Description
Mepolizumab (Nucala^®) is indicated for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype It is also indicated in the treatment of adults with eosinophilic granulomatosis with polyangiitis (EGPA/ Churg-Strauss Syndrome). Mepolizumab (Nucala^®) is not indicated for treatment of other eosinophilic conditions and relief of acute bronchospasm or status asthmaticus.

Mepolizumab (Nucala^®) is an interleukin-5 antagonist (IgG1 kappa). IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation and survival of eosinophils. Mepolizumab binds to IL-5 with a dissociation constant of 100 pM, inhibiting the bioactivity of IL-5 by blocking its binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface. 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. Mepolizumab, by inhibiting IL-5 signaling, reduces the production and survival of eosinophils; however, the mechanism of mepolizumab action in asthma has not been definitively established. 

Policy 
Mepolizumab is considered MEDICALLY NECESSARY for the treatment of severe eosinophilic asthma when the following criteria are met:

1. Individual is 6 years of age or older; AND
2. Symptoms are inadequately controlled with use of either combination therapy:
   • 12 months of high-dose inhaled corticosteroid (ICS) given in combination with a minimum of 3 months of controller medication (either a long-acting beta2-agonist [LABA], or leukotriene receptor antagonist [LTRA], or theophylline), unless the individual is intolerant of, or has a medical contraindication to these agents; OR
   • 6 months of ICS with daily oral glucocorticoids given in combination with a minimum of 3 months of controller medication (either an LABA or LTRA or theophylline), unless the individual is intolerant of or has a medical contraindication to these agents; AND
3. 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):
   • Greater than or equal to 150 cells/microliter* at initiation of therapy; OR
   • Greater than or equal to 300 cells/microliter* in the prior 12 months; AND
     *Note: 1 microliter (ul) is equal to 1 cubic millimeter (mm³)
4. Evidence of asthma as demonstrated by both of the following:
   • A pretreatment forced expiratory volume in 1 second (FEV₁) less than 80% predicted; AND
   • FEV₁ reversibility of at least 12% and 200 milliliters (ml) after albuterol (salbutamol) administration. 
5. Patient has had at least one or more asthma exacerbations requiring systemic corticosteroids within the past 12 months OR any prior intubation for an asthma exacerbation OR prior asthma-related hospitalization within the past 12 months.

Treatment with mepolizumab is considered MEDICALLY NECESSARY for eosinophilic granulomatosis with polyangiitis (EGPA/Churg-Strauss Syndrome)  

1. Diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA)
2. Patient's disease has relapsed or is refractory to standard of care therapy (i.e., corticosteroid treatment with or without immunosuppressive therapy)
3. Patient is currently receiving corticosteroid therapy (e.g., prednisolone, prednisone) 

Treatment with mepolizumab is considered MEDICALLY NECESSARY for Chronic rhinosinusitis with nasal polyps (CRSwNP) 

1. Diagnosis of chronic rhinosinusitis with nasal polyps (CRSwNP) AND
2. Unless contraindicated, the patient has had an inadequate response to 2 months of treatment with an intranasal corticosteroid (e.g., fluticasone, mometasone) AND
3. Used in combination with another agent for CRSwNP

Treatment with mepolizumab is considered MEDICALLY NECESSARY for Hypereosinophilic Syndrome (HES) 

1. Diagnosis of hypereosinophilic syndrome (HES) for at least 6 months
2. Verification that other non-hematologic secondary causes have been ruled out (e.g., drug hypersensitivity, parasitic helminth infection, HIV infection, non-hematologic malignancy)
3. Patient is Fip1-like1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA)-negative
4. Patient has uncontrolled HES defined as both of the following:
   • History of 2 or more flares within the past 12 months
   • Pre-treatment blood eosinophil count greater than or equal to 1000 cells/microliter
5. Trial and failure, contraindication, or intolerance to one of the following:
   • Corticosteroid therapy (e.g., prednisone)
   • Cytotoxic/immunosuppressive therapy (e.g., hydroxyurea, cyclosporine, imatinib)

Continuation of therapy with mepolizumab after 12 months is considered MEDICALLY NECESSARY for the treatment of an individual with documented severe eosinophilic asthma when the following criteria are met:

1. Treatment with mepolizumab has resulted in clinical improvement as documented by one or more of the following:
   • Decreased utilization of rescue medications; OR
   • Decreased frequency of exacerbations (defined as worsening of asthma that requires an increase in ICS dose or treatment with systemic corticosteroids); OR
   • Increase in predicted FEV₁ from pretreatment baseline; OR
   • Reduction in reported asthma-related symptoms, such as asthmatic symptoms upon awakening, coughing, fatigue, shortness of breath, sleep disturbance or wheezing. 

Continuation of therapy with mepolizumab after 12 months is considered MEDICALLY NECESSARY for the treatment of an individual with Chronic rhinosinusitis with nasal polyps (CRSwNP) when the following criteria are met:  

1. Documentation of positive clinical response to therapy (e.g., reduction in nasal polyps score [NPS; 0 – 8 scale], improvement in nasal obstruction symptoms via visual analog scale [VAS; 0 – 10 scale]) AND
2. Used in combination with another agent for CRSwNP

Continuation of therapy with mepolizumab after 12 months is considered MEDICALLY NECESSARY for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA/Churg-Strauss Syndrome) and for Hypereosinophilic Syndrome (HES) when treatment has resulted in clinical improvement.

Mepolizumab is considered investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY when criteria are not met and for all other conditions, including, but not limited to:

• • Aspirin-exacerbated respiratory disease (AERD).
  • Atopic dermatitis.
  • Eosinophilic esophagitis.
  • Nasal polyposis.
  • Hypereosinophilic syndromes (other than severe eosinophilic asthma and EGPA).

Rationale 
Mepolizumab (Nucala) (GlaxoSmithKline, Research Triangle Park, NC) is a humanized monoclonal antibody (IgG1, Kappa, mAb) to human interleukin 5 (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 Nov. 4, 2015, the U.S. Food and Drug Administration (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, 2015).

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% confidence interval [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.

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.

Additional Considerations
To date, there are no published evidence-based practice guidelines or position statements from the American Academy of Allergy, Asthma and Immunology (AAAAI), Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA, 2015) or the Joint Task Force of the European Respiratory Society (ERS)/American Thoracic Society (ATS) (Chung, 2014) recommending the use of mepolizumab in the treatment of severe eosinophilic asthma or other conditions.

References 

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; SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014; 371(13):1189-1197.
3. Bradding P. Asthma: eosinophil disease, mast cell disease, or both? Allergy, Asthma, and Clinical Immunology. 2008; (4)2:84-90.
4. 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.
5. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009; 360(10):973.
6. 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.
7. 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).
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9. 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.
10. Ortega HG, Liu MC, Pavord ID, et al; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014; 371(13):1198-1207. 
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
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31. 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.
32. 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.
33. 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.
34. 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.
35. 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.
36. Specialty Matched Consultant Advisory Panel review 2/2016
37. Senior Medical Director review 2/2016

Coding Section

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This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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