Mepolizumab (Nucala)

Number: 0897

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

---

Policy

Scope of Policy

This Clinical Policy Bulletin addresses mepolizumab (Nucala) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of mepolizumab (Nucala) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of mepolizumab, call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Site of Care Utilization Management Policy applies to mepolizumab (Nucala). For information on site of service for mepolizumab, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with one of the following:

   1. Asthma: allergist/immunologist or pulmonologist
   2. Chronic rhinosinusitis with nasal polyposis: allergist/immunologist or otolaryngologist.

2. Criteria for Initial Approval

   Aetna considers mepolizumab (Nucala) medically necessary for the following indications when criteria are met:

   1. Asthma

      1. For members 6 years of age or older who have previously received a biologic drug (e.g., Dupixent, Cinqair) indicated for asthma; or
      2. For the treatment of severe asthma when all of the following criteria are met:
         
         
         1. Member is 6 years of age or older; and
         2. Member meets either of the following criteria:
            
            
            1. Member has a baseline blood eosinophil count of at least 150 cells per microliter; or
            2. Member is dependent on systemic corticosteroids; and

         3. Member has uncontrolled asthma as demonstrated by experiencing at least one of the following within the past year:

            1. Two or more asthma exacerbations requiring oral or injectable corticosteroid treatment; or
            2. One or more asthma exacerbation resulting in hospitalization or emergency medical care visit; or
            3. Poor symptom control (frequent symptoms or reliever use, activity limited by asthma, night waking due to asthma); and

         4. Member has inadequate asthma control despite current treatment with both of the following medications at optimized doses:

            1. High-dose inhaled corticosteroid; and
            2. Additional controller (i.e., long acting beta2-agonist, long acting muscarinic antagonist, leukotriene modifier, or sustained-release theophylline); and

         5. Member will continue to use maintenance asthma treatments (e.g., inhaled corticosteroid, additional controller) in combination with Nucala; 

   2. Eosinophilic granulomatosis with polyangiitis (EGPA)

      For the treatment of EGPA when all of the following criteria are met:

      1. Member is 18 years of age or older; and
      2. Member has a history or the presence of an eosinophil count of more than 1000 cells per microliter or a blood eosinophil level of greater than 10%; and
      3. Member is currently taking oral corticosteroids, unless contraindicated or not tolerated; and
      4. Member has at least two of the following disease characteristics of EGPA:
         
         
         1. Biopsy showing histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation;
         2. Neuropathy, mono or poly (motor deficit or nerve conduction abnormality);
         3. Pulmonary infiltrates, non-fixed;
         4. sino-nasal abnormality;
         5. Cardiomyopathy (established by echocardiography or magnetic resonance imaging [MRI]);
         6. Glomerulonephritis (hematuria, red cell casts, proteinuria);
         7. Alveolar hemorrhage (by bronchoalveolar lavage);
         8. Palpable purpura;
         9. Anti-neutrophil cytoplasmic anti-body (ANCA) positive (Myeloperoxidase or proteinease 3); and
            

      5. Member has had at least one relapse (i.e., requiring increase in oral corticosteroids dose, initiation/increased dose of immunosuppressive therapy or hospitalization) within 2 years prior to starting treatment with the requested medication or has a refractory disease;

   3. Hypereosinophilic syndrome (HES)

      For the treatment of HES when all of the following criteria are met:

      1. Member is 12 years of age or older; and
      2. Member does not have either of the following:
         
         
         1. HES secondary to a non-hematologic cause (e.g., drug hypersensitivity, parasitic helminth infection, [human immunodeficiency virus] HIV infection, non-hematologic malignancy); or
         2. FIP1L1-PDGFRA kinase-positive HES; and
      3. Member has a history or presence of a blood eosinophil count of at least 1000 cells per microliter; and
      4. Member will not use the requested medication as monotherapy; and
      5. Member has been on a stable dose of HES therapy (e.g., oral corticosteroid, immunosuppressive, and/or cytotoxic therapy); and
      6. Member has had HES for at least 6 months; and
      7. Member has experienced at least two HES flares within the past 12 months.

   4. Chronic rhinosinusitis with nasal polyps (CRSwNP)

      1. For adult members who have previously received a biologic drug (e.g., Dupixent, Xolair) indicated for CRSwNP; or
      2. For the treatment of CRSwNP when all of the following criteria are met:
         
         
         1. Member is 18 years of age or older; and
         2. Member has bilateral nasal polyposis and chronic symptoms of sinusitis despite intranasal corticosteroid treatment for at least 2 months unless contraindicated or not tolerated; and
         3. The member has CRSwNP despite one of the following:
            
            
            1. Prior sino-nasal surgery; or
            2. Prior treatment with systemic corticosteroids within the last two years was ineffective, unless contraindicated or not tolerated; and

         4. Member has one of the following:

            1. A bilateral nasal endoscopy, anterior rhinoscopy, or computed tomography (CT) showing polyps reaching below the lower border of the middle turbinate or beyond in each nostril; or
            2. Meltzer Clinical Score of 2 or higher in both nostrils; or
            3. A total endoscopic nasal polyp score (NPS) of at least 5 with a minimum score of 2 for each nostril; and

         5. Member has symptoms of nasal blockage, congestion, or obstruction plus one additional symptom:

            1. Rhinorrhea (anterior/posterior); or
            2. Reduction or loss of smell; or
            3. Facial pain or pressure; and

         6. Member will continue to use a daily intranasal corticosteroid while being treated with the requested medication, unless contraindicated or not tolerated. 

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

3. Continuation of Therapy

   Aetna considers continuation of mepolizumab (Nucala) therapy medically necessary for the following indications when criteria are met:

   1. Asthma

      For treatment of severe asthma when all of the following criteria are met:

      1. Member is 6 years of age or older; and
      2. Asthma control has improved on the requested medication as demonstrated by at least one of the following:
         
         
         1. A reduction in the frequency and/or severity of symptoms and exacerbations; or
         2. A reduction in the daily maintenance oral corticosteroid dose; and

      3. Member will continue to use maintenance asthma treatments (e.g., inhaled corticosteroid, additional controller) in combination with the requested medication; 

   2. Eosinophilic granulomatosis with polyangiitis (EGPA)

      For treatment of EGPA when all the following criteria are met:

      1. Member is 18 years of age or older; and
      2. Member has beneficial response to treatment with the requested medication as demonstrated by any of the following:
         
         
         1. A reduction in the frequency of relapses; or
         2. A reduction in the daily oral corticosteroid dose; or
         3. No active vasculitis;

   3. Hypereosinophilic syndrome (HES)

      For treatment of HES when all of the following criteria are met:

      1. Member is 12 years of age or older; and
      2. Member has experienced a reduction in HES flares since starting treatment with the requested medication; and
      3. Member will not use the requested medication as monotherapy;

   4. Chronic rhinosinusitis with nasal polyps (CRSwNP)

      For treatment of CRSwNP when all of the following are met: 

      1. Member is 18 years of age or older; and
      2. Member has achieved or maintained positive clinical response to with the requested medication as evidenced by improvement in signs and symptoms of CRSwNP (e.g., improvement in nasal congestion, nasal polyp size, loss of smell, anterior or posterior rhinorrhea, sinonasal inflammation, hyposmia and/or facial pressure or pain or reduction in corticosteroid use); and
      3. Member will continue to use a daily intranasal corticosteroid while being treated with the requested medication, unless contraindicated or not tolerated.  

4. Other

   For all indications: Member cannot use the requested medication concomitantly with any other biologic drug or targeted synthetic drug for the same indication.

   Note: If the member is a current smoker or vaper, they should be counseled on the harmful effects of smoking and vaping on pulmonary conditions and available smoking and vaping cessation options.

