Coverage Policy Manual
Policy #: 2016010
Category: Pharmacy
Initiated: April 2016
Last Review: December 2023
  Mepolizumab (e.g., 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 individuals. Unlike omalizumab, a monoclonal antibody that is effective in treating IgE related asthma, mepolizumab is designed to prevent exacerbations related to individuals with eosinophil mediated disease. Eosinophils have a variety of functions in inflammatory immune reactions. They can bind worms 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 relief of acute bronchospasm or status asthmaticus.  
 
Regulatory Status
 
Mepolizumab (e.g., Nucala) was approved by the U.S. Food and Drug Administration (FDA) on November 4, 2015, for the add-on maintenance treatment of severe eosinophilic asthma.
 
On December 12, 2017, the FDA approved mepolizumab (e.g., Nucala) for the treatment of adult individuals with eosinophilic granulomatosis with polyangiitis.
 
On September 25, 2020, the FDA approved mepolizumab (e.g., Nucala) for the treatment of adult and pediatric individuals aged 12 years and older with hypereosinophilic syndrome (HES) for > 6 months without an identifiable non-hematologic secondary cause.
 
On July 29, 2021, the FDA approved mepolizumab for add-on maintenance treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in adult individuals 18 years and older with inadequate response to nasal corticosteroids.  
 
Coding
 
See CPT/HCPCS Code section below.

Policy/
Coverage:
PRIOR APPROVAL IS REQUIRED FOR MEPOLIZUMAB (e.g., NUCALA)
 
Effective January 1, 2022, Mepolizumab (e.g., Nucala) is not covered under the medical benefit. Please check the member’s pharmacy benefit for coverage. This policy applies to members whose plan utilizes AR BCBS pharmacy and has Mepolizumab as a formulary option. (Please see Coverage Policy 2020005, Self-Administered Medication)
 
The initial use of this drug requires documentation of direct physician involvement (MD/DO) in the ordering and evaluation, as well as signature, in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.
 
The Step Therapy Medication Act is applicable to fully-insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, Tyson or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard request is up to 1 year.
 
Effective July 1, 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
Severe Eosinophilic Asthma
 
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
    1. Individual is 6 years of age or older; AND
    2. Individual has a diagnosis of severe eosinophilic asthma; AND
    3. *Evidence of asthma as demonstrated by both of the following (GINA, 2022):
a. A pretreatment forced expiratory volume in 1 second (FEV1) < 80% predicted for adults or < 90% for children (< 18 years of age); AND
b. Positive bronchodilator responsiveness test evidenced by an increase in FEV1 of > 12% and > 200 mL for adults and > 12% for children (< 18 years of age); AND  
4. Symptoms are inadequately controlled with use of one of the following combination therapies (ERS/ATS, 2014), unless the individual is intolerant of, or has a medical contraindication to these agents:
a. 12 months of high-dose inhaled corticosteroid (ICS) (equivalent to those defined in the policy guidelines) 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); OR  
b. 6 months of ICS with daily oral glucocorticoids; AND
5. Individual has a blood eosinophil count of > 300 cells/microliter at baseline prior to other eosinophil lowering therapy (e.g., systemic corticosteroids) and (in the absence of other potential causes of eosinophilia, including hypereosinophilic syndromes, neoplastic disease, and known or suspected parasitic infection) (Albers, 2019):
6. Individual has one of the following (ERS/ATS, 2014):
a. A history of 2 or more exacerbations in the previous year, requiring bursts of systemic steroids (> 3 days each); OR
b. At least one exacerbation requiring hospitalization, ICU stay or mechanical ventilation in the previous year; AND
7. Individual will continue to use maintenance asthma treatments (e.g., inhaled corticosteroid, LABA, LTRA or theophylline) in combination with mepolizumab; AND
8. Individual is not being treated concurrently with another biologic agent for the same or similar condition (such as benralizumab, dupilumab, omalizumab, reslizumab or tezepelumab); AND
9. Must be dosed in accordance with the FDA label; AND
10. Must be prescribed by or in consultation with an Allergist/Immunologist or Pulmonologist.
 
