Medical Policy



Subject: Monoclonal Antibodies for the Treatment of Eosinophilic Asthma
Document #: DRUG.00080 Current Effective Date:    09/27/2017
Status: Revised Last Review Date:    08/03/2017

Description/Scope

This document addresses the use of monoclonal antibodies against interleukin-5 in the treatment of individuals with severe eosinophilic asthma not well-controlled despite current asthma care.

The U.S. Food and Drug Administration (FDA) has approved mepolizumab (Nucala® , GlaxoSmithKline, Research Triangle Park, NC) and reslizumab (Cinqair® , Teva Pharmaceutical, LLC, Frazer, PA) for this indication.

Position Statement

Medically Necessary:

  1. Mepolizumab
    For an initial 12-month period, mepolizumab is considered medically necessary for the treatment of severe eosinophilic asthma when the following criteria are met:
    1. Individual is 12 years of age or older; and
    2. Symptoms are inadequately controlled with use of either combination therapy:
      1. 12 months of high-dose inhaled corticosteroid given in combination with a minimum of 3 months of controller medication (either a long-acting beta2-agonist, or leukotriene receptor antagonist , or theophylline), unless the individual is intolerant of, or has a medical contraindication to these agents; or
      2. 6 months of inhaled corticosteroid with daily oral glucocorticoids given in combination with a minimum of 3 months of controller medication (either a long-acting beta2-agonist, or leukotriene receptor antagonist, or theophylline), unless the individual is intolerant of, or has a medical contraindication to these agents; and
    3. Individual has one of the following blood eosinophil counts (in the absence of other potential causes of eosinophilia, including hypereosinophilic syndromes, neoplastic disease, and known or suspected parasitic infection):
      1. Greater than or equal to 150 cells/microliter* at initiation of therapy; or
      2. Greater than or equal to 300 cells/microliter* in the prior 12 months; and
        *Note: 1 microliter (µL) is equal to 1 cubic millimeter (mm3)
    4. Evidence of asthma is demonstrated by both of the following:
      1. A pretreatment forced expiratory volume in 1 second (FEV1) less than 80% predicted; and
      2. FEV1 reversibility of at least 12% and 200 milliliters (ml) after albuterol (salbutamol) administration.
  2. Reslizumab
    For an initial 12-month period, reslizumab is considered medically necessary for the treatment of severe eosinophilic asthma when the following criteria are met:
    1. Individual is 18 years of age or older; and
    2. Symptoms are inadequately controlled with a minimum of 12 months of maintenance inhaled corticosteroid (for example, daily fluticasone at a dosage of 440 micrograms [or equivalent]), unless the individual is intolerant of, or has a medical contraindication to these agents; and
    3. Individual has experienced at least one asthma exacerbation in the prior 12 months requiring uninterrupted oral, intramuscular, or intravenous corticosteroid administration for 3 or more days; and  
    4. Individual has blood eosinophil counts (in the absence of other potential causes of eosinophilia, including hypereosinophilic syndromes, neoplastic disease, and known or suspected parasitic infection) greater than or equal to 400 cells/microliter* in the prior 12 months; and
      *Note: 1 microliter (µL) is equal to 1 cubic millimeter (mm3 )
    5. Evidence of asthma is demonstrated by all of the following:
      1. A pretreatment FEV1 less than 80% predicted; and
      2. FEV1 reversibility of at least 12% and 200 ml after albuterol (salbutamol) administration; and
      3. A baseline Asthma Control Questionnaire-7 score of greater than or equal to 1.5.
  3. Continuation of therapy with mepolizumab or reslizumab after 12 months is considered medically necessary for an individual with documented severe eosinophilic asthma when treatment with either drug has resulted in clinical improvement as documented by one or more of the following:
    1. Decreased utilization of rescue medications; or
    2. Decreased frequency of exacerbations (defined as worsening of asthma that requires an increase in inhaled corticosteroid dose or treatment with systemic corticosteroids); or
    3. Increase in predicted FEV1 from pretreatment baseline; or
    4. Reduction in reported asthma-related symptoms, such as, asthmatic symptoms upon awakening, coughing, fatigue, shortness of breath, sleep disturbance, or wheezing.

Investigational and Not Medically Necessary:

Mepolizumab or reslizumab is considered investigational and not medically necessary when criteria are not met and for all other conditions, including but not limited to:

Rationale

Benralizumab

Benralizumab (MedImmune/AstraZeneca US, Gaithersburg, Maryland) is an investigational anti-eosinophil monoclonal antibody against interleukin-5 (IL-5) that induces direct and near-complete depletion of eosinophils via antibody dependent cell-mediated cytotoxicity. To date, the FDA has not approved the use of benralizumab for any indication. The FDA has a Prescription Drug User Fee Act (PDUFA) target action date of November 2017 for benralizumab.

The efficacy and safety of benralizumab given in combination with high-dose inhaled corticosteroids (ICSs) and long-acting beta2-agonists (LABAs) was evaluated in three multicenter, randomized, double-blind, parallel-group, placebo-controlled, phase III clinical trials: CALIMA (NCT01914757) (FitzGerald, 2016), SIROCCO (NCT01928771) (Bleecker, 2016), and ZONDO (NCT02075255) (Nair, 2017).

