Archived Policies - Prescription Drugs
Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, Hayes, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.
Mepolizumab (Nucala®) may be considered medically necessary for the treatment of severe eosinophilic asthma when the following criteria are met:
• Individual is 12 years of age or older; AND
• Patient meets definition of severe asthma as defined by the following:
12 months of treatment with high-dose inhaled corticosteroid (ICS) in combination with long-acting beta2-agonist (LABA) or leukotriene receptor antagonist [LTRA]/theophylline for the previous year or systemic corticosteroids for 50% or more of the previous year to prevent asthma from becoming uncontrolled or remaining uncontrolled; AND
NOTE: Patients who do not meet the criteria for uncontrolled asthma, but whose asthma worsens on tapering off corticosteroids, will also meet this definition of severe asthma. For definition of uncontrolled asthma see description section.
• History of 2 or more exacerbations requiring systemic glucocorticoids while being treated with fluticasone propionate 880μg or more or its equivalent in the last year; AND
• Eosinophil count of the following (in the absence of other potential causes of eosinophilia, including hypereosinophilic syndromes, neoplastic disease, and known or suspected parasitic infection):
o 150 cells/μL or more in peripheral blood at screening or
o 300 cells/μL or more during the previous year;
NOTE: 1 microliter (ul) is equal to 1 cubic millimeter (mm3).
Mepolizumab (Nucala®) is considered experimental, investigational and/or unproven when not meeting criteria as outlined above and for all other indications, including but not limited to:
• Eosinophilic chronic obstructive pulmonary disease;
• Eosinophilic esophagitis;
• Eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome);
• Nasal polyposis; or
• Hypereosinophilic syndromes (other than severe eosinophilic asthma)
Asthma affects about 235 million people worldwide and approximately 18.7 million in the United States. In most cases, it can be effectively controlled with standard treatment that includes short-acting β2-agonists, long-acting β2-agonists (LABA), inhaled corticosteroids (ICSs), oral corticosteroids, and omalizumab if allergies present. However, 5% to 10% of patients suffer from severe or refractory asthma who cannot achieve control with standard treatment.
Much remains unclear about the best approaches to managing severe asthma and specifically eosinophilic asthma. Patients with eosinophilic asthma are generally responsive to corticosteroid therapy and are at an increased risk of exacerbation after corticosteroid withdrawal. In contrast, non?eosinophilic asthma is associated with a significantly poorer response to treatment with ICSs. New treatments, particularly monoclonal antibodies currently being developed, target specific pathophysiologic mechanisms and therefore have to be tailored to each patient to match the disease heterogeneity.
Mepolizumab (GlaxoSmithKline) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody specific to interleukin-5 (IL-5), which binds to IL-5, stopping IL-5from binding to its receptor on the surface of eosinophils. Inhibiting IL-5 binding in this way reduces blood, tissue, and sputum eosinophil levels. Mepolizumab is the first drug to be approved and indicated as add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype.
In November 2015, the Food and Drug Administration (FDA) approved mepolizumab (Nucala®) as an add-on maintenance therapy for patients aged 12 years or older who have severe eosinophilic asthma with a history of exacerbations. FDA dosage for 12 years or older is noted as 100 mg subcutaneous once every 4 weeks injected into the upper arm, thigh or abdomen. (1)
Definition of Uncontrolled Asthma
At least one of the following:
• Asthma Control Questionnaire (ACQ) score consistently >1.5, Asthma Control Test (ACT) score <20 (or ‘‘not well controlled’’ by National Asthma Education and Prevention Program (NAEPP) /Global Initiative for Asthma (GINA) guidelines)
• Frequent severe exacerbations: ≥2 bursts of systemic corticosteroids (CS) (>3 days each) in the previous year Serious exacerbations: at least 1 hospitalization, ICU 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). (2)
The evidence for Mepolizumab (Nucala®) consists of 1 phase 2b dose-finding trial (DREAM) and 2 phase 3 trials (MENSA, SIRIUS). All 3 were randomized, double-blind, placebo-controlled, parallel-design trials.
• The DREAM trial (N=621) had 2 main objectives:
o To assess the most efficacious dose of mepolizumab between 75, 250, and 750 mg monthly, and
o To identify a less invasive biomarker that could be more applicable in clinical practice than induced sputum to assess eosinophilic airway inflammation.
