (SC) injection in the following dosage forms and strengths: 

• 10 mg/0.5 mL solution in a single-dose prefilled syringe
• 30 mg/mL solution in a single-dose prefilled syringe
• 30 mg/mL solution in a single-dose autoinjector Fasenra Pen

The prefilled syringe is for administration by a healthcare provider.

Asthma

Adult and adolescents 12 years of age and older:

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

Pediatrics 6 years to 11 years of age:

• The recommended dose is based on body weight:
  
  
  • Less than 35 kg: 10 mg (one injection) administered subcutaneously every 4 weeks for the first 3 doses, and then every 8 weeks thereafter;
  • 35 kg or more: 30 mg (one injection) administered subcutaneously every 4 weeks for the first 3 doses, and then every 8 weeks thereafter.

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

The recommended dosage of Fasenra is 30 mg (one injection) administered once every 4 weeks by subcutaneous injection.

Source: AstraZeneca, 2024

Experimental, Investigational, or Unproven

Aetna considers benralizumab experimental, investigational, or unproven for the following indications including other eosinophilic conditions (not an all-inclusive list):

• Acute bronchospasm
• Chronic obstructive pulmonary disease
• Eosinophilic annular erythema
• Eosinophilic cystitis
• Eosinophilic pneumonia
• Laryngeal papillomatosis
• Status asthmaticus.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
85004	Blood count; automated differential WBC count
85048	Blood count; leukocyte (WBC), automated
94010 - 94799	Pulmonary diagnostic testing and therapies
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular.
99406	Smoking and tobacco use cessation counseling visit: intermediate, greater than 3 minutes up to 10 minutes
99407	intensive, greater than 10 minutes
HCPCS codes covered if selection criteria are met:
J0517	Injection, benralizumab, 1 mg
Other HCPCS codes related to the CPB:
Dupixent- no specific code
J0702	Injection, betamethasone acetate 3mg and betamethasone sodium phosphate 3mg
J1020	Injection, methylprednisolone acetate, 20 mg
J1030	Injection, methylprednisolone acetate, 40 mg
J1040	Injection, methylprednisolone acetate, 80 mg
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphate, 1 mg
J1700	Injection, hydrocortisone acetate, up to 25 mg
J1710	Injection, hydrocortisone sodium phosphate, up to 50 mg
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg
J2182	Injection, mepolizumab, 1 mg
J2356	Injection, tezepelumab-ekko, 1 mg
J2357	Injection, omalizumab, 5 mg
J2650	Injection, prednisolone acetate, up to 1 ml
J2786	Injection, reslizumab, 1 mg
J2920	Injection, methylprednisolone sodium succinate, up to 40 mg
J2930	Injection, methylprednisolone sodium succinate, up to 125 mg
J3300	Injection, triamcinolone acetonide, preservative free, 1 mg
J3301	Injection, triamcinolone acetonide, not otherwise specified, 10 mg
J3302	Injection, triamcinolone diacetate, per 5 mg
J3303	Injection, triamcinolone hexacetonide, per 5 mg
J7509	Methylprednisolone oral, per 4 mg
J7510	Prednisolone oral, per 5 mg
J7512	Prednisone, immediate release or delayed release, oral, 1 mg
J7622	Beclomethasone, inhalation solution, compounded product, administered through dme, unit dose form, per milligram
J7624	Betamethasone, inhalation solution, compounded product, administered through dme, unit dose form, per milligram
J7637	Dexamethasone, inhalation solution, compounded product, administered through dme, concentrated form, per milligram
J7638	Dexamethasone, inhalation solution, compounded product, administered through dme, unit dose form, per milligram
J7677	Revefenacin inhalation solution, fda-approved final product, non-compounded, administered through DME, 1 microgram
J7683	Triamcinolone, inhalation solution, compounded product, administered through dme, concentrated form, per milligram
J7684	Triamcinolone, inhalation solution, compounded product, administered through dme, unit dose form, per milligram
J8540	Dexamethasone, oral, 0.25 mg
ICD-10 codes covered if selection criteria are met:
J45.40	Moderate persistent asthma, uncomplicated
J45.41	Moderate persistent asthma with (acute) exacerbation
J45.50	Severe persistent asthma, uncomplicated
J45.51	Severe persistent asthma with (acute) exacerbation
M30.1	Polyarteritis with lung involvement [Churg-Strauss]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
D14.1	Benign neoplasm of larynx [Laryngeal papillomatosis]
J20.0 - J20.9	Acute bronchitis
J21.9	Acute bronchiolitis, unspecified
J44.0 - J44.9	Other chronic obstructive pulmonary disease
J45.22	Mild intermittent asthma with status asthmaticus
J45.32	Mild persistent asthma with status asthmaticus
J45.42	Moderate persistent asthma with status asthmaticus
J45.52	Severe persistent asthma with status asthmaticus
J45.902	Unspecified asthma with status asthmaticus
J45.990	Exercise induced bronchospasm
J82.81	Chronic eosinophilic pneumonia
J82.82	Acute eosinophilic pneumonia
J98.01	Acute bronchospasm
L53.1	Erythema annulare centrifugum
N30.80 - N30.81	Other cystitis