In the CALIMA study (FitzGerald, 2016), 1306 participants aged 12-75 years with severe asthma uncontrolled by medium-dosage to high-dosage ICS plus LABA and a history of two or more exacerbations in the previous year were randomly assigned 1:1:1 to receive 56 weeks of benralizumab 30 mg every 4 weeks (Q4W) (n=425), benralizumab 30 mg every 8 weeks (Q8W; first three doses 4 weeks apart) (n=441), or placebo (n=440) (all subcutaneous injection). Participants were stratified (2:1) by baseline blood eosinophil counts 300 cells per μL or greater and less than 300 cells per μL, respectively. The primary endpoint was the annual exacerbation rate ratio versus placebo for participants receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per μL or greater (intention-to-treat analysis). Secondary endpoints assessed pre-bronchodilator FEV1 and total asthma symptom score. A total of 728 participants were included in the primary intention-to-treat analysis population. For the primary endpoint, 56 weeks of treatment with benralizumab resulted in significant reductions in the annual rate of asthma exacerbations compared to placebo for participants receiving high-dosage ICS plus LABA with baseline blood eosinophils ≥ 300 cells per μL. Annual exacerbation rates were approximately 36% (rate ratio, 0.64; 95% confidence interval [CI], 0.49-0.85; p=0.0018; n=241) and 28% (rate ratio, 0.72; 95% CI, 0.54-0.95; p=0.0188, n=239) lower compared to placebo for participants treated with benralizumab Q4W and Q8W regimens, respectively. For key secondary endpoints, 56 weeks of treatment with benralizumab Q4W and Q8W resulted in significant increases in pre-bronchodilator FEV1 , and total asthma symptom score (Q8W only) compared to placebo for participants receiving high-dosage ICS plus LABA with baseline blood eosinophils ≥ 300 cells per μL. Most participants (n=984 [75%]) had adverse events during the on-treatment period. The most common adverse events were nasopharyngitis (n= 90 [21%] in the Q4W group; n=79 [18%] in the Q8W group; and, n=92 [21%] in the placebo group) and worsening asthma (n=61 [14%] in the Q4W group; n=47 [11%] in the Q8W group; and, n=68 [15%] in the placebo group).

In the SIROCCO study (Bleecker, 2016), 1205 participants aged 12-75 years with a physician-based diagnosis of asthma for at least 1 year and at least two exacerbations while on high-dosage ICSs plus LABA in the previous year were randomly assigned (1:1:1) benralizumab 30 mg either every 4 weeks (Q4W) (n=400) or every 8 weeks (Q8W; first three doses every 4 weeks) (n=398) or placebo Q4W (n=407) for 48 weeks as add-on to their standard treatment. Participants were stratified 2:1 according to blood eosinophil counts of at least 300 cells per μL and less than 300 cells per μL. The primary endpoint was annual exacerbation rate ratio versus placebo. Secondary endpoints assessed pre-bronchodilator FEV1 and total asthma symptom score at week 48. A total of 267 participants in the placebo group, 275 in the benralizumab 30 mg Q4W group, and 267 in the benralizumab 30 mg Q8W group had blood eosinophil counts at least 300 cells per μL and were included in the primary intention-to-treat analysis population. Compared with placebo, benralizumab reduced the annual asthma exacerbation rate over 48 weeks when given Q4W (rate ratio, 0.55; 95% CI, 0.42-0.71; p<0.0001) or Q8W (rate ratio, 0.49; 95% CI 0.37-0.64; p<0.0001). Both benralizumab dosing regimens significantly improved pre-bronchodilator FEV1 in participants at week 48 compared to placebo (least-squares mean change from baseline: Q4W group, 0.106 L; 95% CI, 0.016-0.196; Q8W group, 0.159 L; 95%, 0.068-0.249). 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 (least-squares mean difference, -0.08; 95% CI, -0.27 to 0.12) when compared to placebo. The most common adverse events were worsening asthma (105 [13%] in 797 benralizumab-treated participants vs. 78 [19%] of 407 placebo-treated participants) and nasopharyngitis (93 [12%] vs. 47 [12%]).

Nair and colleagues (2017) performed a 28-week clinical trial (ZONDO) evaluating if benralizumab was effective as an oral glucocorticoid-sparing therapy in individuals with severe uncontrolled asthma requiring treatment with high-dosage ICS plus a LABA, chronic oral corticosteroid use, and blood eosinophil counts of at least 150 cells/µL. The study evaluated the effects of benralizumab administered at a dose of 30 mg subcutaneously every 4 weeks or every 8 weeks (with the first three doses administered every 4 weeks) versus placebo on oral corticosteroid dose reduction while maintaining asthma control. The primary endpoint was the percentage change in oral glucocorticoid dose from baseline to the final dose at the end of the maintenance phase (week 28). Secondary endpoints included assessment of annual asthma exacerbation rates, lung function, symptoms, and safety. A total of 220 participants were randomized at baseline (week 0) to receive benralizumab (Q4W, n=72; Q8W, n=73) or placebo (n=75), and entered the 4-week induction phase, during which optimized oral corticosteroid doses were maintained. In the subsequent reduction phase (weeks 4-24), oral corticosteroid doses were reduced by 2.5-5.0 mg/d at 4-weekly intervals. Participants with optimized baseline oral corticosteroid doses ≤ 12.5 mg/d were eligible for 100% dose reduction. The two 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). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. 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 FEV1 , as compared to placebo. A total of 166 participants (75%) had a least one adverse event during the intervention phase. The most frequent reported adverse events were nasopharyngitis (17% of participants), worsening asthma (13% of participants), and bronchitis (10% of participants). Frequencies of adverse events were similar between each benralizumab group and the placebo group.