*FeNO testing is non-covered and is not considered adequate for establishing the diagnosis of asthma.  Please see AR policy 2005020
 
CONTINUED APPROVAL for up to 1 year:
    1. Treatment with mepolizumab has resulted in clinical improvement as documented by one or more of the following:
a. Decreased utilization of rescue medications; OR
b. Decreased frequency of exacerbations (defined as worsening of asthma that requires an increase in ICS dose or treatment with systemic corticosteroids), hospitalizations, and/or ER/urgent visits; OR
c. Increase in predicted FEV1 from pretreatment baseline; AND
2. Must be dosed in accordance with the FDA label.
 
Eosinophilic Granulomatosis with Polyangiitis
 
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
1. Individual is 18 years of age or older; AND  
2. Individual is diagnosed with relapsing or refractory eosinophilic granulomatosis with polyangiitis for 6 months or greater, defined as (Wechsler 2017):  
a. A hisotry or presence of asthma; AND
b. 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  
c. 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).
 
CONTINUED APPROVAL for up to 1 year:
    1. Treatment with mepolizumab has resulted in clinical improvement as documented by the achievement of remission at some point during treatment, defined as the following (Wechsler, 2017):
a. Birmingham Vasculitis Activity Sore (BVAS, version 3, of 0 (on a scale of 0 to 63); AND
b. Receipt of prednisolone or prednisone at a dose of 4.0 mg or less per day; AND
2.  Must be dosed in accordance with the FDA label.
 
Hypereosinophilic Syndrome (HES)
 
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
    1. Individual is 12 years of age and older; AND
    2. Individual is diagnosed with hypereosinophilic syndrome for > 6 months without an identifiable non hematologic secondary cause; AND
    3. Individual is FIP1L1-PDGFRA negative (Roufosse 2020); AND
    4. Individual has experienced 2 or more flares in the previous 12 months as defined by (Roufosse 2020):
a. Worsening of HES-related symptoms; AND
b. Blood eosinophil count requiring therapeutic escalation; AND
5. A blood eosinophil level >1000 cells/microliter uL on two examinations (at least one month apart) (Roufosse 2020); AND
6. Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for up to 1 year:
    1. Treatment with mepolizumab has resulted in clinical improvement as documented by (Roufosse, 2020):
a. Decreasing HES-related clinical symptoms; OR
b. Decrease in number of flares; AND
2. Must be dosed in accordance with the FDA label.
 
Chronic Rhinosinusitis with Nasal polyposis (CRSwNP)
 
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
    1. Individual is 18 years of age or older; AND
    2. Individual is diagnosed with CRSwNP; AND
    3. Mepolizumab is prescribed by a physician with expertise in the treatment of CRSwNP, e.g., an otolaryngologist [ear, nose, and throat (ENT) specialist] or an allergist/immunologist; AND
    4. Individual has moderate to severe symptoms of nasal obstruction; AND  
    5. Individual has one of the following:  
a. Rhinorrhea; OR
b. Decreased sense of smell for at least 12 weeks; AND
6. Individual has bilateral sinonasal polyposis reaching the lower border of the middle turbinate or beyond, which has been confirmed by nasal endoscopy, anterior rhinoscopy, or sinus CT scan (AAO-HNSF, 2015); AND
7. Individual has had at least one prior sinonasal surgery for CRSwNP or is not a candidate for sinonasal surgery to remove polyps – reason(s) for non-candidacy must be provided (AAO-HNS, 2015 and Al-Ahmad, 2022); AND
8. Individual has tried and failed systemic corticosteroids, unless contraindicated, in the past 2 years (AAAAI/ACAAI 2014); AND
9. Individual has tried and failed (e.g., lack of significant reduction in size or resolution of nasal polyps), within the last 6 months, at least 8 weeks of continuous treatment with an intranasal corticosteroid post-sinonasal surgery (individuals who are ineligible for sinonasal surgery are still required to have tried intranasal corticosteroids) (AAO-HNS, 2015); AND
10. Individual will be using a daily intranasal corticosteroid during treatment with mepolizumab, unless contraindicated or not tolerated; AND
11. Individual is not being treated concurrently with a biologic agent for the same or similar condition (such as benralizumab, dupilumab, or omalizumab); AND
12. Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for up to 1 year:
    1. Individual has had documented clinical improvement in clinical signs and symptoms of the disease (including but not limited to improvement in nasal polyp score or nasal congestion score); AND
    2. Individual meets ALL the following initial approval criteria:
        1. Mepolizumab is prescribed by a physician with expertise in the treatment of CRSwNP, e.g., an otolaryngologist [ear, nose, and throat (ENT) specialist] OR an allergist/immunologist; AND
        2. The individual will be using a daily intranasal corticosteroid during treatment with mepolizumab, unless contraindicated or not tolerated; AND
        3. Individual is not being treated concurrently with a biologic agent for the same or similar condition (such as benralizumab, dupilumab, or omalizumab); AND
3. Must be dosed in accordance with the FDA label.
 
