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  • IMMUNOMODULATORS - ASTHMA
    • NOTE: This page is intended to be a quick reference for properties of immunomodulators used in asthma. It is NOT a comprehensive review of this medication. Other drug interactions, side effects, precautions, and contraindications may exist for each drug.

Immunomodulators Immunomodulator studies



Drug Dosage form Dosage Generic/Price Mechanism/FDA-approved
indications
Side Effects
P = % of patients on placebo
who experienced side effect
Drug Interactions Precautions/
Contraindications
Mepolizumab

(Nucala®)
Single-dose vial
  • 100 mg
  • Must be reconstituted
  • Store below 25°C (77°F). Do not freeze.
Severe asthma (≥ 12 years old)
  • Dosing: 100 mg subcutaneously every 4 weeks
  • Give in upper arm, thigh, or abdomen
  • Nucala should be administered by a healthcare professional
NO/$$$$ Mechanism
  • IL-5 is the major cytokine responsible for the growth, differentiation, recruitment, activation, and survival of eosinophils
  • Mepolizumab is a humanized IL-5 antagonist monoclonal antibody
  • Mepolizumab binds IL-5 and prevents it from binding to its receptor on the surface of eosinophils. This decreases the inflammatory response seen in asthma.

FDA-approved indications
  • Asthma - add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype
NOTE: Only side effects that occurred at an incidence of ≥ 3% overall, and ≥ 1% more than placebo are listed

  • Headache - 19%, P - 18%
  • Injection site reactions - 8% of patients; reactions included pain, erythema, swelling, itching, and burning sensation
  • Back pain - 5%, P - 4%
  • Fatigue - 5%, P - 4%
  • Influenza - 3%, P - 2%
  • Urinary tract infection - 3%, P - 2%
  • Upper abdominal pain - 3%, P - 2%
  • Itching - 3%, P - 2%
  • Eczema - 3%, P - < 1%
  • Muscle spasms - 3%, P - < 1%
  • No clinically relevant drug interactions have been documented
  • Hypersensitivity reactions - hypersensitivity reactions including angioedema, bronchospasm, hypotension, urticaria, and rash have occurred. Reactions were typically seen within hours of administration, but may be delayed by days.
  • Acute asthma exacerbation - do not use to treat acute asthma exacerbations
  • Herpes zoster - rare cases of herpes zoster have occurred in patients receiving Nucala
  • Parasitic (Helminth) infections - mepolizumab may suppress the immune response to helminth infections. Treat known helminth infections before starting mepolizumab. If infection occurs during treatment and the patient does not respond to anti-helminth therapy, discontinue mepolizumab.
  • Anti-mepolizumab antibodies - in trials, 6% of patients developed anti-mepolizumab antibodies. It's unclear if antibody development is associated with reduced efficacy and/or an increased risk for hypersensitivity reactions.
  • Liver disease - has not been studied. Unlikely to affect elimination.
  • Kidney disease - has not been studied. Mepolizumab is not cleared renally.

Drug Dosage form Dosage Generic/Price Mechanism/FDA-approved
indication
Side Effects
P = % of patients on placebo
who experienced side effect
Drug Interactions Precautions/
Contraindications
Omalizumab

(Xolair®)
Single-use vial
  • 150 mg
  • Must be reconstituted
  • Store vials in refrigerator
Asthma (6 years of age and older)
  • Omalizumab is given via subcutaneous injection every 2 - 4 weeks
  • Omalizumab dosing is based on pre-treatment IgE levels and body weight
  • Doses are adjusted for significant changes in body weight, but not IgE levels
  • A dosing table is available in the omalizumab PI under section 2 - Omalizumab dosing tables
  • Omalizumab should be administered in a healthcare setting

Chronic idiopathic urticaria (12 years of age and older)
  • Omalizumab 150 - 300 mg sub-Q every 4 weeks
  • Dosing in chronic idiopathic urticaria is not dependent on serum IgE or body weight
  • The appropriate duration of therapy has not been determined
NO/$$$$ Mechanism
  • Omalizumab is a recombinant DNA-derived humanized IgG1κ monoclonal antibody that selectively binds to human immunoglobulin E (IgE)
  • Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor (FcεRI) on the surface of mast cells and basophils
  • Reduction in surface-bound IgE on FcεRI-bearing cells limits the degree of release of mediators of the allergic response

FDA-approved indications
  • Asthma - Omalizumab is indicated for patients 6 years of age and older with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids
  • Chronic idiopathic urticaria - in adults and adolescents (≥ 12 years) who remain symptomatic despite H₁ antihistamine treatment
NOTE: Only side effects that occurred at an incidence of ≥ 3% overall, and more than placebo are listed. Data below is from asthma studies.