Other Proposed Uses of Benralizumab

Benralizumab has being investigated for use in the treatment of other conditions including, but not limited to, chronic obstructive pulmonary disease and sputum eosinophilia (Brightling, 2014) and mild to moderate, persistent asthma (Ferguson, 2017). In the randomised, double-blind, placebo-controlled, phase III BISE trial (Ferguson, 2017), improvement in pre-bronchodilator FEV1 after 12 weeks was observed in participants with mild to moderate, persistent asthma who received ICSs and benralizumab (n=106) compared to those treated with placebo (n=105); however, the investigators concluded that use of benralizumab was not warranted in this population because the primary outcome did not reach the minimum clinically important difference of 10%, suggesting that "further studies to assess this finding should be considered." To date, the FDA has not approved benralizumab for the treatment of either of these conditions.

Mepolizumab

Mepolizumab is a humanized monoclonal antibody (IgG1, Kappa, mAb) to human IL-5. Several cytokines can affect eosinophils, but IL-5 is the primary one involved in the regulation of blood and tissue eosinophils. Mepolizumab prevents IL-5 from binding to the alpha chain of the IL-5 receptor complex that is expressed on the eosinophil cell, which inhibits IL-5 signaling, inhibiting signaling and overexpression of eosinophils in the peripheral blood and tissues.

On November 4, 2015, the FDA approved the use of mepolizumab, "...indicated for add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype." Mepolizumab is not intended for treatment of other eosinophilic conditions and not for relief of acute bronchospasm or status asthmaticus (Nucala Product Information [PI] label, 2017).

The safety and effectiveness of mepolizumab was established in three multicenter, double-blind, randomized, placebo-controlled trials and two open-label extension studies of the initial trials in individuals with severe eosinophilic asthma confirmed by blood eosinophils ≥ 150 cells/microliter at initiation of treatment or blood eosinophils ≥ 300 cells/microliter in the past 12 months. Study data confirms the efficacy of mepolizumab in reducing exacerbations that require hospitalization and/or emergency department visits and improvement in asthma control (that is, a longer time to the first exacerbation) and quality of life measures. 

Pavord and colleagues (2012) evaluated the efficacy and safety of mepolizumab on rates of exacerbation in individuals with recurrent severe asthma. In the international, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging dose selection trial (DREAM), participants aged 12 to 74 years were required to be on background maintenance therapy with a high-dose ICS for the prior 12 months (with or without oral corticosteroids) plus an additional controller (LABA, leukotriene inhibitor, or theophylline) medication. A total of 621 participants with severe recurrent asthma exacerbations and evidence of eosinophilic inflammation (such as, sputum eosinophils, peripheral blood eosinophilia, or elevated exhaled nitric oxide) were randomly assigned to receive intravenous mepolizumab at 75 mg, 250 mg, or 750 mg or placebo at 4-week intervals to week 48 for a treatment period of 52 weeks (13 infusions). The primary outcome, an annualized rate of clinically significant asthma exacerbations, was decreased in all mepolizumab groups compared with placebo with the greatest reduction in the 750 mg group (52% reduction; 95% CI, 36%-64%; p<0.0001). It was reported, however, that the effects of mepolizumab on traditional markers of asthma control (that is, symptoms and quality of life) and pulmonary function (FEV1 ) did not differ significantly from those reported with placebo. The frequency of serious adverse events was similar across treatment groups, reported as headache and nasopharyngitis. There were no reports of serious life-threatening anaphylactic reactions.

In a phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (SIRIUS) (Bel, 2014), 135 participants with severe asthma and peripheral blood eosinophilia (300 eosinophils/mcL during the 12 months prior to study entry or 150 eosinophils/mcL during the optimization phase) despite maintenance oral glucocorticoid treatment (5 mg to 35 mg of prednisone or its equivalent per day) were randomly assigned to mepolizumab 100 mg or placebo administered subcutaneously every 4 weeks for 20 weeks. The primary efficacy outcome was the percentage reduction in daily oral glucocorticoid dose during weeks 20-24 compared with baseline dose while maintaining control of asthma. The likelihood of a reduction in the glucocorticoid dose was 2.39 times greater in the mepolizumab group (95% CI, 1.25-4.56; p=0.008). The median percentage reduction from baseline in the daily oral glucocorticoid dose was 50% in the mepolizumab group compared with no reduction in the placebo group (p=0.007). Mepolizumab was associated with a decrease in the number of asthma exacerbations (that is, annualized rates were 1.44 per year in the mepolizumab group vs. 2.12 per year in the placebo group; rate ratio, 0.68; 95% CI, 0.47 to 0.99; p=0.04) and improved control of asthma symptoms. The most frequently reported adverse events were headache and nasopharyngitis (both groups). Local injection-site reactions were increased in the mepolizumab 100-mg subcutaneous treatment group compared with placebo.

