DESCRIPTION:
Fasenra is an IL-5 antagonist monoclonal antibody (IgG1 kappa) indicated for add-on maintenance treatment of patients with severe asthma aged 12 years and older, with an eosinophilic phenotype. IL-5 is expressed on the surface of eosinophils and basophils. IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Fasenra binds to IL-5, inhibiting the bioactivity of IL-5 by blocking its binding to the alpha chain of the IL-5 receptor complex. 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. Fasenra, by inhibiting IL-5 signaling, reduces the production and survival of eosinophils; however, the mechanism of action in asthma has not been definitively established. Fasenra is provided in 30 mg/mL single dose prefilled syringes as well as 30 mg/mL single dose auto-injectors. Fasenra pre-filled syringes should be administered by a healthcare professional, while the auto-injectors are intended for administration by patients/caregivers. The dosing of Fasenra is 30 mg every 4 weeks for the first three doses, followed by once every 8 weeks thereafter.

Background
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 can achieve symptom control with low doses of inhaled corticosteroid; 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 exacerbation 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 Nov. 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.

On Nov. 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.

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 = 1,205) were randomly assigned to receive add-on therapy of subcutaneous injection of benralizumab 30 mg every 4 weeks, benralizumab 30 mg every 8 weeks, 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 = 1,306) were randomly assigned to receive add-on therapy of subcutaneous injection of benralizumab 30 mg every 4 weeks, 30 mg every 8 weeks (first 3 doses 4 weeks 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)

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).

Warnings and precautions include hypersensitivity reactions (e.g., anaphylaxis, angioedema), parasitic (Helminth) infection, and reduction in corticosteroid dosage (not to discontinue systemic or inhaled corticosteroid abruptly upon initiation of therapy, must decrease gradually, if appropriate).

Adverse Reactions include headache 8%, pyrexia 3%, pharyngitis 5%, and hypersensitivity reactions 3%.

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.

Chronic Obstructive Pulmonary Disease
Brightling et al. (2014) discussed their randomized, double-blind, placebo controlled, phase II a 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 was 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.

Policy
Fasenra is considered MEDICALLY NECESSARY for individuals with severe persistent who meet all of the following criteria:

1. Member is 12 years old or older
2. Asthma is an eosinophilic phenotype as defined by a baseline (pre-treatment) peripheral blood eosinophil level greater than or equal to 150 cells per microliter
3. One of the following:
   • Patient has had at least one or more asthma exacerbations requiring systemic corticosteroids (e.g., prednisone) within the past 12 months
   • Any prior intubation for an asthma exacerbation
   • Prior asthma-related hospitalization within the past 12 months
4. Patient is currently being treated with one of the following unless there is a contraindication or intolerance to these medications:
   • High-dose inhaled corticosteroid (ICS) (e.g., greater than 500 mcg fluticasone propionate equivalent/day) with an additional asthma controller medication (e.g., leukotriene receptor antagonist [e.g., montelukast], long-acting beta-2 agonist [LABA] [e.g., salmeterol], tiotropium)
   • One maximally-dosed combination ICS/LABA product (e.g., Advair [fluticasone propionate/salmeterol], Breo Ellipta [fluticasone/vilanterol], Symbicort [budesonide/formoterol])
5. Patient is 12 years of age or older
6. Prescribed by or in consultation with one of the following:
   • Pulmonologist
   • Allergist/Immunologist
7. One of the following (applies to Fasenra Prefilled syringe only):

• Physician attests that the patient or caregiver is not competent or is physically unable to administer the Fasenra product FDA labeled for self-administration;
• Patient has experienced severe hypersensitivity reactions (e.g., anaphylaxis, angioedema, bronchospasm, or hypotension) to Fasenra within the past 6 months and requires administration and direct monitoring by a healthcare professional

Continued treatment with Fasenra is considered MEDICALLY NECESSARY when the following criteria are met:

1. Documentation of a positive clinical response (e.g., reduction in exacerbations, improvement in forced expiratory volume in 1 second [FEV1], decreased use of rescue medications)
2. Patient continues to be treated with an inhaled corticosteroid (ICS) (e.g., fluticasone, budesonide) with or without additional asthma controller medication (e.g., leukotriene receptor antagonist [e.g., montelukast], long-acting beta-2 agonist [LABA] [e.g., salmeterol], tiotropium) unless there is a contraindication or intolerance to these medications
3. Prescribed by or in consultation with one of the following:
   • Pulmonologist
   • Allergist/Immunologist
4. One of the following (applies to Fasenra Prefilled syringe only):
   • Physician attests that the patient or caregiver is not competent or is physically unable to administer the Fasenra product FDA labeled for self-administration
   • Patient has experienced severe hypersensitivity reactions (e.g., anaphylaxis, angioedema, bronchospasm, or hypotension) to Fasenra within the past 6 months and requires administration and direct monitoring by a healthcare professional

