Omalizumab: A New Treatment
for the Management of Asthma
Volume VII, Number 1 | January/February 2004
Bridgette L. Sims, Pharm.D. Candidate
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Introduction
Asthma is a chronic disease with three different components: bronchoconstriction, inflammation of the airways, and airway remodeling. Acute symptoms are usually caused by bronchospasms due to the hyperresponsiveness of the airways. The chronic components of the inflammatory process include inflammatory cells (e.g., basophils, T cells, mast cells, neutrophils, eosinophils, macrophages, and epithelial cells), mast cell degranulation, denudation of the epithelium, and collagen deposits in the subbasement membrane.1 The chronic inflammation results in dyspnea, wheezing, coughing, and chest tightness. Airway remodeling is a new mechanism involved in the pathophysiology of asthma. Previously, it was thought that the symptoms and inflammation of asthma were reversible. However, airways adapt and repair in response to the inflammation which may result in fibrosis. In some asthmatic patients, airflow restriction and structural changes observed in the airways secondary to chronic inflammation may be irreversible. This results in the obstruction of airways, similar to that observed with chronic obstructive pulmonary disease (COPD).
In allergic asthma, IgE antibodies are formed against common aeroallergens such as cats, dogs, dust mites, and mold. There are two components involved in the development of allergic asthma. One involves atopy, which is a genetic predisposition to an IgE response to aeroallergens. The second component is the ability to develop IgE antibodies due to an imbalance between T-helper 1 (Th-1) and T-helper 2 (Th-2) cytokines. In allergic inflammation, Th-2 cytokines, which are expressed to a greater extent than Th-1 cytokines, produce interleukin (IL)-4, -5, -6, -9, and -13, that can mediate allergic inflammation.1,2 When atopic asthmatics come in contact with these common aeroallergens, IgE is released and binds to basophils and mast cells. The activation of basophils and mast cells stimulates the release of histamine, leukotrienes, granulocyte-macrophage colony-stimulating factor (GM-CSF), type II interferon (IFN-γ), interleukin (IL)-1, -2, -3, -4, and -5, and tumor necrosis factor (TNF-α). The release of these mediators causes smooth muscle contraction and bronchoconstriction.
The current classification of asthma severity is based on symptoms and lung function tests (See Table 1), while the current treatment for asthma is based on severity (See Table 2).2,3
Table 1: Asthma Severity Classification
Classification | Symptoms | Lung Function |
---|---|---|
Step
1:
Mild-Intermittent |
Daytime < 2 times per week
|
PEF
Variability < 20% FEV1 > 80% PEF > 80% |
Step
2:
Mild-Persistent |
Daytime > 2
times per week but < 1 time per day Nighttime > 2 times per month Exacerbations may affect activity |
PEF Variability
range of 20%-30% FEV1 > 80% PEF > 80% |
Step
3: Moderate-Persistent |
Daytime symptoms
daily Nighttime symptoms > 1 time per week Exacerbations affect activity Exacerbations > 2 times per week Exacerbations last days Daily use of inhaled short-acting ß2-agonists |
PEF Variability > 30% FEV1 > 60% but < 80% PEF > 60% but
< 80% |
Step
4:
Severe-Persistent |
Daytime symptoms
continual Nighttime symptoms frequent Symptoms limit physical activity Exacerbations frequent |
PEF variability
> 30% FEV1 < 60% PEF < 60%
|
PEF = peak expiratory
flow, FEV1 = forced expiratory volume in 1 second
Adapted from National Asthma Education and Prevention Program. NIH.
1997;97-4051:iii-86.
Kelly HW, et al. Pharmacology: a Pathophysiologic Approach 5th
ed. New York: McGraw-Hill; 2002. p. 475-510.
