What is/are Omalizumab?
Omalizumab (trade name Xolair, Roche/Genentech and Novartis) is a humanized antibody used to reduce sensitivity to inhaled allergens, especially in the control of moderate to severe allergic asthma which does not react to high doses of corticosteroids. It is approved for use in countries across the world, although some countries restrict its use to patients over 12 years old. Omalizumab's cost is high, ranging from $500 to $2,000 a month or $6,000 to $24,000 a year (USD), limiting availability in developing countries and leading to rationing in countries with universal healthcare such as the UK.
Omalizumab is a recombinant DNA-derived humanized IgG1k monoclonal antibody that selectively binds to free human immunoglobulin E (IgE) in the blood and interstitial fluid and to membrane-bound form of IgE (mIgE) on the surface of mIgE-expressing B lymphocytes. Unlike an ordinary anti-IgE antibody, omalizumab does not bind to IgE that is already bound by the high affinity IgE receptor (FcεRI) on the surface of mast cells, basophils, and antigen-presenting dendritic cells. IgE is commonly involved in type I hypersensitivity, which manifests the most prevalent allergic diseases. It has been estimated that as high as 20 to 40% of the populations who live a western lifestyle in economically advanced countries are affected by allergy and seek medical help. In the U.S., 8% of adults and 10% of children have asthma. While allergy occurs more frequently in individuals with higher serum IgE levels, such a correlation is only statistical and not absolute. Some allergic individuals have very low serum IgE, and some people with very high IgE have no allergic problems.
Xolair received approval by the U.S. Food and Drug Administration (FDA) in 2003 for treating patients 12 years and older with moderate to severe allergic asthma. It has also received approval in many other countries for treating patients 12 years and older with severe, persistent allergic asthma. Xolair was approved by the European Union in 2009 for treating patients 6 to 12 years old with severe, persistent allergic asthma. Thus, the primary use of Xolair is for patients mostly with severe, persistent allergic asthma, uncontrollable with oral or injectable corticosteroids. Those patients have already failed step I to step IV treatments and are in step V of treatment. Such a treatment scheme is consistent with the widely adopted guidelines for the management and prevention of asthma, issued by Global Initiative of Asthma (GINA), which was a medical guidelines organization launched in 1993 in collaboration with the National Heart, Lung, and Blood Institute, National Institutes of Health, USA, and the World Health Organization. The efficacy is more evident among severe asthmatics than among those with moderately severe disease. The response rates among treated severe "allergic" asthma patients are 60-80% or higher, probably depending on the patient screening procedures used by the various clinical groups of different specialties. In real-life clinical practice of 142 and 195 patients in Italy and Germany, respectively, 77 to 79% of patients or physicians gave a response of “excellent or good” for GETE (global evaluation of treatment effectiveness) scale after being treated with Xolair for 4 months. Because 20-30% of adult asthma cases are not related to allergy and unresponsive to Xolair, a reliable way to identify treatable patients has been a subject of considerable research interest. The primary benefits for the responding patients are reduced numbers of exacerbations, improved lung function, reduced numbers of emergency visits to the doctors, reduced days of hospitalization, and increased quality of life measurements. The other major benefit is that most responding patients can reduce or spare entirely the use of corticosteroids, which cause multiple serious side effects, when used at high doses for extended periods.
Due to the requirement for long-term administration and hence the high cost of a Xolair treatment regimen, and to the concern over long-term safety, Xolair treatment is not yet very common, especially in developing countries where medical funds are relatively scarce. Another barrier to Xolair's wide use is its injectable dosage form, which requires the patient to visit a physician's office or clinic every 2 to 4 weeks during treatment. In August 2010, the National Institute for Clinical Excellence (NICE) in the United Kingdom ruled that Xolair should not be prescribed on the National Health Service (NHS) to children under 12, causing widespread condemnation from asthma charities. NICE concluded that the high costs of the compound, over £250 per vial, did not represent a sufficiently high increase in quality of life. However, on March 7, 2013, NICE issued “final draft guidance” about the allowance of Xolair. It recommended Xolair as an option for treating severe, persistent allergic asthma in adults, adolescents and children following additional analyses and submission of a patient access scheme (PAS) by Novartis, the manufacturer of Xolair. Some immunologists have also suggested that because IgE may be a natural defense against parasitic diseases, treatment should not be recommended when living in environments where the presence of parasites is common.
The clinical investigators who have performed clinical trials on omalizumab for various indications have generally commented in their reports that omalizumab is safe and well tolerated, and rarely causes major adverse effects. After omalizumab has been in clinical trials for more than 15 years and approved by FDA and used by large numbers of patients for nearly 10 years, it is understood that IgE is dispensable for people living in modern societies. The main adverse effect of omalizumab is anaphylaxis (a life-threatening systemic allergic reaction), with a rate of occurrence of 1 to 2 patients per 1,000. Like other protein and antibody drugs, omalizumab also causes anaphylaxis, although at a relatively low frequency among antibody drugs. The allergic reaction toward omalizumab is probably not due to the binding characteristics of the antibody drug, but to the protein nature of the antibody. The patients who use Xolair are highly allergic. Thus, even though Xolair is administered with the purpose to suppress allergy (including anaphylactic reactions), it does not work immediately after injection.
