Effective Date

Date of Origin   

04-01-2025           

Fasenra®

(benralizumab)

Injection for subcutaneous use

Add-on maintenance treatment of patients with severe asthma aged 6 years and older, and with an eosinophilic phenotype

Treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA)

Limitations of use:

• Not indicated for the relief of acute bronchospasm or status asthmaticus

2

Nucala®

(mepolizumab)

Injection for subcutaneous use

Add-on maintenance treatment of patients aged 6 years and older with severe asthma and with an eosinophilic phenotype

Treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA)

Treatment of adult and pediatric patients aged 12 years and older with hypereosinophilic syndrome (HES) for greater than or equal to 6 months without an identifiable non-hematologic secondary cause

Add-on maintenance treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in adult patients 18 years of age and older with inadequate response to nasal corticosteroids

Limitation of use:

• Not indicated for the relief of acute bronchospasm or status asthmaticus

1

Asthma

Asthma is a chronic inflammatory disorder of the airways. It is characterized by a history of respiratory symptoms along with variable expiratory airflow limitation, and is typically associated with bronchial hyperresponsiveness and underlying inflammation. Symptoms are variable and recurrent and include wheezing, coughing, shortness of breath, and chest tightness. Exercise, exposure to allergens and irritants, infections, and changes in the weather can be contributing factors to the variability in symptoms and airflow limitation.(5) Guidelines recommend evaluating respiratory symptoms, medical history, physical examination, and spirometry to determine a diagnosis of asthma.(4,5) Long-term goals for asthma management are to achieve control of symptoms, maintain normal activity level, and to minimize the future risk of exacerbations, decline in lung function, and medication side effects.(5)

Different types of asthma and levels of severity exist. Moderate asthma is asthma that requires a low- or medium-dose inhaled corticosteroid (ICS) used in combination with a long-acting beta agonist (LABA) to be well controlled. Severe asthma is asthma that remains uncontrolled despite optimized treatment with high-dose ICS-LABA, or that requires high-dose ICS-LABA or biologic therapy to prevent it from becoming uncontrolled (e.g., asthma worsens when high-dose treatment is decreased). Severe asthma needs to be distinguished from difficult-to-treat asthma that remains symptomatic due to poor adherence, poor inhaler technique, comorbidities, and/or continued exposure to environmental agents since treatment and management differs between the two.(5) The European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines (2014; updated 2020) define uncontrolled asthma for adults and pediatric patients 6 years of age and older as a patient having at least one of the following:(3)

• Frequent severe exacerbations (i.e., two or more bursts of systemic corticosteroids within the past 12 months)
• Serious exacerbations (i.e., at least one hospitalization, intensive care unit stay, or mechanical ventilation in the past 12 months)
• Airflow limitation (i.e., FEV1 less than 80% predicted)
• Asthma that worsens upon tapering of high-dose ICS or systemic corticosteroids (or additional biologics)

The Type 2 inflammatory asthma phenotype is found in the majority of people with severe asthma. Type 2 inflammation involves a systemic allergic response and elevated levels of Type 2 inflammatory cytokines such as interleukin (IL)-4, IL-5, and IL-13. Elevated eosinophils or an increased fractional exhaled nitric oxide (FeNO) are characteristics of the eosinophilic subtype of Type 2 inflammatory asthma, while the allergic asthma subtype is additionally characterized by elevated immunoglobulin E (IgE) levels and positive skin prick testing with common environmental allergens. Type 2 inflammation typically responds well to ICS treatment and rapidly improves, however, in severe asthma Type 2 inflammation may be relatively refractory to high-dose ICS. Maintenance oral corticosteroids (OCS) may elicit a response, but the risk of serious adverse effects with daily OCS use deters their usefulness and an alternative treatment should be sought.(5) Type 2 inflammation is considered refractory if any of the following are found while the patient is taking high dose ICS or daily OCS:(5)

• Blood eosinophils greater than or equal to 150 cells/microliter
• FeNO greater than or equal to 20 ppb
• Sputum eosinophils greater than or equal to 2%
• Asthma is clinically allergen-driven

The Global Initiative for Asthma (GINA) guidelines recommend a stepwise approach for managing asthma. The 2024 GINA guidelines recommend all patients 6 years of age and older with asthma should receive ICS-containing controller medication to reduce the risk of serious exacerbation, even in patients with infrequent symptoms. It is recommended that patients with asthma symptoms most days should be started on low dose maintenance ICS-formoterol or an alternative ICS-LABA product. Patients' response to treatment should be reviewed after 2 to 3 months. If symptoms remain uncontrolled despite good adherence and correct inhaler technique, the next step up (Step 4) involves increasing controller therapy to medium or high dose ICS-formoterol (ICS-LABA). Other controller options that may be added on to ICS treatment at Step 4 include a long-acting muscarinic antagonist (LAMA), leukotriene receptor antagonist (LTRA), or theophylline. Both LTRA and theophylline are considered less efficacious than adding on a LABA or LAMA, and also come with safety concerns. Patients with uncontrolled symptoms and/or exacerbations despite being on Step 4 treatment for 3 to 6 months should be assessed for contributory factors, have their treatment optimized, and be referred for expert assessment, phenotyping, and potential add on biologic therapy. Maintenance oral corticosteroids (OCS) should be used only as last resort because short-term and long-term systemic side-effects are common and serious.(5)

Biologic agents should be considered as add-on therapy for patients with refractory Type 2 inflammation with exacerbations and/or poor symptom control despite taking at least high dose ICS-LABA, and who have allergic or eosinophilic biomarkers or need maintenance OCS, and only after treatment has been optimized.(5) Tezepelumab is considered a broad-acting biologic and may be considered in patients without a Type 2 inflammatory phenotype due to it binding to circulating thymic stromal lymphopoietin (TSLP), which is upstream on the inflammatory cascade.(5,19) Based on efficacy results from clinical trials, the indication of use for tezepelumab is not restricted to a biomarker-defined phenotype.(19) 2024 GINA guidelines recommend the use of biologics based on the following patient eligibility factors:(5)

• Anti-IgE (omalizumab) for moderate to severe allergic asthma
  • Sensitization to inhaled allergen(s) on skin prick testing for specific IgE
  • Total serum IgE and body weight within dosing range
  • Exacerbations within the last year
• Anti-IL5 (mepolizumab, reslizumab) /Anti-IL5Ra (benralizumab) for severe eosinophilic asthma
  • Blood eosinophils greater than or equal to 150 cells/microliter or greater than or equal to 300 cells/microliter
  • Severe exacerbations within the last year
• Anti-IL4Ra (dupilumab) for severe eosinophilic/Type 2 asthma or patients requiring maintenance OCS
  • Blood eosinophil greater than or equal to 150 cells/microliter but less than or equal to 1500 cells/microliter, or FeNO greater than or equal to 25 ppb, or taking maintenance OCS
  • Severe exacerbations within the last year
• Anti-TSLP (tezepelumab) for severe asthma
  • Severe exacerbations within the last year

Patient response to biologic therapy should be evaluated 4 months after initiating therapy, and the patient should be re-evaluated every 3 to 6 months. If response is unclear after 4 months, the trial should be extended to 6-12 months.(5)

