Coverage Policy Manual
Policy #: 2016010
Category: Pharmacy
Initiated: April 2016
Last Review: February 2019
  Mepolizumab (Nucala)

Description:
Mepolizumab, a humanized monoclonal antibody (IGg1 kappa), is the first of a novel class of medications capable of treating severe asthma in refractory patients. Unlike omalizumab, a monoclonal antibody that is effective in treating IgE related asthma, mepolizumab is designed to prevent exacerbations related to patients with eosinophil mediated disease. Eosinophils have a variety of functions in inflammatory immune reactions. They can bind worms and and parasites via IgE, present antigens, release pro-inflammatory mediators including IL-5 and leukotrienes, and kill microorganisms. Within their granules they contain peroxidase, major basic protein, and eosinophil-derived neurotoxin. IL-5 acts on eosinophils directly via the alpha chain of IL-5Ra, a type I IL-5 receptor. IL-5 also plays a role in other cytokine cellular mediators such as basophil and mast cells. Mepolizumab binds directly to IL-5 with high specificity and also high affinity, preventing the association of IL-5 with the eosinophil receptor IL-5Ra preventing the inflammatory cascade.
 
Limitations of Use:
    • Not for treatment of other eosinophilic conditions (e.g. eosinophilic esophagitis, nasal polyps, etc)  
    • Not for relief of acute bronchospasm or status asthmaticus.  

Policy/
Coverage:
PRIOR APPROVAL IS REQUIRED FOR MEPOLIZUMAB (NUCALA)
 
Effective February 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
I. Severe Eosinophilic Asthma
Mepolizumab meets primary coverage criteria for the treatment     of severe persistent asthma (defined in ATS guidelines of severe asthma below*) as an add-on maintenance treatment of patients > 12 y/o with an eosinophilic phenotype when the following criteria are met:
 
1) 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
 
2) 6 months of ICS with daily oral glucocorticoids given in combination with a minimum of 3 months of controller medication (either a 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
 
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. AND
 
5) Patient has a history of 2 or more exacerbations in the previous year, requiring bursts of systemic steroids and commonly requiring urgent care visits, ER visits and/or hospitalizations, despite regular use of high-dose inhaled corticosteroids (such as those listed in the table under “Policy Guidelines” section), plus at least one additional controller (such as long-acting beta agonists (LABAs) salmeterol or formoterol; AND
 
6) Patient is not being treated concurrently with another IL5 agent, omalizumab, or another biologic agent for the same or similar condition.
 
Initial treatment requests may be approved for 12 months at a time.
 
Continuation of therapy with mepolizumab after 12 months must demonstrate the following in submitted medical records:
 
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).
 
II. Eosinophilic Granulomatosis with Polyangiitis
The use of mepolizumab for treatment of relapsing or refractory eosinophilic granulomatosis with polyangiitis meets primary coverage criteria when all of the following criteria are met:
        1. Individual is 18 years of age or older; AND  
        2. Individual is diagnosed with eosinophilic granulomatosis with polyangiitis for 6 months or greater, defined as:  
            1. A history or presence of asthma; AND  
            2. A blood eosinophil level of greater than or equal to 10% of leucocytes or an absolute eosinophil count of greater than 1000 cells per cubic millimeter (mm3) AND  
            3. The presence of two or more features of eosinophilic granulomatosis with polyangiitis (such as, a biopsy showing histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatosis inflammation; neuropathy, mono or poly [motor deficit or nerve conduction abnormality]; pulmonary infiltrates, non-fixed; sino-nasal abnormality; cardiomyopathy; glomerulonephritis; alveolar hemorrhage; palpable purpura, or antineutrophil cytoplasmic antibody [ANCA] positive status).
 
Initial treatment requests may be approved for 12 months at a time.
 
