Anti-IgE monoclonal antibody, omalizumab: a new treatment for allergic asthma

Omalizumab (Xolair Genentech, USA/Tanox, Inc., USA/Novartis Pharma AG, Switzerland) - a humanised antibody to IgE that reduces circulating free IgE - has been developed for the treatment of allergic asthma. It inhibits the early- and late-phase response to allergens, suppresses eosinophilic and T cell inflammation in asthmatic airways and reduces the levels of high-affinity IgE receptors on basophils. In clinical trials of moderate-to-severe asthma, omalizumab allowed a reduction in inhaled corticosteroid dosage while improving peak flows and reducing exacerbations, particularly in patients at high-risk of serious asthma-related morbidity and improved quality of life scores. When added to existing therapies of patients with more severe asthma, omalizumab also improved asthma control. Additionally, in asthma patients with concomitant perennial allergic rhinitis, omalizumab provides improvement in these comorbid conditions. Omalizumab is well-tolerated by asthma patients and represents a new approach to the treatment of the moderate-to-severe asthmatic patient. It is likely that it will first be used at the more severe end of the asthmatic diathesis.     

Anti-IgE monoclonal antibody,omalizumab: a new treatment for allergic asthma

Omalizumab (Xolair^?; Genentech, USA/Tanox, Inc., USA/Novartis Pharma AG, Switzerland) – a humanised antibody to IgE that reduces circulating free IgE – has been developed for the treatment of allergic asthma. It inhibits the early- and late-phase response to allergens, suppresses eosinophilic and T cell inflammation in asthmatic airways and reduces the levels of high-affinity IgE receptors on basophils. In clinical trials of moderate-to-severe asthma, omalizumab allowed a reduction in inhaled corticosteroid dosage while improving peak flows and reducing exacerbations, particularly in patients at high-risk of serious asthma-related morbidity and improved quality of life scores. When added to existing therapies of patients with more severe asthma, omalizumab also improved asthma control. Additionally, in asthma patients with concomitant perennial allergic rhinitis, omalizumab provides improvement in these comorbid conditions. Omalizumab is well-tolerated by asthma patients and represents a new approach to the treatment of the moderate-to-severe asthmatic patient. It is likely that it will first be used at the more severe end of the asthmatic diathesis.     

Evaluation of omalizumab from a health plan perspective

OBJECTIVE: To review the pathophysiology of allergic asthma and information on the pharmacology, clinical efficacy, safety profile, and direct drug costs for omalizumab to provide a basis for a defined role of this agent in allergic asthma therapy in managed care organizations. SUMMARY: Omalizumab is a monoclonal antibody targeting the high-affinity receptor binding site on human immunoglobulin E (IgE). When bound by omalizumab, IgE does not bind to basophils. As a result, degranulation is attenuated and allergic asthma symptoms are reduced. In asthma trials, omalizumab reduced inhaled corticosteroid and rescue medication requirements and improved asthma control and asthma quality of life in moderate-to-severe allergic asthmatics with disease poorly controlled by inhaled corticosteroids. Omalizumab has generally been well tolerated. However, injection site reactions occur in nearly 1 of every 2 patients, a problem that generally becomes less with continued dose administration. Severe injection site reactions are reported in 12% of patients. Other adverse events commonly reported in clinical trials include viral infections (23%), upper respiratory infections (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). Because the acquisition cost of omalizumab is high (generally $15,000 to $44,000 per patient per year, before contractual discounts), its use is cost-prohibitive in all but the most severe, poorly controlled allergic asthmatic patients who are utilizing large amounts of emergency health care resources to manage exacerbations. Experience with use of this drug beyond 52 weeks is lacking. CONCLUSION: Although omalizumab has demonstrated efficacy and safety in adults and adolescents with uncontrolled moderate-to-severe allergic asthma, its use should be restricted to a narrowly defined population of allergic asthmatics who utilize large amounts of health care resources. If targeted only toward this population, cost-of-care studies suggest that the high cost of this product in these patients could be offset by savings resulting from the less frequent use of high-intensity medical services for asthma exacerbations. The use of omalizumab beyond 52 weeks needs evaluation.     

Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma

OBJECTIVE: Omalizumab (Xolair), is a recombinant humanised monoclonal anti-immunoglobulin E (IgE) antibody, for the treatment of allergic asthma. This review describes how the correlation between clinical outcomes and a suitable surrogate marker (free serum IgE) led to the development of an individualised dosing strategy for omalizumab. It also demonstrates how subsequent studies using this dosing strategy were able to achieve low levels of IgE and clinical benefit. DATA SOURCES: Published articles and data on file (Novartis Pharma AG, Genentech). RESULTS: Studies in patients with IgE-mediated diseases of the airways have shown that clinical benefit with omalizumab is observed when free IgE levels in serum are reduced to 50 ng/ml (20.8 IU/ml) or less (target 25 ng/ml (10.4 IU/ml)). The ability of omalizumab to reduce free IgE levels to such levels is dependent on dose, the patient's weight and baseline IgE level. To simplify dosing, and ensure that free IgE reduction is achieved, an individualised tiered dosing table was developed from which patients with asthma, depending on weight and starting IgE level, receive omalizumab 150-375 mg by subcutaneous injection every 2 or 4 weeks. This dosing strategy has proved clinically efficacious for improving disease control in patients with allergic asthma, as shown by significantly lower exacerbation rates and decreased dependence on treatment with inhaled corticosteroids, along with improvements in symptoms, lung function and usage of rescue bronchodilators. CONCLUSIONS: The clinical efficacy of omalizumab has been optimised through the development of an individualised dosing table that emerged from an understanding of the pharmacodynamics of this agent.     

Evaluation of IgE Antibodies to Omalizumab (Xolair®) and Their Potential Correlation to Anaphylaxis

Omalizumab (Xolair®) is a recombinant humanized monoclonal antibody that selectively binds to human immunoglobulin E (IgE). Omalizumab is used to treat IgE-mediated diseases such as chronic idiopathic urticaria (CIU) and moderate to severe allergic asthma. In pre-marketing clinical trials in patients with asthma, anaphylaxis was reported in 3 of 3,507 (0.1%) patients. In post-marketing spontaneous reports, the frequency of anaphylaxis attributed to omalizumab use was estimated to be at least 0.2% of patients based on an estimated exposure of about 57,300 patients from June 2003 through December 2006. To better understand the risk of anaphylaxis in patients with allergic asthma receiving omalizumab, a post-marketing pharmacosurveillance study was initiated in 2009. As part of this study, an assay was developed to detect antibodies of IgE isotype to omalizumab. Serum samples from patients in the study were evaluated using this assay. Our results indicated that there was no observable correlation between either anaphylaxis or skin test reactivity and the presence of antibodies of IgE isotype to omalizumab. Here, we discuss the development of this assay as well as the results of the immunogenicity assessment.Key Words: biotin-mutant omalizumab-AAA, DIG-FcεR1-IgG, IgE isotype, omalizumab (Xolair®), omalizumab/total IgE molar ratio     

Role of anti-IgE monoclonal antibody (omalizumab) in the treatment of bronchial asthma and allergic respiratory diseases

IgE molecules play a crucial role in allergic respiratory diseases and may cause chronic airway inflammation in asthma through activation of effector cells via high-affinity (FcepsilonRI) or low-affinity (FcepsilonRII) IgE receptors. Since the discovery of IgE antibodies our understanding of the mechanisms of allergy has improved to such an extent that we can differentiate allergic/atopic from intrinsic respiratory diseases. Therapeutic anti-IgE antibodies, able to reduce free IgE levels and to block the binding of IgE to FcepsilonRI without crosslinking IgE and triggering degranulation of IgE-sensitized cells have been developed. This non-anaphylactogenic anti-IgE monoclonal antibody (omalizumab) binds IgE at the same site as these antibodies bind FcepsilonRI and FcepsilonRII. Consequently, omalizumab inhibits IgE effector functions by blocking IgE binding to high-affinity receptors on IgE effector cells and does not cause mast cell or basophil activation because it cannot bind to IgE on cell surfaces where the FcepsilonR1 receptor already masks the anti-IgE epitope. Studies in patients with atopic asthma showed that omalizumab decreases serum IgE levels and allergen-induced bronchoconstriction during both the early and late-phase responses to inhaled allergen. In several clinical controlled trials omalizumab resulted effective in reducing asthma-related symptoms, decreasing corticosteroid use and improving quality of life of asthmatic patients. Recent studies show the benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled by optimal pharmacological therapy. The anti-IgE approach to asthma treatment has several advantages, including concomitant treatment of other IgE-mediated diseases such as allergic rhinitis, a favorable safety profile and a convenient dosing frequency.     