5. Related Policies

   1. CPB 0670 - Omalizumab (Xolair)
   2. CPB 0897 - Mepolizumab (Nucala)
   3. CPB 0907 - Reslizumab (Cinqair)
   4. CPB 1003 - Tezepelumab-ekko (Tezspire)

Dosage and Administration

Mepolizumab is available as Nucala and supplied as:

• 100-mg of lyophilized powder in a single‐dose vial for reconstitution
• 100 mg/mL, single-dose, prefilled autoinjector or single-dose prefilled syringe
• 40 mg/0.4 mL, single-dose prefilled syringe is only for use in children aged 6 to 11 years and must be administered by the healthcare provider or the child's caregiver.

Nucala is for subcutaneous (SC) use only. Nucala that is to be reconstituted should be administered by a healthcare professional. A person may self-administer Nucala using the prefilled autoinjector or prefilled syringe after the healthcare provider determines it appropriate.

Severe Asthma

• Adults and adolescents aged 12 years and older: the recommended dosage of Nucala is 100 mg administered once every 4 weeks by subcutaneous (SC) injection into the upper arm, thigh, or abdomen.
• Pediatrics aged 6 to 11 years: the recommended dosage of Nucala is 40 mg administered once every 4 weeks by SC injection into the upper arm, thigh, or abdomen.

Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

The recommended dosage of Nucala is 100 mg administered once every 4 weeks by subcutaneous injection into the upper arm, thigh, or abdomen.

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

The recommended dosage of Nucala is 300 mg administered once every 4 weeks by SC injection as 3 separate 100-mg injections into the upper arm, thigh, or abdomen. It is recommended that individual 100-mg injections be administered at least 5 cm (approximately 2 inches) apart.

Hypereosinophilic Syndrome (HES)

The recommended dosage of Nucala is 300 mg administered once every 4 weeks by SC injection as 3 separate 100-mg injections into the upper arm, thigh, or abdomen. It is recommended that individual 100-mg injections be administered at least 5 cm (approximately 2 inches) apart.

Source: GSK, 2022

Experimental and Investigational

Aetna considers mepolizumab experimental and investigational for treatment of the following (not an all-inclusive list):

• Acute bronchospasm
• Allergic broncho-pulmonary aspergillosis
• Bronchiectasis
• Bullous pemphigoid
• Chronic rhinosinusitis without nasal polyposis
• Eosinophilic conditions not listed in Section II (e.g., chronic obstructive pulmonary disease, esophagitis, steroid-resistant eosinophilic gastro-intestinal disease)
• Eosinophilic myocarditis
• Eosinophilic otitis media
• Food allergy
• Gleich's syndrome
• Hemolytic uremic syndrome
• Improvement of clinical outcomes in persons with coronavirus 2 (SARS-CoV-2, COVID-19)
• Inflammatory bowel disease
• Status asthmaticus
• Thrombotic microangiopath
• Thrombotic thrombocytopenia purpura
• Urticaria
• Vocal cord polyps.

---

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
31231	Nasal endoscopy, diagnostic, unilateral or bilateral (separate procedure)
70486 - 70488	Computed tomography, maxillofacial area
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96401	Chemotherapy administration, subcutaneous or intramuscular; non-hormonal anti-neoplastic
99406	Smoking and tobacco use cessation counseling visit; intermediate, greater than 3 minutes up to 10 minutes
99407	intensive, greater than 10 minutes
HCPCS codes covered if selection criteria are met:
J2182	Injection, mepolizumab, 1 mg
Other HCPCS codes related to the CPB:
Dupixent- no specific code
J0702	Injection, betamethasone acetate 3mg and betamethasone sodium phosphate 3mg
J1020	Injection, methylprednisolone acetate, 20 mg
J1030	Injection, methylprednisolone acetate, 40 mg
J1040	Injection, methylprednisolone acetate, 80 mg
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphate, 1mg
J1700	Injection, hydrocortisone acetate, up to 25 mg
J1710	Injection, hydrocortisone sodium phosphate, up to 50 mg
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg
J2357	Injection, omalizumab, 5 mg [not covered in combination with Mepolizumab (Nucala)]
J2650	Injection, prednisolone acetate, up to 1 ml
J2786	Injection, reslizumab, 1 mg [not covered in combination with Mepolizumab (Nucala)]
J2920	Injection, methylprednisolone sodium succinate, up to 40 mg
J2930	Injection, methylprednisolone sodium succinate, up to 125 mg
J7509	Methylprednisolone oral, per 4 mg
J7510	Prednisolone oral, per 5 mg
J7512	Prednisone, immediate release or delayed release, oral, 1 mg
J7622	Beclomethasone, inhalation solution, compounded product, administered through DME, unit dose form, per milligram
J7626	Budesonide, inhalation solution, FDA-approved final product, noncompounded, administered through DME, unit dose form, up to 0.5 mg
J7627	Budesonide, inhalation solution, compounded product, administered through DME, unit dose form, up to 0.5 mg
J7633	Budesonide, inhalation solution, FDA-approved final product, noncompounded, administered through DME, concentrated form, per 0.25 mg
J7634	Budesonide, inhalation solution, FDA-approved final product, noncompounded, administered through DME, concentrated form, per 0.25 mg
J7640	Formoterol, inhalation solution, compounded product, administered through DME, unit dose form, 12 mcg
J7641	Flunisolide, inhalation solution, compounded product, administered through DME, unit dose form, per mg
J8540	Dexamethasone, oral, 0.25 mg
ICD-10 codes covered if selection criteria are met :
J32.0 - J32.9	Chronic sinusitis [with nasal polyposis]
J33.0 - J33.9	Nasal polyp
J45.40	Moderate persistent asthma, uncomplicated
J45.41	Moderate persistent asthma with (acute) exacerbation
J45.50	Severe persistent asthma, uncomplicated
J45.51	Severe persistent asthma with (acute) exacerbation
J82.83	Eosinophilic asthma
M30.1	Polyarteritis with lung involvement [Churg-Strauss]
ICD-10 codes not covered for indications listed in the CPB:
B44.81	Allergic bronchopulmonary aspergillosis
D59.30, D59.31, D59.32, D59.39	Hemolytic-uremic syndrome
D72.10	Eosinophilia, unspecified
H66.90 - H66.93	Otitis media, unspecified [eosinophilic otitis media]
I40.1	Isolated myocarditis [eosinophilic myocarditis]
J38.1	Polyp of vocal cord and larynx
J47.0 - J47.9	Bronchiectasis
J98.01	Acute bronchospasm
K20.0	Eosinophilic esophagitis
K50.00 - K50.919	Crohn's disease [regional enteritis]
K51.00 - K51.919	Ulcerative colitis
K52.0 - K52.9	Other and unspecified noninfective gastroenteritis and colitis
L12.0	Bullous pemphigoid
L50.0 - L50.9	Urticaria
M04.1 - M04.9	Autoinflammatory syndromes [Gleich’'s syndrome]
T78.00xA – T78.09xS	Anaphylactic reaction due to food
U07.1	COVID-19
Z91.010 - Z91.02	Food allergies

---

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Nucala is indicated for add-on maintenance treatment of patients with severe asthma aged 6 years and older, and with an eosinophilic phenotype.

  Limitations of Use: Not for relief of acute bronchospasm or status asthmaticus

• Nucala is indicated for the treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA).
• Nucala is indicated for the treatment of adult and pediatric patients aged 12 years and older with hypereosinophilic syndrome (HES) for 6 months or longer without an identifiable non-hematologic secondary cause.
• Nucala is indicated for add-on maintenance treatment of adult patients 18 years and older with chronic rhinosinusitis with nasal polyps (CRSwNP).

 

Mepolizumab is available as Nucala (GlaxoSmithKline) which is an interleukin-5 (IL-5) antagonist monoclonal antibody (IgG1 kappa). IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Mepolizumab binds to IL-5 with a dissociation constant of 100 pM, inhibiting the bioactivity of IL-5 by blocking its binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface. Inflammation is an important component in the pathogenesis of asthma, eosinophilic granulomatosis with polyangiitis (EGPA), and hypereosinophilic syndrome (HES). Multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) are involved in inflammation. Mepolizumab, by inhibiting IL-5 signaling, reduces the production and survival of eosinophils; however, the mechanism of mepolizumab action in asthma, EGPA, and HES has not been definitively established (GSK, 2022).