Dosage and Administration
Dosing er FDA Guidelines
 
Mepolizumab is administered as a subcutaneous injection.
 
Please refer to the FDA label for dosing.
 
Policy Guidelines
The ERS/ATS definition of high doses of various inhaled glucocorticoids in relation to individual age (in mcg/day):
 
Age 6 to 12 years  
Beclomethasone >  320 (HFA MDI)
Budesonide > 800 (MDI or DPI); (>720 mcg/day of US labeled budesonide DPI)
Ciclesonide > 160 (HFA MDI)
Fluticasone propionate > 500 (HFA MDI or DPI); (> 440 mcg/day of US labeled fluticasone HFA MDI)
Mometasone > 500 (DPI); (> 550 mcg/day of US labeled mometasone DPI)
 
Age >12 years
Beclomethasone > 1000 (HFA MDI)
Budesonide > 1600 (MDI or DPI) ;(> 1440 mcg/day of US labeled budesonide DPI)
Ciclesonide > 320 (HFA MDI)
Fluticasone propionate > 1000 (HFA MDI or DPI); (> 880 mcg/day of US labeled fluticasone HFA MDI)
Mometasone > 800 (DPI); (> 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.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Mepolizumab, for any indication or circumstance not described above, including but not limited to the below listed indications, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
    1. Aspirin-exacerbated respiratory disease (AERD) or NSAID-exacerbated respiratory disease (NERD)- consists of 3 clinical features: asthma, nasal polyps, and sensitivity to aspirin and other NSAIDs.
    2. Atopic dermatitis
    3. Eosinophilic esophagitis
 
For members with contracts without primary coverage criteria, mepolizumab, for any indication or circumstance not described above, including but not limited to the below listed indications, is considered investigational.
    1. Aspirin-exacerbated respiratory disease (AERD)
    2. Atopic dermatitis
    3. Eosinophilic esophagitis
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.  
 
Effective March 1, 2022 to June 30, 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
I. Severe Eosinophilic Asthma
The use of mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence for the effectiveness of the treatment of severe persistent asthma (defined in ATS guidelines of severe asthma below*) as an add-on maintenance treatment for individuals with an eosinophilic phenotype when the following criteria are met:
 
    1. The individual of patients > 6 y/o.
    2. Evidence of asthma as demonstrated by both of the following (NAEPP 2007):
      •   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  
3. Symptoms are inadequately controlled with use of either combination therapy (ERS/ATS, 2013; GINA 2020):
      •   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 a LABA, or LTRA, or theophylline), unless the individual is intolerant of, or has a medical contraindication to these agents; AND
4.  The 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) [Albers 2019]:
      •   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.  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 (ERS/ATS, 2013); 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 when criteria are met will be approved for 6 months.
 
Continuation of therapy with mepolizumab after 6 months must demonstrate the following in submitted medical records and will be approved for 12 months:
    • 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).
 
Dosage and Administration
    •   Age 12 years and older: 100 mg once every 4 weeks subcutaneously into the upper arm, thigh, or abdomen.
    •   Age 6-11 years: 40 mg once every 4 weeks subcutaneously into the upper arm, thigh, or abdomen.
 
II. Eosinophilic Granulomatosis with Polyangiitis
The use of mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of the effectiveness for the treatment of relapsing or refractory eosinophilic granulomatosis with polyangiitis when all 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 (Wechsler 2017):  
      •   A history or presence of asthma; AND  
      •   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  
      •   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 when criteria are met will be approved for 6 months.
 
Continuation of therapy with mepolizumab after the initial 6 months must demonstrate the following in submitted medical records and will be approved for 12 months:
      • Treatment with mepolizumab has resulted in clinical improvement as documented by the achievement of remission at some point during treatment , defined as the following (Wechsler, 2017):
        • Birmingham Vasculitis Activity Sore (BVAS, version 3, of 0 (on a scale of 0 to 63); AND
        • Receipt of prednisolone or prednisone at a dose of 4.0 mg or less per day.
 
