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Omalizumab: A New Treatment for the Management of AsthmaIntroduction: 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 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 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 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 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. References:
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