Warnings and precautions that are included in the Prescribing Information for Nucala include hypersensitivity reactions (e.g., anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash), herpes zoster infections, and parasitic (helminth) infection. Herpes zoster has occurred in subjects receiving Nucala 100 mg in controlled clinical trials. The label states to consider vaccination if medically appropriate. Reductions in corticosteroid dosage, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dosage may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy. Eosinophils may be involved in the immunological response to some helminth infections. Patients with known parasitic infections were excluded from  participation in clinical trials. It is unknown if Nucala will influence a patient’s response against parasitic infections. Treat patients with pre-existing helminth infections before initiating therapy with Nucala. If patients become infected while receiving treatment with Nucala and do not respond to anti-helminth treatment, discontinue treatment with Nucala until infection resolves (GSK, 2022).

The most common adverse reactions (incidence 5% or more) include the following:

• Asthma: headache, injection site reaction, back pain, and fatigue
• CRSwNP: oropharyngeal pain and arthralgia
• EGPA and HES: most common adverse reactions are similar to asthma.

Allergic Broncho-Pulmonary Aspergillosis

Terashima and colleagues (2018) noted that allergic broncho-pulmonary aspergillosis (ABPA) is an allergic pulmonary disease comprising a complex hypersensitivity reaction to Aspergillus fumigatus.  Clinical features of ABPA are wheezing, mucoid impaction, and pulmonary infiltrates.  Oral corticosteroids and anti-fungal agents are standard therapy for ABPA, but long-term use of systemic corticosteroids often causes serious side effects.  These investigators presented the case of a 64-year old woman who was diagnosed with ABPA based on a history of bronchial asthma (from 40 years of age), elevated total IgE, the presence of serum precipitating antibodies and elevated specific IgE antibody to A. fumigatus, and pulmonary infiltration.  Bronchoscopy showed eosinophilic mucoid impaction.  Systemic corticosteroid therapy was initiated, and her symptoms disappeared.  Peripheral eosinophilia and pulmonary infiltration recurred 5 months after cessation of corticosteroid treatment.  Systemic corticosteroids were re-initiated and itraconazole was added as an anti-fungal agent.  The patient was free of corticosteroids, aside from treatment with a short course of systemic corticosteroids for asthma exacerbation, and clinically stable with itraconazole and asthma treatments for 3 years.  In 2017, she experienced significant deterioration.  Laboratory examination revealed marked eosinophilia (3,017/μL) and a chest computed tomography (CT) scan demonstrated pulmonary infiltration in the left upper lobe and mucoid impaction in both lower lobes.  The patient was treated with high-dose inhaled corticosteroid/long-acting beta-agonist, a long-acting muscarinic antagonist, a leukotriene receptor antagonist, and theophylline; spirometry revealed a FEV1 of 1.01 L.  An uncontrolled asthma state was indicated by an Asthma Control Test (ACT) score of 18.  Mepolizumab, 100 mg every 4 weeks, was initiated for the treatment of severe bronchial asthma with ABPA exacerbation.  Bronchial asthma symptoms dramatically improved, and ACT score increased to 24, by 4 weeks after mepolizumab treatment.  Peripheral eosinophil count decreased to 174/μL.  Spirometry revealed improvement of lung function (FEV1: 1.28 L).  A chest CT scan demonstrated the disappearance of pulmonary infiltration and mucoid impaction.  The authors concluded that to their knowledge, this was the 1st case of ABPA to be treated with mepolizumab.  Dramatic improvements were observed in symptoms, lung function, peripheral eosinophil counts, and chest images.  They stated that mepolizumab could serve as an alternative treatment with the potential to provide a systemic corticosteroid-sparing effect.  Moreover, these researchers stated that double-blind, placebo-controlled trials are needed to establish the safety and efficacy of this novel therapeutic intervention for ABPA.

Tsubouchi and associates (2019) noted that ABPA is a complex hypersensitivity reaction that is associated with an allergic immunological response to Aspergillus species via Th2-related inflammation.  The long-term use of a systemic corticosteroid is often needed for the treatment of ABPA.  However, systemic corticosteroid treatment imposes a risk of the onset of a non-tuberculous mycobacterial infection.  These investigators reported the case of a patient with ABPA who needed the long-term use of an oral corticosteroid because her repeated asthmatic attacks were successfully treated with mepolizumab.  The patient, a 60-year old woman, had been treated with an oral corticoid and itraconazole.  Despite the success of the initial treatment for ABPA, it was difficult to discontinue the use of the oral corticosteroid.  In addition, Mycobacterium avium was detected from her bronchial lavage.  These researchers initiated mepolizumab treatment to taper the amount of corticosteroid and control the asthma condition.  The patient's number of blood eosinophils, serum IgE level, fractional exhaled nitric oxide level, dosage of oral prednisolone, and need for inhaled budesonide/formoterol all improved, without an exacerbation of her asthma attacks.  The authors concluded that although further research regarding mepolizumab treatment is needed, they believed that mepolizumab could be considered one of the agents for treating refractory ABPA.

Cavaliere and colleagues (2019) stated that the basis of the development of mepolizumab was the acknowledgment of the crucial importance of this cytokine in promoting eosinophils production, activation, and survival, which is associated with the eosinophilic asthma phenotype, as well as with other disorders characterized by high levels of eosinophils.  All the available literature on the outcomes treatment with mepolizumab in eosinophilic disorders were reviewed, including asthma, CRS, esophagitis, granulomatosis with polyangiitis, eosinophilic COPD, hyper-eosinophilic syndrome, and ABPA.  The authors concluded that the efficacy of mepolizumab in eosinophilic asthma is clearly demonstrated by a number of controlled trials and by meta-analyses.  Among other eosinophilic disorders, controlled trials are available for CRS with nasal polyps, eosinophilic esophagitis, hyper-eosinophilic syndrome, eosinophilic granulomatosis with polyangiitis, and eosinophilic COPD.  These researchers stated that ABPA, as well as other minor eosinophilic disorders, are backed only by case reports and are waiting controlled trials to verify the therapeutic role of mepolizumab.

Asthma

According to the Centers for Disease Control and Prevention, as of 2013, more than 22 million people in the U.S. have asthma, and there are more than 400,000 asthma-related hospitalizations each year (CDC, 2013). For many persons with asthma, existing therapies can provide adequate control of their symptoms if used appropriately. However approximately 5% of patients with asthma cannot achieve symptom control with existing therapies.

A taskforce supported by the European Respiratory Society (ERS) and American Thoracic Society (ATS) has defined severe asthma as “asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy” (Chung, et al., 2014). Persons with severe asthma are also often categorized by long-term use of oral corticosteroids (OCS). In a subset of severe asthma patients, the over-production of eosinophils causes inflammation in the lungs that can affect the airways, limiting breathing and increasing the frequency of asthma attacks (FDA, 2015). Interleukin-5 (IL-5) is the main promoter of eosinophil growth, activation and survival and provides an essential signal for the movement of eosinophils from the bone marrow into the lung (GSK, 2015). Studies suggest that approximately 60% of patients with severe asthma have eosinophilic airway inflammation.

Nucala (mepolizumab is a fully humanized interleukin-5 antagonist monoclonal antibody (IgG1 kappa) produced by recombinant DNA technology in Chinese hamster ovary cells (FDA, 2015). Meprolizumab targets human interleukin (IL)‐5. IL‐5 is the major cytokine responsible for eosinophilic airway inflammation in patients with asthma; it is responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Mepolizumab selectively binds to IL‐5, blocking it from binding to the alpha chain of the IL‐5 receptor complex located on the eosinophil cell surface. This, in turn, inhibits IL‐5 signaling and reduces the production and survival of eosinophils. By inhibiting IL-5 from binding to its receptor on the surface of eosinophils, meprolizumab reduces blood eosinophil levels (GSK, 2015). Other undefined mechanisms of action may also play a role.