Dosage and Administration
    •   300 mg once every 4 weeks (3 separate 100 mg injections) subcutaneously into the upper arm, thigh or abdomen.
 
III. Hypereosinophilic Syndrome (HES)
The use of mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of the effectiveness for  the treatment of hypereosinophilic syndrome when all of the following criteria are met:
    1.  Individual is 12 years of age and older
    2.  Individual is diagnosed with hypereosinophilic syndrome for >6 months without an identifiable non hematologic secondary cause.
    3.  Individual is FIP1L1-PDGFRA negative. (Roufosse 2020)
    4.  Individual has experienced 2 or more flares in the previous 12 months as defined by (Roufosse 2020):
      •   Worsening of HES-related symptoms
      •   Blood eosinophil count requiring therapeutic escalation
5.   A blood eosinophil level >1500 1000 cells/uL on two examinations (at least one month apart) (Roufosse 2020)
 
Initial treatment requests when criteria are met will be approved for 6 months.
 
Continuation of therapy with mepolizumab after the initial 6 months must demonstrate the following in submitted medical records and will be approved for 12 months:
      • Treatment with mepolizumab has resulted in clinical improvement as documented by (Roufosse, 2020):
        • Decreasing HES-related clinical symptoms; or
        • Decrease in number of flares.
 
Dosage and Administration
    • 300 mg once every 4 weeks (3 separate 100 mg injections) subcutaneously into the upper arm, thigh, or abdomen.
 
IV. Chronic Rhinosinusitis with Nasal polyposis (CRSwNP)
The use of mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of the effectiveness as an add-on maintenance treatment of adult patients 18 years and older with chronic rhinosinusitis when ALL of the following criteria are met:
 
    1. Individual is 18 years of age or older AND
    2. Individual is diagnosed with CRSwNP AND
    3. Mepolizumab is prescribed by a physician with expertise in the treatment of CRSwNP, e.g. an otolaryngologist [ear, nose, and throat (ENT) specialist] or an allergist/immunologist
    4. Presence of bilateral nasal polyps confirmed by one of the following (AAO-HNS 2015) with submitted documentation:
        • Anterior rhinoscopy OR
        • Nasal endoscopy OR
        • Computed tomography (CT) AND
5. Individual has had a trial and inadequate response to maintenance intranasal corticosteroids AND
6. Individual is refractory to or is ineligible or intolerant to the following (AAAAI/ACAAI 2014):
        • Systemic corticosteroids unless contraindicated or not tolerated in the past 2 years AND had recent trial and inadequate response to maintenance intranasal corticosteroids (AAO-HNSF 2015) OR
        • Sinonasal surgery for CRSwNP AND
7. Mepolizumab is requested as an add-on therapy to maintenance intranasal corticosteroids.
 
Initial treatment requests may be approved for 6 months at a time.
 
Continuation of therapy with mepolizumab after 6 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:
        •  Clinically significant improvement in clinical signs and symptoms of disease (including but not limited to improvement in nasal congestion or reduced nasal polyp size) AND
        • Individual continues to use mepolizumab in combination with maintenance intranasal corticosteroids.
 
Dosage and Administration
        • 100 mg administered subcutaneously once every 4 weeks.
 
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 that there be scientific evidence of effectiveness 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 aspirin and other NSAIDs.
    •   atopic dermatitis
    •   eosinophilic esophagitis
    •   nasal polyposis
 
For members with contracts without primary coverage criteria, the use of mepolizumab is considered 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
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective December 22, 2021 to February 28, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
I. Severe Eosinophilic Asthma
The use of mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence for the effectiveness of the treatment of severe persistent asthma (defined in ATS guidelines of severe asthma below*) as an add-on maintenance treatment for individuals with an eosinophilic phenotype when the following criteria are met:
 
  1. The individual of patients > 6 y/o.
  2. Evidence of asthma as demonstrated by both of the following (NAEPP 2007):
    •   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  
3. Symptoms are inadequately controlled with use of either combination therapy (ERS/ATS, 2013; GINA 2020):
    •   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 a LABA, or LTRA, or theophylline), unless the individual is intolerant of, or has a medical contraindication to these agents; AND
4.  The 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) [Albers 2019]:
    •   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.  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 (ERS/ATS, 2013); 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).
 
