Omalizumab

Omalizumab, a monoclonal antibody that targets circulating IgE, is approved as add-on therapy for adult and adolescent patients with severe allergic asthma in the EU and moderate to severe allergic asthma in the US. Several randomized, double-blind trials have demonstrated the therapeutic efficacy of subcutaneously administered omalizumab as add-on therapy in patients with allergic asthma. The INNOVATE study included only patients with severe persistent disease, and omalizumab was associated with a statistically significant relative reduction of 26% in the rate of clinically significant asthma exacerbations (primary endpoint) compared with placebo (after adjustment for an imbalance in the exacerbation history at baseline). Results for a number of secondary outcomes also significantly favored omalizumab over placebo. Two large studies in patients with moderate to severe allergic asthma showed that, compared with placebo, omalizumab was associated with statistically significant relative reductions of 41-58% in the mean number of asthma exacerbations (primary endpoint) during the trial. Omalizumab also significantly reduced asthma symptom scores and the use of inhaled corticosteroids and rescue medication. Moreover, all of these trials showed that omalizumab was associated with clinically and statistically significant improvements from baseline in overall asthma-related quality of life.In general, omalizumab was well tolerated in clinical trials. Most adverse events were mild or moderate in severity and occurred at a similar frequency among omalizumab and placebo recipients. Injection-site reactions were the most commonly reported adverse events in clinical trials with omalizumab. Although rare, anaphylactic reactions have occurred following administration of omalizumab, and appropriate precautions should be taken.Results of several large randomized trials, therefore, have established omalizumab as an effective and well tolerated agent for use as add-on therapy in patients with severe persistent allergic asthma (EU labeling) or those with moderate to severe disease (US labeling). In addition, international treatment guidelines acknowledge the importance of omalizumab as a treatment option in these difficult-to-treat patient populations.     

An evaluation of the cost-effectiveness of omalizumab for the treatment of severe allergic asthma

Omalizumab is the first licensed anti-immunoglobulin (Ig) E antibody shown to be effective for treatment of allergic (IgE-mediated) asthma. Recent international guidelines recommend omalizumab as add-on treatment to fixed dose inhaled corticosteroid (ICS) and long-acting β₂-agonist (LABA) combination therapy. However, omalizumab is more expensive than other current asthma treatments and health and reimbursement authorities are increasingly demanding evidence of economic benefit to support pricing and formulary listing. The aims of this article are to (i) summarize data on the human and economic burden of severe asthma, (ii) summarize the efficacy data obtained for omalizumab in clinical trials in patients with inadequately controlled severe persistent allergic asthma despite high-dose ICS plus a LABA, and (iii) discuss the cost-effectiveness evidence published for omalizumab in this patient population. A wealth of evidence exists highlighting that the health, economic and societal burden of asthma is considerable and is highly skewed towards patients with severe asthma, particularly when asthma is inadequately controlled. Omalizumab is clinically beneficial in patients with severe persistent allergic asthma despite high-dose ICS plus a LABA, particularly in a subgroup of patients who respond to therapy. In patients who respond to therapy, the cost-effectiveness of omalizumab compares well with other biologic treatments for chronic illness.     

Omalizumab improves asthma-related quality of life in patients with severe allergic asthma

BACKGROUND: We have previously shown that omalizumab, a recombinant humanized monoclonal anti-IgE antibody, reduces asthma exacerbations and decreases inhaled corticosteroid (ICS) requirement in patients with severe allergic asthma who were symptomatic despite moderate-to-high doses of ICSs. OBJECTIVE: The aim of the present study was to assess the effects of omalizumab on asthma-related quality of life (QOL). METHODS: These analyses were part of a multicenter, 52-week, randomized, double-blind, placebo-controlled study assessing the efficacy, safety, and tolerability of subcutaneous omalizumab (> or =0.016 mg/kg of IgE [in international unit per milliliter] per 4 weeks) in 525 adults with severe allergic asthma. A 16-week steroid-stable phase was followed by a 12-week steroid-reduction phase and a 24-week double-blind extension phase. The effect of treatment on asthma-related QOL was evaluated by using the Asthma Quality of Life Questionnaire (AQLQ) administered at baseline and at weeks 16, 28, and 52. RESULTS: The 2 treatment groups were comparable in terms of baseline AQLQ scores. At weeks 16, 28, and 52, omalizumab-treated patients demonstrated statistically significant improvements across all AQLQ domains, as well as in overall score. Moreover, a greater proportion of patients receiving omalizumab achieved a clinically meaningful improvement in asthma-related QOL during each phase of the study. Greater than 50% of both patients and investigators rated treatment similarly with omalizumab as excellent or good compared with less than 40% of placebo recipients. CONCLUSION: In patients requiring moderate-to-high doses of ICSs for severe allergic asthma, the measurably improved disease control afforded by add-on omalizumab therapy is paralleled by clinically meaningful improvements in asthma-related QOL.     