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Fasenra is indicated for:

  • Add-on maintenance treatment of adult and pediatric patients aged 6 years and older with severe asthma, and with an eosinophilic phenotype. 

    Limitations of Use:

    Not indicated for the relief of acute bronchospasm or status asthmaticus

  • Treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA)

Benralizumab is an interleukin-5 (IL-5) receptor alpha-directed cytolytic monoclonal antibody (IgG1, kappa) that is branded as Fasenra (AstraZeneca Pharmaceuticals LP). 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-5 receptor chain, reduces eosinophils through antibody-dependent cell-mediated cytotoxicity; however, the mechanism of benralizumab action in asthma has not been definitively established.

Fasenra carries labeled warnings and precautions for hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, rash) and parasitic (helminth) infection. The Prescribing Information (PI) advises patients to not abruptly discontinue systemic or inhaled corticosteroids upon initiation of Fasenra therapy. Reductions in corticosteroid dosage, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dosage may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy. Per the PI, eosinophils may be involved in the immunological response to some helminth infections. Patients with known parasitic infections were excluded from participation in clinical trials. Thus, it is unknown if Fasenra will influence a patient’s response against parasitic infections. Healthcare providers are advised to treat patients with pre-existing helminth infections before initiating therapy with Fasenra. If patients become infected while receiving treatment with Fasenra and do not respond to anti-helminth treatment, Fasenra should be discontinued until infection resolves.

The most common adverse reactions (incidence greater than or equal to 5%) include headache and pharyngitis. 

Asthma

Asthma is a chronic lung condition that can cause inflammation and narrowing of the airways, causing wheezing, chest tightness, shortness of breath, and/or coughing.  Asthma affects an estimated 315 million individuals worldwide, of which up to 10% of have severe, or refractory, asthma which may be uncontrolled despite high doses of standard-of-care asthma medicines (AstraZeneca, 2017). Severe asthma can be a complicated disorder and challenging to treat. Most individuals with asthma are able to achieve symptom control with low doses of inhaled corticosteroids; however, those with severe or refractory asthma have ongoing symptoms and airway inflammation despite high-dose corticosteroid treatment (AAAI, 2016).

Eosinophilic asthma is an asthma subtype that is commonly seen in people who develop asthma in adulthood, although it may occur in children and adolescents. In eosinophilic asthma, the numbers of eosinophils are increased in blood, lung tissue, and mucus which correlate with future risk and severity of asthma attacks (Apfed, 2017).  Patients with more than two or three exacerbations during a year tend to have greater peripheral airway obstruction on pulmonary function tests, persistent eosinophilia in blood and bronchoalveolar lavage despite high doses of systemic glucocorticoids. Clinical studies have found that peripheral blood eosinophils appear to be good predictors of response to monoclonal antibodiesinterleukin-5 (IL-5) add-on therapy (Wenzel, 2016).