A common NOS1AP genetic polymorphism is associated with increased cardiovascular mortality in users of dihydropyridine calcium channel blockers

AIMS

Omalizumab, a subcutaneously administered anti-IgE antibody, is effective for moderate-to-severe persistent allergic asthma. The aims were to (i) describe the population pharmacodynamics of free IgE with a mechanism-based, nonlinear, omalizumab–IgE binding model; (ii) deduce a target-free IgE suppression level by correlation with clinical outcomes; and (iii) check the adequacy of current approved dosing tables and explore potential doses and regimens beyond.

METHODS

Concentration data (omalizumab, free and total IgE) were obtained from 1781 patients aged 12–79 years, in four sparsely sampled randomized, placebo-controlled studies and 152 subjects in a richly sampled single-dose study. NONMEM predictive performance across the range of bodyweights (39–150 kg) and baseline IgE (19–1055 IU ml⁻¹) was checked by simulation. Predicted free IgE levels were correlated with time-averaged patient diary clinical outcomes.

RESULTS

The model accurately predicted observed omalizumab, free and total IgE concentrations. Free IgE concentrations correlated well with clinical signs and symptoms, allowing a target concentration of 14 ng ml⁻¹, at the midpoint of 4-week clinical observation periods, to be set for determining the dose and regimen for omalizumab.

CONCLUSIONS

The omalizumab–IgE binding model is predictive for free IgE and demonstrates a nonlinear time-dependent relationship between free IgE suppression and clinical outcomes in asthma. Although currently approved dosing tables are close to optimal, it should be possible to treat patients with higher levels of baseline IgE if higher doses can be administered.     

Anti-IgE monoclonal antibody (omalizumab) in the treatment of atopic asthma and allergic respiratory diseases

Since the discovery of immunoglobulin E (IgE) antibodies thirty-six years ago, our understanding of the mechanisms of allergy has improved to such an extent that we can now better differentiate allergy from non-allergic hypersensitivity, and allergic/atopic from intrinsic/non-atopic bronchial asthma. IgE antibodies are crucial immune mediators of airway inflammation in allergic atopic asthma and IgE-mediated hypersensitivity reactions are the likely mechanisms of allergen-induced airway obstruction. In addition, IgE may cause chronic airway inflammation in asthma through effector cells activated via high-affinity (Fcepsilon RI) or low-affinity (Fcepsilon RII) IgE receptors. Therapeutic anti-IgE antibodies able to reduce free IgE levels and to block the binding of IgE to Fcepsilon RI without cross-linking IgE and triggering degranulation of IgE-sensitised cells have been developed. This non-anaphylactogenic anti-IgE monoclonal antibody (rhuMAb-E25; omalizumab) binds IgE at the same site as these antibodies bind Fcepsilon RI and Fcepsilon RII. As a consequence, omalizumab inhibits IgE effector functions by blocking IgE binding to high-affinity receptors on IgE effector cells and does not cause mast cell or basophil activation because it cannot bind to IgE on cell surfaces where the Fcepsilon R1 receptor already masks the anti-IgE epitope. Studies in patients with atopic asthma demonstrated that omalizumab decreases serum IgE levels and allergen-induced bronchoconstriction during both the early and late-phase responses to inhaled allergen. In several clinical controlled trials omalizumab resulted to be able to reduce asthma-related symptoms, to decrease corticosteroid use and to improve quality of life of asthmatic patients.The anti-IgE approach to asthma treatment has several advantages, including concomitant treatment of other IgE-mediated diseases (allergic rhinitis, allergic conjunctivitis, atopic dermatitis and food allergies), a favourable side-effect profile and a twice-monthly dosing frequency.     