Ortega and colleagues (2014) evaluated 576 individuals aged 12 years or older with severe asthma in a 32-week phase III, multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group trial (MENSA). Participants with severe asthma and markers of eosinophilic airway inflammation (peripheral blood eosinophil count 150/mcL at screening or 300/mcL at some point in the previous year) despite high-dose IHS (with or without systemic glucocorticoids) were randomly assigned to receive mepolizumab 75 mg intravenously, mepolizumab 100 mg subcutaneously, or placebo every 4 weeks for 32 weeks. Study participants were required to have an FEV1 of less than 80% of the predicted value (in the case of adults) or an FEV1 of less than 90% of the predicted value or a ratio of the FEV1 to the forced vital capacity (FVC) of less than 0.8 (in the case of adolescents under the age of 18 years). The primary outcome was the annualized frequency of clinically significant exacerbations, defined as worsening of asthma that required the treating physician to administer systemic glucocorticoids for at least 3 days, an emergency department visit, or hospitalization. The rate of asthma exacerbations was reduced by 47% (95% CI, 28 to 60) in the intravenous mepolizumab group compared with placebo and by 53% (95% CI, 36 to 65) in the subcutaneous mepolizumab group compared with placebo (p<0.001 for both comparisons). At week 32, the mean increase in FEV1 from baseline was reported as 100 mL greater with intravenous mepolizumab compared with placebo (p=0.02) and 98 mL greater with subcutaneous mepolizumab compared with placebo (p=0.03). Adverse events during treatment, including nasopharyngitis and headache, were similar across all groups.

Lugogo and colleagues (2016) evaluated the long-term efficacy and safety of subcutaneous mepolizumab in individuals with severe eosinophilic asthma in a 52-week, open-label, phase III extension study (COSMOS) in participants who received mepolizumab or placebo in the MENSA or SIRIUS trials. Participants received subcutaneous mepolizumab regardless of prior treatment allocation and continued to receive appropriate standard-of-care asthma therapy throughout the study. The primary objective assessed the long-term safety of mepolizumab; endpoints included adverse events and serious adverse events. Efficacy assessments included the annualized exacerbation rate and durability of response (defined as the exacerbation rate and oral corticosteroid dose reduction when combined with the MENSA and SIRIUS data, respectively). A total of 558 participants (86%; previous mepolizumab, 358; previous placebo, 200) and 94 participants (14%; previous mepolizumab, 58; previous placebo, 36) experienced on-treatment adverse events and serious adverse events, respectively; no fatal adverse events were reported. Systemic and local site reactions were experienced by 13 (2%) and 29 (4%) participants, respectively. There were no reports of mepolizumab-related anaphylaxis. Throughout the COSMOS study, a durable response to treatment with mepolizumab was shown in participants who previously received mepolizumab in the MENSA or SIRIUS studies, while maintaining reductions in exacerbation rate and oral corticosteroid dosing. Participants who previously received placebo in the MENSA or SIRIUS studies demonstrated improvements in these endpoints following treatment with mepolizumab in the extension study.

Summary of Safety Information

The overall adverse event profile from the pivotal studies of mepolizumab was similar between participants receiving mepolizumab and those receiving placebo. The most commonly reported adverse events were bronchitis, fatigue, headache, nasopharyngitis, and sinusitis. Hypersensitivity reactions (exposure adjusted values) were higher for the study groups that received 250 mg and 750 mg intravenous compared with placebo. Hypersensitivity reactions were less frequently compared with placebo for the 100-mg subcutaneous dose. Local injection site reactions (that is, pain, redness, swelling, itching, or a burning feeling) were higher in participants receiving subcutaneous mepolizumab, but reactions were transient and not considered as severe. A single case of anaphylaxis occurred; however, the individual had a prior history of sulfite allergy and exposure to sulfite. Herpes zoster infections have occurred in individuals receiving mepolizumab.

Other Proposed Uses of Mepolizumab

Mepolizumab is being investigated for use in the treatment of other conditions, including but not limited to, aspirin-exacerbated respiratory disease (AERD) (Gevaert, 2011), chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis (EoE) (Assa'ad, 2011; Otani, 2013; Straumann, 2011), eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome) (Kim, 2010), and hypereosinophilic syndromes (HES) unresponsive to other treatments ( Rothenberg, 2008; Roufosse, 2013; Stein, 2008). To date, the FDA has not approved mepolizumab for the treatment of any of these conditions.

Reslizumab

Reslizumab is a humanized IgG4K monoclonal antibody which targets IL-5 that stimulates the production, activation and maturation of eosinophils associated with a number of diseases, such as asthma. Reslizumab prevents IL-5 from binding to the alpha chain of the IL-5 receptor complex that is expressed on the eosinophil cell, which inhibits IL-5 signaling, inhibiting signaling and overexpression of eosinophils in the peripheral blood and tissues.

On March 23, 2016 the FDA approved reslizumab "...for the add-on maintenance treatment of patients with severe asthma aged 18 years and older with an eosinophilic phenotype." Reslizumab is not intended for treatment of other eosinophilic conditions and not for relief of acute bronchospasm or status asthmaticus (Cinqair PI label, 2016).

The safety and efficacy of reslizumab was evaluated in two multicenter, parallel-group, double-blind, randomized, placebo-controlled phase III trials of participants aged 12 through 75 years (mean age, 47 years [all participants]) (n=25 participants ages 12 to 17 years [both studies]) whose asthma was inadequately controlled by medium-to-high doses of ICS-based therapy, blood eosinophil concentrations ≥ 400 cells per µL, and one or more asthma exacerbations in the past 12 months (before screening) requiring systemic corticosteroid therapy for at least 3 days (Castro, 2015). Additional study inclusion criteria required that each participant was taking daily inhaled fluticasone at a dosage of at least 440 μg (or equivalent), had airway reversibility of at least 12% to beta-agonist administration, and had an ACQ score of at least 1.5 at screening and baseline visits (before the first dose of study drug). Chronic oral corticosteroid use of no more than 10 mg/day of prednisone or equivalent was allowed. Participants on stable doses of corticosteroids, that is, 2 weeks or more of oral corticosteroid treatment at the time of study enrollment, were required to remain on this dose throughout the study.