Continuation of therapy with mepolizumab after 12 months meets primary coverage criteria when there is documentation that treatment has resulted in clinical improvement as documented by the achievement of remission at some point during treatment, defined as the following:
    • Birmingham Vasculitis Activity Score (BVAS), version 3, of 0 (on a scale from 0 to 63); AND  
    • Receipt of prednisolone or prednisone at a dose of 4.0 mg or less per day.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Policy Guidelines:
 
European Respiratory Society/American Thoracic Society definition of severe asthma for patients aged 6 years*
 
The definition of severe asthma requires that one or both of the following levels of treatment for the previous year has been needed to prevent asthma from becoming uncontrolled or asthma that remains uncontrolled despite this level of treatment:
    • Treatment with guidelines suggested medications for GINA steps 4-5 asthma (high dose inhaled glucocorticoid and long-acting beta agonist [LABA] or leukotriene modifier/theophylline) for the previous year  
    • Treatment with systemic glucocorticoid for 50% of the year
 
Uncontrolled asthma is defined as at least one of the following:
    • Poor symptom control: ACQ (Asthma Control Questionnaire) consistently >1.5, ACT (Asthma Control Test) <20 (or "not well controlled" by NAEPP/GINA guidelines)
    • Frequent severe exacerbations: two or more bursts of systemic glucocorticoids (more than three days each) in the previous year
    • History of serious exacerbation: at least one hospitalization, intensive care unit stay, or mechanical ventilation in the previous year
    • Airflow limitation: after appropriate bronchodilator withhold FEV1 <80% predicted (in the face of reduced FEV1/FVC defined as less than the lower limit of normal)
 
The ERS/ATS definition of high doses of various inhaled glucocorticoids in relation to patient age (in mcg/day):
 
Age 6 to 12 years  
Beclomethasone > or = 320 (HFA MDI)
Budesonide > or = 800 (MDI or DPI); (> or = 720 mcg/day of US labeled budesonide DPI)
Ciclesonide > or =160 (HFA MDI)
Fluticasone propionate > or = 500 (HFA MDI or DPI); (> or = 440 mcg/day of US labeled fluticasone HFA MDI)
Mometasone > or = 500 (DPI); (> or = 550 mcg/day of US labeled mometasone DPI)
 
Age >12 years
Beclomethasone > or = 1000 (HFA MDI)
Budesonide  > or = 1600 (MDI or DPI) ;(> or = 1440 mcg/day of US labeled budesonide DPI)
Ciclesonide  > or = 320 (HFA MDI)
Fluticasone propionate > or = 1000 (HFA MDI or DPI); (> or = 880 mcg/day of US labeled fluticasone HFA MDI)
Mometasone > or = 800 (DPI); (> or = 880 mcg/day of US labeled mometasone DPI)
 
Note: Designation of high doses is provided from manufacturers' recommendations where possible. Equivalent high doses may be expressed differently between countries and some products (e.g., beclomethasone) are available in multiple formulations with different dosing recommendations. Medication inserts should be carefully reviewed by the clinician for the equivalent high daily dosage.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Mepolizumab does not meet member benefit certificate primary coverage criteria when the above requirements are not met and for all other conditions, including but not limited to:
    • aspirin-exacerbated respiratory disease (AERD) or NSAID-exacerbated respiratory disease (NERD)- consists of 3 clinical features: asthma, nasal polyps and sensitivity to asprin and other NSAIDs.
    • atopic dermatitis
    • eosinophilic esophagitis
    • nasal polyposis
    • hypereosinophilic syndromes (other than severe eosinophilic asthma)
 
For members with contracts without primary coverage criteria, the use of mepolizumab is considered to be investigational when the above requirements 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)
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
 
 
Effective February 2019 as above.
 