Fasenra (benralizumab), an anti-eosinophilic monoclonal antibody, in combination with high-dosage inhaled corticosteroids and long-acting β2-agonists (ICS/LABA), was shown in the Phase III SIROCCO and CALIMA trials to significantly reduce asthma exacerbations, improve lung function, and reduce symptoms for patients with severe, uncontrolled asthma with blood eosinophil counts ≥300 cells/μL (AstraZeneca, 2017).

On November 14, 2017, AstraZeneca announced the FDA approval of Fasenra (benralizumab) for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype.  Approval was based on results obtained from Phase III clinical trials SIROCCO, CALIMA, and ZONDA.

The SIROCCO and CALIMA studies were randomized, double-blind, parallel-group, placebo-controlled, exacerbation trials which included patients 12 years of age and older and were 48 and 56 weeks in duration, respectively. “The trials randomized a total of 2510 patients. 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 FEV1 below 80% in adults, and below 90% in adolescents] despite regular treatment with high dose inhaled corticosteroid (ICS) (Trial 1) or with medium or high dose ICS (Trial 2) plus a long-acting beta agonist (LABA) with or without oral corticosteroids (OCS) and additional asthma controller medications. 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” (AstraZeneca, 2017).

Bleecker et al. (2016) conducted a randomized, double-blind, parallel-group, placebo-controlled phase 3 study (SIROCCO) which included patients 12 to 75 years of age with diagnosis of asthma for at least 1 year and have had at least 2 exacerbations while on high-dosage inhaled corticosteroids (ICS) plus long-acting beta-agonist (LABA) in the past 12 months. Patients (n=1205) were randomly assigned to receive add-on therapy of subcutaneous injection of benralizumab 30 mg every 4 wks, benralizumab 30 mg every 8 wks, or placebo for 48 weeks. The primary endpoint was annual exacerbation rate ratio versus placebo. Secondary endpoints were prebronchodilator forced expiratory volume in 1 s (FEV1) and total asthma symptom score at week 48, for patients with blood eosinophil counts of at least 300 cells per μL. Compared with placebo, benralizumab reduced the annual asthma exacerbation rate over 48 weeks when given Q4W (95% CI; p<0·0001) or Q8W (p<0·0001). Both benralizumab dosing regimens significantly improved prebronchodilator FEV1 in patients at week 48 compared with placebo (least-squares mean change from baseline: Q4W group 0·106 L, 95% CI 0·016-0·196; Q8W group 0·159 L, 0·068-0·249). Compared with placebo, asthma symptoms were improved by the Q8W regimen (least-squares mean difference -0·25, 95% CI -0·45 to -0·06), but not the Q4W regimen (-0·08, -0·27 to 0·12). Bleecker and colleagues concluded that the study results confirm the efficacy and safety of the add-on treatment of benralizumab for patients with severe asthma and elevated eosinophils who have been uncontrolled by high-dosage ICS plus LABA. (NCT01928771)

FitzGerald et al. (2016) conducted a randomized, double-blind, parallel-group, phase 3 study (CALIMA) which included patients 12 to 75 yrs of age with severe asthma not controlled by medium- to high-dosage ICS plus LABA and with history of two or more exacerbations in the 12 months. Patients (n=1306) were randomly assigned to receive add-on therapy of subcutaneous injection of benralizumab 30 mg every 4 wks, 30 mg every 8 wks (first 3 doses 4 wks apart), or placebo for 56 weeks. The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per μL or greater. Secondary endpoints were pre-bronchodilator forced expiratory volume in 1 s (FEV1) and total asthma symptom score. Benralizumab resulted in significantly lower annual exacerbation rates with the Q4W regimen (rate 0·60 [95% CI 0·48-0·74], rate ratio 0·64 [95% CI 0·49-0·85], p=0·0018, n=241) and Q8W regimen (rate 0·66 [95% CI 0·54-0·82], rate ratio 0·72 [95% CI 0·54-0·95], p=0·0188, n=239) compared with placebo (rate 0·93 [95% CI 0·77-1·12], n=248). Benralizumab also significantly improved pre-bronchodilator FEV1 (Q4W and Q8W) and total asthma symptom score (Q8W only) in these patients. FitzGerald and colleagues concluded that benralizumab significantly reduced annual exacerbation rates for patients with uncontrolled severe asthma and blood eosinophils ≥300 cells/μL. Benralizumab was also shown to be generally well tolerated. (NCT01914757)