Study 1 was conducted between April 2011 and March 2014 and study 2 between March 2011 and April 2014. Of the 2597 participants screened, 953 were randomly assigned (1:1) to receive either intravenous reslizumab (3.0 mg/kg) (n=477 [245 in study 1; 232 in study 2]) or placebo (n=476 [244 in study 1; 232 in study 2]) every 4 weeks for a total of 13 doses. Both investigators and participants were masked to treatment assignment during the studies. All efficacy endpoints were assessed in the intention-to-treat population (all randomly assigned participants) and safety endpoints were assessed in the safety population (all participants who received at least one dose of study treatment).The primary outcome measure was the frequency of clinical asthma exacerbations in 52 weeks. Most clinical asthma exacerbations were defined by use of systemic corticosteroid for 3 or more days. Secondary outcome measures included lung function as measured by FEV1 , time to first clinical asthma exacerbation, short-acting beta-agonist usage, blood eosinophil count, Asthma Symptom Utility Index (ASUI) scores, ACQ scores, and Asthma Quality of Life Questionnaire (AQLQ) scores measured at intervals from baseline to week 52, or early withdrawal. Adverse events were monitored through the end of the follow-up period (approximately 64 weeks). In both studies, the primary outcome measure reported that participants who received reslizumab versus placebo experienced a significant reduction in the frequency of asthma exacerbations (study 1, rate ratio [RR]=0.50; study 2, RR=0.41; both, p<0.0001). Treatment with reslizumab also resulted in significant improvements compared to placebo in AQLQ total score, ACQ-7 score, and ASUI score, reported as early as the first on-treatment assessment (week 4 for ACQ-7 and ASUI; week 16 for AQLQ) and sustained through week 52. In addition, the proportion of participants achieving a 0.5 point reduction in ACQ-7 score from baseline to endpoint was significantly higher in the reslizumab group than in the placebo group (study 1, 184 [76%] vs. 152 [63%]; p=0.0002) (study 2, 178 [77%] vs. 140 [61%]; p=0.0002) (Castro, 2015).

Bjemer and colleagues (2016) conducted a phase III study in individuals aged 12 to 75 years with inadequately controlled asthma per the ACQ while receiving at least a medium dose ICS, and with blood eosinophil level of ≥ 400 cells per µL. Reslizumab was administered at a dosage of 0.3 or 3.0 mg/kg once every 4 weeks for 16 weeks (four total doses). The primary endpoint was improvement in lung function as assessed by a change from baseline in pre-bronchodilator FEV1 over 16 weeks. At 16 weeks, reslizumab significantly improved FEV1 (difference vs. placebo [reslizumab 0.3 and 3.0 mg/kg], 115 ml [95% CI, 16-215; p=0.0237] and 160 ml [95% CI, 60-259; p=0.0018]). In addition, reslizumab improved scores on the ACQ and AQLQ versus placebo (greater effects seen with 3.0 mg/kg; p<0.05). The most common adverse events which were mild to moderate in severity included worsening of asthma, headache, and nasopharyngitis.

Corren and colleagues (2016) conducted a phase III study of reslizumab in adults with inadequately controlled asthma on at least a medium dose of ICS and not receiving systemic corticosteroids. A specific baseline eosinophil count was not required for inclusion in the study. Participants were randomly assigned to receive intravenous reslizumab 3.0 mg/kg or placebo once every 4 weeks for 16 weeks. The primary endpoint was the change in FEV1 from baseline to week 16. A total of 492 individuals received ≥ one dose of placebo (n=97) or reslizumab (n=395). At 16 weeks, a significant difference was not reported between reslizumab and placebo in the mean change in FEV1 , and no significant relationship was detected between treatment, baseline blood eosinophils, and change in FEV1 . In the subgroup analysis of participants with baseline eosinophils < 400 cells per µL, those treated with reslizumab showed no significant improvement in FEV1 compared with those receiving placebo. In the subgroup with eosinophils ≥ 400 cells per µL, reslizumab was associated with greater improvements in FEV1 , ACQ-7, and FVC; however, the study was not powered to assess differences in the subgroups based on specific eosinophil levels.

Summary of Safety Information

The overall adverse event profile from the pivotal studies of reslizumab was similar between participants receiving reslizumab and those receiving placebo. The most common adverse events were reported as worsening asthma symptoms (study 1, 40% for reslizumab vs. 52% for placebo; study 2, 29% for reslizumab vs. 51% for placebo), upper respiratory tract infections (study 1, 16% for reslizumab vs. 13% for placebo; study 2, 3% for reslizumab vs. 7% for placebo), and nasopharyngitis (study 1, 11% for reslizumab vs. 14% for placebo; study 2, 19% for reslizumab vs. 24% for placebo). Anaphylactic reactions were reported in 2 participants in the reslizumab group; both responded to standard treatment and were withdrawn from the study.

Other Proposed Uses of Reslizumab

Reslizumab has been investigated for use in children and adolescents between 5 and 18 years of age with active, long-standing eosinophilic esophagitis (that is, a mean of 4 years of eosinophilic esophagitis symptoms). In this study, Spergel and colleagues (2012) reported that reslizumab significantly reduced intraepithelial esophageal eosinophil counts; however, these reductions were not accompanied by significant differences between the reslizumab and placebo groups in assessments of clinical symptoms and quality of life. To date, the FDA has not approved reslizumab for the treatment of this condition.