2024 GINA guidelines recommend the following step-down therapy process in patients responding well to targeted biologic therapy:(5)

• Re-evaluate the need for each asthma medication every 3 to 6 months, but inhaled therapy (e.g., ICS-containing therapy) should not be completely stopped
• The order of reduction of treatments should be based on observed benefit, potential side-effects, cost, and patient preference. However, minimizing the use of OCS is a very high priority.
• First, consider decreasing/stopping OCS due to their significant adverse effects. Then consider stopping other add-on asthma medications.
• Then, if asthma is well controlled for 3-6 months, consider reducing maintenance ICS dose, but do not stop maintenance ICS-containing therapy (e.g., ICS-LABA)
• Re-evaluate the need for ongoing biologic therapy, but a trial of withdrawal of the biologic should not be considered until after at least 12 months of treatment and only if asthma remains well controlled on medium-dose ICS-containing therapy
  • For allergic asthma, also confirm there is no further exposure to an allergic trigger

Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory condition affecting the paranasal sinuses.(16) The exact cause of CRSwNP is unknown, but biopsies of nasal polyps have shown elevated levels of eosinophils. Sinus computed tomography (CT) and/or nasal endoscopy are needed to determine the presence of sinonasal inflammation and nasal polyps.(15)

The International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) indicates that the diagnostic criteria for CRSwNP consist of ALL the following:(18)

• Symptoms greater than or equal to 12 weeks
• Two of the following symptoms:
  • Nasal discharge (rhinorrhea or post-nasal drainage)
  • Nasal obstruction or congestion
  • Hyposmia (loss or decreased sense of smell)
  • Facial pressure or pain
• One or more of the following findings:
  • Evidence of inflammation on nasal endoscopy or computed tomography
  • Evidence of purulence coming from paranasal sinuses or ostiomeatal complex
• Presence of nasal polyps

Topical saline irrigation and intranasal corticosteroids (INCS) are recommended in the guidelines as initial treatment for CRSwNP.(16,18,24) Nasal saline irrigation used as adjunct treatment with other therapies improves symptoms and quality of life (QoL) outcomes and is considered an important aspect of management of CRSwNP. Saline irrigation can improve nasal mucosa function through the mechanical clearance of thick mucus and inflammatory mediators, including eosinophilic mucin.(18,24)

INCS can have a positive impact on the disease and improve symptoms, reduce nasal polyp size, and improve sense of smell.(18,24) The ICAR-RS strongly recommends INCS before or after sinus surgery.(18) INCS are well tolerated and long term treatment is effective and safe. Many different INCS have been used in the treatment of CRSwNP, including triamcinolone, mometasone, fluticasone, and budesonide, but no differences were shown to recommend a specific formulation.(24) For patients using INCS for at least 4 weeks and who continue to have high disease burden, biologics may be considered and preferred over other medical treatment choices.(16)

Oral systemic corticosteroids (OCS), used as a short course, can result in a significant reduction in symptoms and nasal polyps for up to three months after the start of treatment. Up to 2 courses per year, taken in addition to INCS, can be useful for patients with partially or uncontrolled disease.(24) The ICAR-RS strongly recommends the use of OCS in the short term management of CRSwNP, but does not recommend longer term use due to the increased risk of adverse effects.(18)

Endoscopic sinus surgery (ESS) is aimed at improving symptoms and creating better conditions for local treatment. Sinus surgery should be considered when disease is refractory and remains symptomatic despite trial of primary medical therapy (e.g., nasal sinus irrigation, INCS, oral corticosteroids). Based on current evidence, delaying surgical intervention can be detrimental to symptom improvement and outcomes.(18,24) After surgery, patients need to continue other treatments due to the chronic nature of the disease and nasal polyps potentially reoccurring despite surgery.(15,24) INCS can help to prevent nasal polyp recurrence.(18,24)

Biologics can be considered in patients where their disease remains uncontrolled despite appropriate medical treatment and sinus surgery.(16,25) Biologics vary in their magnitude of benefits and harms and certainty of evidence across outcomes. Dupilumab and omalizumab are the most beneficial for most patient important outcomes when comparing with other biologics, followed by mepolizumab.(16)

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Eosinophilic granulomatosis with polyangiitis (EGPA), formally known as Churg-Strauss Syndrome, is a chronic inflammatory disorder causing vasculitis of small- to medium-sized vessels. It is characterized by a histopathology of eosinophil infiltration into tissues causing multiple organ damage.(6) The most common clinical manifestation is asthma, which occurs in greater than 90% of patients. Ear-nose-throat (ENT) symptoms, such as chronic rhinosinusitis, are found in 60-80% of patients.(20) Other clinical characteristics include peripheral eosinophilia, peripheral neuropathy, lung infiltrates, cardiomyopathy, gastroenteritis, purpura, and renal disease.(7,20)

The diagnosis of EGPA is often challenging due to its heterogeneous clinical presentation, and at this time there are no diagnostic criteria for EGPA, only classification criteria. Although the diagnosis of EGPA should be based on histopathological findings, a diagnostic biopsy is often lacking and not required. The diagnosis of EGPA is typically based on the presence of highly suggestive clinical features included in the available classification criteria, and when other eosinophilic and vasculitic disorders have been ruled out. Antineutrophil cytoplasmic antibody (ANCA) and blood eosinophilia testing are also indicative laboratory tests to confirm the diagnosis. However, ANCA positive disease is only found in 30-40% of patients with EGPA but can be considered for the diagnosis of EGPA.(20) The American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) 2022 classification criteria highly weights a blood eosinophil count of greater than or equal to 1000 cells/microliter as being indicative of EGPA.(8) Eosinophilia can also be defined as a blood eosinophil level of greater than 10% of the total leukocyte count. Eosinophilia is observed in almost all patients with EGPA, although the use of systemic glucocorticoids can reduce blood eosinophil counts and mask the presence of this indicator.(20)

Treatment of EGPA should be differentiated by disease severity. Severe disease is defined as the presence of life- or organ-threatening manifestations, such as alveolar hemorrhage, glomerulonephritis, central nervous system vasculitis, mononeuritis multiplex, cardiac involvement, mesenteric ischemia, and limb/digit ischemia. Non-severe disease is vasculitis without life- or organ-threatening manifestations, and involves the presence of rhinosinusitis, asthma, mild systemic symptoms, uncomplicated cutaneous disease, and/or mild inflammatory arthritis.(7)

The goals of treatment are to improve quality of life, preserve organ function, and prevent disease flares.(20) Treatment begins with the induction of remission through the use of glucocorticoids. For severe disease, glucocorticoids are used in combination with either cyclophosphamide or rituximab. After induction, the goals are the maintenance of remission, the tapering of glucocorticoid dosing to prevent adverse effects, and to prevent relapse of active disease.(7,20,21) Remission is defined as the absence of clinical signs or symptoms attributable to active disease, including the control of asthma and ENT manifestations.(7,20) Refractory disease is defined as unchanged or increased disease activity after 4 weeks of appropriate remission-induction therapy.(20) Per current guidelines for severe disease, glucocorticoids used in combination with cyclophosphamide, rituximab, or methotrexate are the recommended treatments at the different stages of the algorithm, with mepolizumab only being stated as a consideration based on limited observational studies.(7,20,21)