Omalizumab in allergic diseases, a recent review

Omalizumab is a biological engineered molecule, targeting the Cepsilon3 domain of the IgE molecule. It binds with free IgE and prevents free IgE from attaching to high-affinity IgE receptor (FcepsilonRI) on effector cells such as mast cells, basophils and also on dendritic cells. The result is a blocking of mediator release from these cells and the inhibition of antigen presentation by dendritic cells. In addition, omalizumab downregulates FcepsilonRI expression on these effector cells. Omalizumab prevents early and late phase allergic reactions of skin and lungs. Omalizumab has been investigated extensively in moderate-to-severe asthma in adults and children. It effectively reduces rates of asthma exacerbation, emergency visits for asthma and hospital admissions among these patients. Currently, omalizumab is primarily indicated for patients, age 6 years and over, with moderate to severe asthma (GINA step 4). Omalizumab was investigated in patients with seasonal allergic rhinitis (to ragweed, birch and grass pollens) and has been found to improve rhinitis symptoms and to reduce medication use among these patients. Administered together with allergen immunotherapy, omalizumab reduced incidence of side effects and rates of anaphylaxis from allergen immunotherapy. Omalizumab has been investigated in the treatment of food allergy, atopic dermatitis and urticaria. Despite benefits observed from these initial trials, it further deserves investigations to clarify optimal conditions for use in these conditions. Side effects from omalizumab were few, however, it requires careful considerations in administration of this agent. An observational period (up to 2 hours after the first three doses) and the availability of auto-injectable epinephrine are recommended. Pharmacoeconomics of omalizumab is briefly reviewed. Omalizumab represents a major breakthrough of translational medicine in allergy.     

Omalizumab therapy for children and adolescents with severe allergic asthma

Omalizumab, a therapeutic humanized monoclonal antibody specific for human IgE, was introduced in clinical practice more than a decade ago as an add-on therapy for moderate-to-severe allergic asthma in patients aged ≥12 years. Omalizumab has been demonstrated to be effective in adults with uncontrolled persistent asthma, with an excellent safety profile. In simple terms, omalizumab works by inhibiting the allergic cascade, that is, by neutralization of the circulating free IgE. This leads to reduction in the quantity of cell-bound IgE, downregulation of high-affinity IgE receptors, and, eventually, prevention of mediator release from effector cells. Evidence is far less abundant on the role of omalizumab in pediatric asthma. Although efficacy and safety of omalizumab in children and adolescents with uncontrolled, persistent allergic asthma has been recognized as well, further studies are needed to clarify a number of open questions in this specific patient population.     

The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation

Anti-IgE therapy with omalizumab reduces serum levels of free IgE and downregulates expression of IgE receptors (Fc epsilonRI) on mast cells and basophils. In the airways of patients with mild allergic asthma, omalizumab reduces Fc epsilonRI+ and IgE+ cells and causes a profound reduction in tissue eosinophilia, together with reductions in submucosal T-cell and B-cell numbers. In patients with seasonal allergic rhinitis, omalizumab inhibits the allergen-induced seasonal increases in circulating and tissue eosinophils. Omalizumab decreases Fc epsilonRI expression on circulating dendritic cells, which might lead to a reduction in allergen presentation, T(H)2 cell activation, and proliferation. As a systemic anti-IgE agent, omalizumab has demonstrated clinical efficacy in patients with moderate and severe allergic asthma and in those with seasonal and perennial allergic rhinitis, as well as in patients with concomitant allergic asthma and allergic rhinitis. The anti-inflammatory effects of omalizumab at different sites of allergic inflammation and the clinical benefits of anti-IgE therapy in patients with allergic asthma and allergic rhinitis emphasize the fundamental importance of IgE in allergic inflammation.     

Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma

BACKGROUND: Patients with severe asthma are often inadequately controlled on existing anti-asthma therapy, constituting an unmet clinical need. OBJECTIVE: This randomized, double-blind, placebo-controlled trial evaluated the ability of omalizumab, a humanized monoclonal anti-IgE antibody, to improve disease control sufficiently to enable inhaled corticosteroid reduction in patients with severe allergic asthma. METHODS: After a run-in period when an optimized fluticasone dose (> or =1000 microg/day) was received for 4 weeks, patients were randomized to receive subcutaneous omalizumab [minimum 0.016 mg/kg/IgE (IU/mL) per 4 weeks; n=126] or matching placebo (n=120) at intervals of 2 or 4 weeks. The study comprised a 16-week add-on phase of treatment followed by a 16-week fluticasone-reduction phase. Short-/long-acting beta(2)-agonists were allowed as needed. RESULTS: Median reductions in fluticasone dose were significantly greater with omalizumab than placebo: 60% vs. 50% (P=0.003). Some 73.8% and 50.8% of patients, respectively, achieved a > or =50% dose reduction (P=0.001). Fluticasone dose reduction to < or =500 microg/day occurred in 60.3% of omalizumab recipients vs. 45.8% of placebo-treated patients (P=0.026). Through both phases, omalizumab reduced rescue medication requirements, improved asthma symptoms and asthma-related quality of life compared to placebo. CONCLUSION: Omalizumab treatment improves asthma control in severely allergic asthmatics, reducing inhaled corticosteroid requirements without worsening of symptom control or increase in rescue medication use.     

Anti-immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy

Omalizumab is a humanized monoclonal anti-IgE antibody developed for the treatment of allergic disease, with established efficacy in patients with moderate-to-severe allergic asthma and in patients with intermittent (seasonal) and persistent (perennial) allergic rhinitis (AR). Omalizumab is known to result in a marked reduction in serum levels of free IgE and down-regulation of IgE receptors on circulating basophils. Recent work has shed further light on its mechanism of action, showing significant and profound reductions in tissue (nasal and bronchial) eosinophils and in bronchial IgE+ cells (mast cells), as well as T cells and B cells. Omalizumab treatment was also shown to be associated with down-regulation of IgE receptors on circulating (precursor) dendritic cells, suggesting that blocking IgE may inhibit more chronic aspects of allergic inflammation involving T cell activation. Further work with omalizumab demonstrated it to have important benefits in patients with poorly controlled asthma despite high-dose inhaled corticosteroid therapy, and analysis of clinical data suggests that the patients who are the best 'responders' to anti-IgE treatment are those with asthma at the more severe end of the spectrum. Notably, systemic anti-IgE therapy with omalizumab has been shown to improve symptoms, quality of life and disease control (asthma exacerbations) in patients with concomitant asthma and persistent AR. These impressive clinical data and the studies elucidating the anti-inflammatory profile of omalizumab also serve to emphasize the fundamental importance of IgE in the pathogenesis of allergic diseases.     

Impact of omalizumab on quality-of-life outcomes in patients with moderate-to-severe allergic asthma.

BACKGROUND: Moderate-to-severe allergic asthma has a substantial impact on patients' quality of life (QOL). Despite care consistent with treatment guidelines, many patients with moderate-to-severe asthma still experience variability in asthma control, signaling an unmet need within this population. Omalizumab has recently demonstrated clinical efficacy and safety in treating IgE-mediated asthma. OBJECTIVE: To summarize asthma-related QOL outcomes associated with omalizumab therapy in moderate-to-severe allergic asthma. METHODS: A systematic review and meta-analysis of asthma-related QOL on data from published clinical trials and unpublished clinical study reports were conducted on omalizumab. The Juniper Asthma Quality of Life Questionnaire (AQLQ) measured asthma-related QOL. RESULTS: Statistically significant results for asthma-related QOL end points consistently favored omalizumab over placebo. Moderate to large effect sizes in the omalizumab groups were observed across the clinical trials and during study extension phases. A meta-analysis indicated a 1.6- to 2-fold increase in moderate (> or = 1 point) and a 1.8- to 2.1-fold increase in large (> or = 1.5 point) improvements in AQLQ overall scores in the omalizumab-treated group compared with placebo during the steroid-stabilization and steroid-reduction phases of the trials. CONCLUSIONS: Significant differences and large effect sizes favoring omalizumab were observed despite the control group receiving active, guideline-consistent treatment. The meta-analysis findings demonstrate that omalizumab treatment provides QOL benefits in patients with moderate-to-severe allergic asthma.     