Nair et al. (2017) conducted a 28-week randomized, controlled trial (ZONDA) to assess if benralizumab would be effective as an oral glucocorticoid-sparing therapy in patients who were relying on oral glucocorticoids to manage severe asthma associated with eosinophilia. Patients (n=220) were randomized and started on benralizumab 30 mg administered subcutaneously either every 4 weeks or every 8 weeks [with the first three doses administered every 4 weeks] or a placebo. Both benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). Secondary outcomes revealed that benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P=0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P<0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. Nair and colleagues concluded that benralizumab significantly showed benefits, compared to placebo, on reduction of oral glucocorticoid use and exacerbation rates. (NCT02075255)

Goldman et al. (2017) evaluated the association between blood eosinophil count and benralizumab efficacy for patients with severe, uncontrolled asthma from the subanalyses of the Phase III SIROCCO and CALIMA studies. The objective was to understand the efficacy and safety of benralizumab for patients with eosinophil-driven disease with blood eosinophil counts lower than 300 cells/μL. The authors evaluated the effect of applying an eosinophil cutoff of ≥150 cells/μL. Efficacy measures including annual exacerbation rate, pre-bronchodilator FEV1, and total asthma symptom score were analyzed by baseline blood eosinophil counts ≥150 vs. <150 cells/μL. They noted that in patients with blood eosinophil counts greater than or equal to 150 cells/μL, benralizumab reduced asthma exacerbation rates by 42% in SIROCCO (p < 0.001, n=325) and 36% in CALIMA (p < 0.001, n=300). Furthermore, benralizumab increased pre-bronchodilator FEV1 (both studies, p ≤ 0.002) and improved total asthma symptom score in SIROCCO (p = 0.009) at end of treatment vs. placebo for patients with blood eosinophil counts ≥150 cells/μL. The authors concluded that benralizumab is safe and effective for patients with severe asthma and blood eosinophil counts ≥150 cells/μL. In addition, the authors note that the ZONDA study demonstrated that benralizumab treatment substantially reduced oral glucocorticoid use for adult patients with blood eosinophil counts ≥150 cells/μL, further supporting potential use of this agent in this patient population. The ZONDA study protocol included baseline blood eosinophil count to be assessed at Visit 1 (initial enrollment) 10 weeks prior to the induction phase of benralizumab administration, which was randomized at Visit 6 (AstraZenica, 2014).

While there were two dosing regimens studied in the three trials, the recommended dosing regimen selected is 30 mg every 4 weeks for the first 3 doses, then every 8 weeks thereafter (AstraZeneca, 2017).

Tian et al. (2017) discussed their systematic review and meta-analysis of RCT on the efficacy and safety of benralizumab for eosinophilic asthma. Tian and colleagues conducted a literature search of PubMed, Embase, and the Cochrane Library to identify randomized controlled trials of benralizumab and clinic outcomes in asthmatics. In total, 7 articles with 2,321 subjects met inclusion criteria. From this pooled analysis, they found that benralizumab significantly reduces exacerbations (RR: 0.63, 95% CI: 0.52-0.76, p < 0.00001; I2 = 52%, p = 0.06) compared to placebo in eosinophilic asthma. There was no statistical trend for improvement in forced expiratory volume in 1 second or asthma control indices such as Quality of Life Assessment (AQLQ) and Asthma Control Questionnaire score in benralizumab-treated patients. In addition, safety data indicated that benralizumab administration did not result in increasing incidence of adverse events and was found to be well tolerated (RR: 1.00, 95% CI: 0.95-1.05, p = 0.96; I2 = 40%, p = 0.13). The authors concluded that their findings demonstrate the efficacy and safety of benralizumab for the treatment of asthma patients with severe or uncontrolled symptoms and elevated eosinophils.

