ASTHMA IMMUNOMODULATORS









Benralizumab (Fasenra®)

Dosage forms

Prefilled syringe
  • 30 mg
  • Syringe should be refrigerated

Dosing

Severe asthma with eosinophilic phenotype (≥ 12 years old)
  • Dosing: 30 mg subcutaneously once every 4 weeks for the first 3 doses, and then once every 8 weeks thereafter
  • Give in upper arm, thigh, or abdomen
  • Fasenra should be administered by a healthcare professional
  • Prior to administration, warm Fasenra by leaving carton at room temperature for about 30 minutes. Administer Fasenra within 24 hours or discard into sharps container.

Efficacy


Generic / Price

- NO/$$$$

Mechanism of action

  • IL-5 is the major cytokine responsible for the growth, differentiation, recruitment, activation, and survival of eosinophils
  • Benralizumab is a humanized IL-5 monoclonal antibody that directly binds to the alpha subunit of the human interleukin-5 receptor (IL-5Rα) that is expressed on the surface of eosinophils and basophils.
  • Benralizumab facilitates binding of immune effector cells, such as natural killer (NK) cells, leading to apoptosis of eosinophils and basophils through antibody-dependent cell-mediated cytotoxicity
  • Reduction in eosinophils is thought to decrease inflammation and improve asthma

FDA-approved indications

  • Asthma - add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. In trials eosinophilic phenotype was typically defined as blood eosinophils ≥ 300 cells/mcL

Side effects


Side effect Benralizumab Placebo
Headache 8% 6%
Pyrexia 3% 2%
Pharyngitis 5% 3%


Drug interactions

  • No clinically relevant drug interactions have been identified

Contraindications / Precautions

  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis, angioedema, urticaria, and rash have been reported. Reactions typically occur within hours of administration, but may be delayed by days.
  • Acute asthma exacerbation - do not use to treat acute asthma exacerbations
  • Parasitic (Helminth) infections - benralizumab may suppress the immune response to helminth infections. Treat known helminth infections before starting benralizumab. If infection occurs during treatment and the patient does not respond to anti-helminth therapy, discontinue benralizumab.
  • Anti-benralizumab antibodies - in trials, 13% of patients developed anti-benralizumab antibodies during 48 - 56 weeks of treatment. Anti-benralizumab antibodies were associated with increased clearance of benralizumab and increased blood eosinophil levels. No evidence of an association of anti-benralizumab antibodies with efficacy or safety was observed.
  • Liver disease - has not been studied. Unlikely to affect elimination.
  • Kidney disease - has not been studied. Benralizumab is not cleared renally.

Mepolizumab (Nucala®)

Dosage forms

Single-dose vial
  • 100 mg
  • Must be reconstituted
  • Store below 25°C (77°F). Do not freeze.
Single-dose autoinjector
  • 100 mg/ml
  • Keep refrigerated
Single-dose prefilled syringe
  • 100 mg/ml
  • Keep refrigerated

Dosing

Severe asthma with eosinophilic phenotype (6 - 11 years old)
  • Dosing: 40 mg subcutaneously every 4 weeks
  • Give in upper arm, thigh, or abdomen
Severe asthma with eosinophilic phenotype (≥ 12 years old)
  • Dosing: 100 mg subcutaneously every 4 weeks
  • Give in upper arm, thigh, or abdomen
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
  • Dosing: 300 mg subcutaneously every 4 weeks
  • Give 3 separate 100 mg injections in upper arm, thigh, or abdomen
  • Administer at least 5 cm (approximately 2 inches) apart if more than 1 injection is administered at the same site

Efficacy


Generic / Price

- NO/$$$$

Mechanism of action

  • 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 6 years and older, and with an eosinophilic phenotype (typically defined in trials as blood eosinophils ≥ 150 cells/mcL within 6 weeks of dosing or ≥ 300 cells/mcL within 12 months of enrollment)
  • Eosinophilic granulomatosis with polyangiitis in adults - formerly known as Churg-Strauss syndrome

Side effects


Side effect Mepolizumab Placebo
Headache 19% 18%
Back pain 5% 4%
Fatigue 5% 4%
Influenza 3% 2%
Urinary tract infection 3% 2%
Upper abdominal pain 3% 2%
Itching 3% 2%
Eczema 3% < 1%
Muscle spasms 3% < 1%
Other
  • Injection site reactions - 8% of patients; reactions included pain, erythema, swelling, itching, and burning sensation


Drug interactions

  • No clinically relevant drug interactions have been documented

Contraindications / Precautions

  • 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.