For non-severe disease (without life- or organ-threatening manifestations), mepolizumab plays a role in the recommended treatments based on the state of the disease and to allow a tapering of the glucocorticoid dose. Other traditional immunosuppressant treatments (e.g., methotrexate, cyclophosphamide, azathioprine, rituximab, mycophenolate mofetil) are sometimes also used clinically in combination with glucocorticoids, but evidence supporting their use is limited.(7,20,21) Treatment recommendations for non-severe EGPA are as follows:

• For remission induction in patients with new-onset, active disease, glucocorticoids alone should be used.(20,21)
• For remission maintenance, glucocorticoids plus mepolizumab should be used, with mepolizumab being added on as a glucocorticoid-sparing agent and to maintain remission.(7,20)
• For relapsing/refractory disease, mepolizumab should be used in combination with glucocorticoids for remission induction and continued for remission maintenance.(7,20,21)

Hypereosinophilic Syndrome (HES)

Hypereosinophilic syndrome (HES) is a rare heterogeneous group of disorders characterized by blood or tissue eosinophilia that leads to end organ damage.(13,14) The eosinophilias, in general, include a broad range of non‐hematologic (secondary or reactive) and hematologic (primary or clonal) disorders.(12) HES can be divided into three groups - primary HES, where eosinophils are clonal cells and a myeloid or stem cell neoplasm is typically present; secondary (reactive) HES, where an underlying reactive disease causes secondary eosinophil expansion and activation; and idiopathic HES, where no underlying (primary or secondary) etiology is identified.(13) Secondary (non-hematologic) causes of eosinophilia include infection, allergy/atopy, medications, collagen vascular disease, metabolic (e.g., adrenal insufficiency), and solid tumor/lymphoma.(12)

A consensus, published in 2012 by the Working Conference on Eosinophil Disorders and Syndromes, defines hypereosinophilia (HE) as the following:(11)

• Peripheral blood eosinophil count greater than 1500 cells/microliter on 2 examinations at least 1 month apart AND/OR
• Tissue HE defined by at least one of the following:
  • Percentage of eosinophils in bone marrow section exceeds 20% of all nucleated cells
  • Marked deposition of eosinophil granule proteins is found
  • Tissue infiltration by eosinophils is extensive in the opinion of the pathologist

Per the same consensus, to establish a diagnosis of HES all three of the following criteria must be met:(11,22)

• Criteria for HE fulfilled
• Organ damage and/or dysfunction attributable to tissue HE (e.g., fibrosis of lung, heart, digestive tract, skin, etc.; thrombosis with or without thromboembolism; cutaneous erythema, edema/angioedema, ulceration, pruritis, or eczema; peripheral or central neuropathy with chronic or recurrent neurologic deficit; other organ system involvement such as liver, pancreas, kidney)
• Exclusion of other conditions as a major reason for organ damage

The consensus definition provides a broad approach and includes multiple clinical classifications of HES, including idiopathic, primary (clonal/neoplastic), secondary (including lymphocytic variant), and hereditary.(11,22) The World Health Organization (WHO) differs in their definition of HES (last updated 2022) and describes only idiopathic HES as fulfilling the requirements.(12,22) The WHO definition of HES states all of the following must be met:(12,22)

• Peripheral blood eosinophil count greater than 1500 cells/microliter for greater than 6 months
• Tissue damage is present
• Evidence of end-organ manifestations
• Exclusion of reactive HE, lymphocytic variant HES, chronic eosinophilic leukemia-not otherwise specified, WHO-defined malignancies, eosinophilia-associated myeloproliferative neoplasms, or acute myeloid leukemia/acute lymphocytic leukemia with rearrangements of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 ("idiopathic")

Although differences in the definitions of HES exist between the consensus group and the WHO, the treatment approaches are similar. For example, if a secondary cause of eosinophilia, such as helminth infection, or an underlying etiology is identified or suspected, specific treatment should be initiated to treat the underlying cause appropriately. This includes identifying primary HES so that the correct therapeutic approach is initiated.(22) The goals of therapy are to reduce blood and tissue eosinophil levels and prevent disease progression and organ damage.(12,14,23)

Clinical manifestations can be similar irrespective of the cause of the eosinophilia, and the choice of the initial therapeutic agent(s) for a given patient depends mainly on whether the patient has clinical features consistent with a myeloid disorder. Patients with myeloid variants of HES (e.g., PDGFRA-positive HES) often have an aggressive course with disabling complications and high mortality in the absence of treatment, and are treated initially with imatinib; those with other types of HES are treated with an initial trial of glucocorticoids. Oral corticosteroids have been used for decades in the treatment of HES and, with the exception of imatinib for PDGFRA-associated HES as noted above, and remain the first-line treatment for most patients. Hydroxyurea is a typical second-line agent, whether used as monotherapy or in conjunction with corticosteroids as a steroid-sparing agent.(12,14,22) Additional immunomodulatory and cytotoxic agents that are commonly used as second-line/steroid-sparing treatment include interferon-α, cyclosporine, and methotrexate.(22,23)

Biologics, including monoclonal anti–interleukin (IL)-5 antibody therapy, may be beneficial for patients with HES who are treatment-refractory or experience treatment-related toxicity with immunomodulatory or cytotoxic agents.(14) IL-5 inhibitors, including mepolizumab, have a glucocorticoid sparing effect and have shown to be efficacious in the treatment of HES with lower toxicity compared to other secondary treatment options.(14,22) Mepolizumab has been found to be effective in PDGFRA-negative, glucocorticoid responsive HES (including idiopathic HES).(13,14,22)

Efficacy

Asthma

Fasenra 
Benralizumab was approved through 3 confirmatory clinical trials. Trial 1 and Trial 2 were exacerbation trials in patients 12 years of age and older. All subjects continued their background asthma therapy throughout the duration of the trials. The primary endpoint was the rate of asthma exacerbations in patients who were taking high-dose ICS and LABA. Asthma exacerbation was defined as a worsening of asthma requiring use of oral/systemic corticosteroids for at least 3 days, and/or emergency department visits requiring use of oral/systemic corticosteroids and/or hospitalization. For patients on maintenance oral corticosteroids, an asthma exacerbation requiring oral corticosteroids was defined as a temporary increase in stable oral/systemic corticosteroids for at least 3 days or a single depo-injectable dose of corticosteroids. In Trial 1, 35% of patients receiving benralizumab experienced an asthma exacerbation compared to 51% on placebo. In Trial 2, 40% of patients receiving benralizumab experienced an asthma exacerbation compared to 51% on placebo.(2)

Trial 3 was a randomized OCS reduction trial in asthma patients. Patients were required to be treated with daily OCS (7.5 to 40 mg per day) in addition to regular use of high-dose ICS and LABA with or without additional controller(s). The trial included an 8-week run-in period during which the OCS was titrated to the minimum effective dose without losing asthma control. For the purposes of the OCS dose titration, asthma control was assessed by the investigator based on a patient’s FEV1, peak expiratory flow, nighttime awakenings, short-acting bronchodilator rescue medication use or any other symptoms that would require an increase in OCS dose. Fasenra achieved greater reductions in daily maintenance OCS dose while maintaining asthma control compared to placebo (median reduction of 75% for Fasenra vs 25% for placebo).(2)