Per Global Initiative for Asthma (GINA, 2020), in severe asthma, participants in randomized controlled trials may not be representative of patients seen in clinical practice. An example that was provided includes a registry study which found that over 80 percent of patients with severe asthma would have been excluded from recent studies evaluating biologic therapy.

A 2020 GINA update on the "Global Strategy for Asthma Management and Prevention" recommends, as a treatment option, an add-on anti-interleukin-5 treatment for persons with severe eosinophilic asthma that is uncontrolled on Step 4, which is low dose ICS-formoterol as maintenance and reliever therapy (adults and adolescents), or medium dose ICS-LABA maintenance plus as-needed SABA (adults, adolescents and children) and Step 5, which may include high dose ICS-LABA plus oral corticosteroids. The GINA panel recommends that patients with persistent symptoms or exacerbations despite correct inhaler technique and good adherence with Step 4 treatment, and in whom other controller options have been considered, should be referred to a specialist with expertise in investigation and management of severe asthma. 

A 2023 GINA update on the "Global Strategy for Asthma Management and Prevention" emphasizes their recommendation for biologic therapy for asthma is only if the asthma is severe and when existing treatment has been optimized. The guidelines continue to recommend add-on treatment with benralizumab for patients 12 years or older who have severe eosinophilic asthma despite optimization of treatment.

On April 11, 2024, the FDA approved a label expansion for use of Fasenra as add-on maintenance treatment for patients with severe asthma aged 6 to 11 with an eosinophilic phenotype. FDA approval was based on the safety data from the TATE trial, which was a 48-week, open-label, parallel group, pharmacokinetic (PK) and pharmacodynamic (PD) trial of 28 pediatric patients aged 6 to 11 years with severe asthma who had an eosinophilic phenotype. Patients received subcutaneous dose of 10 mg (for those weighing less than 35 kg) or 30 mg (for those weighing 35 kg or more) of Fasenra administered every 4 weeks for the first 3 doses, then every 8 weeks thereafter. No new safety signals were observed in these patients. In summary, Fasenra met the primary endpoints, demonstrating PK and PD in children aged 6 to 11 years old with severe eosinophilic asthma, which were consistent with those seen in prior trials. The safety and tolerability were also consistent with the known profile of the benralizumab.

Chronic Obstructive Pulmonary Disease

Brightling et al. (2014) discussed their randomized, double-blind, placebo-controlled, phase IIa study on benralizumab for chronic obstructive pulmonary disease (COPD). Brightling and colleagues conducted their study between Nov 18, 2010, and July 13, 2013, at 26 sites in the UK, Poland, Germany, Canada, the USA, Denmark, and Spain. Adults aged 40-85 years, with moderate-to-severe COPD, at least one acute exacerbation of COPD, and a sputum eosinophil count of 3·0% or more within the previous year, were randomly assigned (1:1) via computer-generated permuted block randomization, to receive placebo or 100 mg benralizumab subcutaneously, every 4 weeks (three doses), then every 8 weeks (five doses) over 48 weeks. The primary endpoint was the annualized rate of acute exacerbations of COPD at week 56, defined as the number of acute exacerbations divided by total duration of person-year follow-up. Secondary and exploratory endpoints included COPD-specific Saint George's Respiratory Questionnaire (SGRQ-C), Chronic Respiratory Questionnaire self-administered standardized format (CRQ-SAS), pre-bronchodilator forced expiratory volume in 1 second (FEV1), and safety. The investigators assigned 101 patients to receive placebo (n=50) or benralizumab (n=51), of whom 88 (87%) patients completed the study. Six patients who completed the study were excluded from the per-protocol population because of major protocol violations; the per-protocol population thus included 82 patients. The authors found that benralizumab did not reduce the annualized rate of acute exacerbations of COPD compared with placebo in the per-protocol population, with rates of 0·95 (0·68-1·29; n=40) versus 0·92 (0·67-1·25; n=42). Mean pre-bronchodilator FEV1 change from baseline to week 56 was -0·06 L (SD 0·24) with placebo, and 0·13 L (0·41) with benralizumab (p=0·014). Numerical, albeit non-significant, improvement in acute exacerbations of COPD, SGRQ-C, CRQ-SAS, and FEV1 were greater in benralizumab-treated patients with baseline blood eosinophil concentrations of 200 cells per μL or more or 300 cells per μL or more. A higher incidence of serious treatment-emergent adverse events were recorded in patients in the benralizumab group than in those in the placebo group (14 vs nine patients), although none of these events were considered by the investigator to be benralizumab related. The authors concluded that compared with placebo, benralizumab did not reduce the rate of acute exacerbations of COPD. However, they state that further investigation of benralizumab in patients with COPD and eosinophilia is warranted. Trial is registered with ClinicalTrials.gov, number NCT01227278.