Dosage and Administration:
    •   Age 12 years and older: 100 mg once every 4 weeks subcutaneously into the upper arm, thigh, or abdomen.
    •   Age 6-11 years: 40 mg once every 4 weeks subcutaneously into the upper arm, thigh, or abdomen.
 
II. Eosinophilic Granulomatosis with Polyangiitis
The use of mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of the effectiveness for the treatment of relapsing or refractory eosinophilic granulomatosis with polyangiitis when all 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 (Wechsler 2017):  
    •   A history or presence of asthma; AND  
    •   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  
    •   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 after 12 months
The use of mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence for the effectiveness 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 (Wechsler 2017):
    •   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.
 
Dosage and Administration:
    •   300 mg once every 4 weeks (3 separate 100 mg injections) subcutaneously into the upper arm, thigh or abdomen.
 
 
III. Hypereosinophilic Syndrome (HES)
The use of mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of the effectiveness for  the treatment of hypereosinophilic syndrome when all of the following criteria are met:
  1. Individual is 12 years of age and older
  2.  Individual is diagnosed with hypereosinophilic syndrome for >6 months without an identifiable non hematologic secondary cause.
  3.  Individual is FIP1L1-PDGFRA negative. (Roufosse 2020)
  4.  Individual has experienced 2 or more flares in the previous 12 months as defined by (Roufosse 2020):
    •   Worsening of HES-related symptoms
    •   Blood eosinophil count requiring therapeutic escalation
5.   A blood eosinophil level >1500 1000 cells/uL on two examinations (at least one month apart) (Roufosse 2020)
 
Dosage and Administration:
    • 300 mg once every 4 weeks (3 separate 100 mg injections) subcutaneously into the upper arm, thigh, or abdomen.
 
IV. Chronic Rhinosinusitis with Nasal polyposis (CRSwNP)
The use of mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of the effectiveness as an add-on maintenance treatment of adult patients 18 years and older with chronic rhinosinusitis when ALL of the following criteria are met:
 
    1. Individual is 18 years of age or older AND
    2. Individual is diagnosed with CRSwNP AND
    3. Mepolizumab is prescribed by a physician with expertise in the treatment of CRSwNP, e.g. an otolaryngologist [ear, nose, and throat (ENT) specialist] or an allergist/immunologist
    4. Presence of bilateral nasal polyps confirmed by one of the following (AAO-HNS 2015) with submitted documentation:
        • Anterior rhinoscopy OR
        • Nasal endoscopy OR
        • Computed tomography (CT) AND
5. Individual has had a trial and inadequate response to maintenance intranasal corticosteroids AND
6. Individual is refractory to or is ineligible or intolerant to the following (AAAAI/ACAAI 2014):
        • Systemic corticosteroids unless contraindicated or not tolerated in the past 2 years AND had recent trial and inadequate response to maintenance intranasal corticosteroids (AAO-HNSF 2015) OR
        • Sinonasal surgery for CRSwNP AND
7. Mepolizumab is requested as an add-on therapy to maintenance intranasal corticosteroids.
 
Initial treatment requests may be approved for 6 months at a time.
 
Continuation of therapy with mepolizumab after 6 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:
        •  Clinically significant improvement in clinical signs and symptoms of disease (including but not limited to improvement in nasal congestion or reduced nasal polyp size) AND
        • Individual continues to use mepolizumab in combination with maintenance intranasal corticosteroids.
 
Dosage and Administration
      • 100 mg administered subcutaneously once every 4 weeks.
 
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 that there be scientific evidence of effectiveness 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 aspirin and other NSAIDs.
    •   atopic dermatitis
    •   eosinophilic esophagitis
    •   nasal polyposis
 
For members with contracts without primary coverage criteria, the use of mepolizumab is considered 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
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective October 2021 to December 21, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
I. Severe Eosinophilic Asthma
The use of mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence for the effectiveness of the treatment of severe persistent asthma (defined in ATS guidelines of severe asthma below*) as an add-on maintenance treatment for individuals with an eosinophilic phenotype when the following criteria are met:
 
  1. The individual of patients > 6 y/o.
  2. Evidence of asthma as demonstrated by both of the following (NAEPP 2007):
    •   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  
3. Symptoms are inadequately controlled with use of either combination therapy (ERS/ATS, 2013; GINA 2020):
    •   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 a LABA, or LTRA, or theophylline), unless the individual is intolerant of, or has a medical contraindication to these agents; AND
4.  The 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) [Albers 2019]:
    •   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.  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 (ERS/ATS, 2013); 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).
 