  • Injection site reactions - up to 45% of patients; reactions include bruising, redness, warmth, burning, stinging, itching, hive formation, pain, indurations, mass, and inflammation
  • Joint ache - 8%, P - 6%
  • Pain (general) - 7%, P - 5%
  • Leg pain - 4%, P - 2%
  • Fatigue - 3%, P - 2%
  • Dizziness - 3%, P - 2%
  • No clinically relevant drug interactions have been documented
  • Anaphylaxis - anaphylactic reactions have occurred in up to 0.2% of patients. Reactions may occur at any time during treatment. Patients with a history of anaphylaxis to foods, medications, and other causes may be at increased risk. Omalizumab should be administered in a healthcare setting.
  • Acute asthma exacerbation - do not use to treat acute asthma exacerbations
  • Cancers - malignant neoplasms were observed in 20 of 4127 (0.5%) omalizumab-treated patients compared with 5 of 2236 (0.2%) control patients in clinical studies. Cancers were of various types. A 5-year observational study found no increased risk of cancer (see FDA communication).
  • Syndrome of fever, joint pain, lymphadenopathy, and rash - has been seen in some patients 1 - 5 days after injection
  • Parasitic (Helminth) infections - omalizumab may increase the risk of geohelminthic infections (roundworm, hookworm, whipworm, threadworm) in patients at high-risk for these infections
  • Increased vascular events - omalizumab may increase the risk of cardio- and cerebrovascular events (see FDA communication). The increased risk, if any, is small. Causality has not been proven.
  • Serum IgE levels - serum IgE levels increase with omalizumab therapy and may remain elevated up to one year after stopping
  • Anti-omalizumab antibodies - anti-omalizumab antibodies were detected in approximately 1/1723 (< 0.1%) of patients. It's unclear if antibody development is associated with decreased efficacy and/or an increased risk of hypersensitivity reactions.
  • Liver disease - has not been studied
  • Kidney disease - has not been studied

Drug Dosage form Dosage Generic/Price Mechanism/FDA-approved
indication
Side Effects
P = % of patients on placebo
who experienced side effect
Drug Interactions Precautions/
Contraindications
Reslizumab

(Cinqair®)
Single-use vial
  • 100 mg/10 ml (10 mg/ml)
  • Store vials in refrigerator
Asthma (18 years of age and older)
  • 3 mg/kg once every 4 weeks
  • Given as IV infusion over 20 - 50 minutes
NO/$$$$ Mechanism
  • Reslizumab is an interleukin-5 (IL-5) antagonist (IgG4, kappa)
  • IL-5 is the major cytokine responsible for the growth, differentiation, recruitment, activation, and survival of eosinophils. Eosinophils play an important role in the inflammatory component of asthma.
  • Reslizumab binds to IL-5 and blocks its binding to IL-5 receptors on eosinophils
  • By inhibiting IL-5 signaling, reslizumab reduces the production and survival of eosinophils

FDA-approved indications
  • Asthma - reslizumab is indicated for the add-on maintenance treatment of patients with severe asthma aged 18 years and older with an eosinophilic phenotype. In trials, eosinophilic phenotype was defined as blood eosinophil level ≥ 400 cells/μl.
NOTE: only side effects that occurred at a greater incidence than placebo are listed

