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|Anti-IgE therapy in pediatric allergic asthma||
Licari A, Marseglia GL
Department of Cinical Surgical Diagnostic and Pediatrics Sciences, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
The therapeutic application of monoclonal antibodies in children is a developing field, though a number of promising results have already been obtained, such as the approval of anti-IgE therapy in pediatric allergic asthma. The aim of this review is to provide a clinical ovierview of anti-IgE therapy, in particular focusing on omalizumab, the first biologic treatment in the field of respiratory allergy.
Keywords: omalizumab, anti-IgE treatment, severe asthma, allergic asthma, children.
Asthma is one of the most common chronic diseases in childhood. Although the majority of children control symptoms through avoidance of triggering factors and/or with the help of low to moderate doses of current available medications, an estimated 5–10% of patients remain symptomatic despite receiving large amounts of treatment1. Children with uncontrolled severe asthma have poor quality of life (QoL), frequent asthma exacerbations and lung function impairment, are at high risk of side-effects from medication and account for significant medical and social costs1. The aim of this review is to provide a clinical ovierview of anti-IgE therapy, in particular focusing on omalizumab, the first biologic treatment approved for pediatric uncontrolled allergic asthma.
Omalizumab in pediatric allergic asthma
Omalizumab is the most advanced humanized anti-IgE mAb approved for the treatment of allergic asthma, both in adults and children2, 3. Omalizumab received FDA regulatory approval in 2003 for moderate to severe persistent asthma, in patients 12 years of age and older, with a positive skin test or in vitro reactivity to a perennial aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids. In 2009 EMEA approved the use of omalizumab in children from 6 years and above. International asthma guidelines1, 4, also supported by the latest international consensus on pediatric asthma5, currently recommend omalizumab for children with moderate to severe allergic asthma not controlled with other medications, which in many cases will include high-dose inhaled corticosteroids in combination with a long-acting b 2-agonist. The anti-IgE mAb omalizumab expresses a high degree of isotype specificity and can neutralize serum free IgE without affecting other antibody classes. It acts specifically binding serum-free IgE and interrupting the allergic cascade by preventing binding of IgE with its high- (FceRI) and low-affinity (FceRII) receptors on mast cells, basophils, antigen presenting cells and other inflammatory cells6. The reduction of free IgE levels following omalizumab administration leads to a downregulation of FceRI expression on inflammatory cells7. In addition, it has been demonstrated that omalizumab also reduces FceRI in vivo expression on dendritic cells, which may lead to a reduction in allergen presentation to T cells and attenuation in the Th2 -mediated allergic pathway8. Thanks to these effects, omalizumab decreases proinflammatory mediator release, thus reducing allergic inflammation. In particular, treatment with omalizumab decreases mast-cell activation and sensitivity and reduces eosinophil infiltration and activation8. The pharmacokinetics of omalizumab have been studied in adult and adolescent patients with allergic asthma. Omalizumab is recommended to be administered as a subcutaneous injection. The dose and frequency of dosing are guided by a nomogram that is derived from the total serum IgE level and the body mass index. After subcutaneous administration, omalizumab is absorbed with an average absolute bioavailability of 62%. Peak serum concentrations are reached after an average of 7 - 8 days, and the half-life is ~ 26 days9 (McKeage).
Free IgE levels in serum are reduced in a dose-dependent manner within 1 h following the first dose and maintained between doses. Total IgE levels (bound and unbound) in serum increase after the first dose due to the formation of omalizumab-IgE complexes, which have a slower elimination rate compared with free IgE, and standard clinical lab assays detect IgE in both free and complexed forms. At 16 weeks after the first dose, average serum total IgE levels are fivefold higher compared with pre-treatment levels. After discontinuation of omalizumab, the increase in total IgE and decrease in free IgE are reversible, with no observed rebound in IgE levels after drug washout. Due to the requirement of neartotal suppression of IgE levels for clinical efficacy, the drug is only FDA approved for pretreatment IgE levels of 30 -1500 IU/ml10 (scheda tecnica). Considering the distribution of the drug, omalizumab forms complexes of limited size with IgE. Depending on the relative concentrations of both free serum IgE and omalizumab, stable and biologically inert omalizumab: IgE complexes are formed, typically trimers of ~ 490 - 530 kD or hexamers of approximately 1.000 kD9.