Nucala 
The efficacy of mepolizumab for the treatment of severe eosinophilic asthma was established in three double-blind, randomized, placebo-controlled trials: A dose-ranging and exacerbation reduction trial (trial 1) and two confirmatory trials (trial 2 and 3). All subjects continued their background asthma therapy throughout the duration of the trials. Trial 1 enrolled subjects with uncontrolled asthma despite use of high dose inhaled corticosteroids (ICS) plus additional controller(s), with or without OCS. Trial 2 was a placebo- and active-controlled trial in subjects with asthma not adequately controlled on high-dose inhaled corticosteroids plus additional controller(s) with or without OCS. The primary end point for trial 1 and 2 was frequency of asthma exacerbations. Compared to placebo, subjects receiving mepolizumab experienced significantly fewer exacerbations and had a longer time to first exacerbation.(1)   

Trial 3 was an OCS-reduction study in asthma patients who required daily OCS in addition to regular controller medications. The primary end point was percent reduction of OCS dose during weeks 20 to 24 without loss of asthma control. The baseline mean oral corticosteroid use was similar between the Nucala and placebo group. Overall, mepolizumab achieved greater reduction in oral corticosteroid use while maintaining asthma control when compared to placebo. However, the difference between the mepolizumab and placebo groups was not statistically significant.(1)

EGPA

Fasenra
The efficacy of Fasenra for eosinophilic granulomatosis with polyangiitis (EGPA) was evaluated in a randomized, double-blind, active-controlled, noninferiority clinical trial (MANDARA [NCT04157348]) of 52-weeks duration. The trial enrolled a total of 140 adults aged 18 years and older with a documented diagnosis of EGPA for at least 6 months. Patients were required to have asthma, eosinophilia (1,000 cells/uL or greater than 10% of leukocytes) and a history of relapsing or refractory disease treated with background prednisolone/prednisone with or without immunosuppressive therapy. Patients who had organ- or life-threatening EGPA within 3 months before the first visit were excluded. Patients were randomized to receive Fasenra 30 mg administered subcutaneously every 4 weeks or mepolizumab 300 mg administered subcutaneously every 4 weeks in addition to continued background therapy. Starting at Week 4, the oral corticosteroid (OCS) dose was tapered at the discretion of the investigator. The MANDARA trial was a non-inferiority trial and was not designed to assess whether Fasenra was superior to mepolizumab. The pre-specified noninferiority (NI) margin was a treatment difference of -25%. The secondary endpoints (accrued duration of remission, relapse, OCS reduction and the asthma control questionnaire-6) were not included in the pre-specified multiple testing procedure for statistical significance.(2,17)

The primary endpoint in MANDARA was the proportion of patients in remission, defined as Birmingham Vasculitis Activity Score (BVAS)=0 (no active vasculitis) plus prednisolone/prednisone dose less than or equal to 4 mg/day, at both Week 36 and Week 48. The BVAS is a clinician-completed tool, that is divided into 9 organ-based systems, to assess clinically active vasculitis that would likely require treatment, after exclusion of other causes. Fasenra demonstrated noninferiority to mepolizumab for the primary endpoint of remission and the components of remission. Using an alternative remission definition of BVAS=0 plus prednisolone/ prednisone less than or equal to 7.5 mg/day, consistent efficacy between groups for these endpoints was observed.(2)

Total accrued duration of remission was similar in Fasenra compared to mepolizumab (odds ratio 1.4, 95% CI: 0.75, 2.5). The proportion of patients achieving remission within the first 24 weeks of treatment and remaining in remission through Week 52 was 42% for Fasenra and 37% for mepolizumab (difference in responder rate 5.5%, 95% CI: -9.3, 20). This result was not statistically significant as there was no pre-specified multiple testing procedure. The hazard ratio for time to first relapse (defined as worsening related to vasculitis, asthma, or sino-nasal symptoms requiring an increase in dose of corticosteroids or immunosuppressive therapy or hospitalization) was 0.98 (95% CI: 0.53, 1.8). Relapse was observed in 30% of patients on Fasenra and 30% of patients on mepolizumab. The annualized relapse rate was 0.50 for patients receiving Fasenra versus 0.49 for patients receiving mepolizumab (rate ratio 1.0, 95% CI: 0.56, 1.9). The types of relapse were consistent for patients receiving Fasenra or mepolizumab. During Weeks 48 to 52, a 100% reduction in the OCS dose was observed in 41% of patients receiving Fasenra compared to 26% of those receiving mepolizumab (difference 16%, 95% CI: 0.67, 31). During Weeks 48 to 52, reductions of 50% or higher were observed in 86% of patients receiving Fasenra compared to 74% of those receiving mepolizumab (difference 12%, 95% CI: -0.57, 25).(2) Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients in the benralizumab group and 26% of those in the mepolizumab group (difference 16%; 95% CI: 1,31).(17) These results were not statistically significant as there was no pre-specified multiple testing procedure. ACQ-6 is a 6-item questionnaire that is completed by the patient to measure the adequacy of asthma control and change in asthma control. The ACQ-6 responder rate during Weeks 48 to 52 (defined as a decrease in score of 0.5 or more compared with baseline) was 42% for Fasenra and 48% for mepolizumab (difference -6.2%, 95% CI: -19, 6.2).(2)

Nucala 
A total of 136 subjects with EGPA were evaluated in a randomized, placebo-controlled, multicenter, 52-week trial. Subjects enrolled had a diagnosis of EGPA for at least 6 months prior to enrollment with a history of relapsing or refractory disease and were on a stable dosage of oral prednisolone or prednisone of greater than or equal to 7.5 mg/day (but not greater than 50 mg/day) for at least 4 weeks prior to enrollment (with or without additional immunosuppressive therapy). Patients were required to have a history or presence of asthma and either a blood eosinophil level of 10% or an absolute eosinophil count of more than 1000 cells per cubic millimeter. Exclusion criteria included patients who had organ-threatening or life-threatening EGPA within 3 months before screening.(1,9) Subjects received 300 mg of mepolizumab or placebo administered subcutaneously once every 4 weeks while continuing their stable OCS therapy. Starting at Week 4, OCS was tapered during the treatment period at the discretion of the investigator. The co-primary endpoints were the total accrued duration of remission over the 52-week treatment period, defined as Birmingham Vasculitis Activity Score (BVAS) = 0 (no active vasculitis) plus prednisolone or prednisone dose less than or equal to 4 mg/day, and the proportion of subjects in remission at both Week 36 and Week 48 of treatment. The BVAS is a clinician-completed tool to assess clinically active vasculitis that would likely require treatment, after exclusion of other causes.(1)

A significantly higher proportion of subjects receiving mepolizumab achieved remission at both Week 36 and Week 48 compared with placebo. In addition, significantly more subjects receiving mepolizumab achieved remission within the first 24 weeks and remained in remission for the remainder of the 52-week study treatment period compared with placebo (19% for mepolizumab versus 1% for placebo; OR 19.7; 95% CI: 2.3, 167.9).(1)