Effective February 2018 to January 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
I. Severe Eosinophilic Asthma
Mepolizumab meets primary coverage criteria for the treatment     of severe persistent asthma (defined in ATS guidelines of severe asthma below*) as an add-on maintenance treatment of patients > 12 y/o with an eosinophilic phenotype when the following criteria are met:
 
1) 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
 
2) 6 months of ICS with daily oral glucocorticoids given in combination with a minimum of 3 months of controller medication (either a 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
 
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. AND
 
5) Patient has a history of 2 or more exacerbations in the previous year, requiring bursts of systemic steroids and commonly requiring urgent care visits, ER visits and/or hospitalizations, despite regular use of high-dose inhaled corticosteroids (such as those listed in the table under “Policy Guidelines” section), plus at least one additional controller (such as long-acting beta agonists (LABAs) salmeterol or formoterol; AND
 
6) Patient is not being treated concurrently with another IL5 agent, omalizumab, or another biologic agent for the same or similar condition.
 
Initial treatment requests may be approved for 12 months at a time.
 
Continuation of therapy with mepolizumab after 12 months must demonstrate the following in submitted medical records:
 
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).
 
II. Eosinophilic Granulomatosis with Polyangiitis
The use of mepolizumab for treatment of relapsing or refractory eosinophilic granulomatosis with polyangiitis meets primary coverage criteria when all of the following criteria are met:
        1. Individual is 18 years of age or older; AND  
        2. Individual is diagnosed with eosinophilic granulomatosis with polyangiitis for 6 months or greater, defined as:  
                1. A history or presence of asthma; AND  
                2. A blood eosinophil level of greater than or equal to 10% of leucocytes or an absolute eosinophil count of greater than 1000 cells per cubic millimeter (mm3) AND  
                3. The presence of two or more features of eosinophilic granulomatosis with polyangiitis (such as, a biopsy showing histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatosis inflammation; neuropathy, mono or poly [motor deficit or nerve conduction abnormality]; pulmonary infiltrates, non-fixed; sino-nasal abnormality; cardiomyopathy; glomerulonephritis; alveolar hemorrhage; palpable purpura, or antineutrophil cytoplasmic antibody [ANCA] positive status).
 
Initial treatment requests may be approved for 12 months at a time.
 
Continuation of therapy with mepolizumab after 12 months meets primary coverage criteria when there is documentation that treatment has resulted in clinical improvement as documented by the achievement of remission at some point during treatment, defined as the following:
 
            • Birmingham Vasculitis Activity Score (BVAS), version 3, of 0 (on a scale from 0 to 63); AND  
            • Receipt of prednisolone or prednisone at a dose of 4.0 mg or less per day.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Mepolizumab does not meet member benefit certificate primary coverage criteria when the above requirements 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)
 
For members with contracts without primary coverage criteria, the use of mepolizumab is considered to be investigational when the above requirements 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)
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Policy Guidelines:
 
European Respiratory Society/American Thoracic Society definition of severe asthma for patients aged 6 years*
 
The definition of severe asthma requires that one or both of the following levels of treatment for the previous year has been needed to prevent asthma from becoming uncontrolled or asthma that remains uncontrolled despite this level of treatment:
 
        • Treatment with guidelines suggested medications for GINA steps 4-5 asthma (high dose inhaled glucocorticoid and long-acting beta agonist [LABA] or leukotriene modifier/theophylline) for the previous year  
        • Treatment with systemic glucocorticoid for 50% of the year
 
Uncontrolled asthma is defined as at least one of the following:
 
        • Poor symptom control: ACQ (Asthma Control Questionnaire) consistently >1.5, ACT (Asthma Control Test) <20 (or "not well controlled" by NAEPP/GINA guidelines)
        • Frequent severe exacerbations: two or more bursts of systemic glucocorticoids (more than three days each) in the previous year
        • History of serious exacerbation: at least one hospitalization, intensive care unit stay, or mechanical ventilation in the previous year
        • Airflow limitation: after appropriate bronchodilator withhold FEV1 <80% predicted (in the face of reduced FEV1/FVC defined as less than the lower limit of normal)
 
The ERS/ATS definition of high doses of various inhaled glucocorticoids in relation to patient age (in mcg/day):
 