Omalizumab is effective in the long-term control of severe allergic asthma.

BACKGROUND: Previous reports show that addition of omalizumab to standard therapy reduces asthma exacerbations and simultaneously decreases use of inhaled corticosteroids (ICSs) and rescue medication in patients with allergic asthma. OBJECTIVE: To determine the effect of omalizumab on long-term disease control in patients with severe allergic asthma. METHODS: The present study concerns the 24-week, double-blind extension phase to a previous 28-week core study in which patients received subcutaneous omalizumab or matching placebo (at least 0.016 mg/kg/IgE [IU/mL] every 4 weeks) for 16 weeks in addition to their existing ICS therapy (beclomethasone dipropionate [BDP]; steroid-stable phase), followed by a 12-week phase in which controlled attempts were made to gradually reduce ICS therapy (steroid-reduction phase). During the extension phase patients were maintained on randomized treatment (omalizumab or placebo) and the lowest sustainable dose of BDP. The use of other asthma medications was permitted during the extension phase. Investigators were also allowed to switch patients from BDP to other ICS medications if considered necessary. RESULTS: A total of 460 patients (omalizumab, n = 245; placebo, n = 215) entered the extension phase. Overall, omalizumab-treated patients experienced significantly fewer exacerbations vs placebo during the extension phase (0.60 and 0.83 exacerbations per patient, respectively; P = 0.023), despite a sustained significant reduction in their use of ICS (mean BDP equivalent dose: omalizumab, 227 microg/d; placebo, 335 microg/d; P < 0.001). Treatment with omalizumab was well tolerated and the incidence of adverse events was similar in both treatment groups. CONCLUSIONS: These results indicate that omalizumab is effective in the long-term control of severe allergic asthma.     

Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE

BACKGROUND: Patients with severe persistent asthma who are inadequately controlled despite Global Initiative for Asthma (GINA) 2002 step 4 therapy are a challenging population with significant unmet medical need. We determined the effect of omalizumab on clinically significant asthma exacerbations (requiring systemic corticosteroids) in the first omalizumab study to exclusively enrol patients from this difficult-to-treat patient population. METHODS: Following a run-in phase, patients (12-75 years) inadequately controlled despite therapy with high-dose inhaled corticosteroids (ICS) and long-acting beta(2)-agonists (LABA) with reduced lung function and a recent history of clinically significant exacerbations were randomized to receive omalizumab or placebo for 28 weeks in a double-blind, parallel-group, multicentre study. RESULTS: A total of 419 patients were included in the efficacy analyses. The clinically significant asthma exacerbation rate (primary efficacy variable), adjusted for an observed relevant imbalance in history of clinically significant asthma exacerbations, was 0.68 with omalizumab and 0.91 with placebo (26% reduction) during the 28-week treatment phase (P = 0.042). Without adjustment, a similar magnitude of effect was seen (19% reduction), but this did not reach statistical significance. Omalizumab significantly reduced severe asthma exacerbation rate (0.24 vs 0.48, P = 0.002) and emergency visit rate (0.24 vs 0.43, P = 0.038). Omalizumab significantly improved asthma-related quality of life, morning peak expiratory flow and asthma symptom scores. The incidence of adverse events was similar between treatment groups. CONCLUSIONS: In patients with inadequately controlled severe persistent asthma, despite high-dose ICS and LABA therapy, and often additional therapy, omalizumab significantly reduced the rate of clinically significant asthma exacerbations, severe exacerbations and emergency visits. Omalizumab is effective and should be considered as add-on therapy for patients with inadequately controlled severe persistent asthma who have a significant unmet need despite best available therapy.     