Reslizumab (Cinqair®)

Dosage forms

Single-use vial
  • 100 mg/10 ml (10 mg/ml)
  • Store vials in refrigerator

Dosing

Severe asthma with eosinophilic phenotype (≥ 18 years old)
  • 3 mg/kg once every 4 weeks
  • Given as IV infusion over 20 - 50 minutes

Efficacy


Generic / Price

- NO/$$$$

Mechanism of action

  • 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.

Side effects


Side effect Reslizumab Placebo
CPK elevations 20% 18%
Myalgia 1% 0.5%
Malignancy 0.6% 0.3%
Anaphylaxis 0.3% 0%


Drug interactions

  • No clinically relevant drug interactions have been documented

Contraindications / Precautions

  • 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



Omalizumab (Xolair®)

Dosage forms

Single-use vial
  • 150 mg
  • Must be reconstituted
  • Store vials in refrigerator

Dosing

Asthma (≥ 6 years old)
  • 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 old)
  • Omalizumab 150 - 300 mg subcutaneous 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

Efficacy


Generic / Price

- NO/$$$$

Mechanism of action

  • 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

Side effects


Side effect Omalizumab Placebo
Joint ache 8% 6%
Pain (general) 7% 5%
Leg pain 4% 2%
Fatigue 3% 2%
Dizziness 3% 2%
Other
  • Injection site reactions - up to 45% of patients; reactions include bruising, redness, warmth, burning, stinging, itching, hive formation, pain, indurations, mass, and inflammation


Drug interactions

  • No clinically relevant drug interactions have been documented

Contraindications / Precautions

  • 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.
  • Pregnancy - A registry study of omalizumab exposure during pregnancy showed no increase in the rate of major birth defects or miscarriage. Reproductive animal studies have also shown no adverse effects. There are no controlled trials that prove the safety of omalizumab in pregnancy, but based on the available data, omalizumab appears to be safe.
  • Liver disease - has not been studied
  • Kidney disease - has not been studied



Dupilumab (Dupixent®)

Dosage forms

Single-dose prefilled syringe
  • 200 mg
  • 300 mg

Dosing

Asthma (≥ 12 years old)
  • Initial dose of 400 mg (two 200 mg injections) followed by 200 mg given every other week or an initial dose of 600 mg (two 300 mg injections) followed by 300 mg given every other week
  • For patients with oral corticosteroid-dependent asthma or with moderate-to-severe atopic dermatitis, use the 300 mg dosing
  • If a dose is missed, instruct the patient to administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule.
  • Administer subcutaneous injection into the thigh or abdomen, except for the 2 inches (5 cm) around the navel. The upper arm can also be used if a caregiver administers the injection.
  • For initial dose, give injections at different sites
Atopic dermatitis (12 - 17 years old)
  • Body weight < 132 lbs (60 kg): Initial dose of 400 mg (two 200 mg injections), followed by 200 mg given every other week
  • Body weight ≥ 132 lbs (60 kg): Initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week
  • If a dose is missed, instruct the patient to administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule.
  • Administer subcutaneous injection into the thigh or abdomen, except for the 2 inches (5 cm) around the navel. The upper arm can also be used if a caregiver administers the injection.
  • For initial dose, give injections at different sites
Atopic dermatitis (≥ 18 years old)
  • Initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week
  • If a dose is missed, instruct the patient to administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule.
  • Administer subcutaneous injection into the thigh or abdomen, except for the 2 inches (5 cm) around the navel. The upper arm can also be used if a caregiver administers the injection.
  • For initial dose, give injections at different sites
Chronic rhinosinusitis with nasal polyposis (adults)
  • Dosing: 300 mg every other week
  • If a dose is missed, instruct the patient to administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule.
  • Administer subcutaneous injection into the thigh or abdomen, except for the 2 inches (5 cm) around the navel. The upper arm can also be used if a caregiver administers the injection.

Efficacy


Other

  • Store in refrigerator
  • If necessary, may be kept at room temperature up to 77°F (25°C) for a maximum of 14 days
  • Do not expose to light

Generic / Price

- NO/$$$$

Mechanism of action

  • Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. Dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling through the Type II receptor.
  • Inflammation is an important component in the pathogenesis of asthma and atopic dermatitis. Multiple cell types that express IL-4Rα (e.g., mast cells, eosinophils, macrophages, lymphocytes, epithelial cells, goblet cells) and inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines, chemokines) are involved in inflammation.