In the DREAM trial, all 3 doses of mepolizumab had an equivalent clinical effect and therefore allowed study investigators to pool data across the 3 dose arms to investigate baseline factors associated with a treatment response with adequate power. History of prior asthma exacerbation and the baseline blood eosinophil above 0.15x109/L were the strongest predictors of response. Therefore, in subsequent confirmatory MENSA and SIRIIUS trials, eosinophil blood counts of 150 cells/μL or higher in peripheral blood instead of sputum eosinophil counts was used as inclusion criteria to select patients with eosinophilic airway inflammation. Because the lowest dose of 75 mg intravenous (IV) studied in the DREAM trial was as effective as the higher dose, evaluation of a subcutaneous (SC) dose in the subsequent MENSA trial was tested as a possible alternative. Regarding efficacy, compared with placebo, all 3 doses of mepolizumab reduced clinically significant exacerbations by similar proportions (mepolizumab 75 mg by 48%, mepolizumab 250 mg by 39%, mepolizumab 750 mg by 52%).
• The objective of the MENSA trial (N=580) was to evaluate 2 doses of mepolizumab 75 mg IV and 100 mg SC and to compare them with placebo to assess whether mepolizumab decreases the annualized rate of asthma exacerbations. Regarding efficacy, compared with placebo, both 75 mg IV or 100 mg SC mepolizumab reduced clinically significant exacerbations (75 mg IV by 47% and 100 mg SC by 53% vs placebo). A prespecified analysis of clinical end points in a subgroup of patients with a blood eosinophil count of 500 cells/μL or more showed an enhanced response to mepolizumab. Compared with placebo, both 75 mg IV or 100 mg SC mepolizumab reduced clinically significant exacerbations (75 mg IV by 74% and 100 mg SC by 80% vs placebo) in 177 patients with blood eosinophil count of 500 cells/μL or more. The annualized rates of asthma exacerbation in mepolizumab 75 mg IV, mepolizumab 100 mg SC, and placebo were 0.58, 0.46, and 2.26, respectively.
• The objective of the SIRIUS trial (N=135) was to assess whether adjunctive treatment with 100 mg SC mepolizumab could reduce use of maintenance oral glucocorticoids while maintaining asthma control. In the MENSA trial, 25% of patients randomized were using daily oral glucocorticoids while in the SIRIUS trial 100% patients were. The trial design consisted of 4 distinct phases; optimization, induction, reduction, and maintenance:
o In the run-in optimization phase, the oral glucocorticoid dose was reduced weekly over 3 to 8 weeks until there was an exacerbation in asthma symptoms or a worsening in asthma control. Patients then underwent randomization and entered the next phase.
o In the induction phase (from week 0 through week 4), patients received the assigned study drug plus the optimized dose of oral glucocorticoids.
o In the reduction phase (from week 4 through 20), the oral glucocorticoid dose was reduced according to a prespecified schedule by 1.25 to 10 mg/d every 4 weeks on the basis of asthma control and symptoms of adrenal insufficiency.
o In the maintenance phase from (week 20 through week 24), no further adjustment was made in the oral glucocorticoid dose.
The authors of the SIRIUS trial reported an odds ratio (OR) of 2.39 (95% confidence interval [CI], 1.25 to 4.56) in favor of mepolizumab versus placebo in reducing daily oral glucocorticoid dose (>0% to 100%) versus no decrease in oral glucocorticoid dose, a lack of asthma control, or withdrawal from treatment. Given frequent reductions in the placebo arm, the OR is substantively larger than the estimated relative risk (RR). For example, the proportion of patients who experienced daily oral glucocorticoid dose reduction between more than 0% and 100% was 64% (44/69) and 44% (29/66) in the mepolizumab 100 mg SC and placebo groups, respectively, with an RR of 1.45 (95% CI, 1.05 to 2.01) and absolute risk reduction (ARR) of 19.8% (95% CI, -35.2% to -3%). Although optimizing the oral glucocorticoid dose at baseline and reducing the glucocorticoid dose in a standardized fashion, 44% of those receiving placebo were able to reduce their asthma doses between more than 0% and 100%, with 34% of patients reducing their doses by more than 50%. It is impossible to determine whether the effect seen in the control arm was a placebo effect, natural history, or other nonspecific effect. The authors noted that the placebo effect seen in the SIRIUS trial was lower than the placebo effect seen in other glucocorticoid reduction studies using mepolizumab, methotrexate, and cyclosporine. Reductions of 50% compared with reductions less than 49% were more than twice as frequent with mepolizumab as with placebo (40% vs 19%). ARR was 20% but accompanied by a confidence interval (a high of 35% to a low as 3%) suggesting uncertainty in the estimate. The annualized rates of exacerbations were 1.44 per year in the mepolizumab group and 2.12 per year in the placebo group. (2)
In patients aged 12 years and older with severe eosinophilic asthma, identified by blood eosinophil counts of at least 150 cells/μL at the start of treatment or 300 cells/μL in the past 12 months and with a positive history of exacerbations, treatment with mepolizumab consistently demonstrated benefits in the 3 pivotal trials in terms of reduced episodes of asthma exacerbation and reduced use of oral corticosteroids.