  • CPK elevations - 20%, P - 18%
  • Myalgia - 1%, P - 0.5%
  • Malignancy - 0.6%, P - 0.3%
  • Anaphylaxis - 0.3%, P - 0%
  • No clinically relevant drug interactions have been documented
  • Anaphylaxis - in trials, anaphylactic reactions occurred in 0.3% of reslizumab-treated patients. Reactions occurred during or within 20 minutes of an infusion and were reported as early as the second dose. Reslizumab should be administered in a healthcare setting.
  • Acute asthma exacerbation - do not use to treat acute asthma exacerbations
  • CPK elevations - in trials, transient CPK elevations occurred in 20% of reslizumab-treated patients compared to 18% of placebo-treated patients. Elevations > 10 X the upper limit of normal occurred in 0.8% of reslizumab-treated patients and 0.4% of placebo-treated patients.
  • Malignancies - malignancies were observed in 0.6% (6/1028) of reslizumab-treated patients compared with 0.3% (2/730) of placebo-treated patients. Malignancies were diverse in nature and a majority were diagnosed within 6 months of starting reslizumab.
  • Reduction of corticosteroids - no studies have been conducted to assess the reduction of corticosteroids after initiating reslizumab therapy. Use caution when reducing oral or inhaled steroids after starting reslizumab.
  • Parasitic (Helminth) infections - reslizumab may increase the risk of geohelminthic infections (roundworm, hookworm, whipworm, threadworm). Known helminth infections should be treated before initiating therapy. If patients become infected while on reslizumab and they do not respond to anti-helminth therapy, reslizumab should be stopped.
  • Anti-reslizumab antibodies - in trials, anti-reslizumab antibodies developed in up to 5.4% of reslizumab-treated patients. It's unknown if antibody development is associated with reduced efficacy and/or hypersensitivity reactions.
  • Liver disease - has not been studied
  • Kidney disease - has not been studied




Study Criteria Intervention Outcomes Results
Reslizumab
vs
Placebo
in uncontrolled asthma with elevated
eosinophil count

Lancet Respir 2015

PubMed abstract


Main inclusion criteria:
  • Age 12 - 75 years
  • Asthma inadequately controlled by medium-to-high doses of inhaled corticosteroid
  • Blood eosinophils ≥ 400 cells/μL
  • ≥ 1 exacerbation requiring systemic steroids in the previous year

Baseline characteristics:
  • Average age 47 years
  • Average duration of asthma - 19 years
  • Average % predicted FEV₁ - 64%
  • Average eosinophil count - 660 cells/μL
  • Average # of exacerbations in previous year - 1.99
Group 1 (245 patients) - Reslizumab 3 mg/kg IV every 4 weeks for 52 weeks

Group 2 (244 patients) - Placebo every 4 weeks for 52 weeks

All patients had to be on inhaled corticosteroids. Other controller meds were allowed.
Primary outcome - frequency of asthma exacerbations for each patient during the 52-week treatment period.

Asthma exacerbation was defined as any 1 of the following:
  • Use of systemic steroids
  • ≥ 2-fold increase in the use of ICS for ≥ 3 days
  • Unscheduled emergency visit to provider for worsening asthma
Primary outcome
  • Group 1 - 0.90 exacerbations/year
  • Group 2 - 1.80 exacerbations/year
  • RR 0.50, 95%CI (0.37 - 0.67), significant

Exacerbations requiring systemic steroids
  • Group 1 - 0.72 exacerbations/year
  • Group 2 - 1.60 exacerbations/year
  • RR 0.45, 95%CI (0.33 - 0.62), significant

Hospitalization and/or ER visit
  • Group 1 - 0.14 visits/year
  • Group 2 - 0.21 visits/year
  • RR 0.66, 95%CI (0.32 - 1.36), nonsignificant

Adverse events
  • Rates of adverse events were similar between the 2 groups

Study Criteria Intervention Outcomes Results
Mepolizumab
vs
Placebo
in
eosinophilic asthma

MENSA study

NEJM 2014

PubMed abstract


Main inclusion criteria:
  • Age 12 - 82 years
  • Pulmonary function tests consistent with asthma
  • Two asthma exacerbations in the previous year that required steroids
  • Receiving maximum inhaled corticosteroid
  • At least 3 months of treatment with an additional controller
  • Eosinophil count of at least 150 cells/mm³ in the peripheral blood at screening or at least 300 cells/mm³ at some time during the previous year

Baseline characteristics:
  • Average age 50 years
  • Former smoker - 27%
  • Average duration of asthma - 20 years
  • Using maintenance oral steroids - 25%
  • Average % predicted FEV₁ - 60%
  • Average # of severe exacerbations in previous year - 3.6
Group 1 (194 patients) - Mepolizumab 100 mg subcutaneously every 4 weeks

Group 2 (191 patients) - Mepolizumab 75 mg intravenously every 4 weeks

Group 3 (191 patients) - Placebo injections and infusions

Patients continued their other asthma medications throughout the study
Primary outcome - annualized frequency of clinically significant exacerbations, which were defined as worsening of asthma such that the treating physician elected to administer systemic glucocorticoids for at least 3 days or the patient visited an emergency department or was hospitalized. The treatment phase of the study lasted 32 weeks.
Secondary outcome - change in FEV₁ from baseline at 32 weeks
Primary outcome
  • Group 1 - 0.83 exacerbations/year
  • Group 2 - 0.93 exacerbations/year
  • Group 3 - 1.74 exacerbations/year
  • Group 1 and 2 were both significantly better than placebo (p<0.001)