Table 2: Treatment Guidelines for Asthma
Classification | Short-Term Treatment | Long-Term Treatment | Additional Treatment |
---|---|---|---|
Step
1: Mild-Intermittent |
Short-acting inhaled
ß2-agonist Use of rescue inhaler > 2 times per week consider long-term treatment |
None needed | None needed |
Step
2: Mild-Persistent |
Short-acting inhaled
ß2-agonist Use of rescue inhaler daily or increased frequency need additional long-term treatment |
Inhaled low doses
of corticosteroids, cromolyn sodium (Intal®), or nedocromil (Tilade®) Sustained-release theophylline, zafirlukast (Accolate®) or zileuton (Zyflo®)
| None needed |
Step
3: Moderate-Persistent |
Short-acting inhaled
ß2-agonist Use of rescue inhaler daily or increased frequency need additional long-term treatment |
Inhaled
medium dose corticosteroids OR Inhaled low-medium dose corticosteroids plus long-acting inhaled ß2-agonist |
Medium-high dose
inhaled corticosteroids AND Long-acting inhaled ß2-agonist, sustained-release theophylline, or long-acting ß2-agonist tablets |
Step
4: Severe-Persistent |
Short-acting inhaled
ß2-agonist Use of rescue inhaler daily or increased frequency need additional long-term treatment |
High dose inhaled
corticosteroid AND Long-acting inhaled ß2-agonist, sustained-release theophylline, or long-acting ß2-agonist tablets |
Long-term oral corticosteroids |
Adapted
from: National Asthma Education and Prevention Program. Expert Panel Report
2: Guidelines for the diagnosis and management of asthma. NIH 1997;97-405:iii-86.
Kelly HW, Sorkness CA. Asthma In: Dipiro JT, Talbert RL, Yee GC, Matzke
GR, Wells BG, Posey LM, et al. editors. Pharmacology: A Pathophysiologic
Approach 5th ed. New York: McGraw-Hill; 2002. p. 475-510.
Omalizumab
The Food and Drug Administration (FDA) approved omalizumab (Xolair®; Genentech/Novartis) in June of 2003.
Indications
Omalizumab is FDA-approved for use in moderate-persistent to severe-persistent asthma. Eligible patients for therapy need to be >12 years of age, have a positive skin test to a perennial aeroallergen (e.g., dust mites, cats, dogs, and mold), and be symptomatic with inhaled corticosteroids. An unlabeled use of omalizumab is for the treatment of allergic rhinitis, and it is also being studied for use in patients with peanut allergies.
Pharmacology and Pharmacokinetics
Omalizumab is an IgG monoclonal antibody that inhibits IgE from binding to the surface of basophils and mast cells.4 This removes and deactivates free, circulating IgE and any IgE that has detached from cell surface receptors. Decreasing and eliminating IgE prevents the activation of basophils and mast cells, thus, preventing allergic mediated early- and late-phase hyperresponsiveness of asthma.5
The bioavailability of omalizumab is 62% after subcutaneous administration. It reaches a peak concentration within 7 to 8 days after subcutaneous administration and has a half-life of approximately 26 days. Omalizumab is eliminated by the liver through the reticuloendothelial system.4
Selected Clinical Trials
Omalizumab has been studied in both pediatric and adult patients (See Tables 3 and 4). The trials mainly focus on the reduction of asthma exacerbations, the ability to decrease or eliminate inhaled corticosteroids, and the ability to increase the quality of life in asthmatic patients.
In several of the trials described, patients were only taking inhaled corticosteroids.6-8 In a study by Milgrom and colleagues (1999), patients were allowed to use inhaled corticosteroids or both inhaled and oral corticosteroids.9 There were, however, no trials that allowed patients to be treated with long-acting inhaled ß2-agonists. The current guidelines for asthma recommend that patients with moderate-persistent to severe-persistent asthma should be maximized on inhaled corticosteroids with either a long-acting inhaled or oral ß2-agonist or theophylline. Additionally, in severe-persistent asthma, long-term oral corticosteroids can be added to maximize treatment.2 Thus, none of the trials maximized patients on the accepted current standards of practice. Since the study by Milgrom (1999) included treatment that was more similar to the standards, its results may be more applicable to practice.9
Table 3. Selected Pediatric Omalizumab Clinical Trials6,7
Study | Patients and Baseline Treatment | Omalizumab Study Treatment | Primary Endpoints | Results |
---|---|---|---|---|
Milgrom
et al.6 RDBPC |
n = 334 Age: 6-12 years Well controlled with inhaled corticosteroids (doses equivalent to 168 to 420 mcg/day of BDP) and bronchodilators |
Inhaled BDP and OMX
SC 0.016 mg/kg/IgE (IU/mL) for 28 weeks or placebo OMZ n=225 Placebo n=109 Steroid-stable phase: BDP dose kept constant for 16 weeks Steroid-reduction phase: BDP dose reduced over 8 weeks to minimum tolerated dose: Minimum dose maintained for 4 additional weeks |