Initial studies with omalizumab showed attenuation of allergen-induced asthmatic responses11, followed by studies demonstrating improvements in asthma symptoms and health-related QoL12 and a significant reduction in the frequency of asthma exacerbations in allergic asthmatic patients13. Since the first launch of omalizumab, its earliest efficacy and safety data have been assessed in adults and adolescents (> 12 years; the adolescent group (12–17 years) included in these studies represented only a small percentage of the overall sample (between 6 and 8 %)14-19. In the last 10 years, evidence from randomized clinical trials conducted in pediatric populations has shown that adding omalizumab to current asthma therapy is effective and well tolerated in children (aged 6–12 years) with uncontrolled allergic asthma20-22. Several multicenter, observational studies support results of randomized trials, demonstrating that omalizumab is effective as add-on therapy in adults, adolescents and children with severe persistent allergic asthma in the real-world setting23, 24. Moreover, a recent systematic review established the efficacy and safety of subcutaneous omalizumab as an add-on therapy to corticosteroids in school-age children and adolescents with moderate-to-severe persistent allergic asthma25.
The safety profile of omalizumab has been extensively studied and shows an overall incidence of adverse events similat to that in the placebo or control groups25, 26. Hypersensitivity reactions including urticaria, skin rush, and anaphylaxis had a low incidence rate. Post-marketingdata, based on an estimated exposure of 57300 patients between 2003 and 2006, showed that the frequency of anaphylaxis attributed to omalizumab use was estimated to be at least 0.2 % of patients, comparable to the incidence of anaphylactic reactions for other drugs, such as oral penicillin, aspirin and nonsteroidal anti-inflammatory drugs, as well as to the incidence of anaphylaxis reported in the general population (about 0.05 - 2%)27. There were no unusual safety issues, no cases of serum sickness, no deaths, nor malignancies reported in patients receiving omalizumab. Additional long-term safety data come from the 5-year EXCELS study, which specifically evaluated the incidence of all malignant tumors and other serious adverse events reported from greater than 7000 patients with moderate-to-severe persistent allergic asthma in a real-world clinical practice setting28. Initiated at the request of the FDA, this observational cohort study did not show any increase in the risk of primary malignancy with long-term omalizumab therapy28.
The expading field of anti-IgE treatment in asthma
To overcome limitations of omalizumab, first represented by dosing restrictions based on IgE levels, an expected progress has been the production of a new set of mAbs with greater avidity for IgE: RG7449, a new humanized mAb that binds to the M1 segment of membrane IgE and has as a target the B-lymphocytes before they are activated to produce IgE; QGE031/ligelizumab, an highly potent inhibitor of the high-affinity IgE receptor, that is currently under investigation in patients with allergic asthma, (4/5 clinical severity stage according to GINA guidelines), in a Phase IIa clinical trial, with omalizumab as active comparator3.
Omalizumab is the first and, at present, the only mAb available in clinical respiratory medicine for the treatment of moderate-to-severe allergic asthma. Several clinical trials and observational studies, involving adults, adolescents and children, have repeatedly shown that omalizumab is safe and effective in reducing exacerbations and reducing corticosteroid use, as well as baseline control of asthma. Additional studies are still required to characterize the potential benefit of anti-IgE therapy in airway wall remodelling in asthma and to identify potential biomarkers of response.
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|www.thechild.it Four-monthly Journal of Pediatrics edited by Genetics and Pediatric Association (APIG)
Law March 7th, 2001, n. 62 - Press Register Court of Messina n. 4/2012
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