‘Real‐life’ effectiveness studies of omalizumab in adult patients with severe allergic asthma: systematic review

We reviewed 24 ‘real‐life’ effectiveness studies of omalizumab in the treatment of severe allergic asthma that included 4117 unique patients from 32 countries with significant heterogeneity in patients, clinicians and settings. The evidence underscores the short‐ and long‐term benefit of anti‐IgE therapy in terms of the following: improving lung function; achieving asthma control and reducing symptomatology, severe exacerbations and associated work/school days lost; reducing healthcare resource utilizations, in particular hospitalizations, hospital lengths of stay and accident specialist or emergency department visits; reducing or discontinuing other asthma medications; and improving quality of life – thus confirming, complementing and extending evidence from randomized trials. Thus, omalizumab therapy is associated with signal improvements across the full objective and subjective burden of illness chain of severe allergic asthma. Benefits of omalizumab may extend up to 2–4 years, and the majority of omalizumab‐treated patients may benefit for many years. Omalizumab has positive short‐ and long‐term safety profiles similar to what is known from randomized clinical trials. Initiated patients should be monitored for treatment response at 16 weeks. Those showing positive response at that time are highly likely to show sustained treatment response and benefit in terms of clinical, quality of life and health resource utilization outcomes.     

Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with poorly controlled (moderate-to-severe) allergic asthma

BACKGROUND: Patients with poorly controlled asthma have greater morbidity and mortality. This study evaluated the efficacy and tolerability of omalizumab in patients with poorly controlled, moderate-to-severe allergic asthma. METHODS: This was a randomized, open-label, multicentre, parallel-group study. A total of 312 patients (12-73 years) receiving >/=400 microg/day (adolescent) or >/=800 microg/day (adult) inhaled beclomethasone dipropionate, or equivalent were included. Patients received best standard care (BSC) with or without omalizumab [at least 0.016 mg/kg/IgE (IU/ml) every 4 weeks] for 12 months. RESULTS: The annualized mean number of asthma deterioration-related incidents was reduced from 9.76 with BSC alone (n = 106) to 4.92 per patient-year with omalizumab (n = 206) (P < 0.001). Mean clinically significant asthma exacerbation rates were 2.86 and 1.12 per patient-year, respectively (P < 0.001). Omalizumab-treated patients (41.4%) required rescue medication <1 day/week compared with 20.7% for BSC alone (P < 0.001). Omalizumab improved absolute forced expiratory volume in 1 s (FEV(1)) compared with BSC alone (2.48 and 2.28 l, respectively; P < 0.05) and reduced symptom scores relative to BSC alone (decrease of 6.5 and 0.7 respectively; P < 0.001). Omalizumab was well-tolerated. CONCLUSIONS: Omalizumab administered as add-on therapy to BSC benefits patients with poorly controlled, moderate-to-severe allergic asthma.     

Efficacy and safety of treatment with biologicals (benralizumab,dupilumab and omalizumab) for severe allergic asthma: A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma

Allergic asthma is a frequent asthma phenotype. Both IgE and type 2 cytokines are increased, with some degree of overlap with other phenotypes. Systematic reviews assessed the efficacy and safety of benralizumab, dupilumab and omalizumab (alphabetical order) vs standard of care for patients with uncontrolled severe allergic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma-related outcomes were evaluated. The risk of bias and the certainty of the evidence were assessed using GRADE. All three biologicals reduced with high certainty the annualized asthma exacerbation rate: benralizumab incidence rate ratios (IRR) 0.63 (95% CI 0.50 − 0.81); dupilumab IRR 0.58 (95%CI 0.47 − 0.73); and omalizumab IRR 0.56 (95%CI 0.42 − 0.73). Benralizumab and dupilumab improved asthma control with high certainty and omalizumab with moderate certainty; however, none reached the minimal important difference (MID). Both benralizumab and omalizumab improved QoL with high certainty, but only omalizumab reached the MID. Omalizumab enabled ICS dose reduction with high certainty. Benralizumab and omalizumab showed an increase in drug-related adverse events (AEs) with low to moderate certainty. All three biologicals had moderate certainty for an ICER/QALY value above the willingness to pay threshold. There was high certainty that in children 6-12 years old omalizumab decreased the annualized exacerbation rate [IRR 0.57 (95%CI 0.45-0.72)], improved QoL [relative risk 1.43 (95%CI 1.12 −1.83)], reduced ICS [mean difference (MD) −0.45 (95% CI −0.58 to −0.32)] and rescue medication use [ MD −0.41 (95%CI −0.66 to −0.15)].     