Eosinophilic Annular Erythema

Masaki et al (2021) reported on the case of a 56-year-old woman who presented with repeated swelling of the lips and face.  She had a history of childhood asthma; she had a recurrence of asthma when she was 54 years old and was taking inhaled corticosteroids, and other anti-asthma drugs. The swelling of her lips and face improved temporarily with OCS; but recurred soon after discontinuing OCS. Her peripheral blood eosinophil count was 632/μL (9.3 %), and her serum was negative for myeloperoxidase-anti-neutrophil cytoplasmic antibody and serine proteinase3-anti-neutrophil cytoplasmic antibody. Hematoxylin and eosin staining of her back skin revealed abundant eosinophilic infiltrate around the vascular area of the shallow dermis layer, but no evidence of vasculitis and these investigators diagnosed the subject as eosinophilic annular erythema (EAE). Punctate staining of galectin-10, chromatolytic eosinophils, and net-like DNA was also evident in close proximity to the free granules, indicating extracellular vesicles and eosinophil extracellular traps (ETosis). These researchers started daily OCS to control the subject’s asthma and skin eruption/edema. Three months following administering daily OCS, benralizumab was initiated for withdrawal from OCS dependence and treatment of severe asthma. After initiation of benralizumab, her skin and subcutaneous tissue symptoms promptly improved. OCS was discontinued, and no edematous erythema has been observed since then. Bronchial asthma has also been well-controlled. The authors conclude that this was the 1st report on the evidence of eosinophil ETosis in the dermis of EAE patients and the effectiveness of benralizumab in a patient with EAE. These researchers stated that benralizumab may be a useful in the treatment of refractory EAE with severe eosinophilic asthma. They stated that the effectiveness of benralizumab in the treatment of diseases other than asthma is promising. 

Moro-Bolado et al (2023) noted that EAE is a rare cutaneous condition of undetermined etiology that is characterized by the presence of erythematous and edematous plaques following an annular or polycyclic morphology. Skin lesions develop commonly on the trunk and proximal extremities and have a recurrent course. Given the few cases reported in the literature, to the authors’ knowledge there are no clear treatment recommendations. These investigators described a case of EAE in an 83-year-old woman who was successfully treated with benralizumab. These preliminary findings need to be validated by well-designed studies.

Eosinophilic Cystitis

Konstantinou and Voukelatou (2023) reported on a case of a 66-year-old man who was diagnosed with OCS-refractory eosinophilic cystitis (EoC). Hematuria was the first and only sign of the disease that was otherwise asymptomatic, and the only abnormal laboratory finding he had was peripheral eosinophilia (700 cells/μL). Due to cardiovascular issues, an invasive surgical procedure was declined. As an alternative, benralizumab was administered. The patient responded rapidly with clinical and histological complete remission (CR) of the EoC 4 months after benralizumab started. He continued benralizumab 30 mg Q4-weeks for 12 months without experiencing any side effects. Six months after the last dose, he was completely healthy with no peripheral eosinophilia. EoC is a rare condition with no standardized treatment. Those with OCS-refractory EoC are eligible for surgery. These investigators noted that benralizumab has an excellent safety profile; thus, it should be considered before deciding on invasive surgical procedures in selected, refractory to non-specific treatment cases, especially with EoC of unclear etiology. It is unclear if benralizumab may immunomodulate the unknown underlying mechanisms of EoC, considering that EoC did not relapse after benralizumab was deemed eliminated. The authors concluded that further studies are needed to examine this possibility.