Rationale
Fasenra had three confirmatory trials and one 12 week lung function trial. Trials 1 and 2 were randomized, double-blind, parallel-group, placebo controlled exacerbation trials in patients 12 years of age and older for 48 and 56 weeks, respectively. Patients were required to be on asthma medications (inhaled corticosteroids, long acting beta agonists, oral corticosteroids, etc.) and were also stratified as having a baseline eosinophil count of greater than or equal to 300 cells/microliter OR less than 300 cells per microliter. Fasenra was given per the package insert labeled dosing. The primary endpoint for these trials was the rate of asthma exacerbations in patients with baseline blood eosinophil counts of greater than or equal to 300 cells per microliter who were taking high dose inhaled corticosteroids and long acting beta agonists. In trial 1, 35% of patients receiving Fasenra experienced an asthma exacerbation compared to 51% on placebo. In trial 2, 40% of patients receiving Fasenra experienced an asthma exacerbation compared to 51% on placebo. In a subgroup analysis, reductions in exacerbation rates for those with baseline eosinophil counts greater than or equal to 300 cells/microliter showed a numerically greater response that those with a baseline count of less than 300 cells/microliter.

In a pooled analysis of the two confirmatory asthma exacerbation studies, patients with baseline eosinophil levels ≥150 cells/microliter experienced 37% reduction in the annual asthma exacerbation rate with Fasenra (at the recommended dose) compared with placebo.

Trial 3 was a randomized, double-blind, parallel-group, oral corticosteroid reduction trial. Patients were required to have daily treatment with oral corticosteroids in addition to asthma inhalers. There was an 8 week run-in period during which the oral corticosteroid was titrated to the minimum effective dose without losing asthma control. Patients were required to have eosinophils greater than or equal to 150 cells/microliter and a history of at least one exacerbation. Fasenra was given as per the package insert dosing. The primary endpoint was the percent reduction from baseline of the final oral corticosteroid 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. The median percent reduction in daily OCS dose from baseline was 75% in those receiving Fasenra compared to 25% in patients receiving placebo. Reductions of 50% or higher in oral corticosteroid dose were observed in 66% of those receiving Fasenra compared to 37% receiving placebo. The proportion of patients with a mean final dose less than or equal to 5 mg at weeks 24 to 28 was 59% for Fasenra and 33% for placebo. Only patients with an optimized baseline oral corticosteroid dose of 12.5 mg or less were eligible to achieve a 100% reduction in oral corticosteroid dose during the study. Of those patients, 52% receiving Fasenra and 19% on placebo achieved a 100% reduction in the oral corticosteroid dose.

Change from baseline in mean FEV1 was assessed in these 3 trials as a secondary endpoint. Compared with placebo, Fasenra provided consistent improvements over time in the mean change from baseline in FEV1.

References

1. Fasenra [package insert]. AstraZeneca. Wilmington, Delaware. Updated October 2019.
2. Fasenra Prior Authorization Policy. Express Scripts. December 2018.
3. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3). National Heart, Lung, and Blood Institute. www.nhlbi.nih.gov/guidelines/asthma.
4. 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.
5. American Academy of Allergy Asthma & Immunology (AAAAI). Severe asthma in children: What have we learned? San Francisco, CA: AAAAI; Jan 2016. Available at: https://www.aaaai.org/global/latest-research summaries/New-Research-from-JACI-In-Practice/severe-asthma-children. Accessed December 13, 2017.
6. American Partnership for Eosinophilic Disorders (Apfed). Eosinophilic asthma. Atlanta, GA: Apfed; Feb 2017. Available at: http://apfed.org/about-ead/eosinophilic-asthma/. Accessed December 13, 2017.
7. AstraZeneca Pharmaceutics LP. Fasenra (benralizumab) injection, for subcutaneous use. Prescribing Information. Reference ID: 4181236. Wilmington, DE: AstraZeneca; November 2017.
8. Wenzel S. Severe asthma phenotypes. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2016.
9. Bleecker ER, FitzGerald JM, Chanez P, et al; SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long acting β2-agonists (SIROCCO): a randomised, multicentre, placebo controlled phase 3 trial. Lancet. 2016;388(10056):2115-2127.
10. FitzGerald JM, Bleecker ER, Nair P, et al.; CALIMA study investigators. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128-2141.
11. Nair P, Wenzel S, Rabe KF,et al.; ZONDA Trial Investigators. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N Engl J Med. 2017;376(25):2448-2458.
12. Tian BP, Zhang GS, Lou J, et al. Efficacy and safety of benralizumab for eosinophilic asthma: A systematic review and meta-analysis of randomized controlled trials. J Asthma. 2017:1-10.
13. Brightling CE, Bleecker ER, Panettieri RA Jr, et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2014;2(11):891-901.

Coding Section

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