Omalizumab

Omalizumab, sold under the trade name Xolair, is a medication originally designed to reduce sensitivity to allergens. It has been used to try to control severe allergic asthma, which does not respond to high doses of corticosteroids and less widely for chronic spontaneous urticaria. Omalizumab, sold under the trade name Xolair, is a medication originally designed to reduce sensitivity to allergens. It has been used to try to control severe allergic asthma, which does not respond to high doses of corticosteroids and less widely for chronic spontaneous urticaria. Omalizumab is a recombinant DNA-derived humanized IgG1k monoclonal antibody that specifically 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, it 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. Omalizumab is used to treat people 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. It is also used to treat people 12 years and above with chronic spontaneous urticaria (also called chronic idiopathic urticaria), which cannot be treated with elevated doses of H1-antihistamines. The main adverse effect 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 is probably not due to the binding characteristics of the antibody drug, but to the protein nature of the antibody. The patients who use omalizumab are generally highly allergic. Thus, even though the drug is administered with the purpose to suppress allergy (including anaphylactic reactions), it does not work immediately after injection. It also increases the risk of strokes and heart disease by approximately 60%. 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 eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), a rare form of systemic vasculitis associated with asthma, in patients receiving the drug. 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 this treatment. 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., wheat (gluten), 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.