Eosinophilic Granulomatosis with Polyangiitis

Eosinophilic granulomatosis with Polyangiitis (EGPA), formerly known as Churg-Strauss syndrome, is a rare, immune-mediated vasculitis that can result in damage to multiple organs. The most common signs and symptoms include extreme fatigue, weight loss, muscle and joint pain, rash, nerve pain, sinus and nasal symptoms, and shortness of breath. Without treatment, the condition may be fatal.

Matsuno and Minamoto (2022) noted that eosinophils play an important pathogenetic role in the development of eosinophilic granulomatosis with polyangiitis (EGPA). EGPA has long been treated with systemic corticosteroids and immunosuppressive agents; however, in recent years, biologic agents targeting eosinophils (anti-IL-5 antibody; mepolizumab) have also been used. Evidence regarding the effectiveness of benralizumab has been growing. Benralizumab is used as a steroid-sparing treatment option for EGPA. Clinical studies have examined the effects of using mepolizumab or benralizumab in combination with steroids for the treatment of EGPA. However, currently, there have been no reports of using biologics alone. These researchers described the case of a patient with active EGPA refractory to benralizumab monotherapy. The patient achieved significant improvement in symptoms after administration of corticosteroids during hospitalization. The authors concluded that benralizumab monotherapy might not be considered a therapeutic option for patients with active EGPA in whom corticosteroids are initially indicated. Moreover, these investigators stated that it remains to be clarified whether the increased dose of benralizumab alone or in combination with steroids could adequately control eosinophilic inflammation in patients with active EGPA. 

Koga et al (2022) stated that 2 types of IL-5 antibody biologics, anti-IL-5 antibodies (mepolizumab) and anti-IL-5α receptor antibodies (benralizumab), are indicated for the treatment of patients with severe asthma. While high-dose mepolizumab is also indicated for EGPA, benralizumab is indicated only for severe asthma. Benralizumab is characterized by antibody-dependent cell-mediated cytotoxicity activity, giving them specific and rapid anti-IL-5α receptor binding abilities and the ability to target a high number of eosinophils in tissues as well as peripheral blood. Recently, studies on the effectiveness of benralizumab as a treatment for EGPA have been published, along with reports on some cases that were difficult to treat with existing OCS and mepolizumab. In a review, these researchers focused on the perspective of the safety and effectiveness of benralizumab as a treatment for EGPA patients with steroid dependence. A total of 41 patients with EGPA were treated with benralizumab. After the introduction of benralizumab, OCS could be reduced to 10 mg/day or less in all cases and to less than 5 mg/day in 80 % or more of the cases. Discontinuation of OCS was achieved in more than 40 % of patients with EGPA. Benralizumab was effective in patients with mepolizumab-refractory EGPA and intractable cardiac and neuropathy complications. Efficient elimination of eosinophils is expected to improve the remission rate of EGPA with benralizumab treatment.  The authors concluded that although the total number of patients was small, benralizumab was safe and tolerable in a wide range of age groups, suggesting effectiveness in severe cases with EGPA. These researchers stated that future clinical trials are needed to examine the safety and effectiveness of benralizumab for the treatment of refractory EGPA.

Spataro and colleagues (2024) conducted a systematic review and meta-analysis of 8 studies to evaluate the efficacy and safety of benralizumab in patients with eosinophilic granulomatosis with polyangiitis (EGPA). The studies included both randomized controlled trials (RCTs) and observational studies involving a total of 396 EGPA patients. The pooled analysis demonstrated a significant reduction in oral corticosteroid dose, with an overall estimated effect of -8.25 mg/day (95% CI, -9.39 to -7.10). Complete remission was achieved in 56.8% of patients, and immunosuppressants were reduced or discontinued in 28.1% of cases. Adverse events (AE) were reported in 21.9% of patients, with only one discontinuation due to an AE. The authors concluded that their findings provide robust evidence supporting the use of benralizumab as an effective and well-tolerated treatment option for EGPA. However, future research should focus on larger, multicenter RCTs to confirm these findings and further elucidate the long-term benefits and safety profile of benralizumab in EGPA.