Dosage and Administration:
    •   Age 12 years and older: 100 mg once every 4 weeks subcutaneously into the upper arm, thigh, or abdomen.
    •   Age 6-11 years: 40 mg once every 4 weeks subcutaneously into the upper arm, thigh, or abdomen.
 
II. Eosinophilic Granulomatosis with Polyangiitis
The use of mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of the effectiveness for the treatment of relapsing or refractory eosinophilic granulomatosis with polyangiitis when all 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 (Wechsler 2017):  
    •   A history or presence of asthma; AND  
    •   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  
    •   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 after 12 months
The use of mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence for the effectiveness 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 (Wechsler 2017):
    •   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.
 
Dosage and Administration:
    •   300 mg once every 4 weeks (3 separate 100 mg injections) subcutaneously into the upper arm, thigh or abdomen.
 
 
III. Hypereosinophilic Syndrome (HES)
The use of mepolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of the effectiveness for  the treatment of hypereosinophilic syndrome when all of the following criteria are met:
  1. Individual is 12 years of age and older
  2.  Individual is diagnosed with hypereosinophilic syndrome for >6 months without an identifiable non hematologic secondary cause.
  3.  Individual is FIP1L1-PDGFRA negative. (Roufosse 2020)
  4.  Individual has experienced 2 or more flares in the previous 12 months as defined by (Roufosse 2020):
    •   Worsening of HES-related symptoms
    •   Blood eosinophil count requiring therapeutic escalation
5.   A blood eosinophil level >1500 1000 cells/uL on two examinations (at least one month apart) (Roufosse 2020)
 
Dosage and Administration:
    • 300 mg once every 4 weeks (3 separate 100 mg injections) subcutaneously into the upper arm, thigh, or abdomen.
 
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 that there be scientific evidence of effectiveness 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 aspirin and other NSAIDs.
    •   atopic dermatitis
    •   eosinophilic esophagitis
    •   nasal polyposis
 
For members with contracts without primary coverage criteria, the use of mepolizumab is considered 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
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to October 2021 are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com

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).
 
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.
 
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).
 
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.
 
September 2019 Update
A multi-center, open-label study was conducted to assess the pharmacokinetics and pharmacodynamics of mepolizumab subcutaneously administered to participants with severe eosinophilic asthma aged 6-11 years. Thirty-six children with severe eosinophilic asthma participated in this study. Mepolizumab was administered subcutaneously at bodyweight-defined doses of 40 or 100 mg. This provided higher than predicted drug exposure in children aged 6 to 11 years, but remained within twofold of adult levels. This difference was likely due to the increased bioavailability of Mepolizumab SC in children versus adults. Mepolizumab SC was associated with similar therapeutic effect in children to adults, with marked reductions in blood eosinophil counts, a trend toward improved asthma control compared with baseline, and a favorable safety profile. The 40 and 100 mg SC dosing regimens were deemed acceptable for children aged 6 to 11 years with severe eosinophilic asthma based on Mepolizumab’s wide therapeutic index. (Gupta, et al., 2019).
 
A systematic review and meta-analysis on randomized, placebo-controlled, clinical trials were conducted to assess efficacy, adverse events, and inter-drug comparison of mepolizumab and reslizumab for treating severe eosinophilic asthma.
 
Five studies (N = 2197) contributed with data for exacerbation rate, showing a reduction of 53% (95% CI 46; 59) in favour of anti-IL-5, corresponding to –0.94 annual exacerbations (95% CI –1.08;–0.82), thus exceeding the predefined minimal clinical important difference (MCID) of 25% reduction of the estimated 2 annual exacerbations. Quality of evidence was considered moderate, with low heterogeneity in study findings (I2 = 0%). One study (N = 135) contributed with data on percentage of patients experiencing 50% reduction in oral corticosteroid treatment, showing an effect of 20% (95% CI 2.3;47) in favour of anti-IL-5 treatment (mepolizumab), thus exceeding the predefined MCID of 10%. Quality of evidence was considered low.
 