Age 6 to 12 years  
Beclomethasone > or = 320 (HFA MDI)
Budesonide > or = 800 (MDI or DPI); (> or = 720 mcg/day of US labeled budesonide DPI)
Ciclesonide > or =160 (HFA MDI)
Fluticasone propionate > or = 500 (HFA MDI or DPI); (> or = 440 mcg/day of US labeled fluticasone HFA MDI)
Mometasone > or = 500 (DPI); (> or = 550 mcg/day of US labeled mometasone DPI)
 
Age >12 years
Beclomethasone > or = 1000 (HFA MDI)
Budesonide  > or = 1600 (MDI or DPI) ;(> or = 1440 mcg/day of US labeled budesonide DPI)
Ciclesonide  > or = 320 (HFA MDI)
Fluticasone propionate > or = 1000 (HFA MDI or DPI); (> or = 880 mcg/day of US labeled fluticasone HFA MDI)
Mometasone > or = 800 (DPI); (> or = 880 mcg/day of US labeled mometasone DPI)
 
Note: Designation of high doses is provided from manufacturers' recommendations where possible. Equivalent high doses may be expressed differently between countries and some products (e.g., beclomethasone) are available in multiple formulations with different dosing recommendations. Medication inserts should be carefully reviewed by the clinician for the equivalent high daily dosage.
 
Effective Prior to February 2018
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Mepolizumab meets primary coverage criteria for the treatment of severe persistent asthma (defined in ATS guidelines of severe asthma below*) as an add-on maintenance treatment of patients > 12 y/o with an eosinophilic phenotype when the following criteria are met:
 
1) 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
 
2) 6 months of ICS with daily oral glucocorticoids given in combination with a minimum of 3 months of controller medication (either a LABA, or LTRA, or theophylline), unless the individual is intolerant of, or has a medical contraindication to these agents; AND
 
3) Independent of other therapies, in patients with atopic severe asthma, who have a serum IgE level of 30 to 700 IU/mL and documented sensitivity to a perennial allergen, the patient must first have either failed or is intolerant of omalizumab for a minimum of 4 months. [If asthma control does not improve after a reasonable trial, omalizumab should be discontinued]. AND
 
4) 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
 
5) 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. AND
 
6) Patient has a history of 2 or more exacerbations in the previous year, requiring bursts of systemic steroids and commonly requiring urgent care visits, ER visits and/or hospitalizations, despite regular use of high-dose inhaled corticosteroids (such as those listed in the table under “Policy Guidelines” section), plus at least one additional controller (such as long-acting beta agonists (LABAs) salmeterol or formoterol.
 
Initial treatment requests may be approved for 12 months at a time.
 
Continuation of therapy with mepolizumab after 12 months must demonstrate the following in submitted medical records:
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).
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Mepolizumab does not meet member benefit certificate primary coverage criteria when the above requirements are not met and for all other conditions, including but not limited to:
 
•aspirin-exacerbated respiratory disease (AERD)
•atopic dermatitis
•eosinophilic esophagitis
•eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome)
•nasal polyposis
•hypereosinophilic syndromes (other than severe eosinophilic asthma)
 
For members with contracts without primary coverage criteria, the use of mepolizumab is considered to be investigational when the above requirements are not met and for all other conditions, including but not limited to:
 
•aspirin-exacerbated respiratory disease (AERD)
•atopic dermatitis
•eosinophilic esophagitis
•eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome)
•nasal polyposis
•hypereosinophilic syndromes (other than severe eosinophilic asthma)
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Policy Guidelines:
 
European Respiratory Society/American Thoracic Society definition of severe asthma for patients aged 6 years*
 
The definition of severe asthma requires that one or both of the following levels of treatment for the previous year has been needed to prevent asthma from becoming uncontrolled or asthma that remains uncontrolled despite this level of treatment:
 
        • Treatment with guidelines suggested medications for GINA steps 4-5 asthma (high dose inhaled glucocorticoid and long-acting beta agonist [LABA] or leukotriene modifier/theophylline) for the previous year  
        • Treatment with systemic glucocorticoid for 50% of the year
 
