Benralizumab (Fasenra)

Number: 0925

Policy

Note: REQUIRES PRECERTIFICATIONFootnote for precertification*

Benralizumab (Fasenra) is considered medically necessary for the add-on maintenance treatment of persons with severe asthma aged 12 years and older who meet the following criteria:

  • Member is 12 years of age or older; and
  • Member has an eosinophilic phenotype as determined by blood eosinophils of 150 cells/μL or higher prior to initiation of therapy (within 4 weeks of initial dosing); and
  • Member has a history of severe asthma attacks of 2 or more exacerbations requiring systemic corticosteroid treatment (intramuscular, intravenous, or oral) in the past 12 months; and
  • Member has reduced lung function at baseline (pre-bronchodilator FEV1 below 80% in adults, and below 90% in adolescents (12-17 yrs)) despite regular treatment with high-dose inhaled corticosteroids (ICS) and long-acting beta-agonist (LABA), with or without oral corticosteroid therapy and additional asthma controller medications.

 Note: Criteria for Continuation of Therapy:

  • Member has experienced a reduction in asthma signs and symptoms including wheezing, chest tightness, coughing, shortness of breath; or
  • Member has experienced a decrease in administration of rescue medication (e.g., albuterol (salbutamol); or
  • Member has experienced a decrease in exacerbation frequency (no increase in ICS, LABA or systemic corticosteroid dose); or
  • Member has experienced an increase in predicted forced expiratory volume in 1 second (FEV1) from the pretreatment baseline.


Aetna considers the use of benralizumab with mepolizumab (Nucala), reslizumab (Cinqair) or omalizumab (Xolair) experimental and investigational because the safety and effectiveness of these combinations has not been established.

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

  • Acute bronchospasm
  • Chronic obstructive pulmonary disease
  • Status asthmaticus.

Note: Footnote for precertification* Precertification of benralizumab (Fasenra) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of benralizumab call (866) 503-0857, or fax (866) 267-3277.

Also see CPB 0897 - Mepolizumab (Nucala), CPB 0907 - Reslizumab (Cinqair).

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 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.

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 hypersensitivy 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 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.

Appendix

Dosing Recommendations

Fasenra is available as an injection for subcutaneous use, 30 mg/mL in a single-dose prefilled syringe. Recommended dose is 30 mg every 4 weeks for the first 3 doses, followed by once every 8 weeks thereafter by subcutaneous injection into the upper arm, thigh, or abdomen.

Fasenra should be administered by a healthcare professional. In line with clinical practice, monitoring of patients after administration of biologic agents is recommended.

Source: AstraZeneca, 2017

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

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.

HCPCS codes covered if selection criteria are met:

C9466 Injection, benralizumab, 1 mg

Other HCPCS codes related to the CPB:

J2182 Injection, mepolizumab, 1 mg
J2357 Injection, omalizumab, 5 mg
J2786 Injection, reslizumab, 1 mg

ICD-10 codes covered if selection criteria are met:

J45.50 - J45.51 Severe persistent asthma

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

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
J98.01 Acute bronchospasm

The above policy is based on the following references:

  1. 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.
  2. 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.
  3. AstraZeneca Pharmaceutics LP. Fasenra (benralizumab) injection, for subcutaneous use. Prescribing Information. Reference ID: 4181236. Wilmington, DE: AstraZeneca; November 2017.
  4. Wenzel S. Severe asthma phenotypes. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2016.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Goldman M, Hirsch I, Zangrilli JG, et al. The association between blood eosinophil count and benralizumab efficacy for patients with severe, uncontrolled asthma: Subanalyses of the Phase III SIROCCO and CALIMA studies. Curr Med Res Opin. 2017;33(9):1605-1613.