Additional Considerations

The National Heart, Lung, and Blood Institute (NHLBI) and the 2007 National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3, Guidelines for the Diagnosis and Management of Asthma , includes recommendations for use of long-term control medications in managing persistent asthma in a step protocol for individuals ≥ 12 years of age and older. The most recent guideline update (2008), however, was prior to the FDA approval of mepolizumab and reslizumab for the treatment of uncontrolled eosinophilic asthma.

Step 5 of the protocol states:

Step 6 of the protocol recommends adding "…oral corticosteroids to step 5 therapy. Patients who are not controlled on Step 5 therapy may require regular oral corticosteroids to achieve well-controlled asthma."

Global Initiative for Asthma (GINA)

In 2016, GINA updated their global recommendations for asthma management and prevention. For individuals with severe asthma who are uncontrolled on Step 4 treatment (that is, use of two or more controllers plus as-needed reliever medication, such as medium- to high-dose plus a LABA or other controller medication), mepolizumab is listed as a Step 5 add-on treatment option for individuals aged 12 years or older with severe eosinophilic phenotype (Level of Evidence B: randomized controlled trials and meta-analyses. Limited body of data). To date, GINA's recommendations do not address the use of reslizumab for the treatment of severe eosinophilic asthma.

To date, there are no published evidence-based practice guidelines or position statements from the American Academy of Allergy, Asthma and Immunology (AAAAI), or the Joint Task Force of the European Respiratory Society (ERS)/American Thoracic Society (ATS) (Chung, 2014) recommending the use of mepolizumab or reslizumab in the treatment of severe eosinophilic asthma, HES unresponsive to other treatments, or other conditions.

Background/Overview

Asthma and Eosinophilic Asthma

According to the Centers for Disease Control and Prevention (CDC, 2017) and the National Center for Health Statistics, asthma affected approximately 18.4 million (7.6%) adults and 6.2 million (8.4%) children under 18 years of age in the United States in 2015 and accounted for approximately 1.6 million emergency department visits in 2013, 430,000 hospitalizations in 2010, and 3651 deaths in 2014.

Asthma is a common chronic inflammatory disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and an underlying inflammation. The airway hyperresponsiveness is reversible either spontaneously or through therapy. Symptoms include wheezing, cough, and dyspnea, which can vary widely in severity and duration, although a typical attack does not last for more than several hours. The onset of asthma for most individuals begins early in life with the pattern of disease persistence determined by early, recognizable risk factors including atopic disease, recurrent wheezing, and a parental history of asthma (Akinbami, 2012). In some individuals, persistent changes in airway structure occur, including sub-basement fibrosis, mucus hypersecretion, injury to epithelial cells, and smooth muscle hypertrophy. In susceptible individuals, this inflammation causes recurrent episodes of coughing (particularly at night or early in the morning), wheezing, breathlessness, and chest tightness. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment (NAEPP, 2008). Attacks can be triggered by a number of factors, including allergic triggers, smoke and pollution, cold air, colds and other respiratory infections, exercise, and strong emotions. For many individuals with asthma, existing therapies can provide adequate control of their symptoms if used appropriately. However approximately 5% of individuals with severe asthma cannot achieve symptom control with existing therapies. 

Researchers have discovered that eosinophils play a pivotal role in immune development and asthma. Eosinophils are a type of white blood cell whose natural role is to defend the body against disease and environmental substances and accumulate wherever allergic reactions take place, including those in allergic asthma. In individuals with eosinophilic asthma, white blood cells accumulate and release chemicals that may damage the lining of the lungs. Studies examining individuals with mild asthma have shown that airway inflammation due to eosinophils is a typical characteristic, and, in fact, eosinophilic airway inflammation appears to be closely related to the risk of severe asthma exacerbations. Although the role eosinophils play in the pathophysiology of asthma is unclear, they represent a biomarker for predicting whether individuals will respond to corticosteroids, predicting which persons are at risk of exacerbations, and for guiding steroid therapy in these events (Bradding, 2008).

Approximately 30% to 40% of individuals with severe asthma are steroid-dependent. Associated side effects of steroid use include adrenal suppression, difficulty sleeping, hypertension, lipodystrophy, metabolic syndrome, and weight gain. Mepolizumab is proposed as an alternative for use in individuals requiring long-term corticosteroid use and who are unresponsive to other combination therapies.

Hypereosinophilic Syndromes (HES)

HES is a group of rare blood disorders occurring when an individual's peripheral blood has very high numbers of eosinophils. People with HES usually have > 1500 eosinophils/microliter (µL) in the peripheral blood persisting for ≥ 6 months. Symptoms of HES include manifestations of organ system involvement or dysfunction directly related to eosinophilia in the absence of parasitic, allergic, or other causes of eosinophilia. Symptoms are dependent on which organs are involved, most commonly the heart, lungs, spleen, skin, and nervous system. Cardiac involvement can cause significant morbidity and mortality.

According to the American Academy of Allergy Asthma, and Immunotherapy (AAAAI, 2015):

The goal of HES treatment is to reduce eosinophil levels in the blood and tissues, thereby preventing tissue damage–especially in the heart. Standard HES treatment includes glucocorticosteroid medications such as prednisone, and chemotherapeutic agents such as hydroxyurea, chlorambucil and vincristine. Interferon-alpha may also be used as a treatment...but must be administered by frequent injections...Monoclonal antibody therapy has also shown promise for treatment of HES.