The U.S. Food and Drug Administration (FDA) approved mepolizumab (Nucala) as an add-on maintenance treatment of patients with severe asthma aged 6 years and older, and with an eosinophilic phenotype (FDA, 2019). Mepolizumab is not approved for the treatment of other eosinophilic conditions or relief of acute bronchospasm or status asthmaticus.

Mepolizumab is administered as a 100mg fixed dose subcutaneous injection by a health care professional every four weeks. Patients receive mepolizumab in addition to their normal medications for severe asthma, which include high-dose inhaled corticosteroids plus at least one additional asthma control medicine, and may include oral corticosteroids. Patients who were shown to benefit from treatment with mepolizumab in the Phase III clinical trials were those with blood eosinophil levels of 150 cells/mcL or greater just prior to treatment (GSK, 2015). 

The mepolizumab Phase II/III clinical development program involved nine studies and approximately 1,300 patients (GSK, 2015). Three randomized, double-blind, placebo-controlled clinical trials – DREAM (MEA112997), MENSA (MEA115588) and SIRIUS (MEA115575) have established the efficacy and safety profile of mepolizumab in patients with severe asthma on currently available therapies (GSK, 2015; Ortega, et al., 2014; Bel, et al., 2014; Pavord, et al., 2012). Mepolizumab or a placebo was administered to patients every four weeks as an add-on asthma treatment (FDA, 2015). Compared with placebo, patients with severe asthma receiving mepolizumab had fewer exacerbations requiring hospitalization and/or emergency department visits, and a longer time to the first exacerbation. In addition, patients with severe asthma receiving mepolizumab experienced greater reductions in their daily maintenance oral corticosteroid dose, while maintaining asthma control compared with patients receiving placebo. Treatment with mepolizumab did not result in a significant improvement in lung function, as measured by forced expiratory volume in 1 second (FEV1) (FDA, 2015).

In September 2019, the U.S. FDA approved Nucala (mepolizumab) for use in children as young as 6 years of age who have severe eosinophilic asthma. FDA approval is based on an open-label clinical trial (NCT #02377427) which was conducted in 36 children aged 6 to 11 years who have severe asthma. Based upon the pharmacokinetic data from this trial, a dose of 40 mg SC every 4 weeks was determined to have similar exposure to adults and adolescents administered a dose of 100 mg SC. The efficacy of Nucala in children aged 6 to 11 years is extrapolated from efficacy in adults and adolescents with support from pharmacokinetic analyses showing similar drug exposure levels for 40 mg administered subcutaneously every 4 weeks in children aged 6 to 11 years compared with adults and adolescents. The safety profile and pharmacodynamic response observed in this trial for children aged 6 to 11 years were similar to that seen in adults and adolescents. The safety and efficacy in pediatric patients aged younger than 6 years with severe asthma have not been established (GlaxoSmithKline, 2019).

Per Gobal Initiative for Asthma (GINA, 2020), in severe asthma, participants in randomized controlled trials may not be representative of patients seen in clinical practice. An example provided includes a registry study which found that over 80 percent of patients with severe asthma would have been excluded from recent studies evaluating biologic therapy.

A 2020 GINA update on the "Global Strategy for Asthma Management and Prevention" recommends, as a treatment option, an add-on anti-interleukin-5 treatment for persons with severe eosinophilic asthma that is uncontrolled on Step 4, which is low dose ICS-formoterol as maintenance and reliever therapy (adults and adolescents), or medium dose ICS-LABA maintenance plus as-needed SABA (adults, adolescents and children) and Step 5, which may include high dose ICS-LABA plus oral corticosteroids. The GINA panel recommends that patients with persistent symptoms or exacerbations despite correct inhaler technique and good adherence with Step 4 treatment, and in whom other controller options have been considered, should be referred to a specialtist with expertise in investigation and management of severe asthma. 

Asthma with Bronchiectasis

Carpagnano and colleagues (2019) stated that asthma and bronchiectasis are different conditions that frequently co-exist.  The prevalence of bronchiectasis rises considerably in subjects with severe asthma (25 % to 51 %).  In a pilot study, these researchers examined the clinical and biological efficacy of mepolizumab on severe uncontrolled asthmatics with bronchiectasis not related to other pathologies.  A total of 4 patients with severe uncontrolled asthma and diagnosed as bronchiectasis were recruited and started biological treatment with mepolizumab.  Standard investigations were performed in all 4 patients at baseline (T0), after 3 months (T1) and after 1 year (T2) of treatment.  After 1 year (T2) of therapy with mepolizumab, patients showed a significant increment of asthma control test value (12 ± 1.1 versus 24.5 ± 0.3, p < 0.01), a reduction of the number of exacerbations/year (5 ± 0.7 versus 0.75 ± 0.75, p < 0.01), an increase of pre-bronchodilator FEV1 (1,680 ± 500 versus 1,860 ± 550 ml, p < 0.01) and a reduction of eosinophils in blood (0.75 ± 0.14 versus 0.12 ± 0.02 cells/µL, p < 0.01), in the sputum (9.6 % ± 2.1 % versus 5.6 % ± 2.7 %, p < 0.05) and in nasal cytology (++ versus +).  The authors concluded that the efficacy of mepolizumab in terms of reduction of inflammation and increase of control observed in these patients suggested that targeting the IL-5 in severe eosinophilic asthma with bronchiectasis may be a good therapeutic strategy.  These researchers stated that prospective studies on routine CT scan and active treatment of bronchiectasis in subjects with severe asthma are needed to help guide management in this population.

The authors stated that the limitations of this study were mainly related to the small number of cases (n = 4) and to the absence of a comparison with a control group of patients with severe eosinophilic asthma without bronchiectasis and a group of male subjects.  The bronchiectasis documented by high-resolution chest CT scan was furthermore not classified or scored according to severity and was all included in the analysis, clinically significant or not.

Bullous Pemphigoid

Simon and colleagues (2020) reported that mepolizumab failed to affect bullous pemphigoid in a randomized, placebo-controlled, double-blind phase-II, pilot study.

Furthermore, an UpToDate review on “Management and prognosis of bullous pemphigoid” (Murrell and Ramirez-Quizon, 2019) does not mention mepolizumab as a therapeutic option.

Chronic Rhinosinusitis

Chiarella and colleagues (2017) noted that chronic rhino-sinusitis (CRS) can be divided into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps.  Some individuals with CRSwNP do not respond to standard-of-care medical and surgical management.  For these individuals, targeted biologic agents are emerging as a therapeutic alternative.

An UpToDate review on “Chronic rhinosinusitis: Management” (Hamilos, 2017) states that “Biologic agents that have been studied for the treatment of CRS with NP include omalizumab, mepolizumab, and dupilumab.  In the United States, none of these drugs are approved for the treatment of CRS, although omalizumab and mepolizumab are approved for treatment of severe asthma, so these would be available to patients with both conditions”.

In a systematic review, Tsetsos and colleagues (2018) evaluated the safety and efficacy monoclonal antibody therapies in patients suffering from CRSwNP).  These investigators carried out a literature search in Medline, Web of Science, the Cochrane Library and multiple trial registries followed by extensive hand-searching for the identification of relevant studies.  Only RCTs comparing the use of monoclonal antibodies with placebo or another therapy in adult patients with CRSwNP were included.  Anti-immunoglobin E (IgE) therapy with omalizumab was assessed in 2 studies, anti-interleukin (IL)-5 therapy in 3 studies (1 reslizumab, 2 mepolizumab) and finally anti-IL-4 and anti-IL-13 therapy in only 1.  With the exception of 1 study, biologic therapy was proved to be effective in reducing total nasal endoscopic polyp score (TPS) in treatment as compared to placebo groups.  Monoclonal antibodies brought about improvement in several other outcomes, such as opacification in computed tomography (CT), quality of life (QOL) measures, nasal airflow, olfaction and type 2 helper T-cell (Th2) associated biomarkers. Overall, the use of these agents was deemed safe and well-tolerated.  The authors concluded that this was the first systematic review showing encouraging results for the use of all 3 main categories of monoclonal antibodies in CRSwNP patients and highlighted the need for further well-designed and with larger sample sizes RCTs.