Immunological and clinical changes in allergic asthmatics following treatment with omalizumab

IgE plays a key role in allergic asthma. We investigated whether omalizumab treatment of patients with moderate to severe allergic asthma leads to changes in inflammatory mediators and clinical symptoms. This sub-study was conducted on 35 patients with a positive skin prick test (SPT) requiring daily administration of beclomethasone dipropionate (500-1,000 microg), who participated in a multicentre, randomised, double-blind, placebo-controlled study. Omalizumab or placebo was administered at 0.016 mg/kg/IgE every 4 weeks. Patients recorded peak expiratory flow, asthma symptom score and beta(2)-agonist use in daily diaries and spirometry was performed at each visit. beta(2)-Agonist use and SPT wheal reaction decreased significantly (p < 0.05). Circulating levels of IL-5, IL-6, IL-8, IL-10, IL-13 and s-ICAM were measured before and after 16 weeks of treatment. IL-13 and s-ICAM were measured before and after 16 weeks of treatment. IL-13 decreased significantly (p < 0.01). IL-5 and IL-8 decreased in the omalizumab group compared to baseline. The other circulating mediators did not demonstrate any changes. Histamine release was significantly reduced (p < 0.01). Airway resistance (p < 0.05) and the provocative concentration inducing a 20% decrease in FEV(1) (p < 0.05) were measured before, after 16 weeks, and 3 months after completion of treatment. Both parameters decreased significantly (p < 0.05). Peripheral eosinophil count decreased significantly compared to placebo (p < 0.01). These findings suggest that omalizumab has potential as a novel treatment for allergic asthma.     

Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma

BACKGROUND: A recombinant humanized anti-IgE mAb, omalizumab, forms complexes with free IgE, blocking its interaction with mast cells and basophils; as a consequence, it might be effective in the treatment of asthma. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of omalizumab in the treatment of inhaled corticosteroid-dependent asthma. METHODS: In this phase III, double-blinded, placebo-controlled trial, 525 subjects with severe allergic asthma requiring daily inhaled corticosteroids were randomized to receive placebo or omalizumab subcutaneously every 2 or 4 weeks, depending on baseline IgE level and body weight. Inhaled corticosteroid doses were kept stable over the initial 16 weeks of treatment and tapered during a further 12-week treatment period. RESULTS: Omalizumab treatment resulted in significantly fewer asthma exacerbations per subject and in lower percentages of subjects experiencing an exacerbation than placebo treatment during the stable steroid phase (0.28 vs 0.54 [P =.006] and 14.6% vs 23.3% [P =.009], respectively) and during the steroid reduction phase (0.39 vs 0.66 [P =.003] and 21.3% vs 32.3% [P =.004], respectively). Beclomethasone dipropionate reduction was significantly greater with omalizumab treatment than with placebo (median 75% vs 50% [P <.001]), and beclomethasone dipropionate discontinuation was more likely with omalizumab (39.6% vs 19.1% [P <.001]). Improvements in asthma symptoms and pulmonary function occurred along with a reduction in rescue beta-agonist use. Omalizumab was well tolerated, with an adverse-events profile similar to that of placebo. CONCLUSION: The addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use.     

Omalizumab therapy is associated with reduced circulating basophil populations in asthmatic children

Basophils have been implicated in promoting the early development of T_H2 cell responses in some murine models of T_H2 cytokine‐associated inflammation. However, the specific role of basophils in allergic asthma remains an active area of research. Recent studies in animal models and human subjects suggest that IgE may regulate the homeostasis of human basophil populations. Here, we examine basophil populations in children with severe asthma before and during therapy with the IgE‐directed monoclonal antibody omalizumab. Omalizumab therapy was associated with a significant reduction in circulating basophil numbers, a finding that was concurrent with improved clinical outcomes. The observation that circulating basophils are reduced following omalizumab therapy supports a mechanistic link between IgE levels and circulating basophil populations, and may provide new insights into one mechanism by which omalizumab improves asthma symptoms.     

