Omalizumab (Xolair) is a recombinant humanized IgG1 monoclonal antibody that selectively neutralizes soluble human IgE through binding at the same site utilized by the native high affinity receptor, Fc RI (Presta et al., 1994). Omalizumab is FDA approved for use by patients with allergic asthma inadequately controlled by inhaled corticosteroids, and is not only the first drug in this class of selective IgE inhibitors but also the first biologic therapy approved for asthma (package insert for Xolair, 2006).
Asthma is a syndrome of airway hyper-reactiv-ity, which can result in potentially life-threatening bronchospasm. Bronchospastic exacerbations of asth-ma are triggered by noxious stimuli, most typically by airway inflammation resulting from either a viral respiratory infection or an aeroallergen (like dust mite, animal dander, pollen or mold). About 60% of asthmatics have allergic triggers of attacks.
IgE is a key intermediate in all forms of allergic disease because it is the interface between the inciting allergen and the resultant activation of effector cells (like mast cells and basophils), which can release histamine and other mediators of the allergicresponse. By directly neutralizing soluble IgE, omali-zumab intervenes in this key intermediate step in the cascade of allergic inflammation and the resultant clinical exacerbation of allergic disease.
Doses of 150 to 375 mg of omalizumab are administered SC every 2 to 4 weeks using a table that adjusts target exposure based upon body weight and baseline levels of total IgE, aiming to achieve at least 0.016 mg/kg/IU in order to suppress free IgE levels below at least 50 ng/ml (package insert for Xolair, 2006; Hochhaus et al., 2003). With an average absolute bioavailability of 62% following a SC injection, peak serum concentrations of omalizumab are achieved after 7 to 8 days, with an apparent volume of distribution of 78 – 32 mL/kg and linear PK at doses greater than 0.5 mg/kg. Following multiple doses SC, the serum omalizumab AUCs at steady state days 0 to 14 are up to 6-fold of those after the first dose. Omalizumab forms multiple stoichiometric com-plexes with IgE and is eliminated as complexes from the circulation via Fcg receptors via the reticuloen-dothelial system at a rate generally faster than standard IgG clearance. It is also excreted in bile. Serum elimination half-life of omalizumab averaged 26 days, with apparent clearance averaging 2.4 – 1.1 mL/kg/day; a doubling of body weight was noted to double apparent clearance. Serum free IgE levels decreased greater than 96% using the dosing table, with 98% of individuals having free IgE levels at or below 50 ng/mL by 3 months of multiple dosing per schedule. Because omalizumab forms complexes with IgE and these complexes has a slower elimina-tion rate than free (unbound, monomeric) IgE, after omalizumab therapy there is an apparent increase in total IgE using standard laboratory tests which cannot distinguish bound from free IgE. Following disconti-nuation of omalizumab there is a slow (up to 12 months) washout of drug:IgE complexes without an apparent rebound increase in free IgE levels. No dose adjustment appears necessary for age (12–76 years), race, ethnicity, or gender (package insert for Xolair, 2006).
Pivotal safety and efficacy trials evaluated patients with moderate to severe persistent asthma per National Heart, Lung and Blood Institute criteria who were defined as having allergic-type asthma based upon a positive test to a perennial allergen. Total baseline IgE had to be between 30 and 700 IU/ mL and body weight not more than 150 kg in order to use the dosing table.
Though some therapeutic effects on allergic and asthma symptoms, pulmonary function and need for concomitant medications were seen, omalizumab efficacy was based primarily on the reduction of asthma exacerbations, which were defined as a worsening of asthma that required treatment withsystemic corticosteroids or a doubling of baseline inhaled corticosteroid dose.
Omalizumab was very well tolerated in the clinical trials, with only a slight increase in injection site reactions compared to controls. The incidence of anti-drug antibodies was reported as 1/1723 (< 0.1%), which is an extremely low immunogenicity rate compared to nearly every other biologic therapy (package insert for Xolair, 2006).
Warnings were placed on the label regarding malignancy and anaphylaxis based on a numerically higher incidence of these events in the active vs. control groups. Malignant neoplasms were seen in 20 of 4127 (0.5%) of omalizumab-treated patients vs. 5 of 2236 (0.2%) of controls, with no specific pattern noted in terms of tumor types. Anaphylactoid reactions (with urticaria and throat and/or tongue edema) within 2 hours of the first or subsequent infusion of omalizumab were noted in 3 (< 0.1%) patients without other identifiable allergic triggers (package insert for Xolair 2006). Therefore omalizu-mab is to be administered under appropriate medical observation with medications for the treatment of severe hypersensitivity reactions including anaphy-laxis available.