The time to first relapse (defined as worsening related to vasculitis, asthma, or sino-nasal symptoms requiring an increase in dose of corticosteroids or immunosuppressive therapy or hospitalization) was significantly longer for subjects receiving mepolizumab compared with placebo with a hazard ratio of 0.32 (95% CI: 0.21, 0.5). Additionally, subjects receiving mepolizumab had a reduction in rate of relapse compared with subjects receiving placebo (rate ratio 0.50; 95% CI: 0.36, 0.70 for mepolizumab compared with placebo). The incidence and number of relapse types (vasculitis, asthma, sino-nasal) were numerically lower with mepolizumab compared with placebo.(1)

Subjects receiving mepolizumab had a significantly greater reduction in average daily OCS dose compared with subjects receiving placebo during Weeks 48 to 52.(1)

HES

Nucala 
A total of 108 adult and adolescent patients aged 12 years and older with HES for at least 6 months were evaluated in a randomized, double-blind, placebo-controlled, multicenter, 32-week trial (NCT #02836496). Patients with non-hematologic secondary HES (e.g., drug hypersensitivity, parasitic helminth infection, HIV infection, non-hematologic malignancy) or FIP1L1-PDGFRα kinase-positive HES were excluded from the trial. Patients received 300 mg of Nucala or placebo subcutaneously once every 4 weeks while continuing their stable HES therapy. Patients entering the trial had experienced at least 2 HES flares within the past 12 months and a blood eosinophil count of 1,000 cells/microliter or higher during screening. Historical HES flares for the trial entry criteria were defined as HES-related worsening of clinical symptoms or blood eosinophil counts requiring an escalation in therapy. Patients must have been on stable background HES therapy for a minimum of 4 weeks prior to randomization, and included oral corticosteroids (OCS), hydroxyurea, cyclosporine, imatinib, methotrexate, tacrolimus, and azathioprine. Existing HES therapy was maintained throughout the treatment period unless there was symptom worsening that required a dose increase. HES therapy could include chronic or episodic OCS, immunosuppressive, and/or cytotoxic therapy.(1,10)

The efficacy of Nucala in HES was established based upon the proportion of patients who experienced a HES flare during the 32-week treatment period. A HES flare was defined as worsening of clinical signs and symptoms of HES or increasing eosinophils (on at least 2 occasions), resulting in the need to increase OCS or increase/add cytotoxic or immunosuppressive HES therapy. Over the 32-week treatment period, the incidence of HES flare over the treatment period was 56% for the placebo group and 28% for the group treated with Nucala (50% reduction).(1,10)

CRSwNP

Nucala 
A randomized, double-blind, multicenter, placebo-controlled 52-week trial (NCT03085797) evaluated Nucala in patients with CRSwNP. The trial inclusion requirements included adult patients on background intranasal corticosteroids (INCS), with recurrent and symptomatic CRSwNP despite at least 1 surgery for the removal of nasal polyps within the previous 10 years. A total of 407 subjects were randomized to receive either 100 mg Nucala (N=206) or placebo (N=201) every 4 weeks for 52 weeks (13 doses). All study participants received mometasone furoate 400 mcg (intolerant participants received 200mcg) daily along with Nucala or placebo. Participants were not required to have sinus CT scans, but were required to have endoscopic confirmation of diagnosis.(1)

The co-primary efficacy endpoints were change from baseline to Week 52 in total endoscopic nasal polyps score (NPS; 0-8 scale) as graded by independent blinded assessors and change from baseline in nasal visual analog scale (VAS; 0-10 scale) during weeks 49 to 52.(1)

Statistically significant efficacy was observed regarding improvement (decrease) in bilateral endoscopic NPS score at week 52, and nasal obstruction VAS score from weeks 49 to 52. Total endoscopic NPS 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 less than 0.001) and nasal obstruction VAS score during weeks 49–52 also significantly improved (-3.14, -4.09 to -2.18; p less than 0.001).(1)

Treatment with Nucala resulted in significant reduction of systemic corticosteroid use and need for sinonasal surgery versus placebo. The proportion of subjects who required surgery was reduced by 57% (HR of 0.43; 95% CI: 0.25, 0.76). Treatment with Nucala also significantly reduced the need for systemic steroids for nasal polyps versus placebo.(1)

Safety

Fasenra (benralizumab) is contraindicated in those with known hypersensitivity to benralizumab or any of its excipients.(2)
Nucala (mepolizumab) is contraindicated in patients with a history of hypersensitivity to mepolizumab or excipients in the formulation.(1)

1

Nucala prescribing information. GlaxoSmithKline LLC. March 2023.

2

Fasenra prescribing information. AstraZeneca Pharmaceuticals LP. September 2024.

3

Chung KF, Wenzel SE, Brozek J, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. The European Respiratory Journal. 2014;43(2):343-373. doi:10.1183/09031936.00202013

4

Louis R, Satia I, Ojanguren I, et al. European Respiratory Society guidelines for the diagnosis of asthma in adults. European Respiratory Journal. 2022;60(3):2101585. doi:10.1183/13993003.01585-2021

5

Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, 2024. Updated May 2024. Available from: http://www.ginasthma.org

6

Watanabe R, Hashimoto M. Eosinophilic Granulomatosis with Polyangiitis: Latest Findings and Updated Treatment Recommendations. Journal of Clinical Medicine. 2023;12(18):5996. doi:10.3390/jcm12185996

7

Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis. Arthritis & Rheumatology. 2021;73(8):1366-1383. doi:10.1002/art.41773

8

Grayson PC, Ponte C, Suppiah R, et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis. Annals of the Rheumatic Diseases. 2022;81(3):309-314. doi:10.1136/annrheumdis-2021-221794

9

Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. New England Journal of Medicine. 2017;376(20):1921-1932. doi:10.1056/nejmoa1702079

10

Roufosse F, Kahn JE, Rothenberg ME, et al. Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial. Journal of Allergy and Clinical Immunology. 2020;146(6):1397-1405. doi:10.1016/j.jaci.2020.08.037

11

Valent P, Klion AD, Horny HP, et al. Contemporary Consensus Proposal on Criteria and Classification of Eosinophilic Disorders and Related Syndromes. J Allergy Clin Immunol. 2012;130(3):607-612.

12

Shomali W, Gotlib J. World Health Organization‐defined eosinophilic disorders: 2022 update on diagnosis, risk stratification, and management. American Journal of Hematology. 2021;97(1):129-148. doi:10.1002/ajh.26352

13

Valent P. Mepolizumab in hypereosinophilic syndromes: Proposed therapeutic algorithm. The Journal of Allergy and Clinical Immunology in Practice. 2022;10(9):2375-2377. doi:10.1016/j.jaip.2022.06.027

14

Kuang FL, Klion AD. Biologic Agents for the Treatment of Hypereosinophilic Syndromes. J Allergy Clin Immunol Pract. 2017;5(6):1502-1509.