Uncontrolled asthma is defined as at least one of the following:
 
        • Poor symptom control: ACQ (Asthma Control Questionnaire) consistently >1.5, ACT (Asthma Control Test) <20 (or "not well controlled" by NAEPP/GINA guidelines)
        • Frequent severe exacerbations: two or more bursts of systemic glucocorticoids (more than three days each) in the previous year
        • History of serious exacerbation: at least one hospitalization, intensive care unit stay, or mechanical ventilation in the previous year
        • Airflow limitation: after appropriate bronchodilator withhold FEV1 <80% predicted (in the face of reduced FEV1/FVC defined as less than the lower limit of normal)
 
The ERS/ATS definition of high doses of various inhaled glucocorticoids in relation to patient age (in mcg/day):
 
Age 6 to 12 years  
Beclomethasone > or = 320 (HFA MDI)
Budesonide > or = 800 (MDI or DPI); (> or = 720 mcg/day of US labeled budesonide DPI)
Ciclesonide > or =160 (HFA MDI)
Fluticasone propionate > or = 500 (HFA MDI or DPI); (> or = 440 mcg/day of US labeled fluticasone HFA MDI)
Mometasone > or = 500 (DPI); (> or = 550 mcg/day of US labeled mometasone DPI)
 
Age >12 years
Beclomethasone > or = 1000 (HFA MDI)
Budesonide  > or = 1600 (MDI or DPI) ;(> or = 1440 mcg/day of US labeled budesonide DPI)
Ciclesonide  > or = 320 (HFA MDI)
Fluticasone propionate > or = 1000 (HFA MDI or DPI); (> or = 880 mcg/day of US labeled fluticasone HFA MDI)
Mometasone > or = 800 (DPI); (> or = 880 mcg/day of US labeled mometasone DPI)
 
Note: Designation of high doses is provided from manufacturers' recommendations where possible. Equivalent high doses may be expressed differently between countries and some products (e.g., beclomethasone) are available in multiple formulations with different dosing recommendations. Medication inserts should be carefully reviewed by the clinician for the equivalent high daily dosage.
 
Effective Prior to February 2018
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Mepolizumab meets primary coverage criteria for the treatment of severe persistent asthma (defined in ATS guidelines of severe asthma below*) as an add-on maintenance treatment of patients > 12 y/o with an eosinophilic phenotype when the following criteria are met:
 
1) 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
 
2) 6 months of ICS with daily oral glucocorticoids given in combination with a minimum of 3 months of controller medication (either a LABA, or LTRA, or theophylline), unless the individual is intolerant of, or has a medical contraindication to these agents; AND
 
3) Independent of other therapies, in patients with atopic severe asthma, who have a serum IgE level of 30 to 700 IU/mL and documented sensitivity to a perennial allergen, the patient must first have either failed or is intolerant of omalizumab for a minimum of 4 months. [If asthma control does not improve after a reasonable trial, omalizumab should be discontinued]. AND
 
4) 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
 
5) 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. AND
 
6) Patient has a history of 2 or more exacerbations in the previous year, requiring bursts of systemic steroids and commonly requiring urgent care visits, ER visits and/or hospitalizations, despite regular use of high-dose inhaled corticosteroids (such as those listed in the table under “Policy Guidelines” section), plus at least one additional controller (such as long-acting beta agonists (LABAs) salmeterol or formoterol.
 
Initial treatment requests may be approved for 12 months at a time.
 