Compared to placebo, anti-IL-5 showed significant improvements in lung function, asthma control, and asthma-related quality of life, but below the MCIDs. No differences were observed for serious adverse events and number of patients, who dropped out. No studies evaluating sick leave or head-to-head comparisons were identified. By indirect comparison, no significant difference was found between mepolizumab and reslizumab in any of the predefined clinical outcomes. OCS treatment reduction could not be compared due to lack of reslizumab studies investigating this outcome.
Mepolizumab and reslizumab provide significant and clinically relevant improvements in exacerbation rate and OCS reduction. Indirect, inter-study comparisons revealed no differences between the anti-IL-5 drugs in efficacy or safety measures. (Henriksen, et al., 2018).
 
2020 Update
A post hoc individual patient-level meta-analysis of data from two Phase 3, placebo-controlled, randomised, double-blind, parallel-group, multicentre studies, MENSA and MUSCA, which assessed the licensed dose of mepolizumab (100 mg SC) in patients with severe eosinophilic asthma was conducted. Results of these studies have been reported previously. In brief, patients enrolled in MENSA were randomised (1:1:1) to receive mepolizumab 75 mg intravenously (IV), mepolizumab 100 mg SC or placebo, plus standard of care (high-dose inhaled corticosteroids [ICS] and another controller), every 4 weeks for 32 weeks. Patients enrolled in MUSCA were randomised (1:1) to receive mepolizumab 100 mg SC or placebo, plus standard of care, every 4 weeks for 24 weeks. This post hoc analysis reports data from patients who received placebo or mepolizumab 100 mg SC only.
 
In total, 1136 patients who participated in the MENSA and MUSCA studies received 1 dose of study treatment and were included in the analysis. Of these, 936 were randomised to receive either placebo (n = 468) or mepolizumab 100 mg SC (n = 468). At baseline, patients had a mean weight of 78.1 kg and BMI of 28.0 kg/m2. In general, mean age was similar across body weight and BMI subgroups. Patients in the higher BMI and weight categories generally had worse SGRQ scores compared with those in the lower categories. Across subgroups, around one-quarter of patients were receiving OCS maintenance therapy at baseline.
 
In summary, results from this post hoc analysis of the MENSA and MUSCA studies demonstrate that mepolizumab 100 mg SC is associated with improvements in exacerbation rate, HRQoL and asthma control in patients with severe eosinophilic asthma, across a range of patient body weights and BMI categories. The reason for a lower improvement in FEV1 in the highest body weight category remains to be investigated. The findings support the use of a simple, fixed-dose regimen of mepolizumab 100 mg SC for treating patients with severe eosinophilic asthma. (Albers,Papi, Raille, et.al., 2019)
 
December  2020 Update
A randomized, multicenter, double-blind, placebo-controlled, phase III trial (ClinicalTrials.gov No. NCT02836496) was conducted across 39 centers in 13 countries. Eligible patients had FIP1L1-PDGFRA-negative HES, experienced 2 or more flares (worsening of HES-related symptoms or blood eosinophil count requiring therapeutic escalation) in the previous 12 months, and had a screening blood eosinophil count greater than or equal to 1000 cells/μL. Patients were randomized (1:1) to subcutaneous mepolizumab (300 mg) or placebo every 4 weeks for 32 weeks, plus existing HES therapy. The primary outcome was the proportion of patients with 1 or more flares (worsening of HES-related symptoms necessitating therapy escalation or ≥2 courses of blinded rescue oral corticosteroids) during the study; in addition, patients who withdrew early from the study were counted as having a flare. Safety end points were also assessed.
 
The proportion of patients experiencing 1 or more flares/withdrawing from the study was 50% lower with mepolizumab versus placebo (15 of 54 [28%] vs 30 of 54 [56%]; P = .002). Logistic regression analysis was consistent with the primary analysis (odds ratio, 0.28; 95% CI, 0.12-0.64; P = .003). Similar proportions of patients in the mepolizumab and placebo groups experienced on-treatment adverse events (48 of 54 [89%] vs 47 of 54 [87%]).
 
Compared with placebo, mepolizumab significantly reduced the occurrence of flares in patients with HES, with no new safety signals identified. (Roufosse F, Kahn JE, Rothenberg ME, et. al., 2020)
 
2021 Update
SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49-52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797.
 