In July 2021, the U.S. FDA approved mepolizumab (Nucala; GlaxoSmithKline) as add-on maintenance treatment for adult patients 18 years and older with chronic rhinosinusitis with nasal polyps (CRSwNP) who have had inadequate response to nasal corticosteroids. Mepolizumab is the first anti-IL-5 biologic to be approved for adult patients with CRSwNP in the US. FDA approval is based on data from the pivotal SYNAPSE study (NCT03085797), a randomized, double-blind, placebo-controlled, multicenter, 52-week trial that evaluated the effect of mepolizumab vs. placebo in 407 patients with CRSwNP. Patients received mepolizumab 100 mg or placebo administered subcutaneously once every 4 weeks while continuing nasal corticosteroid therapy. Patients must have received background nasal corticosteroid for 8 weeks or more pre-screening, had recurrent and symptomatic CRSwNP, and had at least 1 surgery for the removal of nasal polyps within the previous 10 years. Patients were required to have nasal obstruction symptoms with a visual analog scale (VAS) score of more than 5 out of a maximum score of 10. Patients were also required to have an endoscopic bilateral nasal polyp score (NPS) of 5 or more out of 8 with NPS 2 or more in each nasal cavity. For NPS, polyps on each side of the nose were graded on a categorical scale (0 = no polyps, 1 = small polyps in the middle meatus not reaching below the inferior border of the middle concha, 2 = polyps reaching below the lower border of the middle turbinate, 3 = large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle concha, 4 = large polyps causing almost complete congestion/obstruction of the inferior meatus) for a total score of 0 to 8. Sinus CT scans were not performed at baseline nor during treatment to evaluate for sinus opacification. The co-primary endpoints were change from baseline to Week 52 in total endoscopic NPS (0 to 8 scale) as graded by independent blinded assessors and change from baseline in nasal obstruction VAS score (0 to 10 scale) during Weeks 49 to 52. The key secondary endpoint was the time to first nasal surgery (nasal polypectomy) up to Week 52 in this trial. Other secondary endpoints were change from baseline in loss of smell VAS score during Weeks 49 to 52, and proportion of patients requiring systemic steroids for nasal polyps up to Week 52. Patients who received mepolizumab 100 mg had a statistically significant improvement (decrease) in bilateral NPS at Week 52 and nasal obstruction VAS score from Weeks 49 to 52 at the end of the 52 week treatment period. In summary, the SYNAPSE study showed that 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 (GSK, 2021, 2022; Han et al., 2021).

Eosinophilic Esophagitis

In a systematic review and meta-analysis, Tomizawa and colleagues (2018) provided a comparative evaluation of available pharmacologic treatments for eosinophilic esophagitis (EoE).  These investigators searched randomized controlled trials (RCTs) using Medline, Embase, and Cochrane Central Register of Controlled Trials database through December 2014.  Studies were analyzed using a random-effects network meta-analysis to identify the most effective therapy.  Subgroup analysis was performed among studies that excluded gastro-esophageal reflux disease (GERD) or proton-pump inhibitor (PPI) responsive esophageal eosinophilia, and also among pediatric and adult populations.  The ranking probability for the efficacy of each treatment was analyzed.  Consistency of the included RCTs was checked by applying inconsistency and node-splitting models.  A total of 11 studies (456 patients) were identified; 6 pharmacologic treatments (budesonide suspension and viscous, fluticasone, prednisone, esomeprazole, and mepolizumab) and placebo were included in this analysis.  Meta-analysis showed superiority of budesonide viscous, budesonide suspension, and fluticasone over placebo.  Network meta-analysis demonstrated the rank order of efficacy as budesonide viscous, esomeprazole, prednisone, budesonide suspension, fluticasone, mepolizumab, and placebo.  The results were consistent from the inconsistency model analysis and node-splitting analysis.  Subgroup analysis demonstrated prednisone, budesonide suspension, and esomeprazole were the most effective when network meta-analyses were performed among studies that excluded GERD or PPI responsive esophageal eosinophilia, and among pediatric and adult populations, respectively.  The authors concluded that on the basis of this network meta-analysis, viscous budesonide was shown to be the most effective pharmacologic therapy for EoE among the reported pharmacologic treatments.

Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss) / Eosinophilic Chronic Obstructive Pulmonary Disease

Varricchi and colleagues (2016) noted that although eosinophils represent approximately 1 % of peripheral blood leukocytes, they have the propensity to leave the blood stream and migrate into inflamed tissues.  Eosinophils and their mediators are critical effectors to asthma and eosinophilic granulomatosis with polyangiitis (EGPA).  Eosinophils are equipped with a large number of cell-surface receptors and produce specific cytokines and chemokines.  Eosinophils are the major source of iIL-5 and highly express the IL-5Rα on their surface.  Clinical trials evaluating monoclonal antibodies (MAbs) to IL-5 (mepolizumab and reslizumab) and its receptor IL-5Rα (benralizumab) have been or are underway in patients with eosinophilic asthma, EGPA and chronic obstructive pulmonary disease (COPD).  Overall, targeting IL-5/IL-5Rα is associated with a marked decrease in blood and sputum eosinophilia, the number of exacerbations and improvement of some clinical parameters in adult patients with severe eosinophilic asthma.  Preliminary findings from pilot studies suggested that mepolizumab might be a glucocorticoid-sparing treatment in patients with EGPA.  A preliminary study found that benralizumab did not reduce the exacerbations and did modify lung function in patients with eosinophilic COPD.  The authors concluded that this review examined recent advances in the biology of eosinophils and how targeting the iIL-5 pathway might offer benefit to some patients with severe asthma, EGPA, and COPD.  They stated that IL-5/IL-5Rα-targeted treatments offer promises to patients with eosinophilic respiratory disorders.  These researchers noted that ongoing studies will provide information whether IL-5/IL-5Rα inhibition is safe and effective in children with eosinophilic asthma and selected patients with EGPA or COPD.

Pagnoux and Groh (2016) stated that the prevalence of EGPA (previously known as Churg-Strauss syndrome) is lower than that of other anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV's), and only a few randomized controlled trials (RCTs) have been conducted for this rare disease.  However, recent international efforts have helped delineate the best treatment approach.  Currently, EGPA conventional therapy is by default similar to that of other AAVs.  Limited, non-severe EGPA can initially be treated with glucocorticoids (GCs) alone.  Patients with life-threatening manifestations and/or major organ involvement must receive a combination of GCs and an immunosuppressant, mainly cyclophosphamide.  Remission can be achieved in greater than 85 % of patients with these 1st-line treatments, but vasculitis relapses occur in more than 1/3 of patients, and about 85 % cannot stop GC treatment because of GC-dependent asthma and/or ENT manifestations.  A few biologic agents, including rituximab or mepolizumab, are now under investigation after interesting preliminary results.  The authors concluded that treatment for EGPA still has several unmet needs.  Several biologic agents are now under investigation in RCTs, but a few others should be considered soon.  Their benefit should be demonstrated for devising more EGPA-tailored therapeutic strategies (ideally GC-free).