15

Stevens WW, Schleimer RP, Kern RC. Chronic Rhinosinusitis with Nasal Polyps. J Allergy Clin Immunol Pract. 2016;4(4):565-572. doi:10.1016/j.jaip.2016.04.012

16

Rank MA, Chu DK, Bognanni A, et al. The Joint Task Force on Practice Parameters GRADE guidelines for the medical management of chronic rhinosinusitis with nasal polyposis. J Allergy Clin Immunol. 2023;151(2):386-398. doi:10.1016/j.jaci.2022.10.026

17

Wechsler M, Nair P, Terrier B, et al. Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis. New England Journal of Medicine. 2024;390(10):911-921. doi:10.1056/nejmoa2311155

18

Orlandi RR, Kingdom TT, Smith TL, et al. International consensus statement on allergy and rhinology: rhinosinusitis 2021. International Forum of Allergy & Rhinology. 2021;11(3):213-739. doi:10.1002/alr.22741

19

Bourdin A, Brusselle G, Couillard S, et al. Phenotyping of severe asthma in the era of broad-acting anti-asthma biologics. The Journal of Allergy and Clinical Immunology in Practice. 2024;12(4):809-823. doi:10.1016/j.jaip.2024.01.023

20

Emmi G, Bettiol A, Gelain E, et al. Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis. Nature Reviews Rheumatology. 2023;19(6):378-393. doi:10.1038/s41584-023-00958-w

21

Hellmich B, Sanchez-Alamo B, Schirmer JH, et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Annals of the Rheumatic Diseases. 2023;83(1):30-47. doi:10.1136/ard-2022-223764

22

Klion AD. Approach to the patient with suspected hypereosinophilic syndrome. Hematology. 2022;2022(1):47-54. doi:10.1182/hematology.2022000367

23

Nguyen L, Saha A, Kuykendall A, Zhang L. Clinical and therapeutic intervention of hypereosinophilia in the era of molecular diagnosis. Cancers. 2024;16(7):1383. doi:10.3390/cancers16071383

24

Fokkens W, Lund VJ, Mullol J, et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology. 2020;0(0):1-464. doi:10.4193/rhin20.600

25

Fokkens WJ, Viskens A, Backer V, et al. EPOS/EUFOREA update on indication and evaluation of Biologics in Chronic Rhinosinusitis with Nasal Polyps 2023. Rhinology. 2023;0(0):194-202. doi:10.4193/rhin22.489

Fasenra pen

benralizumab subcutaneous soln auto-injector

30 MG/ML

M ; N ; O ; Y

N

Nucala

mepolizumab subcutaneous solution auto-injector

100 MG/ML

M ; N ; O ; Y

N

Nucala

mepolizumab subcutaneous solution pref syringe

100 MG/ML ; 40 MG/0.4ML

M ; N ; O ; Y

N

Fasenra pen

Benralizumab Subcutaneous Soln Auto-injector 30 MG/ML

30 MG/ML

1

Pen

28

DAYS

*NOTE: Fasenra loading dose of 3 syringes for the first three months is approvable

Nucala

Mepolizumab Subcutaneous Solution Auto-injector 100 MG/ML

100 MG/ML

3

Syringes

28

DAYS

Severe eosinophilic asthma and CRSwNP: 1 syringe/28 days

Nucala

Mepolizumab Subcutaneous Solution Pref Syringe

40 MG/0.4ML

1

Syringe

28

DAYS

Nucala

Mepolizumab Subcutaneous Solution Pref Syringe 100 MG/ML

100 MG/ML

3

Syringes

28

DAYS

Severe eosinophilic asthma and CRSwNP: 1 syringe/28 days

4460402000D520

Fasenra pen

Benralizumab Subcutaneous Soln Auto-injector 30 MG/ML

30 MG/ML

*NOTE: Fasenra loading dose of 3 syringes for the first three months is approvable

Fasenra pen

benralizumab subcutaneous soln auto-injector

30 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Nucala

mepolizumab subcutaneous solution auto-injector

100 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Nucala

mepolizumab subcutaneous solution pref syringe

100 MG/ML ; 40 MG/0.4ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Fasenra pen

Benralizumab Subcutaneous Soln Auto-injector 30 MG/ML

30 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Nucala

Mepolizumab Subcutaneous Solution Auto-injector 100 MG/ML

100 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Nucala

Mepolizumab Subcutaneous Solution Pref Syringe

40 MG/0.4ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Nucala

Mepolizumab Subcutaneous Solution Pref Syringe 100 MG/ML

100 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

PA

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. ONE of the following:
   1. The requested agent is eligible for continuation of therapy AND ONE of the following: 