Safety of omalizumab in asthma

INTRODUCTION: Omalizumab is the first mAb to be introduced for the management of asthma. It is also the first agent designed to block the effects of IgE in initiating the allergic cascade resulting in asthma manifestations. Introduced in 2003, it is now widely used as an effective therapeutic tool in moderate-to-severe allergic asthmatics who are uncontrolled on maximal conventional therapy, including high-dose inhaled steroids and long-acting β-agonists. There is still understandable concern regarding the long-term effects of this drug. AREAS COVERED: The authors provide a review of safety data generated by controlled clinical trials and post-marketing surveillance as well as a brief overview of the clinical indications and efficacy of omalizumab. They also address specific issues of concern, including the risk of anaphylaxis and malignancy. The reader will gain a working knowledge of the role of omalizumab in current guidelines for the management of asthma. EXPERT OPINION: Omalizumab appears to be safe and well-tolerated. The possible association of malignancy with omalizumab has been of the greatest concern to patients and physicians. Analysis of clinical study data shows that this incidence is rare and the relative risk of cancer with omalizumab is not significantly different from that which is expected in the general population of people with asthma. As part of a relatively new class of agents, continued surveillance is needed as its indications expand and its use in the population continues to grow.     

Patient-reported outcomes in moderate-to-severe allergic asthmatics treated with omalizumab: a systematic literature review of randomized controlled trials

Objective: Randomized controlled trials (RCTs) have established the safety and efficacy of omalizumab on clinical parameters, and have also evaluated its impact on patient-reported outcomes (PROs). The purpose of this systematic literature review was to review published data based on PRO endpoints in order to determine the benefit of omalizumab as add-on therapy to inhaled corticosteroids in patients with moderate-to-severe persistent allergic asthma.

Methods: A systematic literature review was conducted of reference databases and recent conferences. RCTs of add-on omalizumab therapy in adults, adolescents, and children with moderate-to-severe persistent asthma were included. Two researchers independently screened and reviewed articles with regards to inclusion and exclusion criteria for relevant studies.

Results: Twenty-six trials met the criteria for inclusion. Of these, PRO measures were included in 19 trials to capture the impact of omalizumab on symptoms, 11 assessed patients for health-related quality-of-life (HRQoL), and four evaluated asthma control. Other PROs related to global evaluation of treatment effectiveness and work productivity. Overall, results demonstrated a significant difference across most PROs in favor of omalizumab add-on therapy vs placebo or comparators.

Conclusions: PROs are an integral part of outcome assessment in clinical trials related to asthma. The RCTs reviewed demonstrate that omalizumab treatment improves PROs in patients with moderate-to-severe persistent allergic asthma, particularly symptom control and HRQoL.     

Anti-IgE therapy with omalizumab in asthma and allergic rhinitis

The pharmacology, efficacy, dosage, adverse effects, and economics of anti IgE (omalizumab) are discussed. Omalizumab is the generic name for the human/murine chimeric (recombinant humanized) monoclonal IgG antibody. Anti-IgE prevents IgE from attaching to effector cells, and thereby blunts IgE-mediated inflammatory responses. After subcutaneous administration its absorption is slow, reaching peak concentration in serum after an average of 7-8 days. At recommended doses, serum free IgE levels decrease within 1 hour following the first dose and are maintained between doses. Dose and dosing frequency are adjusted according to body mass and serum total IgE concentration before the start of treatment. Omalizumab administered subcutaneously is an effective treatment for add-on therapy in patients with poorly controlled, moderate-to-severe allergic asthma and allergic rhinitis (adults and adolescents > 12 years). It reduces the requirement for inhaled corticosteroids while protecting against disease exacerbation. Omalizumab is well tolerated, but the safety profile requires long-term assessment in adults as well as in children.     

Omalizumab

* Omalizumab is a recombinant humanised monoclonal antibody which specifically binds to the C epsilon3 domain of immunoglobulin (Ig) E, the site of high-affinity IgE receptor binding. * Improvements in asthma symptoms and health-related quality-of-life, and a significant reduction in the frequency of asthma exacerbations were seen in allergic asthmatic patients treated with omalizumab. * Omalizumab was also effective in the treatment of children with allergic asthma demonstrating improvements in health-related quality-of-life and significant dosage reductions of inhaled corticosteroids. * Administration of omalizumab to patients with allergic rhinitis resulted in a rapid dose-dependent suppression of serum free IgE levels. * Omalizumab significantly improved health-related quality-of-life and nasal symptoms in patients with seasonal allergic rhinitis. Antihistamine requirements were also significantly reduced following treatment. * Adverse events were infrequent in clinical trials of omalizumab, and not significantly different from placebo. The most frequent drug-related event was mild to moderate urticaria.     