FDA PI Limitations of Use, Contraindications, and Warnings and Precautions

The PI label for Nucala (2017) includes the following information:

Limitations of Use

Contraindications

Warnings and Precautions

The PI label for Cinqair (2016) includes the following information:

Black Box Warning: Anaphylaxis

Limitations of Use

Contraindications

Warnings and Precautions

Definitions

Asthma Control Questionnaire-7 (ACQ-7): A 7-item questionnaire (1 week recall for items on symptoms and rescue inhaler use) that measures the adequacy of asthma control and change in asthma control which occurs either spontaneously or as a result of treatment. The ACQ-7 assesses symptoms (5 items, self-administered), rescue in-bronchodilator use (1 item, self-administered), and FEV1 % (1 item) completed by a healthcare professional. The 7-point scale reports symptoms as: 0 = no impairment; 6 = maximum impairment for symptoms and rescue use; and, 7 categories for FEV1 %.

Asthma Quality of Life Questionnaire (AQLQ): A 32-item disease-specific questionnaire used to reflect areas of function important to individuals with asthma; available in both interviewer- and self-administered forms. The 4 domains measured by the AQLQ include activity limitations, emotional function, exposure to environmental stimuli, and symptoms.

Dyspnea: Shortness of breath; subjective difficulty or distress in breathing.

Eosinophilic granulomatosis with polyangiitis (EGPA): Previously called Churg-Strauss syndrome (CSS) or allergic granulomatosis and angiitis, is a multisystem disorder characterized by allergic rhinitis, asthma, and prominent peripheral blood eosinophilia. CSS is classified as a vasculitis of the small and medium sized arteries, although the vasculitis is often not apparent in the initial phases of the disease.

Forced expiratory volume in 1 second (FEV1 ): A measure of airway obstruction determined using spirometry; individual FEV1 values are compared to predicted values based on age, height, sex and race.

Hypereosinophilia (HE): An absolute eosinophil count (AEC) in the peripheral blood of greater than 1.5 x 109/L (or greater than 1500 cells/microL) on 2 examinations separated in time by at least 1 month and/or pathologic confirmation of tissue HE.

Hypereosinophilic syndrome (HES): The association of HE with eosinophil-mediated organ damage, with or without dysfunction, provided other potential causes for the damage have been excluded.

Hyperresponsiveness: Also referred to as the early phase of asthma, occurs when the airways of the lungs get smaller when exposed to certain allergens or environmental triggers, making it more difficult to breathe.

Inflammatory response: Also referred to as the late phase of asthma.  Swelling and irritation of the lining of the lung that can cause bronchoconstriction and increased mucus that leads to asthma symptoms.

Inhaled corticosteroid(s) (ICS or ICSs): A class of medications also referred to as inhaled steroids; used for the treatment of asthma and COPD. A potent anti-inflammatory medication that improves asthma control more effectively than any other agent used as a single treatment; helps to prevent chronic asthma symptoms such as wheezing, chest tightness, shortness of breath, and chronic cough.

Long-acting beta-agonist(s) (LABA or LABAs): Also referred to as long-acting beta2 -adrenergic agonists. A type of bronchodilator whose effects last for 12 hours or more when used as adjunctive treatment for the prevention of asthma symptoms such as wheezing, chest tightness, shortness of breath, and cough; improves asthma symptoms by increasing airflow through the lungs.

Peak expiratory flow (PEF): Often described as a percent of personal best measurement; personal best PEF is the highest PEF value attained after 2 to 3 weeks of testing when asthma is in good control.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met: 

HCPCS    
J2182 Injection, mepolizumab, 1 mg [Nucala]  
J2786 Injection, reslizumab, 1 mg [Cinqair]  
   
ICD-10 Diagnosis  
J45.20-J45.998 Asthma
J82 Pulmonary eosinophilia, not elsewhere classified

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications: 