IgE may play an important role in the immune system's recognition of cancer cells. Therefore, indiscriminate blocking of IgE-receptor interaction with omalizumab may have unforeseen risks. The data pooled in 2003 from the earlier phase I to phase III clinical trials showed a numeric imbalance in malignancies arising in omalizumab recipients (0.5%) compared with control subjects (0.2%). To clarify this imbalance, a more recent study was performed based on pooled analysis using much more comprehensive data from 67 phase I to IV clinical trials. The prespecified primary analysis assessed the incidence of primary malignancy in 32 randomized, double-blind, placebo-controlled (RDBPC) trials. In this analysis, there were 11,459 unique patients in all clinical trials (7,789 received omalizumab). The primary analysis identified malignancies in 25 patients (RDBPC trials): 14 in 4,254 omalizumab-treated patients and 11 in 3,178 placebo-treated patients. Incidence rates per 1,000 patient-years of observation time for omalizumab- and placebo-treated patients were 4.14 (95% CI, 2.26-6.94) and 4.45 (95% CI, 2.22-7.94), respectively; the corresponding rate ratio was 0.93 (95% CI, 0.39-2.27). Primary malignancies were of varying histologic type and occurred in a number of different organ systems; no cluster of histologies was identified. The study thus concluded that in this pooled analysis no association was observed between omalizumab treatment and risk of malignancy in RDBPC trials; the rate ratio was below unity. The data suggest that a causal relationship between omalizumab therapy and malignancy is unlikely.
Concerns were raised earlier about possible induction of Churg-Strauss syndrome, a rare form of systemic vasculitis associated with asthma, in patients receiving omalizumab. A retrospective review, which identified and analyzed cases of Churg-Strauss syndrome using the Novartis Argus global drug safety database for omalizumab in asthma patients, has indicated that Churg-Strauss syndrome may develop in patients who have an underlying eosinophilic disorder that is unmasked by the withdrawal of corticosteroids, which is common among patients receiving omalizumab treatment.
Mechanism of action
Persons with allergy are sensitized to make immune response to several or many proteins contained in one or more of the hundreds of harmless environmental substances, which they take in by inhalation (e.g., house dust mites, pollens, molds, pet animal dander, and other airborne allergens) and ingestion (e.g., peanuts, nuts, shellfish, and other food allergens), or through the skin (e.g., bee and fire ant stings, latex gloves). In these individuals, the IgE molecules, both allergen-specific and allergen-nonspecific ones, in their bodies bind to the high affinity IgE receptor (FcεRI) on the surface of mast cells and basophils. Under certain conditions, including but not limited to when the allergenic substances are taken in by a sensitized individual at substantial amounts, the allergenic proteins bind to the allergen-specific IgE bound by FcεRI on the surface of mast cells and basophils and trigger the activation of those inflammatory cells, which release a host of pharmacological mediators, such as histamine, leukotrienes, tryptase, inflammatory cytokines, and others, causing various allergic symptoms/diseases.
The rationale for designing the anti-IgE therapeutic antibodies and the pharmacological mechanisms of anti-IgE therapy have been summarized in review articles by the inventor of the anti-IgE therapy, Tse Wen Chang, and his colleagues. Omalizumab inhibits the binding of IgE to FcεRI on mast cells and basophils by binding to an antigenic epitope on IgE that overlaps with the site to which FcεRI binds. This feature is critical to omalizumab's pharmacological effects because a typical anti-IgE antibody can cross-link cell surface FcεRI-bound IgE, thereby aggregate FcεRI, and activate mast cells and basophils to discharge the horde of chemical mediators stored in the densely packed sacs inside the cells. However, when IgE is bound to the receptor, the antigenic epitope on IgE to which omalizumab binds is sterically hindered by the receptor and is not accessible to omalizumab binding, thus averting the anaphylactic effects presumably unavoidable with an ordinary anti-IgE antibody . Furthermore, although the peptide elements on IgE involved in binding to low affinity IgE receptor (FcεRII) on many cell types are different from the peptide elements involved in binding to FcεRI, omalizumab, by steric hindrance, also prevents binding of IgE to FcεRII. The reduced binding of IgE to both FcεRI and FcεRII has profound effects on the attenuation of IgE-mediated allergic responses.
Perhaps the most dramatic effect of omalizumab, which was not foreseen at the time when the anti-IgE therapy was designed and which was discovered during the clinical trials of omalizumab, is that as the free IgE in patients is depleted by omalizumab, the FcεRI receptors on basophils, mast cells, and dendritic cells are gradually down-regulated with somewhat different kinetics, rendering those cells much less sensitive to the stimulation by allergens. Many investigators have identified or elucidated a host of pharmacological effects, which help bring down the inflammatory status in the omalizumab-treated patients.
This article uses material from the Wikipedia article Omalizumab, which is released under the Creative Commons Attribution-Share-Alike License 3.0.