FDA-approved indications

  • Asthma - as an add-on maintenance treatment in patients with moderate-to-severe asthma aged 12 years and older with an eosinophilic phenotype or with oral corticosteroid dependent asthma. In trials, a minimum blood eosinophil count was not required.
  • Atopic dermatitis - patients ≥ 12 years old with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Dupilumab can be used with or without topical corticosteroids.
  • Chronic Rhinosinusitis with Nasal Polyposis - as an add-on maintenance treatment in adult patients with inadequately controlled chronic rhinosinusitis with nasal polyposis (CRSwNP)

Side effects



Atopic dermatitis trials
Side effect Dupilumab Placebo
Injection site reactions 10% 5%
Conjunctivitis 10% 2%
Oral herpes 4% 2%
Other herpes infections 2% 1%
Eye itching 1% <1%
Asthma trials
Side effect Dupilumab Placebo
Injection site reactions 18% 6%
Oropharyngeal pain 2% 1%
Blood eosinophilia (≥ 3000 cells/mcL) 2% <1%


Drug interactions

  • No clinically relevant drug interactions have been documented

Contraindications / Precautions

  • Hypersensitivity reactions - in trials, hypersensitivity reactions occurred in < 1% of dupilumab-treated patients. Reactions included generalized urticaria, rash, erythema nodosum and serum sickness or serum sickness-like reactions.
  • Conjunctivitis and keratitis - in atopic dermatitis trials, conjunctivitis occurred in 10% of dupilumab-treated patients and 2% of placebo-treated patients. Keratitis was reported in 4% of dupilumab-treated patients and 0% of placebo-treated patients. Patients should be advised to report eye symptoms to their provider.
  • Eosinophilic conditions - cases of eosinophilic pneumonia and cases of vasculitis consistent with eosinophilic granulomatosis with polyangiitis have been reported in asthmatics being treated with dupilumab. A causal relationship between dupilumab and these conditions has not been established.
  • Eosinophilia - dupilumab may raise serum eosinophil levels. In asthma trials, the average increase in the eosinophil count was 130 cells/mcL at 4 weeks of treatment. Treatment-emergent eosinophilia (‰¥5,000 cells/mcL) was reported in < 2% of dupilumab-treated patients and < 0.5% in placebo-treated patients. Blood eosinophil counts declined to near baseline levels during study treatment.
  • Acute bronchospasm - dupilumab does not treat acute bronchospasm
  • Reduction of corticosteroids - do not abruptly stop oral, inhaled, or topical corticosteroids when starting dupilumab. Reductions in corticosteroids should be done gradually to prevent withdrawal symptoms.
  • Parasitic (Helminth) infections - dupilumab 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 dupilumab and they do not respond to anti-helminth therapy, dupilumab should be stopped.
  • Anti-dupilumab antibodies - in adult trials, anti-dupilumab antibodies developed in up to 9% of dupilumab-treated patients. In some patients, antibodies were associated with lower serum levels of dupilumab. Two patients with high titer antibodies developed serum sickness. In pediatric atopic dermatitis trials, 16% of patients developed anti-dupilumab antibodies and 5% had neutralizing antibodies.
  • Vaccines - avoid live vaccines in patients receiving dupilumab. See live vaccines for more. In trials, antibody responses to non-live vaccines were not reduced in dupilumab-treated patients.
  • Liver disease - has not been studied
  • Kidney disease - has not been studied



Benralizumab vs Placebo in Severe Asthma with Eosinophilic Phenotype, Lancet (2016) [PubMed abstract]
  • The trial enrolled 809 patients with uncontrolled, severe asthma and elevated eosinophil count
Main inclusion criteria
  • Aged 12 – 75 years weighing at least 40 kg
  • Asthma needing treatment with high-dose ICS + LABA for at least 1 year
  • 2 exacerbations requiring oral corticosteroid treatment or temporary increase in oral corticosteroids within 1 year
  • Blood eosinophil count ≥ 300 cells/μL
Main exclusion criteria
  • Pulmonary disease other than asthma
  • Current smokers or former smokers (≥ 10 pack/years)
  • Helminthic parasitic infection diagnosed within 24 weeks
Baseline characteristics
  • Average age - 48 years
  • Median eosinophil count - 500 cells/mcL
  • Mean FEV1 (% predicted) - 55%
  • Mean # of asthma exacerbations in previous 12 months - 3
Randomized treatment groups
  • Group 1 (267 patients): Placebo
  • Group 2 (275 patients): Benralizumab 30 mg SQ every 4 weeks
  • Group 3 (267 patients): Benralizumab 30 mg SQ every 8 weeks (first three doses every 4 weeks)
  • All patients were uncontrolled on ICS + LABA therapy
  • All patients had baseline eosinophil counts ≥ 300 cells/mcL
Primary outcome: Annual exacerbation rate ratio versus placebo in patients with blood eosinophil counts of at least 300 cells per μL
Results