In a multi-center, double-blind, parallel-group, phase III clinical trial, Wechsler and associates (2017) randomly assigned participants with relapsing or refractory EGPA who had received treatment for at least 4 weeks and were taking a stable prednisolone or prednisone dose to receive 300-mg of mepolizumab or placebo, administered subcutaneously every 4 weeks, plus standard care, for 52 weeks.  The 2 primary end-points were the accrued weeks of remission over a 52-week period, according to categorical quantification, and the proportion of participants in remission at both week 36 and week 48.  Secondary end-points included the time to first relapse and the average daily glucocorticoid dose (during weeks 48 through 52).  The annualized relapse rate and safety were assessed.  A total of 136 participants underwent randomization, with 68 participants assigned to receive mepolizumab and 68 to receive placebo.  Mepolizumab treatment led to significantly more accrued weeks of remission than placebo (28 % versus 3 % of the participants had greater than or equal to 24 weeks of accrued remission; odds ratio [OR], 5.91; 95 % confidence interval [CI]: 2.68 to 13.03; p < 0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32 % versus 3 %; OR, 16.74; 95 % CI: 3.61 to 77.56; p < 0.001).  Remission did not occur in 47 % of the participants in the mepolizumab group versus 81 % of those in the placebo group.  The annualized relapse rate was 1.14 in the mepolizumab group, as compared with 2.27 in the placebo group (rate ratio, 0.50; 95 % CI: 0.36 to 0.70; p < 0.001).  A total of 44 % of the participants in the mepolizumab group, as compared with 7 % of those 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 (OR, 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.  The authors concluded that in participants with EGPA, mepolizumab resulted in significantly more weeks in remission and a higher proportion of participants in remission than did placebo, thus allowing for reduced glucocorticoid use; however, only approximately 50 % of the participants treated with mepolizumab had protocol-defined remission.

An UpToDate review on “Treatment and prognosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)” (King, 2017) states that “Preparations of anti-interleukin (IL)-5 antibodies are approved for use in severe asthma and appear to have a glucocorticoid sparing effect in patients with hypereosinophilic syndrome.  The efficacy of mepolizumab, a humanized monoclonal antibody to IL-5, has been assessed in patients with EGPA in case reports and in a randomized trial.  In a multicenter trial, 136 patients with relapsing or refractory EGPA were randomly assigned to receive mepolizumab 300 mg (3 times the currently available, FDA-approved dose of 100 mg) or placebo, subcutaneously every 4 weeks for 52 weeks.  Mepolizumab led to significantly more accrued weeks of remission (Birmingham Vasculitis Activity Score 0 and prednisone less than or equal to 4mg/day), than placebo (odds ratio [OR] 5.91; 95 % CI: 2.68 to 13.03) and a higher percentage of participants in remission at weeks 36 and 48 (OR 16.74; 95 %: CI 3.61 to 77.56).  Overall, 44 % of mepolizumab-treated subjects were able to taper prednisolone or prednisone to 4 mg/day or less, compared with 7 % of subjects taking placebo.  However, 47 %of participants in the mepolizumab group did not achieve remission … Defining the role of rituximab in EGPA that is resistant to standard therapy requires prospective, randomized trials”. 

Eosinophilic Myocarditis

Song and colleagues (2017) stated that eosinophilic myocarditis (EM) is a rare myocardial disease that results from various eosinophilic diseases, such as idiopathic hyper-eosinophilic syndrome, helminth infection, medications and vasculitis.  Patients with EM may present with different severities, ranging from mild symptoms to a life-threatening condition.  Diagnosis of EM is a challenge and requires an extensive work-up, including endomyocardial biopsy.  Therapeutic options are limited because EM is rare and there is a lack of RCTs.  These investigators reported a case of EM that presented as cardiac tamponade, which was initially treated with high-dose prednisone and immunosuppressant medications without significant improvement; mepolizumab was then applied, leading to an increased ejection fraction and stabilized cardiac function.  The authors concluded that this case-report showed, for the first time, that mepolizumab has novel effects in treating EM.  They stated that these findings suggested that mepolizumab can be used as a steroid-sparing agent for treating EM.  These preliminary findings need to be further investigated.

Eosinophilic Otitis Media

Suzaki and associates (2019) noted that eosinophilic otitis media (EOM), which is characterized by the accumulation of eosinophils in middle ear effusion and the middle ear mucosa, is a refractory type of otitis media that is often associated with asthma.  Although an early diagnosis and appropriate treatment are necessary to prevent the progression of hearing loss in patients with EOM, there are currently no well-established treatments for this condition.  These investigators treated a 60-year old man with asthma and EOM.  The patient's asthma was poorly controlled, despite the use of high-dose inhaled corticosteroids, long-acting beta-agonist treatment, and the regular use of systemic corticosteroids.  Mepolizumab was started to treat the patient's refractory asthma.  At 4 months after the initiation of mepolizumab treatment, the patient's asthma, hearing, and middle ear effusion improved.  The authors concluded that the findings of the present case suggested that mepolizumab therapy can control EOM and asthma.

In a retrospective study, Iino and colleagues (2019) examined if mepolizumab is effective in the treatment of EOM.  A total of 9 patients with EOM associated with bronchial asthma received mepolizumab as an add-on therapy for at least 6 months (mepolizumab group).  They were evaluated by EOM severity scores, symptom scores, bone conduction hearing levels, and surrogate markers before and after receiving mepolizumab; 13 EOM patients associated with bronchial asthma who did not receive the anti-IL-5 therapy were also included as controls (control group).  The severity scores of most patients in the mepolizumab group were dramatically reduced at 3 months after the initiation of this therapy and, as therapy continued, they further decreased to levels significantly lower than the baseline.  However, 2 patients with a granulation type of EOM showed minimal improvement from the therapy.  The severity scores of control patients showed no significant changes during the study period.  Significant deterioration of the bone conduction hearing levels was not observed in either group.  The number of peripheral blood eosinophils was significantly reduced, and eosinophils were scarcely observed in the middle ear effusion and middle ear mucosa after the mepolizumab therapy.  The authors concluded that mepolizumab was effective at inhibiting eosinophilic recruitment to the middle ear in patients with EOM.  However, this therapy showed minimal effect on patients with the granulation type of EOM.  They stated that this therapy may be a viable therapeutic option for refractory EOM without severe mucosal change.

Food Allergy and Inflammatory Bowel Diseases

Yanagibashi and colleagues (2017) noted that T-helper 2 cells produce a number of cytokines including IL-5, IL-4 and IL-13.  Group 2 innate lymphoid cells (ILC2s) also produce IL-5 under sterile conditions.  IL-5 is inter-digitating homo-dimeric glycoprotein and a member of the 4 α helical bundle motifs conserved among hematopoietic cytokines.  IL-5 exerts its effects on target cells via IL-5 receptor (IL-5R), composed of an IL-5R α and βc subunit.  The membrane proximal proline-rich motif of the cytoplasmic domain of both IL-5R α and βc subunits is essential for IL-5 signal transduction.  Although IL-5 was initially identified by its ability to support the growth and terminal differentiation of mouse B-cells into antibody-secreting cells, recombinant IL-5 exerts pleiotropic activities on various target cells.  For example, IL-5 is now recognized as the major maturation and differentiation factor for eosinophils in mice and humans.  Over-expression of IL-5 in mouse significantly increases eosinophil numbers and antibody levels in-vivo, while mice lacking a functional gene for IL-5 or IL-5R display developmental and functional impairments in B-cell and eosinophil lineages.  In mice, the role of the IL-5/IL-5R system in the production and secretion of immunoglobulin (Ig) M and IgA in mucosal tissues has been reported.  Although eosinophils protect against invading pathogens including virus, bacteria and helminthes, they are also involved in the pathogenesis of various diseases (e.g., food allergy, asthma, and inflammatory bowel diseases).  The recent expansion in the understanding in the context of IL-5 and IL-5-producing ILC2s in eosinophil activation and the pathogenesis of eosinophil-dependent inflammatory diseases has led to advances in therapeutic options.  A new therapy currently under investigation in clinical trials uses humanized monoclonal antibodies against IL-5 or the IL-5R.