In a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial (MANDARA), Wechsler et al (2024) evaluated the efficacy and safety of benralizumab as compared with mepolizumab in adults with EGPA. The study included 140 adults with relapsing or refractory EGPA who were receiving standard care. The patients were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecified noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety. The study found that the adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P = 0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per microliter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per microliter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively. Benralizumab was found to be noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. 

In September 2024, the FDA approved benralizumab, branded as Fasenra, for the treatment of adults with EGPA. The approval was based on the safety and efficacy results from the MANDARA phase 3 trial (Wechsler et al, 2024). MANDARA was the first head-to-head non-inferiority trial of biologics in patients with EGPA.

Eosinophilic Pneumonia

Angeletti et al (2022) stated that relapsing eosinophilic pneumonia and severe eosinophilic asthma are rare and disabling diseases, which share common inflammatory backgrounds and often require long-term systemic steroid therapy. Benralizumab is a humanized antibody targeting IL-5 receptor that reduces corticosteroid dependence and flares up in severe eosinophilic asthma on long-term. In this case report, these researchers described successful treatment of eosinophilic pneumonia and severe eosinophilic asthma with benralizumab after a 2-year follow up, showing that benralizumab may be a promising therapeutic option for chronic eosinophilic pneumonia and asthma, especially in patients with frequent relapses or relapses caused by corticosteroid dose reduction.

Laryngeal Papillomatosis

Krause et al (2023) noted that recurrent respiratory papillomatosis (RRP) or laryngeal papillomatosis is the result of human papillomavirus (HPV)-mediated benign tumor growth on the larynx and is challenging to manage. Benralizumab is a monoclonal antibody targeted against the alpha subunit of the IL-5 receptor on eosinophils. These researchers reported o the case of a 61-year-old man who presented with refractory RRP following multiple surgical excisions.  His disease course improved substantially when benralizumab was added to his asthma regimen. There was no clear mechanistic role suggested for benralizumab directly treating RRP.  The authors concluded that this case may represent a novel use of benralizumab as an adjuvant treatment for patients with RRP and co-morbid asthma.

Vaping Precautions

Vapes, vaporizers, vape pens, hookah pens, electronic cigarettes (e-cigarettes or e-cigs), and e-pipes are some of the many terms used to describe electronic nicotine delivery systems (ENDS). ENDS are noncombustible tobacco products. These products use an “e-liquid” that may contain nicotine, as well as varying compositions of flavorings, propylene glycol, vegetable glycerin, and other ingredients. The liquid is heated to create an aerosol that the user inhales.

Vaping products may contain nicotine and/or THC, Vitamin E acetate, along with other ingredients. The FDA and CDC have found that e-cigarette, or vaping, product use-associated lung injury (EVALI) have mainly been linked with THC and/or Vitamin E acetate ingredients. However, there are many different substances and product sources that are being investigated, and there may be more than one cause of EVALI. The FDA is continuing to analyze patient samples for the presence of a broad range of chemicals, including nicotine, THC and other cannabinoids along with cutting agents/diluents and other additives, pesticides, opioids, poisons, and toxins (CDC, 2020; FDA, 2020).

The FDA and CDC recommend that people not use THC-containing e-cigarette, or vaping, products, particularly from informal sources like friends, or family, or in-person or online dealers. E-cigarette, or vaping, products (nicotine- or THC-containing) should never be used by youths, young adults, or women who are pregnant. The CDC encourages healthcare providers to reinforce the importance of abstinence from e-cigarette, or vaping, product use during the post-discharge follow-up for patients s/p EVALI, in addition to connecting patients to needed social, mental health, and substance use disorder resources (CDC, 2020; FDA, 2020).

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References