Safety of omalizumab in asthma

Introduction: Omalizumab is the first mAb to be introduced for the management of asthma. It is also the first agent designed to block the effects of IgE in initiating the allergic cascade resulting in asthma manifestations. Introduced in 2003, it is now widely used as an effective therapeutic tool in moderate-to-severe allergic asthmatics who are uncontrolled on maximal conventional therapy, including high-dose inhaled steroids and long-acting β-agonists. There is still understandable concern regarding the long-term effects of this drug.

Areas covered: The authors provide a review of safety data generated by controlled clinical trials and post-marketing surveillance as well as a brief overview of the clinical indications and efficacy of omalizumab. They also address specific issues of concern, including the risk of anaphylaxis and malignancy. The reader will gain a working knowledge of the role of omalizumab in current guidelines for the management of asthma.

Expert opinion: Omalizumab appears to be safe and well-tolerated. The possible association of malignancy with omalizumab has been of the greatest concern to patients and physicians. Analysis of clinical study data shows that this incidence is rare and the relative risk of cancer with omalizumab is not significantly different from that which is expected in the general population of people with asthma. As part of a relatively new class of agents, continued surveillance is needed as its indications expand and its use in the population continues to grow.     

Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma

SUMMARY

Objective: Omalizumab (Xolair), is a recombinant humanised monoclonal anti-immunoglobulin E (IgE) antibody, for the treatment of allergic asthma. This review describes how the correlation between clinical outcomes and a suitable surrogate marker (free serum IgE) led to the development of an individualised dosing strategy for omalizumab. It also demonstrates how subsequent studies using this dosing strategy were able to achieve low levels of IgE and clinical benefit.

Data sources: Published articles and data on file (Novartis PharmaAG, Genentech).

Results: Studies in patients with IgE-mediated diseases of the airways have shown that clinical benefit with omalizumab is observed when free IgE levels in serum are reduced to 50ng/ml (20.8?IU?ml^?1) or less (target 25?ng?ml^?1 (10.4IU?ml^?1)). The ability of omalizumab to reduce free IgE levels to such levels is dependent on dose, the patient's

weight and baseline IgE level. To simplify dosing, and ensure that free IgE reduction is achieved, an individualised tiered dosing table was developed from which patients with asthma, depending on weight and starting IgE level, receive omalizumab 150–375?mg by subcutaneous injection every 2 or 4 weeks. This dosing strategy has proved clinically efficacious for improving disease control in patients with allergic asthma, as shown by significantly lower exacerbation rates and decreased dependence on treatment with inhaled corticosteroids, along with improvements in symptoms, lung function and usage of rescue bronchodilators.

Conclusions: The clinical efficacy of omalizumab has been optimised through the development of an individualised dosing table that emerged from an understanding of the pharmacodynamics of this agent.     

Effect of omalizumab on the need for rescue systemic corticosteroid treatment in patients with moderate-to-severe persistent IgE-mediated allergic asthma: a pooled analysis

ABSTRACT

Background: Allergic asthma is an immunoglobulin E (IgE)-mediated disease characterized by frequent exacerbations following exposure to relevant allergens that leads to the development of chronic airway inflammation. Omalizumab, an anti-IgE antibody, reduces asthma exacerbation and hospitalization rates in patients with IgE-mediated allergic asthma. We investigated the effect of omalizumab on asthma outcomes in a retrospective pooled analysis of data from phase III clinical trials in patients (≥ 12 years) with moderate-to-severe persistent IgE-mediated allergic asthma.

Methods: Systemic corticosteroid bursts and physician and patient overall assessments of asthma control were assessed in patients who received add-on omalizumab or current asthma therapy (control). The association of physician and patient overall assessments with the number of steroid bursts were also evaluated.