The risk ratios for the 3 doses of mepolizumab suggest that the drug reduced the rate of exacerbations by approximately one-half in the 2 trials. These results were statistically significant. On an absolute scale, patients treated with mepolizumab versus placebo avoided approximately 1 exacerbation per year. Given the morbidity associated with frequent asthma exacerbations, a significant reduction in this clinical outcome represents a clinically meaningful improvement in the lives of severe asthma patients. For exacerbations associated with all criteria mepolizumab reduced the absolute exacerbation rate by slightly less than 1 event per patient-year. For exacerbations defined using criteria limited to hospitalization and/or emergency department visits, mepolizumab reduced the average absolute exacerbation rate by approximately 0.1 events per patient-year. Patients taking mepolizumab achieved significantly higher reductions in oral corticosteroids dose than those on placebo. The OR was 2.4 (p=0.009). Because use of higher doses of corticosteroids is associated with frequent side effects that impact quality of life, reduction in oral corticosteroid is also considered a clinically meaningful outcome to patients.
No obvious safety concerns with mepolizumab 100 mg SC administered once every 4 weeks were noted in the 3 pivotal trials of mepolizumab. However, the limited period during which mepolizumab was used and studied does not rule out the potential for cancers of the lung, herpes zoster, and parasitic infections.
Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.
Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.
The following codes may be applicable to this Medical policy and may not be all inclusive.
C9473, J2182, J3490, J3590
ICD-9 Diagnosis Codes
Refer to the ICD-9-CM manual
ICD-9 Procedure Codes
Refer to the ICD-9-CM manual
ICD-10 Diagnosis Codes
Refer to the ICD-10-CM manual
ICD-10 Procedure Codes
Refer to the ICD-10-CM manual
The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.
A national coverage position for Medicare may have been developed or changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
1. FDA – NUCALA (mepolizumab) – Product Label. Food and Drug Administration (November 2015). Available at <http://www.fda.gov> (accessed March 22, 2016).
2. Mepolizumab (Nucala). Chicago, Illinois: Blue Cross Blue Shield Association (BCBSA) Specialty Pharmacy Report. November 2015.
3. ECRI Institute. AHRQ Healthcare Horizon Scanning System Potential High-Impact Interventions: Priority Area 13: Pulmonary Disease, Including Asthma. (Prepared by ECRI Institute under Contract No. HHSA290-2010-00006-C.) Rockville, MD: Agency for Healthcare Research and Quality. December 2015. Available at: <http://effectivehealthcare.ahrq.gov>.
|4/1/2016||New medical document. Mepolizumab may be considered medically necessary for the treatment of severe eosinophilic asthma when the following criteria are met: 10 Individual is 12 years of age or older; AND 2) Patient meets definition of severe asthma as defined by the following: 12 months of treatment with high-dose inhaled corticosteroid (ICS) in combination with long-acting beta2-agonist (LABA) or leukotriene receptor antagonist [LTRA]/theophylline for the previous year or systemic corticosteroids for 50% or more of the previous year to prevent asthma from becoming uncontrolled or remaining uncontrolled; AND NOTE: Patients who do not meet the criteria for uncontrolled asthma, but whose asthma worsens on tapering off corticosteroids, will also meet this definition of severe asthma. For definition of uncontrolled asthma see description section; 3) History of 2 or more exacerbations requiring systemic glucocorticoids while being treated with fluticasone propionate 880μg or more or its equivalent in the last year; AND 4) Eosinophil count of the following (in the absence of other potential causes of eosinophilia, including hypereosinophilic syndromes, neoplastic disease, and known or suspected parasitic infection): 150 cells/μL or more in peripheral blood at screening or 300 cells/μL or more during the previous year; NOTE: 1 microliter (ul) is equal to 1 cubic millimeter (mm3). Mepolizumab is considered experimental, investigational and/or unproven when not meeting criteria as outlined above and for all other indications, including but not limited to: Eosinophilic chronic obstructive pulmonary disease, Eosinophilic esophagitis, Eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), Nasal polyposis and Hypereosinophilic syndromes (other than severe eosinophilic asthma).|