Continuation of therapy with mepolizumab after 12 months must demonstrate the following in submitted medical records:
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).
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Mepolizumab does not meet member benefit certificate primary coverage criteria when the above requirements are not met and for all other conditions, including but not limited to:
 
•aspirin-exacerbated respiratory disease (AERD)
•atopic dermatitis
•eosinophilic esophagitis
•eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome)
•nasal polyposis
•hypereosinophilic syndromes (other than severe eosinophilic asthma)
 
For members with contracts without primary coverage criteria, the use of mepolizumab is considered to be investigational when the above requirements are not met and for all other conditions, including but not limited to:
 
•aspirin-exacerbated respiratory disease (AERD)
•atopic dermatitis
•eosinophilic esophagitis
•eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome)
•nasal polyposis
•hypereosinophilic syndromes (other than severe eosinophilic asthma)
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Policy Guidelines:
 
European Respiratory Society/American Thoracic Society definition of severe asthma for patients aged 6 years*
 
The definition of severe asthma requires that one or both of the following levels of treatment for the previous year has been needed to prevent asthma from becoming uncontrolled or asthma that remains uncontrolled despite this level of treatment:
 
    • Treatment with guidelines suggested medications for GINA steps 4-5 asthma (high dose inhaled glucocorticoid and long-acting beta agonist [LABA] or leukotriene modifier/theophylline) for the previous year
    • Treatment with systemic glucocorticoid for 50% of the year
 
Uncontrolled asthma is defined as at least one of the following:
 
    • Poor symptom control: ACQ (Asthma Control Questionnaire) consistently >1.5, ACT (Asthma Control Test) <20 (or "not well controlled" by NAEPP/GINA guidelines)
    • Frequent severe exacerbations: two or more bursts of systemic glucocorticoids (more than three days each) in the previous year
    • History of serious exacerbation: at least one hospitalization, intensive care unit stay, or mechanical ventilation in the previous year
    • Airflow limitation: after appropriate bronchodilator withhold FEV1 <80% predicted (in the face of reduced FEV1/FVC defined as less than the lower limit of normal)
 
The ERS/ATS definition of high doses of various inhaled glucocorticoids in relation to patient age (in mcg/day):
 
Age 6 to 12 years  
Beclomethasone > or = 320 (HFA MDI)
Budesonide > or = 800 (MDI or DPI); (> or = 720 mcg/day of US labeled budesonide DPI)
Ciclesonide > or =160 (HFA MDI)
Fluticasone propionate > or = 500 (HFA MDI or DPI); (> or = 440 mcg/day of US labeled fluticasone HFA MDI)
Mometasone > or = 500 (DPI); (> or = 550 mcg/day of US labeled mometasone DPI)
 
Age >12 years
Beclomethasone > or = 1000 (HFA MDI)
Budesonide  > or = 1600 (MDI or DPI) ;(> or = 1440 mcg/day of US labeled budesonide DPI)
Ciclesonide  > or = 320 (HFA MDI)
Fluticasone propionate > or = 1000 (HFA MDI or DPI); (> or = 880 mcg/day of US labeled fluticasone HFA MDI)
Mometasone > or = 800 (DPI); (> or = 880 mcg/day of US labeled mometasone DPI)
 
Note: Designation of high doses is provided from manufacturers' recommendations where possible. Equivalent high doses may be expressed differently between countries and some products (e.g., beclomethasone) are available in multiple formulations with different dosing recommendations. Medication inserts should be carefully reviewed by the clinician for the equivalent high daily dosage.

Rationale:
Pavord and colleagues evaluated the efficacy and safety of mepolizumab on rates of exacerbation in individuals with recurrent severe asthma (Pavord, 2012). 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) (Ortega, 2014). 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 a 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.
 