1. 1. 1. The patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days OR
      2. The prescriber states the patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days AND is at risk if therapy is changed OR
   2. BOTH of the following:
      1. ONE of the following:
         1. The patient has a diagnosis of severe eosinophilic asthma and ALL of the following:
            1. The patient’s diagnosis has been confirmed by a baseline (prior to therapy with the requested agent) blood eosinophil count of 150 cells/microliter or higher AND
            2. The patient has a history of uncontrolled asthma while on asthma control therapy as demonstrated by BOTH of the following:
               1. Two or more exacerbations in the previous year AND
               2. Require daily oral corticosteroids for at least 3 days (in addition to the regular maintenance therapy defined below) AND
            3. The patient has severe disease as indicated by at least ONE of the following:
               1. Symptoms throughout the day
               2. Nighttime awakenings, often 7 times/week
               3. SABA use for symptom control occurs several times per day
               4. Extremely limited normal activities
               5. Lung function (percent predicted FEV1) less than 60%
               6. Exacerbations requiring oral systemic corticosteroids are generally more frequent and intense relative to moderate asthma
               7. Another guideline-defined component of severity for classifying asthma AND
            4. The requested agent will NOT be used for treatment of acute bronchospasm or status asthmaticus OR
         2. The patient has a diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) and ALL of the following:
            1. Blood eosinophil level of greater than 10% or an absolute count greater than 1000 cells/microliter AND
            2. The patient’s diagnosis of EGPA was confirmed by BOTH of the following:
               1. History or presence of asthma AND
               2. The patient has at least 2 of the following:
                  1. Histopathologic evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration or eosinophil rich granulomatous inflammation
                  2. Neuropathy
                  3. Pulmonary infiltrates
                  4. Sinonasal abnormalities
                  5. Cardiomyopathy
                  6. Glomerulonephritis
                  7. Alveolar hemorrhage
                  8. Palpable purpura
                  9. Antineutrophil Cytoplasmic Antibody (ANCA) positivity AND
            3. ONE of the following:
               1. BOTH of the following:
                  1. The patient is currently treated within the past 90 days with oral corticosteroid (OCS) therapy for at least 4 weeks AND
                  2. The patient will be using oral corticosteroid (OCS) therapy in combination with the requested agent OR
               2. The patient has an intolerance or hypersensitivity to therapy with an oral corticosteroid (OCS) OR
               3. The patient has an FDA labeled contraindication to ALL oral corticosteroids OR
         3. The patient has a diagnosis of hypereosinophilic syndrome (HES) and ALL of the following:
            1. The requested agent is FDA labeled or compendia supported for HES AND
            2. The patient has had a diagnosis of HES for at least 6 months AND
            3. The patient’s diagnosis of HES was confirmed by a peripheral blood eosinophil count greater than 1000 cells/microliter AND
            4. The patient does NOT have an identifiable non-hematologic secondary (reactive) cause of HES (e.g., infection [e.g., HIV infection or parasitic helminth infection], allergy/atopy, medications [e.g., drug hypersensitivity], collagen vascular disease, metabolic [e.g., adrenal insufficiency], solid tumor/lymphoma [e.g., non-hematologic malignancy]) AND
            5. The patient does NOT have FIP1L1-PDGFRA-positive disease AND
            6. The patient has a history of at least 2 HES flares within the past 12 months (i.e., worsening of clinical symptoms and/or blood eosinophil counts requiring an escalation in therapy) AND
            7. ONE of the following:
               1. The patient has tried and had an inadequate response to ONE of the following:
                  1. Oral corticosteroid (OCS) therapy OR
                  2. Hydroxyurea OR
                  3. Interferon-a OR
                  4. Another immunosuppressive agent (e.g., cyclosporine, methotrexate) OR
               2. The patient has an intolerance or hypersensitivity to therapy with an oral corticosteroid, hydroxyurea, interferon-a, or an immunosuppressive agent (e.g., cyclosporine, methotrexate) used in the treatment of HES OR
               3. The patient has an FDA labeled contraindication to hydroxyurea, interferon-a, and ALL oral corticosteroids and immunosuppressive agents (e.g., cyclosporine, methotrexate) used in the treatment of HES OR
         4. The patient has a diagnosis of chronic rhinosinusitis with nasal polyps (CRSwNP) AND ALL of the following:
            1. The requested agent is FDA labeled or compendia supported for CRSwNP AND
            2. The patient has at least TWO of the following symptoms consistent with chronic rhinosinusitis (CRS): 
               1. Nasal discharge (rhinorrhea or post-nasal drainage) 
               2. Nasal obstruction or congestion
               3. Loss or decreased sense of smell (hyposmia)
               4. Facial pressure or pain AND
            3. The patient has had symptoms consistent with chronic rhinosinusitis (CRS) for at least 12 consecutive weeks AND
            4. The patient has at least THREE of the following indicators for biologic treatment:
               1. The patient has evidence of type 2 inflammation (e.g., tissue eosinophils greater than or equal to 10/hpf, blood eosinophils greater than or equal to 150 cells/microL, or total IgE greater than or equal to 100 IU/mL) OR
               2. The patient has required two or more short courses of systemic corticosteroids per year or greater than 3 months of low dose corticosteroids, unless contraindicated OR
               3. Disease significantly impairs the patient’s quality of life OR
               4. The patient has experienced significant loss of smell OR
               5. The patient has a comorbid diagnosis of asthma AND
            5. ONE of the following:
               1. The patient has tried and had an inadequate response to ONE intranasal corticosteroid therapy (e.g., fluticasone nasal spray, mometasone nasal spray, Sinuva) after at least a 4-week duration of therapy OR
               2. The patient has an intolerance or hypersensitivity to ONE intranasal corticosteroid therapy (e.g., fluticasone nasal spray, mometasone nasal spray, Sinuva) OR
               3. The patient has an FDA labeled contraindication to ALL intranasal corticosteroids AND
            6. The patient does NOT have any of the following:
               1. Antrochoanal polyps
               2. Nasal septal deviation that would occlude at least one nostril
               3. Disease with lack of signs of type 2 inflammation
               4. Cystic fibrosis
               5. Mucoceles AND
            7. Other causes of nasal congestion/obstruction have been ruled out (e.g., acute sinusitis, nasal infection or upper respiratory infection, rhinitis medicamentosa, tumors, infections, granulomatosis, etc.) AND
            8. The prescriber has assessed baseline severity utilizing an objective measurement AND
         5. The patient has another FDA labeled indication for the requested agent and route of administration AND
      2.  If the patient has an FDA labeled indication, then ONE of the following:
         1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
         2. There is support for using the requested agent for the patient’s age for the requested indication OR
   3. The patient has another indication that is supported in compendia for the requested agent and route of administration AND
2. If the patient has a diagnosis of severe eosinophilic asthma, then ALL of the following:
   1. ONE of the following:
      1. The patient is NOT currently treated with the requested agent AND is currently treated with a maximally tolerated inhaled corticosteroid for at least 3 months AND has been adherent for 90 days within the past 120 days OR
      2. The patient is currently treated with the requested agent AND ONE of the following:
         1. The patient is currently treated with an inhaled corticosteroid for at least 3 months that is adequately dosed to control symptoms AND has been adherent for 90 days within the past 120 days OR
         2. The patient is currently treated with a maximally tolerated inhaled corticosteroid for at least 3 months AND has been adherent for 90 days within the past 120 days OR
      3. The patient has an intolerance or hypersensitivity to therapy with an inhaled corticosteroid OR
      4. The patient has an FDA labeled contraindication to ALL inhaled corticosteroids AND
   2. ONE of the following:
      1. The patient is currently treated for at least 3 months AND has been adherent for 90 days within the past 120 days with ONE of the following:
         1. A long-acting beta-2 agonist (LABA) OR
         2. A long-acting muscarinic antagonist (LAMA) OR
         3. A leukotriene receptor antagonist (LTRA) OR
         4. Theophylline OR
      2. The patient has an intolerance or hypersensitivity to therapy with a long-acting beta-2 agonist (LABA), a long-acting muscarinic antagonist (LAMA), a leukotriene receptor antagonist (LTRA), or theophylline OR
      3. The patient has an FDA labeled contraindication to ALL long-acting beta-2 agonists (LABA) AND long-acting muscarinic antagonists (LAMA) AND
   3. The patient will continue asthma control therapy (e.g., ICS, ICS/LABA, LTRA, LAMA, theophylline) in combination with the requested agent AND
3. If the patient has a diagnosis of hypereosinophilic syndrome (HES), then the patient will continue existing HES therapy (e.g., OCS, hydroxyurea, interferon-a, immunosuppressant) in combination with the requested agent AND
4. If the patient has a diagnosis of chronic rhinosinusitis with nasal polyps (CRSwNP), then BOTH of the following:
   1. The patient is currently treated with standard nasal polyp maintenance therapy (e.g., nasal saline irrigation, intranasal corticosteroids [e.g., fluticasone nasal spray, mometasone nasal spray, Sinuva]) AND
   2. The patient will continue standard nasal polyp maintenance therapy (e.g., nasal saline irrigation, intranasal corticosteroids [e.g., fluticasone nasal spray, mometasone nasal spray, Sinuva]) in combination with the requested agent AND
5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., allergist, immunologist, otolaryngologist, pulmonologist, rheumatologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
6. ONE of the following (Please refer to “Agents NOT to be used Concomitantly” table): 
   1. The patient will NOT be using the requested agent in combination with another immunomodulatory agent (e.g., TNF inhibitors, JAK inhibitors, IL-4 inhibitors, IgG2 lambda monoclonal antibody agents) OR
   2. The patient will be using the requested agent in combination with another immunomodulatory agent AND BOTH of the following:
      1. The prescribing information for the requested agent does NOT limit the use with another immunomodulatory agent AND
      2. There is support for the use of combination therapy (submitted copy of clinical trials, phase III studies, or guidelines required) AND
7. The patient does NOT have any FDA labeled contraindications to the requested agent

Compendia Allowed: AHFS, DrugDex 1 or 2a level of evidence, or NCCN 1 or 2a recommended use