Results: The analysis encompassed 4308 patients with moderate-to-severe persistent IgE-mediated allergic asthma (93% met GINA 2002 criteria for severe persistent asthma) from seven clinical trials. The number of systemic corticosteroid bursts was significantly lower in omalizumab-treated patients than in the control group (relative risk [95% CI]: 0.57 [0.48–0.66], p < 0.001). In addition, 58.5% of omalizumab recipients had complete/marked improvement in asthma control according to the physician's overall assessment (responders) vs. 36.9% in the control group (?p < 0.001). Similarly, 64.2% of omalizumab patients vs. 43.9% of control patients had complete/marked improvement according to the patient's overall assessment (?p < 0.001). There were statistically significant associations between systemic corticosteroid bursts and physician (Goodman–Kruskal gamma [95% CI]: 0.32 [0.26–0.38]) and patient (gamma [95% CI]: 0.29 [0.23–0.36]) overall assessments. This pooled analysis has limitations as it was not pre-specified.

Conclusions: Omalizumab therapy reduced the need for systemic corticosteroid bursts and improved effectiveness of asthma treatment as judged by both physicians and patients.     

抗IgE单克隆抗体奥马珠单抗治疗哮喘的研究进展

哮喘是由免疫球蛋白E（immunoglobulin E, IgE）抗体介导的超敏反应性疾病,其症状发生和气道高反应性与IgE密切相关。奥马珠单抗是重组人源化抗IgE单克隆抗体,能与血清中的游离IgE特异性结合,剂量依赖性地降低游离IgE水平。通过阻断IgE与其受体的结合、降低IgE与其受体的亲和力、阻止嗜碱性粒细胞和肥大细胞脱颗粒、抑制炎症细胞的激活和炎症介质的释放,奥马珠单抗可明显改善哮喘症状评分、减少哮喘急性发作、减少口服或吸入糖皮质激素的用量、改善哮喘患者的生活质量。奥马珠单抗的疗效已得到临床试验的证实,且其耐受性良好。     

Omalizumab modulates bronchial reticular basement membrane thickness and eosinophil infiltration in severe persistent allergic asthma patients

Severe persistent asthma causes a substantial morbidity and mortality burden and is frequently not well controlled, despite intensive guideline-based therapy. The unique monoclonal antibody approved for patients with severe allergic asthma is omalizumab: a recombinant humanised murine against IgE antibodies. The aim of the present study is to investigate the effect of long-term anti-IgE on the thickening of the reticular basement membrane (RBM) and eosinophil infiltration in bronchial biopsies from patients with severe persistent allergic asthma. Biopsies were obtained from 11 patients with severe persistent allergic asthma before and after (12 months) treatment with omalizumab. RBM thickness and eosinophils were measured by using light microscope image analysis. A significant mean reduction in RBM thickness and eosinophil infiltration were measured after one-year omalizumab treatment. No correlation between eosinophil reduction and RBM thickness reduction was found. No correlation between each of the previous two parameters and clinical parameters was detected. In conclusion, our study showed that a substantial proportion of severe asthmatics reduced the original bronchial RBM thickness and eosinophil infiltration after one-year treatment with anti-IgE, thus emphasizing the possible role of omalizumab in affecting airway remodeling in severe persistent allergic asthma.     

Efficacy of omalizumab, an anti-immunoglobulin E antibody, in patients with allergic asthma at high risk of serious asthma-related morbidity and mortality