Duration: 48 weeks
Outcome Placebo Ben Q 4 weeks Ben Q 8 weeks Comparisons
Annual exacerbation rate 1.33 0.73 0.65 p<0.05 for 1 vs 2 or 3
Rate ratio vs placebo N/A 0.55 0.49 p<0.0001 for both comparisons
  • In another arm of the study where patients with baseline eosinophil counts < 300 cells/mcL were compared, results were nonsignificant

Findings: These results confirm the efficacy and safety of benralizumab for patients with severe asthma and elevated eosinophils, which are uncontrolled by high-dosage ICS plus LABA, and provide support for benralizumab to be an additional option to treat this disease in this patient population.
Dupilumab vs Placebo in Glucocorticoid-Dependent Severe Asthma, NEJM (2018) [PubMed abstract]
  • The study enrolled 210 severe asthmatics who were glucocorticoid-dependent
Main inclusion criteria
  • Adults and adolescents with diagnosis of asthma for ≥ 12 months
  • Treatment for ≥ 6 months with corticosteroids (prednisone 5 - 35 mg/d)
  • High-dose ICS + LABA or LRTA for ≥ 3 months
Main exclusion criteria
  • < 12 years old
  • Other lung disease
  • Current smoker or cessation of smoking within 6 months
  • Previous smoker (> 10 pack-years)
Baseline characteristics
  • Average age - 51 years
  • Average # of severe exacerbations in last year - 2
  • Average glucocorticoid dose - 11.8 mg/day
  • Average prebronchodilator FEV1 (% of predicted) - 52%
Randomized treatment groups
  • Group 1 (103 patients): Dupilumab 600 mg loading followed by 300 mg SQ every other week
  • Group 2 (107 patients): Placebo
  • Study drug was added to current asthma meds
  • Treatment had to include a high-dose inhaled glucocorticoid in combination with up to two controllers (e.g. a long-acting beta-2-agonist or leukotriene-receptor antagonist)
  • During the dose-reduction phase, the oral glucocorticoid dose was reduced every 4 weeks as tolerated
Primary outcome: Percentage reduction in the glucocorticoid dose at week 24
Results

Duration: 24 weeks
Outcome Dupilumab Placebo Comparisons
Primary outcome 70% 42% p<0.001
Stopped oral steroids 48% 25% p=0.002
  • In the dupilumab group, prebronchodilator FEV1 increased by 0.22 liters more than placebo (95%CI [0.09 to 0.34])

Findings: In patients with glucocorticoid-dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV1. Transient eosinophilia was observed in approximately 1 in 7 dupilumab-treated patients.
Dupilumab vs Placebo in Moderate-to-Severe Uncontrolled Asthma, NEJM (2018) [PubMed abstract]
  • The trial enrolled 1902 uncontrolled asthmatics
Main inclusion criteria
  • Treatment with ICS + LABA or LRTA for ≥ 3 months
  • Treatment with oral or parenteral steroids or hospitalization/ER visit for asthma within 1 year
Main exclusion criteria
  • < 12 years old
  • Other lung disease
  • Current smoker or cessation of smoking within 6 months
  • Previous smoker (> 10 pack-years)
Baseline characteristics
  • Average age - 48 years
  • Average # of exacerbations in last year - 2
  • Average prebronchodilator FEV1 - 1.78 liters
  • Average prebronchodilator FEV1 (% of predicted) - 58%
Randomized treatment groups
  • Group 1 (631 patients): Dupilumab 400 mg loading followed by 200 mg SQ every other week
  • Group 2 (633 patients): Dupilumab 600 mg loading followed by 300 mg SQ every other week
  • Group 3 (317 patients): Placebo matching Group 1
  • Group 4 (321 patients): Placebo matching Group 2
  • Study drug was added to current asthma meds
  • Treatment had to include an inhaled glucocorticoid in combination with up to two controllers (e.g. a long-acting beta-2-agonist or leukotriene-receptor antagonist)
Primary outcome: Annualized rate of severe exacerbation events (number of severe exacerbations per patient-year) during the 52-week intervention period and the absolute change from baseline in the FEV1 before bronchodilator use at week 12 in the overall trial population
Results