However, a recent Cochrane review found eight studies on 1707 participants met the inclusion criteria. Only two studies included children (over 12 years of age), but they did not report separate findings for the adolescents. Seven studies involved intravenous mepolizumab alone; one included a subcutaneous arm. There was heterogeneity in the severity and clinical pattern of asthma among the participants in the eight studies, varying from mild to moderate atopic asthma, to persistent asthma and eosinophilic asthma with recurrent exacerbations. Selection bias was a concern in several of the studies included in this review. Four trials compared intravenous mepolizumab to placebo in relation to HRQoL. Two studies measured scores from the Asthma Quality of Life Questionnaire (AQLQ), which showed a non-significant difference between mepolizumab and placebo (mean difference (MD) 0.21, 95% confidence interval (CI) - 0.01 to 0.44; participants = 682), in the direction favoring mepolizumab. The third study used the St. George's Respiratory Questionnaire (SGRQ) and found a significant difference between mepolizumab and placebo (MD 6.40, 95% CI 3.15 to 9.65; participants = 576), which indicated a clinically important benefit favoring mepolizumab. A fourth study noted that there was no significant difference but did not provide any data. The two studies in people with eosinophilic asthma showed a reduction in clinically significant exacerbation rates (Risk Ratio 0.52, 95% CI 0.43 to 0.64; participants = 690). However, an analysis of four studies that were not confined to people with eosinophilic asthma indicated considerable heterogeneity and no significant difference in people with one or more exacerbations between mepolizumab and placebo using a random-effects model (Risk Ratio 0.67, 95% CI 0.34 to 1.31; participants = 468; I(2) = 59%).The analysis of serious adverse events indicated a significant difference favoring mepolizumab (Risk ratio 0.49, 95% CI 0.30 to 0.80; participants = 1441; studies = 5; I(2) = 0%). It was not possible to combine the results for adverse events, and we deemed the quality of this evidence to be low. A single study compared subcutaneous mepolizumab to placebo in 385 adults with severe eosinophilic asthma and found an improvement in HRQoL scores and a reduction in asthma exacerbations, including exacerbations requiring admission to hospital.
 
The authors of the review concluded that it was not possible to draw firm conclusions from this review with respect to the role of mepolizumab in patients with asthma.  Confidence in the results of this review were limited by the fact that the intravenous route is not currently licensed for mepolizumab, and the evidence for the currently licensed subcutaneous route was limited to a single study in participants with severe eosinophilic asthma.  Currently available studies provide evidence that mepolizumab can lead to an improvement in health-related quality of life scores and reduce asthma exacerbations in people with severe eosinophilic asthma, but further research is needed to clarify which subgroups of patients with asthma could potentially benefit from this treatment. Dosage, ideal dosing regimens and duration of treatment need to be clarified, as the studies included in this review differed in their protocols. There are no studies reporting results from children. Larger studies using licensed treatment regimens are required to establish the role of mepolizumab in the treatment of severe asthma.
 
2018 Update
The safety and efficacy of mepolizumab was evaluated in a 52-week multicenter, parallel-group, double-blind, phase III trial of adults who had received at least 4 weeks of a stable prednisolone or prednisone dose for relapsing or refractory EGPA (NCT02020889; Wechsler, 2017). The stable glucocorticoid dose between baseline (randomization occurred at visit 2) and week 4 could subsequently be reduced at the investigator’s discretion according to a standardized recommended tapering schedule. Participants receiving immunosuppressive therapy were required to take a stable dose before baseline and for the duration of the trial. The clinical trial inclusion criteria (NCT02020889) defined relapsing and refractory disease as follows:
 
For relapsing disease, a past history of at least one confirmed EGPA relapse (i.e., requiring increase in oral corticosteroids [OCS] dose, initiation/increased dose of immunosuppressive therapy or hospitalization) within the past 2 years which occurred at least 12 weeks prior to screening (Visit 1) while receiving a dose of prednisolone (or equivalent) of greater than or equal to 7.5 mg/day.
 
For refractory disease, failure to attain remission (Birmingham Vasculitis Activity Score [BVAS = 0] and OCS dose less than or equal to 7.5 mg/day prednisolone or equivalent) within the last 6 months following induction treatment with a standard regimen, administered for at least 3 months.
 