BDP does reduction, symptoms, spirometry, AE | Median BDP dose
reduction of 100% with OMZ vs. 66.7% with placebo (p=0.001)
BDP completely withdrawn in 55% receiving OMZ vs. 39% receiving placebo (p=0.004) Steroid stable phase: Asthma exacerbations occurred in 15.6% receiving OMZ vs. 22.9% receiving placebo (p=0.095) Steroid reduction phase: Asthma exacerbations occurred in 18.2% receiving OMZ vs. 38.5% receiving placebo (p<0.001) No statistical difference in symptom scores or spirometry No serious AE |
Lemanske
et al.7 RDBPC |
Same as Milgrom et al.6 | Same as Milgrom et al.6 | Mean change from baseline in asthma-related QOL scores | End of steroid-stable
phase:
No statistical difference in PAQLQ scores between groups End of steroid-reduction phase: -Greater mean change from baseline in activities scores (p<0.05) and symptoms scores (p<0.05) with OMZ vs. placebo -No statistical difference in emotions scores between groups -The overall mean score change from baseline was statistically significant with OMZ vs. placebo (p<0.05) End of study: Greater proportion of OMZ patients achieved a clinical improvement in asthma-related QOL |
AE=Adverse event
BDP=beclomethasone
dipropionate or equivalent inhaled steroid
DBPC=double-blind, placebo-controlled,
n=number of patients in study group
OMZ=omalizumab
PAQLQ=Pediatric Asthma
Quality of Life Questionnaire
QOL=Quality of Life
RDBPC=randomized, double-blind,
placebo-controlled trial
SC=subcutaneous
Table 4. Selected Adult Omalizumab Clinical Trials
Study | Patients and Baseline Treatment |
Omalizumab Study Treatment | Primary Endpoints | Results |
---|---|---|---|---|
Busse et al.8 DBPC parallel trial |
n=525
patients Age: 12-75 years Inhaled corticosteroids (doses equivalent to 168 to 420 mcg/day of BDP) |
Inhaled BDP and
OMZ SC 0.016 mg/kg/igE (IU/mL) for 28 weeks or placebo
OMZ n=268 Placebo n=257 Steroid-stable phase: dose kept constant for 16 weeks Steroid-reduction phase: dose reduced over 12 weeks to minimum tolerated dose |
Number
of exacerbations during steroid stable and reduction phases, steroid dose
reduction |
Steroid-stable
phase: > 1 exacerbations in 14.6% OMZ patients vs. 23.3% placebo patients (p=0.009) Steroid-reduction phase: Fewer OMZ patients with exacerbations vs. placebo (21.3% vs. 32.3%, respectively; p=0.004) More OMZ patients achieved a > 50% reduction in steroid dose (72.4% vs. 54.9%, respectively; p<0.001) |
Milgrom
et al.9 RDBPC |
n=317
patients Age: 11-50 years Inhaled corticosteroids (triamcinolone 200 mcg BID or equivalent) OR Oral prednisone 20 mg daily or 40 mg every other day and inhaled corticosteroids |
High dose (5.8 mcg/kg/IgE [ng/mL]) or low dose (2.5 mcg/kg/IgE [ng/mL]) IV OMZ for 20 weeks or placebo OMZ: -High-dose n=106 -Low-dose n=106 Placebo n=105 Steroid-stable phase: dose kept constant for 12 weeks Steroid-reduction phase: dose reduced over 8 weeks to minimum tolerated dose |
Improvements in
asthma symptoms scores at 12 weeks
Range:
1 (none) to 7 (very great deal)
Baseline mean: 4 |
High dose OMZ Mean symptom score 2.8+ 0.1 (p=0.008 vs. placebo) Reduction in oral steroid dose > 50% in 78% of patients (p=0.04 vs. placebo) Reduction in inhaled steroid dose > 50% in 51% of patients (p=0.07 vs. placebo) Low dose OMZ Mean symptom score 2.8+ 0.1 (p=0.005 vs. placebo) Reduction in oral steroid dose > 50% in 57% of patients (p=0.23 vs. placebo) Reduction in inhaled steroid dose > 50% in 49% of patients (p=0.12 vs. placebo) Placebo Mean symptom score 3.1+ 0.1 Reduction in oral steroid dose > 50% in 33% of patients Reduction in inhaled steroid dose > 50% in 38% of patients |
BDP=beclomethasone
dipropionate or equivalent inhaled steroid
DBPC=double-blind, placebo-controlled
n=number of patients in study group
OMZ=omalizumab
RDBPC=randomized, double-blind,
placebo-controlled trial
SC=subcutaneous
Adverse Drug Reactions
Some of the most common adverse drug reactions of omalizumab include: injection site reactions, viral infections, upper respiratory tract infection, sinusitis, headache, and pharyngitis. Additional adverse drug reactions are described in Table 5.10,11
Table 5. Reported Adverse Drug Reactions of Omalizumab
System | Adverse Reactions |
---|---|
Respiratory | Pharyngitis, upper respiratory tract infection, sinusitis, pneumonia, asthma exacerbation |
CNS | Fatigue, pain, headache, dizziness |
Local | Injection site reactions (swelling, redness) |
Dermatologic | Pruritus, dermatitis, urticaria, rash |
Musculoskeletal | Leg pain, fracture, arm pain, arthralgia |
Gastrointestinal | Vomiting, gastroenteritis, diarrhea |
Otic | Earache |
Miscellaneous | Anaphylaxis, malignancy, eye edema, rhinitis |
Adapted from: Lexi-Drugs® online. Omalizumab monograph. Accessed 14 August 2003.