Gleich's Syndrome

Matucci and colleagues (2018) stated that Gleich's syndrome (GS) is characterized by recurrent episodes of angioedema, increase in body weight, fever, hyper-eosinophilia, and elevated serum IgM.  The exact etiology remains unclear.  Currently, the only treatment strategy is the administration of high-dose of steroids during the acute phases.  These investigators reported the case of a 37-year old man suffering from GS with recurrent episodes of angioedema, fever, hyper-eosinophilia [6,000/mm3 (45 %)], and high eosinophil cationic protein (ECP) (greater than 200 μg/L), treated with oral steroids during the acute phase (prednisone 50 to 75 mg/day), the dose of maintenance being 25 mg/day.  No monoclonal components were identified, and genetic tests exclude mutations including Bcr/Abl, JAK2 V617F, c-KIT D816V, and FIP1L1-PDGFRA.  Using Luminex technology, these researchers observed higher serum levels of IL-5, CCL2, and CCL11 during the acute exacerbations in comparison with the clinical remission phases though CCL11 did not achieve statistical significance.  The flow-cytometric analysis identified a CD3+ CD8- lymphocyte population with high frequency of IL-4-, IL-5-, and IL-13-producing cells.  No clinical benefit was observed after therapeutic strategies with imatinib, interferon-α, cyclosporine-A, and azathioprine.  Due to high IL-5 serum levels, an intravenous treatment with mepolizumab (750 mg every 4 weeks) was started.  A reduction in the rate of exacerbation phases/year (10 ± 3 versus 2 ± 1; p < 0.005), in the eosinophils count both in percentage (28.8 ± 12.8 versus 9.8 ± 3.9; p < 0.001) and absolute value (2,737 ± 1,946 versus 782 ± 333; p < 0.001) were observed as well as the ECP serum levels (132.7 ± 62.7 versus 21 ± 14.2 μg/l; p < 0.05).  The daily dose of prednisone was significantly reduced (25 versus 7.5 mg).  The authors concluded that to the best of their knowledge, this case was the 1st report of the disease successfully treated with mepolizumab, and it could represent a novel therapeutic strategy in GS even though additional studies are needed. 

Hemolytic Uremic Syndrome / Thrombotic Microangiopathy / Tthrombotic Thrombocytopenia Purpura

Mulvey and colleagues (2018) stated that the anaphylatoxins produced by an unbridled complement cascade in atypical hemolytic uremic syndrome (aHUS) can alter the leukocyte environment in tissues and peripheral blood, causing clinically significant eosinophilia.  While the membrane attack complex and C5a anaphylatoxin can be suppressed with anti-C5 biologics, the production of C3a is still capable of driving a destructive hyper-eosinophilic syndrome in spite of anti-complement therapy.  The side-effects of glucocorticoids in treating hyper-eosinophilic syndrome limit their therapeutic index in long-term treatment and this behooves the use of alternative strategies.  While use of mepolizumab has been reported for treatment of primary hypereosinophilic syndromes off-label, its usage in the setting of complement-driven thrombotic microangiopathy has not been attempted.  These investigators reported mepolizumab's rapid resolution of a glucocorticoid-resistant hyper-eosinophilic syndrome that caused multi-organ dysfunction in a patient with a complex immune diathesis.  The patient's long standing thrombotic thrombocytopenia purpura (TTP)/aHUS disease activity, shown to have direct correlation with his eosinophil count, improved with anti-IL-5 therapy, suggesting a reciprocal enhancement between the conditions.

Furthermore, an UpToDate review on “Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)” (George and Nester, 2017) does not mention mepolizumab as a therapeutic option.

Hypereosinophilic Syndrome

Hypereosinophilic syndrome (HES) is a heterogenous group of rare blood disorders that is associated with persistent, elevated eosinophilia. Most people have less than 500 eosinophils/microliter in their blood. People with HES usually have more than 1,500 eosinophils/microliter in their blood for 6 months or more, and the cause cannot be identified. The goal of HES treatment is to reduce eosinophil levels in the blood and tissues, thereby preventing tissue damage–especially in the heart. Standard HES treatment includes glucocorticosteroid medications such as prednisone, and chemotherapeutic agents such as hydroxyurea, chlorambucil and vincristine (AAAAI, 2020). Research is evaluating new therapies for HES.

Schwarz and colleagues (2018) stated that mepolizumab was originally intended as a therapeutic agent for atopic asthma in adults, and consequently, little is known about its use in children.  Up to now, corticosteroids have formed the basis of the initial treatment of hyper-eosinophilic syndrome (HES) and are shown to be effective in most patients.  These researchers examined the effect of mepolizumab in children with HES.  They reported their experience of the effect of mepolizumab in 2 pediatric patients with HES that was not sufficiently controlled by other drugs.  In addition, the literature regarding the treatment with mepolizumab in pediatric and adult patients was reviewed for the most important studies regarding safety and efficacy.  This study showed that mepolizumab therapy in 2 pediatric patients with severe HES was a safe and efficient therapeutic approach.  No significant intolerances appeared.  Furthermore, treatment with systemic corticosteroids was discontinued, and therefore, severe side effects were avoided in these 2 cases.  The authors concluded that anti-IL-5 antibodies, which can be applied without substantial drug intolerances, are a new, safe, and effective therapeutic option for pediatric patients with HES.

The authors stated that until now, no major clinical trials in pediatric patients have been available.  One reason might be the status of a rare disease with only a very low number of patients around the world. Pediatric treatment results with mepolizumab are only summarized in anecdotal reports.  But with the anti‐IL‐5 antibody, the 1st pathogenesis‐oriented intervention is feasible.  These investigators stated that the promising results from the adult cohort and the new promising experience in pediatric patients call for a rethinking of the therapeutic strategies toward a therapy with lower side effects, which is especially important in young patients.  These preliminary findings need to be validated in well-designed studies.

Kay and co-workers (2018) stated that HES is characterized by a persistently elevated eosinophil count associated with eosinophil-related end-organ damage and thromboembolic events, in the absence of an identifiable cause.  These researchers presented a case of idiopathic HES with evidence of peripheral and tissue eosinophilia while on high-dose prednisone, associated with muscle tension dysphonia, colitis, and jackhammer esophagus.  The patient was treated with mepolizumab with resolution of symptoms including dyspnea, diarrhea and dysphonia.  The authors noted that there have been multiple studies evaluating the role of mepolizumab in obstructive lung disease.  It is suggested that decrease in airway inflammation serves as the main pathophysiology in improvement of respiratory symptoms.  Anti-interleukin 5 monoclonal antibody has never been described in resolving other systemic symptoms such as muscle tension dysphonia that can be related to eosinophilic neuropathy, or eosinophilic colitis.  The authors concluded that although treatment with mepolizumab has been shown to be effective in a variety of eosinophilic diseases, there are limited studies on long-term use of the treatment.  At this time, FDA approval has not been established for the use of mepolizumab in the treatment of HES.

Kuang and associates (2018) noted that conventional therapies for HES have variable efficacy and carry significant long-term toxicities.  Mepolizumab has a glucocorticoid (GC)-sparing effect in GC-sensitive HES, but the efficacy of mepolizumab in treatment-refractory HES patients with severe disease has not been examined to-date.  These investigators identified predictors of response to mepolizumab in subjects with severe treatment-refractory HES and compared long-term outcomes in these subjects with HES subjects treated with conventional therapies.  This was a retrospective analysis of clinical and laboratory data from 35 HES subjects treated with mepolizumab and 55 HES subjects on conventional therapy, all followed at a single-center.  Peak eosinophilia, GC sensitivity, pulmonary involvement, HES clinical subtype, and pre-treatment serum IL-5 were correlated with mepolizumab response.  Despite evidence of more severe disease at baseline, mepolizumab-treated subjects had comparable long-term clinical outcomes to HES subjects treated with conventional therapies and reported improvements in therapy-related co-morbidities.  Subjects managed with mepolizumab monotherapy had fewer disease flares than HES subjects on conventional therapies or mepolizumab-treated HES subjects requiring additional HES therapies.  The authors concluded that the findings of this study confirmed that mepolizumab was an effective and well-tolerated therapy for HES, but suggested that response was more likely in GC-responsive subjects with idiopathic or overlap forms of HES.  A primary benefit of treatment was the reduction of co-morbidity due to discontinuation or the reduction of conventional HES therapies.  Although subjects who completely discontinued GC had the most benefit, high-dose mepolizumab was a safe and effective salvage therapy for severe, treatment-refractory HES.  These findings need to be further investigated.