AIM: Add-on therapy with omalizumab, an anti-immunoglobulin E antibody, is effective in improving disease control in patients with allergic asthma of varying severity. The aim of the present study was to determine the efficacy of omalizumab in a subgroup of patients at high risk of serious asthma-related morbidity and mortality. METHODS: A meta-analysis was performed of three randomised, double-blind, placebo-controlled studies (studies 1, 2 and 3) that enrolled 1412 patients with moderate or severe allergic asthma, all requiring daily treatment with inhaled corticosteroids (ICS). Omalizumab was administered subcutaneously every 2 or 4 weeks at a total 4-weekly dose of at least 0.016 mg/kg/IgE [IU/ml]. Each study consisted of a 16-week steroid-stable phase and a 12-16-week steroid-reduction phase, followed by a 24-week extension phase (studies 1 and 2 only). The primary outcome measure was the annualised rate of significant asthma exacerbation episodes (sAEEs) during the steroid-stable phase for the pooled subgroup of 254 high-risk patients (omalizumab, n = 135; placebo, n = 119). sAEEs were those requiring a doubling of baseline ICS dose (studies 1 and 2 only) or use of systemic steroids (all three studies). RESULTS: Overall, the number of patients with at least one sAEE during the steroid-stable phase was reduced from 35% (42/119) with placebo to 18% (24/135) with omalizumab. Mean sAEE rates were 1.56 and 0.69 per patient-year, respectively, a reduction of 56% with omalizumab (p = 0.007). Similar reductions in exacerbations in favour of omalizumab were observed for the whole study period and for all AEEs. In those with a history of hospitalisation in the last year, 6/49 (12%) on placebo vs. 2/44 (4.5%) on omalizumab were re-hospitalised during the study period. Patients treated with omalizumab also showed significantly greater improvements from baseline in PEFR (p = 0.026), overall AQoL (p = 0.042) and mean nocturnal (p = 0.007) and mean total (p = 0.011) asthma symptom scores compared with placebo. CONCLUSIONS: In patients at high risk of serious asthma-related morbidity and mortality, treatment with omalizumab offers the potential to halve the rate of asthma exacerbations and improve disease control.     

Omalizumab: a recombinant humanized anti-IgE antibody for allergic asthma.

PURPOSE: The pharmacology, efficacy, dosage, adverse events, and economics of omalizumab are discussed. SUMMARY: Omalizumab, a recombinant DNA-derived humanized monoclonal antibody, binds to the C epsilon3 domain of immunoglobulin E (IgE) and forms complexes that inhibit the immune system's response to allergens by averting IgE-mediated inflammatory changes. Omalizumab exhibits a similar pharmacokinetic profile in adults, adolescents, and children. Omalizumab is indicated for adults and adolescents with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Because of the limited data regarding the safety and effectiveness of omalizumab in children, the drug is indicated for patients 12 years of age or older. The recommended starting dosage is 150-375 mg s.c. every two or four weeks. Dosages and frequency of dose administration are determined by total serum IgE level, measured before the start of treatment, and body weight. Omalizumab is generally well tolerated in adults and children with allergic asthma. Adverse events most commonly observed are injection-site reaction, viral infection, upper-respiratory-tract infection, sinusitis, headache, and pharyngitis. Three large phase III clinical trials demonstrated that omalizumab is more effective than placebo in controlling moderate to severe allergic asthma in patients who have poor disease control or exacerbations despite recommended therapy. Currently, there are no clinical comparisons of omalizumab with other standard treatments for asthma; therefore, it is difficult to determine its overall place in therapy. CONCLUSION: Omalizumab should be considered as a second-line therapy for patients with moderate to severe persistent allergic asthma.     

Population-Based Efficacy Modeling of Omalizumab in Patients with Severe Allergic Asthma Inadequately Controlled with Standard Therapy

Omalizumab, a recombinant humanized monoclonal antibody, is the first approved anti-immunoglobulin E (IgE) agent for the treatment of subjects with moderate to severe persistent allergic asthma that are inadequately controlled by the standard of care. The objective of this study was to quantitatively characterize relationships between serum free IgE and pulmonary function (as measured by forced expiratory volume in 1 s [FEV1]) as well as serum free IgE and airway inflammation (as measured by fractional exhaled nitric oxide [FeNO]) using population-based efficacy models. Data were collected from patients in the EXTRA trial who received omalizumab or placebo 150 to 375 mg subcutaneously every 2 or 4 weeks from week 0 to 48 with constant standard of care as background therapy. None of the covariates evaluated, including demographics, disease status, and baseline pharmacodynamic biomarkers, were significant in explaining the variability in the FEV1 or FeNO response to omalizumab. Results from the efficacy models further confirmed the current omalizumab dosing rationale based on the mean target free IgE level of 25 ng/ml and quantified the variability for the target. In addition, the resulting population models could be used to predict population FEV1 or FeNO response for omalizumab and/or other anti-IgE therapeutics for which PK-IgE models are constructed.