Length of Approval: 6 months  

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. ONE of the following:
   1. The patient has a diagnosis of severe eosinophilic asthma AND BOTH of the following:
      1. The patient has had improvements or stabilization with the requested agent from baseline (prior to therapy with the requested agent) as indicated by ONE of the following:
         1. Increase in percent predicted Forced Expiratory Volume (FEV1) OR
         2. Decrease in the dose of inhaled corticosteroids required to control the patient’s asthma OR
         3. Decrease in need for treatment with systemic corticosteroids due to exacerbations of asthma OR
         4. Decrease in number of hospitalizations, need for mechanical ventilation, or visits to urgent care or emergency room due to exacerbations of asthma AND
      2. The patient is currently treated within the past 90 days and is compliant with asthma control therapy (e.g., inhaled corticosteroids [ICS], ICS/long-acting beta-2 agonist [ICS/LABA], leukotriene receptor antagonist [LTRA], long-acting muscarinic antagonist [LAMA], theophylline) OR
   2. The patient has a diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) AND the patient has had improvements or stabilization with the requested agent from baseline (prior to therapy with the requested agent) as indicated by ONE of the following:
      1. Remission achieved with the requested agent (defined as a Birmingham Vasculitis Activity Score (BVAS) score=0 and a prednisone/prednisolone daily dose of ≤ 7.5 mg) OR
      2. Decrease in oral corticosteroid maintenance dose required for control of symptoms related to EGPA OR
      3. Improvement in BVAS score compared to baseline OR
      4. Improvement in asthma symptoms or asthma exacerbations OR
      5. Improvement in duration of remission or decrease in the rate of relapses OR
   3. The patient has a diagnosis of hypereosinophilic syndrome (HES) AND BOTH of the following:
      1. The patient has had improvements or stabilization with the requested agent from baseline (prior to therapy with the requested agent) as indicated by ONE of the following:
         1. Decrease in incidence of HES flares OR
         2. Escalation of therapy (due to HES-related worsening of clinical symptoms or increased blood eosinophil counts) has NOT been required AND
      2. The patient will continue existing HES therapy (e.g., OCS, hydroxyurea, interferon-a, immunosuppressant) in combination with the requested agent OR
   4. The patient has a diagnosis of chronic rhinosinusitis with nasal polyps (CRSwNP) AND BOTH of the following:
      1. The patient has had clinical benefit with the requested agent as indicated by improvement in signs and symptoms compared to baseline (prior to therapy with the requested agent) in one or more of the following:
         1. Nasal/obstruction symptoms OR
         2. Improvement of sinus opacifications as assessed by CT-scans OR
         3. Improvement on a disease activity scoring tool (e.g., nasal polyposis score (NPS), nasal congestion (NC) symptom severity score, sino-nasal outcome test-22 (SNOT-22), etc.) OR
         4. Improvement in at least ONE of the following:
            1. Reduction in nasal polyp size OR
            2. Reduction in need for systemic corticosteroids OR
            3. Quality of Life OR
            4. Sense of smell OR
            5. Reduction of impact of comorbidities AND
      2. The patient will continue standard nasal polyp maintenance therapy (e.g., nasal saline irrigation, intranasal corticosteroids [e.g., fluticasone nasal spray, mometasone nasal spray, Sinuva]) in combination with the requested agent OR
   5. The patient has a diagnosis other than severe eosinophilic asthma, EGPA, HES, or CRSwNP AND has had clinical benefit with the requested agent AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., allergist, immunologist, otolaryngologist, pulmonologist, rheumatologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
4. ONE of the following (Please refer to “Agents NOT to be used Concomitantly” table): 
   1. The patient will NOT be using the requested agent in combination with another immunomodulatory agent (e.g., TNF inhibitors, JAK inhibitors, IL-4 inhibitors, IgG2 lambda monoclonal antibody agents) OR
   2. The patient will be using the requested agent in combination with another immunomodulatory agent AND BOTH of the following:
      1. The prescribing information for the requested agent does NOT limit the use with another immunomodulatory agent AND
      2. There is support for the use of combination therapy (submitted copy of clinical trials, phase III studies, or guidelines required) AND
5. The patient does NOT have any FDA labeled contraindications to the requested agent

Compendia Allowed: AHFS, DrugDex 1 or 2a level of evidence, or NCCN 1 or 2a recommended use

Length of Approval: 6 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR  
2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
   1. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
   2. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit

Length of Approval: Initial: 6 months; For Fasenra, approve loading dose for new starts and the maintenance dose for the remainder of the 6 months; 
Renewal: 6 months 

Agents NOT to be used Concomitantly

Abrilada (adalimumab-afzb)
Actemra (tocilizumab)
Adalimumab
Adbry (tralokinumab-ldrm)
Amjevita (adalimumab-atto)
Arcalyst (rilonacept)
Avsola (infliximab-axxq)
Benlysta (belimumab)
Bimzelx (bimekizumab-bkzx)
Cibinqo (abrocitinib)
Cimzia (certolizumab)
Cinqair (reslizumab)
Cosentyx (secukinumab)
Cyltezo (adalimumab-adbm)
Dupixent (dupilumab)
Ebglyss (lebrikizumab-lbkz)
Enbrel (etanercept)
Entyvio (vedolizumab)
Fasenra (benralizumab)
Hadlima (adalimumab-bwwd)
Hulio (adalimumab-fkjp)
Humira (adalimumab)
Hyrimoz (adalimumab-adaz)
Idacio (adalimumab-aacf)
Ilaris (canakinumab)
Ilumya (tildrakizumab-asmn)
Imuldosa (ustekinumab-srlf)
Inflectra (infliximab-dyyb)
Infliximab
Kevzara (sarilumab)
Kineret (anakinra)
Leqselvi (deuruxolitinib)
Litfulo (ritlecitinib)
Nemluvio (nemolizumab-ilto)
Nucala (mepolizumab)
Olumiant (baricitinib)
Omvoh (mirikizumab-mrkz)
Opzelura (ruxolitinib)
Orencia (abatacept)
Otezla (apremilast)
Otulfi (ustekinumab-aauz)
Pyzchiva (ustekinumab-ttwe)
Remicade (infliximab)
Renflexis (infliximab-abda)
Riabni (rituximab-arrx)
Rinvoq (upadacitinib)
Rituxan (rituximab)
Rituxan Hycela (rituximab/hyaluronidase human)
Ruxience (rituximab-pvvr)
Saphnelo (anifrolumab-fnia)
Selarsdi (ustekinumab-aekn)
Siliq (brodalumab)
Simlandi (adalimumab-ryvk)
Simponi (golimumab)
Simponi ARIA (golimumab)
Skyrizi (risankizumab-rzaa)
Sotyktu (deucravacitinib) 
Spevigo (spesolimab-sbzo) subcutaneous injection
Stelara (ustekinumab)
Taltz (ixekizumab)
Tezspire (tezepelumab-ekko)
Tofidence (tocilizumab-bavi)
Tremfya (guselkumab)
Truxima (rituximab-abbs)
Tyenne (tocilizumab-aazg)
Tysabri (natalizumab)
Velsipity (etrasimod)
Wezlana (ustekinumab-auub)
Xeljanz (tofacitinib)
Xeljanz XR (tofacitinib extended release)
Xolair (omalizumab)
Yuflyma (adalimumab-aaty)
Yusimry (adalimumab-aqvh)
Zeposia (ozanimod)
Zymfentra (infliximab-dyyb)