Omalizumab package insert. 1 DNA Way, CA:Genentech Inc.; June 2003.
Food and Drug Administration Center for Biologics Evaluation and Research.
Briefing document on safety BLA STN 103976/0 Rockville, MD: The Department
of Health & Human Services; 2003.
Drug-Drug Interactions
Currently, there are no known drug-drug interactions with omalizumab. During the investigation of omalizumab, no formal drug interaction studies were conducted. The assessment of the concurrent use of omalizumab and allergen immunotherapy has also not been investigated.4
Pregnancy and Lactation
Omalizumab is classified as a pregnancy risk category B.1 A category B drug has either not demonstrated fetal risk in animal-reproduction studies and has no controlled studies in pregnant women or animal studies have shown an adverse effect but the adverse effect in the first trimester has not been confirmed in controlled studies in women and there is no risk in later trimesters.12 Fetal and neonatal growth was not impaired in animal studies. There are no controlled-trials that have evaluated omalizumab in pregnant women. IgG molecules will cross through the placenta, therefore, it is recommended that omalizumab should not be used during pregnancy. Omalizumab should only be used if it is imperative to treatment and the benefit outweighs the risk. Since omalizumab is an IgG antibody and there is evidence that IgG can pass into breast milk, omalizumab may be expected to be present in breast milk. The extent that omalizumab is passed into human milk is unknown, thus, it is unknown whether the infant will absorb a quantity of omalizumab that would be harmful. The adverse effects of omalizumab on infants have not been determined. The use of omalizumab in nursing women should be done cautiously or avoided if possible.4
Monitoring Parameters
It is important to obtain baseline IgE levels and pulmonary function tests including peak flow and FEV1. IgE levels should not be used during treatment to monitor a patient's response since omalizumab and IgE form complexes that increase serum total IgE levels, and available assays only report total levels.13 During treatment, it is important to monitor how often a patient is symptomatic along with pulmonary function tests. IgE levels should not be repeated until at least one year after omalizumab is discontinued since total IgE levels remain elevated for one year after the discontinuation of therapy.10
Dosage and Administration
The dose and frequency of omalizumab are based on body weight in kilograms (kg) and the serum total IgE level (IU/mL) obtained before initiation of treatment. If large fluctuations in weight occur, the dose of omalizumab should be adjusted accordingly. Generally, the average dose is between 150 to 375 mg every 2 or 4 weeks. Omalizumab is administered by subcutaneous injection, with the maximum dose per injection site being 150 mg. If a dose greater than 150 mg is needed, it can be split and administered at multiple injection sites. If a dose greater than 450 mg is needed, the dose can be split in half and administered every 2 weeks instead of every 4 weeks. Specific dosing recommendations are outlined in Table 6.10
Table 6. Omalizumab Doses in Milligrams Administered Every 2 to 4 Weeks
Pre-treatment serum IgE (IU/mL) |
Body Weight (kg) | |||
---|---|---|---|---|
30-60 | >60-70 | >70-90 | >90-150 | |
> 30-100 | 150 q4 weeks | 150 q4 weeks | 150 q4 weeks | 300 q4 weeks |
>100-200 | 300 q4 weeks | 300 q4 weeks | 300 q4 weeks | 225 q2 weeks |
>200-300 | 300 q4 weeks | 225 q2 weeks | 225 q2 weeks | 300 q2 weeks |
>300-400 | 225 q2 weeks | 225 q2 weeks | 225 q2 weeks | 300 q2 weeks |
>400-500 | 300 q2 weeks | 300 q2 weeks | 375 q2 weeks | Do Not Use |
>500-600 | 300 q2 weeks | 375 q2 weeks | Do Not Use | Do Not Use |