Duration: 52 weeks
Outcome Dup 400/200 Dup 600/300 Placebo 400/200 Placebo 600/300 Comparisons
Rate of severe exacerbations per year 0.46 0.52 0.87 0.97 p<0.001 for 1 vs 3 and 2 vs 4
Increase in FEV1 at 12 weeks (liters) 0.32 0.34 0.18 0.21 p<0.001 for 1 vs 3 and 2 vs 4
  • Among patients with a blood eosinophil count of ≥ 300/mm³, the annualized rate of severe asthma exacerbations was 0.37 among those receiving lower-dose dupilumab and 1.08 among those receiving a matched placebo (Diff 65.8%, 95%CI [52.0 to 75.6]);
  • Eosinophilia was reported as an adverse event that emerged during the trial period in 52 patients (4.1%) who received dupilumab versus 4 patients (0.6%) who received placebo

Findings: In this trial, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients.
Mepolizumab vs Placebo in Eosinophilic Asthma, NEJM (2014) [PubMed abstract]
  • The study enrolled 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation
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
Randomized treatment groups
  • 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.
Results

Duration: 32 weeks
Outcome Mepolizumab 100 Mepolizumab 75 Placebo Comparisons
Primary outcome (exacerbations/year) 0.83 0.93 1.74 1 or 2 vs 3 p<0.001
Change in FEV1 before bronchodilation +183 ml +186 ml +86 ml 1 or 2 vs 3 p<0.03
  • Rates of adverse events were similar between the 3 groups

Findings: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control
Omalizumab vs Placebo in in Inner-city Children with Asthma, NEJM (2011) [PubMed abstract]
  • The study enrolled 419 inner-city children, adolescents, and young adults with persistent asthma
Main inclusion criteria
  • Inner-city children (6 - 20 years old)
  • Persistent allergic asthma or evidence of uncontrolled disease as indicated by hospitalization or unscheduled urgent care in the 6 to 12 months preceding study entry
  • At least one positive skin test for a perennial allergen
  • Total serum levels of IgE between 30 and 1300 IU/ml
Baseline characteristics
  • Average age 11 years
  • Average duration of asthma - 7 years
  • Average % predicted FEV1 - 92%
Randomized treatment groups
  • 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
  • Controller medications were not required for enrollment
  • 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.
Results

Duration: 60 weeks
Outcome Omalizumab Placebo Comparisons
Primary outcome (days) 1.48 1.96 Diff 0.48 days 95%CI [CI 0.77 - 0.20], p<0.001
Hospitalizations 1.5% 6.3% p=0.02
Exacerbation 30% 49% p<0.001
Average dose of inhaled steroid 663 mcg/day 771 mcg/day p<0.001
  • 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.

Findings: When added to a regimen of guidelines-based therapy for inner-city children, adolescents, and young adults, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma.
Omalizumab vs Placebo in Poorly-Controlled Allergic Asthma, Ann Intern Med (2011) [PubMed abstract]
  • A study in the Annals of Internal Medicine enrolled 850 patients with inadequately controlled asthma
Main inclusion criteria
  • Age 12 - 75 years
  • Persistent allergic asthma uncontrolled with ICS and LABA (and any other meds)
  • Positive allergen testing
Main 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%
Randomized treatment groups
  • 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 per patient 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).
Results

Duration: 48 weeks
Outcome Omalizumab Placebo Comparisons
Primary outcome 0.66 0.88 Incidence rate ratio = 0.75 (CI 0.61 - 0.92), p=0.006
  • Rates of adverse events were similar between the 2 groups

Findings: In this study, omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy.
Reslizumab vs Placebo in Uncontrolled Asthma with Elevated Eosinophil Count, Lancet Respir (2015) [PubMed abstract]
  • A study in Lancet Respir enrolled 489 patients with inadequately controlled asthma and an elevated eosinophil count
Main inclusion criteria
  • Age 12 - 75 years
  • Asthma inadequately controlled by medium-to-high doses of ICS
  • Blood eosinophils ≥ 400 cells/mcL
  • ≥ 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/mcL
  • Average # of exacerbations in previous year - 1.99
Randomized treatment groups
  • 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 defined as any 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
Results

Duration: 52 weeks
Outcome Reslizumab Placebo Comparisons
Primary outcome 0.90 1.80 RR 0.50, 95%CI [0.37 - 0.67]
Exacerbations requiring systemic steroids 0.72 1.60 RR 0.45, 95%CI [0.33 - 0.62]
Hospitalization and/or ER visit 0.14 0.21 RR 0.66, 95%CI [0.32 - 1.36]
  • Rates of adverse events were similar between the 2 groups

Findings: These results support the use of reslizumab in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroid-based therapy.



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  • $$$$ = > $151
  • Pricing based on one month of therapy at standard dosing in an adult
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