  1. Assa'ad AH, Gupta SK, Collins MH, et al. An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology. 2011; 141:1593.
  2. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014; 371(13):1189-1197.
  3. Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β(2)-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016; 388(10056):2115-2127.
  4. Bjermer L, Lemiere C, Maspero J, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016; 150(4):789-798.
  5. Bradding P. Asthma: eosinophil disease, mast cell disease, or both? Allergy, Asthma, and Clinical Immunology. 2008; (4)2:84-90.
  6. 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.
  7. Castro M, Mathur S, Hargreave F, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011; 184(10):1125-1132.
  8. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015; 3(5):355-366. Erratum in: Lancet Respir Med. 2015; 3(4):e15.
  9. Corren J, Weinstein S, Janka L, et al. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016; 150(4):799-810.
  10. Ferguson GT, FitzGerald JM, Bleecker ER, et al. Benralizumab for patients with mild to moderate, persistent asthma (BISE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2017; 5(7):568-576.
  11. FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor ? 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.
  12. Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011; 128:989-995, e1-e8.
  13. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009; 360(10):973.
  14. Kim S, Marigowda G, Oren E, et al. Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome. J Allergy Clin Immunol. 2010; 125(6):1336-1343.
  15. Liu Y, Zhang S, Li DW, Jiang SJ. Efficacy of anti-interleukin-5 therapy with mepolizumab in patients with asthma: a meta-analysis of randomized placebo-controlled trials. PLoS One. 2013; 8(3):e59872. Erratum in: PLoS One. 2013; 8(6).
  16. Lugogo N, Domingo C, Chanez P, et al. Long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, phase IIIb study. Clin Ther. 2016; 38(9):2058-2070.
  17. Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. Engl J Med. 2009; 360(10):985.
  18. Nair P, Wenzel S, Rabe KF, et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med. 2017; 376(25):2448-2458.
  19. Oldhoff JM, Darsow U, Werfel T, et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy. 2005; 60:693.
  20. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014; 371(13):1198-1207. 
  21. Ortega HG, Yancey SW, Mayer B, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016; 4(7):549-556.
  22. Otani IM, Anilkumar AA, Newbury RO, et al. Anti-IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis. J Allergy Clin Immunol. 2013; 131(6):1576-1582.
  23. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012; 380(9842):651-659.
  24. Prazma CM, Wenzel S, Barnes N, et al. Characterisation of an OCS-dependent severe asthma population treated with mepolizumab. Thorax. 2014; 69(12):1141-1142.
  25. Rothenberg ME, Klion AD, Roufosse FE, et al. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008; 358:1215. Erratum in: N Engl J Med. 2008; 358(23): 2530.
  26. Roufosse FE, Kahn JE, Gleich GJ, et al. Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes. J Allergy Clin Immunol. 2013; 131:461.
  27. Spergel JM, Rothenberg ME, Collins MH, et al. Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2012; 129(2):456-463, 463.e1-e3.
  28. Stein ML, Villanueva JM, Buckmeier BK, et al. Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels. J Allergy Clin Immunol. 2008; 121:1473.
  29. Straumann A, Conus S, Grzonka P, et al. Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. Gut. 2010; 59:21.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Akinbami LJ, Moorman JE, Bailey C, et al. Trends in asthma prevalence, health care use, and mortality in the United States, 2001–2010. National Center for Health Statistics (NCHS) Data Brief No.94; May 2012. Hyattsville, MD: National Center for Health Statistics. Available at: http://www.cdc.gov/nchs/data/databriefs/db94.htm. Accessed on July 5, 2017.
  2. Chung KF, Wenzel SE, Brozek JL, et al. International European Respiratory Society/American Thoracic Society guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014; 43(2):343-373.
  3. Cinqair [Product Information], Frazer, PA. Teva Pharmaceuticals, LLC; March 23, 2016. Available at: http://www.cinqair.com/pdf/PrescribingInformation.pdf. Accessed on July 5, 2017.
  4. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention, Global Initiative for Asthma (GINA) 2016. Available at: http://www.ginasthma.org. Accessed on July 5, 2017.
  5. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology and Joint Council of Allergy, Asthma and Immunology. Attaining optimal asthma control: a practice parameter. J Allergy Clin Immunol. 2005; 116(5):S3-S11.
  6. National Asthma Education and Prevention Program (NAEPP). Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. NIH Publication Number 08-5846. Updated August 5, 2008. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed on July 5, 2017.
  7. Nucala [Product Information], Philadelphia, PA. GlaxoSmithKline LLC; February 16, 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125526s002lbl.pdf . Accessed on July 5, 2017.
  8. Powell C, Milan SJ, Dwan K, et al. Mepolizumab versus placebo for asthma. Cochrane Database Syst Rev. 2015;(7):CD010834.
Websites for Additional Information
  1. American Academy of Allergy Asthma and Immunology (AAAAI). Conditions and treatments. Asthma. Available at: http://www.aaaai.org. Accessed on July 5, 2017.
  2. American Academy of Allergy Asthma and Immunology (AAAAI). AAAAI allergy & asthma medication guide. Available at: http://www.aaaai.org/conditions-and-treatments/treatments/drug-guide/inhaled-corticosteroids.aspx. Accessed on July 5, 2017.
  3. Centers for Disease Control and Prevention (CDC). Asthma FastStats. March 31, 2017. Available at: http://www.cdc.gov/nchs/fastats/asthma.htm. Accessed on July 5, 2017.
  4. National Heart, Lung, and Blood Institute (NHLBI). National Institutes of Health (NIH). Health information for the public. Lung diseases. Available at: http://www.nhlbi.nih.gov/health/. Accessed on July 5, 2017.
Index

Eosinophilic asthma
Mepolizumab
Reslizumab

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Revised 08/03/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Removed abbreviations and other format edits to the Position Statement section. Preliminary discussion pre-FDA approval of benralizumab for the treatment of eosinophilic asthma. Updated Rationale, Background, References, and Websites for Additional Information sections.
Reviewed 02/02/2017 MPTAC review. Updated formatting in Position Statement section. Updated Rationale, Background, References, and Websites for Additional Information sections.
  01/01/2017 Updated Coding section with 01/01/2017 HCPCS changes; removed C9473 and C9481 deleted 12/31/2016.
  10/01/2016 Updated Coding section with 10/01/2016 HCPCS changes.
Revised 04/13/2016 MPTAC review. Revised Subject (title) to: Monoclonal Antibodies for the Treatment of Eosinophilic Asthma. Revised Position Statement adding reslizumab as MN when criteria are met. Added reslizumab to the INV and NMN statement when criteria are not met. Updated Description, Rationale, Definitions, Coding, References and Websites for Additional Information sections.
Revised 02/04/2016 MPTAC review. Clarified medically necessary statement for initiation of mepolizumab. Updated Rationale, Background, Definitions, References and Websites for Additional Information sections. Updated Coding section with 04/01/2016 HCPCS changes.
New 11/05/2015 MPTAC review. Initial document development.