From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score significantly improved at week 52 from baseline with mepolizumab versus placebo (adjusted difference in medians -0·73, 95% CI -1·11 to -0·34; p<0·0001) and nasal obstruction VAS score during weeks 49-52 also significantly improved (-3·14, -4·09 to -2·18; p<0·0001). Adverse events considered related to study treatment were reported in 30 (15%) of 206 patients receiving mepolizumab and 19 (9%) of 201 receiving placebo. On-treatment serious adverse events occurred in 12 (6%) patients receiving mepolizumab and 13 (6%) receiving placebo; none were considered related to treatment in those receiving mepolizumab. One death was reported in the placebo group (myocardial infarction; death occurred 99 days after the last dose) and was considered unrelated to the treatment.
 
Mepolizumab treatment improved nasal polyp size and nasal obstruction compared with placebo, with no new safety indications, in patients with recurrent, refractory severe chronic rhinosinusitis with nasal polyps. These findings suggest that mepolizumab provides an effective add-on treatment option to standard of care in this population.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement.

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

References: Al-Ahmad, M. et al.(2022) Expert Opinion on Biological Treatment of Chronic Rhinosinusitis with Nasal Polyps in the Gulf Region. J Asthma Allergy. 2022 Jan 4;15:1-12. doi: 10.2147/JAA.S321017. PMID: 35018101; PMCID: PMC8742580.

Al-Ahmad, M. et al.(2022) Expert Opinion on Biological Treatment of Chronic Rhinosinusitis with Nasal Polyps in the Gulf Region. J Asthma Allergy. 2022 Jan 4;15:1-12. doi: 10.2147/JAA.S321017. PMID: 35018101; PMCID: PMC8742580.

Albers FC, Papi A, Taillé C, et al.(2019) Mepolizumab reduces exacerbations in patients with severe eosinophilic asthma, irrespective of body weight/body mass index: meta-analysis of MENSA and MUSCA. Respir Res. 2019;20(1):169. Published 2019 Jul 30. doi:10.1186/s12931-019-1134-7

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.

Clinical Practice Guideline (Update): Adult Sinusitis. Otolaryngology-Head and Neck Surgery. 2015;152(2S)SI-S39.(2014) Joint Task Force on Practice Parameters (JTFPP), representing the AAAAI, the ACAAI and the Joint Council of Allergy, Asthma & Immunology. Diagnosis and management of rhinosinusitis: a practice parameter update. American College of Allergy, Asthma & Immunology. 2014;113:347-385.

Global Initiative for Asthma (GINA).(2022) Global Strategy for Asthma Management and Prevention 2022. Available from: www.ginasthma.org.

Gupta, Atul, et al.(2019) “Subcutaneous Mepolizumab in Children Aged 6 to 11 Years with Severe Eosinophilic Asthma.” Pediatric Pulmonology, 2019, doi:10.1002/ppul.24508.

Han JK, Bachert C, Fokkens W, Desrosiers M, Wagenmann M, Lee SE, Smith SG, Martin N, Mayer B, Yancey SW, Sousa AR, Chan R, Hopkins C;(2021) SYNAPSE study investigators. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2021 Oct;9(10):1141-1153. doi: 10.1016/S2213-2600(21)00097-7. Epub 2021 Apr 16. PMID: 33872587.

Henriksen, Daniel P et al.(2018) “Efficacy, adverse events, and inter-drug comparison of mepolizumab and reslizumab anti-IL-5 treatments of severe asthma - a systematic review and meta-analysis.” European clinical respiratory journal vol. 5,1 1536097. 7 Nov. 2018, doi:10.1080/20018525.2018.1536097

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.

Lancet Respir Med. 2021 Oct;9(10):1141-1153. doi: 10.1016/S2213-2600(21)00097-7. Epub 2021 Apr 16. PMID: 33872587.(2015) American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNS). Clinical Practice Guideline (Update): Adult Sinusitis. Otolaryngology-Head and Neck Surgery. 2015;152(2S)SI-S39.

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.

Roufosse F, Kahn JE, Rothenberg ME, Wardlaw AJ, Klion AD, Kirby SY, Gilson MJ, Bentley JH, Bradford ES, Yancey SW, Steinfeld J, Gleich GJ;(2020) HES Mepolizumab study group. Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2020 Sep 18:S0091-6749(20)31276-8. doi: 10.1016/j.jaci.2020.08.037. Epub ahead of print. PMID: 32956756.

Shomali W, Gotlib J.(2019) World Health Organization-defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management. Am J Hematol. 2019 Oct;94(10):1149-1167. doi: 10.1002/ajh.25617. PMID: 31423623.

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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