Secondary outcome - change in FEV₁ before bronchodilation
  • Group 1 - increase of 183 ml
  • Group 2 - increase of 186 ml
  • Group 3 - increase of 86 ml
  • Group 1 and 2 were both significantly better than placebo (p=0.03 and p=0.02, respectively)

Adverse events
  • Rates of adverse events were similar between the 3 groups

Study Criteria Intervention Primary outcome Results
Omalizumab
vs
Placebo
in
poorly-controlled
allergic asthma


Annals of IM 2011


PubMed abstract


Inclusion criteria:
  • Persistent allergic asthma
  • Uncontrolled with ICS and LABA (and any other meds)
  • Positive allergen testing

Exclusion criteria:
  • Systemic steroids within last 30 days
  • Smoking history of ≥ 10 pack-years

Baseline characteristics
  • Average age 44 years
  • Average duration of asthma - 23 years
  • Average % predicted FEV₁ - 65%
Group 1 (427 patients) - Omalizumab every 2-4 weeks. Dosing based on IgE levels and weight as recommended in the PI

Group 2 (421 patients) - Placebo injection

Other meds were not allowed to be adjusted during the trial
Primary outcome - protocol-defined asthma exacerbations during 48 weeks of treatment. A protocol-defined asthma exacerbation was worsening asthma symptoms requiring treatment with systemic corticosteroids for 3 or more days; for patients receiving long-term oral steroids, an exacerbation was a 20 mg or more increase in the average daily dose of oral prednisone (or a comparable dose of another systemic corticosteroid). Primary outcome
  • Group 1 - 0.66 per patient
  • Group 2 - 0.88 per patient
  • Incidence rate ratio = 0.75 (CI 0.61 - 0.92), p-value=0.006

Adverse events
  • Adverse events were similar between the two groups

Study Criteria Intervention Outcomes Results
Omalizumab
vs
Placebo
in inner-city children with asthma


NEJM 2011

PubMed abstract


Inclusion criteria:
  • Inner-city children (6 - 20 years old)
  • Persistent allergic asthma
  • Positive allergen skin testing
  • Controller medications were not required

Baseline characteristics
  • Average age 11 years
  • Average duration of asthma - 7 years
  • Average % predicted FEV₁ - 92%
Group 1 (208 patients) - Omalizumab every 2-4 weeks for 60 weeks. Dosing based on IgE levels and weight.

Group 2 (211 patients) - Placebo injection

Other meds were added and adjusted during the study to control asthma. Adjustments were based on a specified protocol.
Primary outcome - the primary outcome evaluated at each 4-week visit for an injection was the number of days with symptoms during the previous 2 weeks. The number of days with symptoms was calculated as the largest of the following variables during the previous 2 weeks: number of days with wheezing, chest tightness, or cough; number of nights of sleep disturbance; and number of days when activities were affected. The treatment phase of the study lasted 60 weeks.
Secondary outcomes
  • Exacerbations (defined as a need for systemic glucocorticoids, hospitalization, or both)
  • The dose of inhaled glucocorticoids needed to maintain asthma control
Primary outcome
  • Group 1 - 1.48 days
  • Group 2 - 1.96 days
  • Difference = 0.48 days (CI 0.77 - 0.20), p<0.001

Secondary outcomes
  • Hospitalizations - Group 1 - 1.5%, Group 2 - 6.3% (p=0.02)
  • Exacerbation - Group 1 - 30%, Group 2 - 49% (p<0.001)
  • Average dose of inhaled steroid (budesonide equivalent) -
    Group 1 - 663 mcg/day, Group 2 - 771 mcg/day (p<0.001)

Adverse events
  • Rates of adverse events were similar between groups
  • One or more serious adverse events were reported in 13.7% of participants in the placebo group and 6.3% of those in the omalizumab group (P = 0.02). The majority of serious adverse events were asthma-related hospitalizations.



  • PRICING

    • $ = 0 - $50
    • $$ = $51 - $100
    • $$$ = $101 - $150
    • $$$$ = > $151

    • Pricing based on one month of therapy at standard dosing in an adult
    • Pricing based on survey of GoodRX.com® [accessed 3/2015]
    • Pricing may vary by region and availability



  • References:
  • 1 - Manufacturer's Package Insert