Effect of omalizumab treatment on peripheral eosinophil and T-lymphocyte function in patients with allergic asthma

BACKGROUND: Omalizumab is a recombinant monoclonal anti-IgE antibody with proven efficacy in allergic diseases and further anti-inflammatory potency in the treatment of asthma. OBJECTIVES: To explore the anti-inflammatory mechanism of omalizumab, we investigated the induction of immunologic changes leading to eosinophil apoptosis and examined T-lymphocyte cytokine profiles in patients with allergic asthma. METHODS: Nineteen patients with allergic asthma were enrolled and received omalizumab at a dose of at least 0.016 mg/kg/IgE (IU/mL) every 4 weeks. Peripheral eosinophils and T-lymphocyte cytokine profiles were evaluated by fluorescence-activated cell sorting before treatment (baseline), at 12 weeks of treatment, and 12 weeks after discontinuation of treatment with omalizumab or placebo. RESULTS: Markers of eosinophil apoptosis (Annexin V) were significantly increased in omalizumab recipients compared with placebo, whereas no changes in markers of necrosis (7-amino-actinomycin) or eosinophil activation CD69 or Fas receptor (CD95) were detected. GM-CSF+ lymphocytes were reduced in omalizumab recipients compared with placebo. Fewer IL-2+ and IL-13+ lymphocytes were evident in omalizumab recipients than in the placebo group. There were no significant differences in IL-5, IFN-gamma, or TNF-alpha between the omalizumab and placebo groups. CONCLUSION: These findings provide further evidence that omalizumab has additional anti-inflammatory activity demonstrated by induction of eosinophil apoptosis and downregulation of the inflammatory cytokines IL-2 and IL-13. Further studies are needed to determine the underlying mechanisms. CLINICAL IMPLICATIONS: These findings support the critical role of IgE in the regulation of inflammation in allergic asthma: influencing the inflammation is the key to control the more severe type of asthma.     

Omalizumab

Omalizumab, a recombinant humanized monoclonal antibody against immunoglobulin (Ig)E, represents a unique therapeutic approach for the treatment of allergic diseases. This agent acts as a neutralizing antibody by binding IgE at the same site as the high-affinity receptor. Subsequently, IgE is prevented from sensitizing cells bearing high-affinity receptors. Inhibition of the biological effects of IgE targets an early phase of the allergic cascade before the generation of allergic symptoms. Currently, omalizumab has been approved for the treatment of persistent allergic asthma in patients who are poorly controlled with inhaled corticosteroids. However, other allergic disorders may be amenable to treatment with omalizumab because of its ability to inhibit effector functions of IgE. Studies of omalizumab in the treatment of allergic rhinitis comprise the greater part of the literature pertaining to the use of this agent for clinical indications other than asthma. This article summarizes clinical trials of omalizumab in allergic rhinitis and examines the evidence regarding the effects of omalizumab on the pathophysiological mechanisms underlying allergic rhinitis. Additionally, we consider the role of this novel therapeutic agent in combination with specific allergen immunotherapy and discuss other potential indications for omalizumab in IgE-mediated disorders, including food allergy, latex allergy, atopic dermatitis, and chronic urticaria.     

Monoclonal anti-IgE antibody: a novel therapy for allergic airways disease.

LEARNING OBJECTIVES: To familiarize the practitioner with a novel (monoclonal anti-immunoglobulin [Ig]E antibody) form of therapy for allergic airways disease. To understand the relevance of IgE as a therapeutic target. To appreciate the concepts behind the design of the molecule. To learn how anti-IgE was used in clinical trials. To anticipate the likely effects (efficacy and safety) in clinical use in patients with allergic asthma and with allergic rhinitis. To characterize the types of patients who might benefit from this therapy. DATA SOURCES: Published data for preclinical and clinical studies. RESULTS: Omalizumab is a nonimmunogenic, nonanaphylactogenic monoclonal anti-IgE antibody. In clinical use, omalizumab reduces levels of serum-free IgE. Given subcutaneously in patients with moderate-severe allergic asthma, omalizumab reduced exacerbations compared with placebo, and at the same time it allowed inhaled corticosteroids to be reduced or withdrawn. In patients with allergic rhinitis, omalizumab reduced the severity of symptoms and rescue antihistamine usage versus placebo. In both settings, quality of life was improved with active treatment relative to placebo. The drug seems safe and well tolerated. CONCLUSION: As the first clinical anti-IgE agent, omalizumab is an interesting new addition to the currently available therapies for allergic airways disease. The benefits demonstrated underline the importance of IgE in these conditions. The use of anti-IgE in other IgE-mediated allergic diseases warrants further research.