Benralizumab (Fasenra)

Number: 0925

Policy

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 (866) 267-3277.

Note: 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.

Benralizumab (Fasenra) is considered medically necessary for the treatment of asthma when all of the following criteria are met:

• Member is 12 years of age or older; and
• Member meets either of the following criteria:
  
  
  • Member has a baseline blood eosinophil count of at least 150 cells per microliter; or
  • Member is dependent on systemic corticosteroids; and
    
    

• Member has inadequate asthma control (e.g., hospitalization or emergency medical care visit within the past year) despite current treatment with both of the following medications at optimized doses:

  • Inhaled corticosteroid; and
  • Additional controller (long acting beta2-agonist, leukotriene modifier, or sustained-release theophylline); and
    
    
• Member will not use Fasenra as monotherapy; and
• Member will not use Fasenra concomitantly with other biologics indicated for asthma (e.g., Cinqair, Dupixent, Nucala, Xolair).

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

• Member is 12 years of age or older; and
• Asthma control has improved on Fasenra treatment as demonstrated by at least one of the following:
  
  
  • A reduction in the frequency and/or severity of symptoms and exacerbations; or
  • A reduction in the daily maintenance oral corticosteroid dose; and
    
    
• Member will not use Fasenra as monotherapy; and
• Member will not use Fasenra concomitantly with other biologics indicated for asthma (e.g., Cinqair, Dupixent, Nucala, Xolair).
  

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.

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.

Dosing Recommendations

Benralizumab is available as Fasenra for injection as 30 mg/mL in a single-dose prefilled syringe and 30 mg/mL solution in a single-dose autoinjector pen. Fasenra is for subcutaneous (SC) use only. The prefilled syringe is for administration by a healthcare provider.  

The recommended dose of Fasenra is 30 mg administered once every 4 weeks for the first 3 doses, and then once every 8 weeks thereafter by SC injection into the upper arm, thigh, or abdomen.

Source: AstraZeneca, 2019

Background

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

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

• Fasenra is indicated for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype (AstraZeneca, 2019).

Limitations of Use

• Not for treatment of other eosinophilic conditions
• Not for relief of acute bronchospasm or status asthmaticus

Warnings and precautions included in the Prescribing Information include hypersentivity reactions, reduction in corticosteroid dosage, and parasitic (helminth) infection. The label states to not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with Fasenra. Reduction in corticosteroid dose, if appropriate, should be gradual and performed under direct supervision of a physician. Eosinophils may be involved in the immunological response to some helminth infections. Patients with known helminth infections were excluded from participation in clinical studies. It is unknown if Fasenra will influence the immune response against helminth infections. The label states 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, discontinue treatment with Fasenra until infection resolves (AstraZeneca, 2019).

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 definitely established (AstraZeneca, 2019). 

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).

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.

Per Gobal 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 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 specialtist with expertise in investigation and management of severe asthma. 

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.

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).

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.
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:
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
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
J3304	Injection, triamcinolone acetonide, preservative-free, extended-release, microsphere formulation, 1 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	Triamcinolone, inhalation solution, compounded product, administered through dme, concentrated form, per milligram
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:
J45.20	Mild intermittent asthma, uncomplicated
J45.21	Mild intermittent asthma with (acute) exacerbation
J45.30	Mild persistent asthma, uncomplicated
J45.31	Mild persistent asthma with (acute) exacerbation
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
J45.901	Unspecified asthma with (acute) exacerbation
J45.909	Unspecified asthma, uncomplicated
J45.991	Cough variant asthma
J45.998	Other 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
J45.990	Exercise induced bronchospasm
J98.01	Acute bronchospasm

The above policy is based on the following references: