The Journal of Allergy and Clinical Immunology: In Practice
Review and Feature ArticleOmalizumab in Asthma: An Update on Recent Developments
Section snippets
Role of IgE in Allergic Asthma
In allergic asthma, the immune system reacts to a foreign protein as if it were a potentially harmful invader and triggers inflammatory events that contribute to asthma symptoms.16 Allergens that enter the airway are presented to T lymphocytes by dendritic cells, which initiate the cell-mediated immune response, particularly the maturation and migration of Th cells (Figure 1).16, 17 Th2 cells stimulate B cells to produce IgE antibodies as well as stimulate secretion of proallergic cytokines,
Mechanism of Action of Omalizumab
Omalizumab is composed of a human IgG framework and the complementarity-determining region from a murine anti-IgE antibody. Omalizumab specifically binds to free (unbound) IgE forming omalizumab:IgE complexes, thereby reducing free IgE levels and preventing IgE from interacting with FCεRIs as well as low-affinity IgE receptors (Figure 1).21 Because IgE bound to omalizumab cannot interact with FCεRI, omalizumab is able to inhibit the IgE-induced release of inflammatory mediators from mast cells
Effects on IgE
Serum-free IgE levels decline after omalizumab administration, but omalizumab forms a complex with previously unbound IgE, and this contributes to an increase in total IgE (made up of both free IgE and omalizumab:IgE complexes).25 Consequently, it is not possible to assess the treatment response to omalizumab by measuring total IgE. Initially, it was thought that IgE production remained constant over time, but results of recent research indicate that IgE production decreases then equilibrates
Clinical Benefits of Omalizumab Therapy
The clinical efficacy of omalizumab in patients with moderate-to-severe and severe allergic asthma has been well documented in several large-scale clinical trials that involved adults, adolescents, and children.
Effects on Airway Inflammation
Few studies have examined the anti-inflammatory effects of omalizumab. Bronchial biopsy specimens obtained from patients with mild steroid-naive asthma and who received omalizumab show a marked decrease in inflammatory cells (eosinophils, IgE+ cells, FcεRI+ cells, IL-4–secreting cells, and CD3+ T lymphocytes) within the epithelium and submucosa relative to patients who received placebo.56 Omalizumab also has been shown to reduce levels of circulating T lymphocytes and eosinophils.57 Compared
Effects on Remodelling
Cellular events in the allergic cascade lead to the development of airway inflammation and hyperresponsiveness, and repeated cycles of injury and repair contribute to airway remodelling.58 However, data from a recent randomized trial showed that omalizumab significantly reduced airway wall thickness (measured by high-resolution computed tomography) relative to placebo.59 There also is some evidence to suggest that omalizumab may alter the natural history of asthma.60, 61 Long-term (6 years)
Dosing and Administration
Omalizumab is administered as a subcutaneous injection every 2 or 4 weeks, with the dose being based on pretreatment serum total IgE levels and body weight, and selected using a dosing table.15 For omalizumab to cause a sufficient reduction in IgE levels (ie, to a target level of <50 ng/mL), dosing needs to be at a molar excess of approximately 15-fold over baseline IgE. Based on these measurements, 75 to 600 mg of omalizumab may be needed for each administration, with a maximum recommended
Known safety profile
Pooled data from the randomized trials in patients ages 12 to 75 years with allergic asthma indicate an overall incidence of adverse events with omalizumab similar to that in the placebo or control groups.68 The most common adverse events were nasopharyngitis, headache, upper respiratory tract infection, and sinusitis.68 In clinical trials in children, the most frequently reported adverse reactions were nasopharyngitis, upper respiratory tract infection, headache, and sinusitis.69
Anaphylaxis and immune-mediated events
Adverse events
Predictors of response
Not all patients respond to omalizumab treatment, and stopping therapy for nonresponders will minimize unnecessary drug exposure and health care expenditure.79 Therefore, characterizing the factors that could identify patients who are likely to respond to omalizumab treatment would be of benefit. In a 2004 pooled analysis of 2 placebo-controlled phase III studies, factors indicative of more-severe asthma (a history of emergency treatment, poor lung function [FEV1 ≤ 65% predicted] and high-dose
Ongoing Trials in Asthma
A number of trials are underway that are investigating the efficacy and safety of omalizumab in patients with allergic asthma (Table I). These studies include X-PORT and 2 additional observational studies (EXPECT, X-PAND) that are being conducted to further characterize the safety profile of omalizumab. In China, a randomized, placebo-controlled phase III study also is being conducted to evaluate the efficacy of omalizumab in adults with severe allergic asthma in this patient population.
Future Directions
Omalizumab has been actively investigated in several respiratory indications other than allergic asthma. For example, omalizumab has shown efficacy in patients with nonatopic asthma in a proof-of-concept study,23 a randomized, double-blind, placebo-controlled trial,52 and an observational registry.86 Case reports also indicate that omalizumab may have potential in the treatment of severe nonallergic asthma associated with elevated levels of serum IgE,87, 88 allergic bronchopulmonary
Summary
Omalizumab is an important treatment option for patients with moderate-to-severe or severe allergic asthma who remain uncontrolled despite current standard therapies. Recent studies have augmented the already extensive evidence base that supports the efficacy and tolerability of omalizumab in inadequately controlled allergic asthma, and recent changes to the dosing table in the European Union have expanded the population of patients eligible for treatment with omalizumab. Ongoing research will
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Novartis Pharma AG, Basel, Switzerland, provided support for the preparation of this article. Editorial support was provided by professional medical writer Brian Jepson, PhD (CircleScience), funded by Novartis Pharma AG.
Conflicts of interest: M. Humbert has received consulting fees from AstraZeneca, GlaxoSmithKline, TEVA, Novartis and Roche; has been a clinical trial investigator with AstraZeneca, GlaxoSmithKline, TEVA, Novartis and Roche. W. Busse has board membership with Merck; and has received consulting fees from Amgen, Novartis, GlaxoSmithKline, MedImmune, Genentech, Boston Scientific and ICON. N. Hanania has board membership with Novartis and Genentech; has received payment for lectures from Genentech; and his institution has received grants from Genentech and Novartis. S. Holgate has board membership with Synairgen; has received consulting fees from Synairgen, Novartis, Regeneron and Sterna; has received payment for lectures from Stallergene; and has stock options with Synairgen. P. J. Lowe, J. Canvin and V. J. Erpenbeck are employed by and have stock/stock options with Novartis Pharma AG.