        • Subjects who received a cyclophosphamide (CYC) induction regimen may be included a minimum of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of pulsed intravenous CYC prior to baseline (Visit 2), if their total white blood cells are greater than or equal to 4x109/L prior to randomization;
        • Subjects who received a methotrexate, azathioprine, or mycophenolate mofetil induction regimen may be included if on a stable dose for at least 4 weeks prior to baseline (Visit 2);
        • Subjects who received an induction regimen comprising corticosteroids alone may be included only if they have failed to attain remission after 3 months of treatment AND the corticosteroid dose is greater than or equal to 15 mg/day prednisolone or equivalent for the 4 weeks prior to baseline (Visit 2); OR
Within 6 months prior to screening (Visit 1), recurrence of symptoms of EGPA (not necessarily meeting the protocol definition of relapse) while tapering OCS, occurring at any dose level greater than or equal to 7.5 mg/day prednisolone or equivalent.
 
Eligible participants were randomized to receive 300 mg subcutaneous mepolizumab or placebo every 4 weeks, plus standard care (that is, glucocorticoid treatment, with or without immunosuppressive therapy) for 52 weeks, followed by 8 weeks of follow-up. The two primary endpoints were the accrued weeks of disease remission over a 52-week period (defined as BVAS=0 [no active vasculitis]) and the proportion of participants in remission at both week 36 and week 48 of treatment. Secondary endpoints included the time to first relapse (defined as worsening symptoms related to vasculitis, asthma, or sino-nasal symptoms requiring an increased dose of corticosteroids or immunosuppressive therapy or hospitalization) and the average daily glucocorticoid dose during weeks 48 through 52, including assessment of annualized relapse rates and safety outcomes.
 
A total of 136 participants (mean age, 48.5 years; mean duration of EGPA, 5.5 years; refractory disease, n=74) were randomized to receive mepolizumab (n=68) or placebo (n=68). Participants receiving mepolizumab achieved a significantly greater accrued time in remission compared to placebo (28% vs. 3% of participants had 24 weeks of accrued remission; odds ratio, 5.91; 95% CI, 2.68 to 13.03; p<0.001) and a significantly higher proportion of participants in remission at both week 36 and week 48 compared to placebo (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; p<0.001). Significantly more participants in the mepolizumab group achieved remission within the first 24 weeks and remained in remission for the remainder of the 52-week study treatment period compared to placebo (19% vs. 1%, respectively; odds ratio, 19.7; 95% CI, 2.3 to 167.9). Remission did not occur in 47% (n=32) of participants in the mepolizumab group compared to 81% (n=55) of participants in the placebo group. The annualized relapse rate was 1.14 in the mepolizumab group compared to 2.27 in the placebo group (rate ratio, 0.50; 95% CI, 0.36 to 0.70; p<0.001). A total of 44% (n=30) of participants in the mepolizumab group compared to 7% (n=5) of participants in the placebo group had an average daily dose of prednisolone or prednisone of 4.0 mg or less per day during weeks 48 through 52 (odds ratio, 0.20; 95% CI, 0.09 to 0.41; p<0.001). The safety profile of mepolizumab was similar to that observed in previous studies of mepolizumab for eosinophilic asthma.
 
2019 Update
A literature search conducted through January 2019 did not reveal any new information that would prompt a change in the coverage statement.

CPT/HCPCS:
J2182Injection, mepolizumab, 1 mg
J3490Unclassified drugs
J3590Unclassified biologics

References: Bel EH, Wenzel SE, Thompson PJ, et al.(2014) SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014; 371(13):1189-1197.

Kim S, Marigowda G, Oren E, et al.(2010) Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome. J Allergy Clin Immunol. 2010; 125(6):1336-1343.

Ortega HG, Liu MC, Pavord ID, et al; MENSA Investigators.(2014) Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014; 371(13):1198-1207.

Pavord ID, Korn S, Howarth P, et al.(2012) Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012; 380(9842):651-659.

Powell C, Milan SJ, Dwan K, et al.(2015) Mepolizumab versus placebo for asthma. Cochrane Database Syst Rev. 2015 Jul 27;7:CD010834. doi: 10.1002/14651858.CD010834.pub2. Department of Child Health, Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK.

Wechsler ME, Akuthota P, Jayne D, et al.(2017) Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017; 376(20):1921-1932.


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