>600-700 | 375 q2 weeks | Do Not Use | Do Not Use | Do Not Use |
q=every
Adapted from: Omalizumab package insert. 1 DNA Way, CA:Genentech Inc.; June
2003
Cost
The average wholesale price (AWP) for a 150 mg vial of omalizumab is $541. For dosing every 4 weeks, the price will range approximately from $541 to $1,000 (for 150 mg and 300 mg, respectively). For one year of treatment with these doses, the cost will range from $10,000 to $16,000. For dosing every 2 weeks, the price will range from $800 to $1,400 (for 225 mg and 375 mg, respectively). The total price for a month of treatment with dosing every two weeks is $1,600 to $2,700. For a year of treatment with these doses, the cost will range from $20,000 to $32,000.14
Summary
Omalizumab is a new agent indicated for the treatment of uncontrolled, moderate-persistent to severe-persistent allergic asthma. The available studies did not evaluate the efficacy of omalizumab in patients who were maximized on appropriate drug therapy based on the disease severity. Studies need to be conducted in patients with severe-persistent asthma who are still symptomatic with inhaled high-dose corticosteroids, a long-acting ß2-agonist, long-term oral corticosteroids, and even additional treatments.
In the study populations evaluated, there have been improvements in terms of decreased exacerbations, improved quality of life, and decreased doses of inhaled and oral corticosteroids.6-9
It is currently not known where omalizumab fits into the treatment guidelines for asthma; however, it is not considered a first-line agent in the treatment of allergic asthma. It should be reserved as either a second- or third-line agent after combined inhaled corticosteroids and a long-acting ß2 agonist. Omalizumab is currently under formulary review.
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References
- Busse WW, Boushey HA, Buist S, Clark NM, Kelly HW, Lemanske RF, et al. National asthma education and prevention program. Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics 2002. J Allergy Clin Immunol 2002;110(5s):1A-S219.
- National Asthma Education and Prevention Program. Expert panel report 2: Guidelines for the diagnosis and management of asthma. NIH 1997;97-4051: iii-86.
- Kelly HW, Sorkness CA. Asthma. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, et al, editors. Pharmacotherapy: a Pathophysiologic Approach 5th ed. New York: McGraw-Hill; 2002. p. 475-510.
- Omalizumab package insert. 1 DNA Way, CA:Genentech Inc.; June 2003.
- Woodruff PG, Fahy JV. Asthma: prevalence, pathogenesis, and prospects for novel therapies. JAMA 2001;286(4):395-398.
- Milgrom H, Berger W, Nayak A, Gupta N, Pollard S, McAlary M, et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics 2001;108(2):e36.
- Lemanske RF, Nayak A, McAlary M, Everhard F, Fowler-Taylor A, Gupta N. Omalizumab improves asthma-related quality of life in children with allergic asthma. Pediatrics 2002;110(5):e55.
- Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allerg Clin Immunol 2001;108(2):184-190.
- Milgrom H, Fick RB, Su JQ, Reimann JD, Bush RK, Watrous ML, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. N Engl J Med 1999;341(26):1966-1973.
- Lexi-Drugs® online. Omalizumab monograph. Accessed 14 Aug 2003.
- Food and Drug Administration Center for Biologics Evaluation and Research. Briefing document on safety BLASTN 103976/0. Rockville, MD: The Department of Health & Human Services; 2003.
- Briggs GG, Freeman RK, Yaffe SJ, editors. A reference guide to fetal and neonatal risk drugs in pregnancy and lactation 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. v11-xxiv.
- Rambasek TE, Lang DM, Kavuru MS. Omalizumab: where does it fit into current asthma management? Cleve Clin J Med 2004;71:251-61.
- Xolair®. Cardinal wholesaler, Inc. Accessed 22 Aug 2003.