In September 2020, the U.S. Food and Drug Administration (FDA) announced the approval of Nucala (mepolizumab) for the treatment of adult and pediatric patients aged 12 years and older with hypereosinophilic syndrome (HES) for 6 months or longer without another identifiable non-hematologic secondary cause of the disease. FDA approval was based on outcomes from a randomized, double-blind, placebo-controlled, multicenter, 32-week phase 3 trial (NCT #02836496) that compared the proportion of subjects who experienced a HES flare during the 32-week treatment period.

The study (NCT #02836496) evaluated a total of 108 adult and adolescent patients aged 12 years and older with HES for at least 6 months. 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 included in the trial had to have experienced at least 2 HES flares within the past 12 months and had a blood eosinophil count of 1,000 cells/mcL 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 were randomized to receive either 300 mg of mepolizumab or placebo subcutaneously once every 4 weeks while continuing their stable HES therapy. Patients must have been on stable HES therapy for the 4 weeks prior to randomization. HES therapy could include chronic or episodic oral corticosteroids (OCS), immunosuppressive, or cytotoxic therapy. 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. The outcomes of the trial found fewer patients in the Nucala treatment group (28%) had HES flares compared to patients in the placebo group (56%), with a 50% relative reduction. In addition, the time to the first HES flare was later, on average, for patients treated with Nucala vs. placebo. The most common side effects of Nucala in patients with HES include: upper respiratory tract infection and pain in extremities (such as the hands, legs and feet) (FDA, 2020; GlaxoSmithKline, 2020).

Improvement of Clinical Outcomes in Patients with COVID-19

Dhillon et al (2022) noted that patients with multiple co-morbidities who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have a higher risk of mortality; however, treatment with mepolizumab may be a key factor in counteracting the risk of these co-morbidities.  These investigators presented the case of a patient who had an uneventful recovery from coronavirus disease 2019 (COVID-19), despite having 5 independent risk factors for severe disease and increased mortality.  This case entailed a 75-year-old man with a long-standing history of asthma, chronic bronchitis, coronary artery disease (CAD), and hypertension presented to the Emergency Department in November 2020 with a 4-day history of fever, chills, shortness of breath, cough, and fatigue.  Six months before this presentation, the patient was hospitalized for severe chronic bronchitis and acute exacerbation of asthma.  His medications included mepolizumab, aclidinium, ramipril, diltiazem, aspirin, albuterol sulfate, and micronized budesonide/micronized formoterol fumarate dihydrate.  Physical examination was unremarkable, except for cardio-pulmonary distress.  Laboratory tests showed leucocytosis.  His chest X-ray revealed infiltrates and interstitial edema in the lower lung fields.  A PCR test for SARS-CoV-2 was positive.  COVID-19 pneumonia was diagnosed, and the patient was admitted to the hospital, where he was treated with acetaminophen, amoxicillin, dexamethasone, and supplemental oxygen.  The patient remained stable and was discharged from the hospital the following day.  He was free of all symptoms after 21 days.  The authors concluded that this case of a 75-year-old man who presented with mild COVID-19 supported the findings from other reports of improvement in clinical outcomes for some patients with asthma who received treatment with mepolizumab.  These investigators stated that the beneficial role of dexamethasone in the recovery of this patient needs to be considered.  These researchers stated that the association between lung eosinophils and SARS-CoV-2, especially regarding the role of IL-5 antagonists (e.g., mepolizumab) in providing therapeutic benefits, needs to be further investigated.

Steroid-Resistant Eosinophilic Gastrointestinal Disease

Ito et al (2023) presented the case of a treatment-resistant eosinophilic gastro-intestinal disease (EGID).  The patient, a 46-year-old man, presented with a fever, persistent abdominal pain, and an elevated peripheral eosinophil count.  Eosinophil infiltration of the intestinal mucosa was also observed, and EGID was diagnosed.  Corticosteroid therapy was initiated; however, no improvement was observed.  After mepolizumab was given, the patient's disease was controlled.  To-date, the indications for mepolizumab are limited to bronchial asthma and paraneoplastic eosinophilic polyangiitis; however, the experience reported in this case-report suggested its usefulness in the treatment of EGID.  These preliminary findings need to be validated in well-designed studies.

Urticaria

Kocaturk and Zuberbier (2018) noted that symptomatic management of chronic spontaneous urticaria (CSU) basically depends on 2nd-generation H1 anti-histamines and omalizumab.  Omalizumab is a game changer in the management, but still there is a need for new targets and new biologics targeting new pathways in the treatment that would provide long-lasting remission, which will be given orally and which will be cheaper.  This review focused on new biologics that are underway of production or are already under use for different disorders but could be beneficial for the treatment of chronic urticaria.  In this review, the treatment targets are classified according to the cells which are involved in the pathogenesis of CSU.  Those are mast cells/basophils, B cells, T cells and eosinophils.  The treatments that are under clinical trials for CSU are anti-IgE treatments such as ligelizumab, molecules targeting intra-cellular signaling pathways such as spleen tyrosine kinase inhibitors, surface inhibitory molecules such as siglec-8, anti-IL-1s such as canakinumab, Bruton kinase (BTK) inhibitors such as GDC-0853 and anti-IL-5s such as benralizumab and mepolizumab.  The authors concluded that ongoing clinical trials on new targets of treatment hold new hopes not only for a better care of the disease but also a better understanding of the pathomechanisms lying underneath.

Vaping Precautions

Vapes, vaporizers, vape pens, hookah pens, electronic cigarettes (e-cigarettes or e-cigs), and e-pipes are some of the many terms used to describe electronic nicotine delivery systems (ENDS). ENDS are noncombustible tobacco products. These products use an “e-liquid” that may contain nicotine, as well as varying compositions of flavorings, propylene glycol, vegetable glycerin, and other ingredients. The liquid is heated to create an aerosol that the user inhales.

Vaping products may contain nicotine and/or THC, Vitamin E acetate, along with other ingredients. The FDA and CDC have found that e-cigarette, or vaping, product use-associated lung injury (EVALI) have mainly been linked with THC and/or Vitamin E acetate ingredients. However, there are many different substances and product sources that are being investigated, and there may be more than one cause of EVALI. The FDA is continuing to analyze patient samples for the presence of a broad range of chemicals, including nicotine, THC and other cannabinoids along with cutting agents/diluents and other additives, pesticides, opioids, poisons, and toxins (CDC, 2020; FDA, 2020).

The FDA and CDC recommend that people not use THC-containing e-cigarette, or vaping, products, particularly from informal sources like friends, or family, or in-person or online dealers. E-cigarette, or vaping, products (nicotine- or THC-containing) should never be used by youths, young adults, or women who are pregnant. The CDC encourages healthcare providers to reinforce the importance of abstinence from e-cigarette, or vaping, product use during the post-discharge follow-up for patients s/p EVALI, in addition to connecting patients to needed social, mental health, and substance use disorder resources (CDC, 2020; FDA, 2020).

Vocal Cord Polyps

Karim et al (2022) stated that IL-5 plays an important role in development, recruitment, and survival of eosinophils; thus, causing debilitating signs and symptoms associated with severe eosinophilic asthma. Mepolizumab is a MAb against IL-5 that selectively inhibits eosinophilic inflammation and reduces the amounts of eosinophils.  This reduction is observed in both sputum and blood, resulting in a reduction in exacerbations and in time the need for using systemic steroids.  The role of mepolizumab and its effect is still not fully known as there are less real-life studies available.  These investigators presented a case of severe eosinophilic asthma with vocal polyp managed by mepolizumab.  The authors concluded that the effect of mepolizumab on severe eosinophilic asthma and associated with nasal polyposis has been well-documented; however, its effect on vocal cord polyps is still unclear and needs further investigation.

---

References