Omalizumab Group Research Articles

A randomized double-blind, placebo-controlled study to assess the effects of omalizumab (humanized monoclonal anti-IgE antibody) on the early- and late-phase skin reactions and cellular infiltrate after multiple intradermal allergen challenges

Rationale Immunoglobulin E probably plays a key role in early- and late phase- allergic cutaneous reactions (EPR and LPR) as well as the accompanying cellular influx. The aim of the study was to examine the effect of omalizumab on the EPR and LPR, as well as cellular infiltration, using a 14 day repeated skin allergen challenge design. Method Twenty-four allergic volunteers were randomized to receive either omalizumab at a dose of 0.016 mg/kg/IgE (IU/L)/4 weeks or placebo for a period of 12 weeks. On nine occasions, paired intradermal challenges of allergen (30 biological units) and diluent control were administered into the forearm at 2 weekly intervals. Cutaneous reactions were recorded 15 min and 6 hr after challenge and paired skin biopsies performed at 6 hr on weeks 0, 2, 4, 8 and 14 and studied by immunohistochemistry. Results Compared to placebo, omalizumab treated patients had a progressive reduction of both the EPR and the LPR. The LPR was significantly reduced within 2 weeks (p=0.012) and the EPR within 8 weeks (p=0.0093) of commencing treatment. Placebo patients showed a significant increase in cutaneous CD3+ T cells (p=0.016) after 14 weeks and this was paralleled by an increase in allergen-induced skin eosinophilia (p=0.05). These changes were not observed in the omalizumab group where CD3+ T cells (p=0.046) and eosinophils (p=0.019) were significantly lower compared to placebo. Conclusion Omalizumab reduces allergen-induced LPRs more rapidly than EPRs and appears to ameliorate the baseline T cell and allergen-induced eosinophil “priming” response in this multiple cutaneous allergen challenge model.

Omalizumab is effective in reducing asthma exacerbations irrespective of concomitant long-acting beta2-agonist use

Rationale Anti-IgE therapy with omalizumab reduces asthma exacerbations in patients with allergic asthma. Here we evaluate whether the efficacy of omalizumab is similar in moderate-severe allergic asthma patients receiving and not receiving long-acting beta2-agonists (LABAs). Methods Data from 3 randomized controlled studies that allowed the used of LABAs were analyzed. Two of these studies were open-label in patients with allergic asthma and the third was a double-blind, placebo-controlled study in patients with concomitant allergic asthma and persistent allergic rhinitis. All patients had moderate-severe allergic asthma requiring inhaled corticosteroids. 206/312, 1221/1840 and 209/405 patients received omalizumab (at least 0.016 mg/kg/IgE [IU/mL]) in each of the studies, respectively. Poisson regression was used to investigate the effect of omalizumab treatment on asthma exacerbation rates in patients receiving and not receiving concomitant LABAs. Results LABA use was similar between the omalizumab and control groups in each study (77.7 vs 78.3, 87.6 vs 88.2 and 41.1% vs 36.2%, respectively). Omalizumab reduced asthma exacerbation rates in all studies. The relative rates of asthma exacerbations among omalizumab-treated patients compared with control were similar in patients irrespective of whether they received LABAs. The relative rates of asthma exacerbations with and without LABA use were 0.41 and 0.35 in study 1, 0.77 and 0.91 in study 2 and 0.66 and 0.59 in study 3, respectively. Conclusions Omalizumab is an effective add-on therapy in moderate-severe asthma, and its benefit is not affected by whether patients also receive long-acting beta2-agonists.

Omalizumab treatment downregulates dendritic cell FcεRI expression

Background Dendritic cells (DCs) are potent antigen-presenting cells that express FcεRI, the high-affinity IgE receptor. Although the downregulation of basophil FcεRI during anti-IgE therapy with omalizumab is well documented, its effect on FcεRI expression by DCs has not been reported. Objective We hypothesized that IgE regulates surface FcεRI expression by DCs in vivo and that, consequently, anti-IgE therapy decreases FcεRI expression by DCs. Methods In a randomized, double-blind, placebo-controlled clinical trial 24 subjects (16 receiving omalizumab and 8 receiving placebo) with seasonal allergic rhinitis received the study drug on days 0 and 28. Serial blood samples drawn on days 0, 7, 14, 28, and 42 were analyzed for precursor DC1 (pDC1) and pDC2 surface expression of FcεRIα by using flow cytometry. Results Omalizumab caused a significant decrease in surface FcεRI expression at all time points examined in both the pDC1 and pDC2 subsets. No significant change was seen with placebo. The maximum decrease in FcεRI expression in the omalizumab group was 52% and 83%, respectively, for the pDC1 and pDC2 subsets. The decrease in FcεRI expression by both pDC subsets correlated with the decrease in serum-free IgE and was of a similar magnitude to that found in basophils. A 10-fold decrease in IgE corresponded to a 42% and 54% decrease in surface FcεRI expression by the pDC1 and pDC2 subsets, respectively. Conclusion These results demonstrate that anti-IgE therapy causes a rapid decrease in DC surface FcεRI expression and establish that IgE is an important regulator of FcεRI expression by DCs.

Evaluation of long-term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma

To evaluate the long-term effects of the anti-IgE antibody omalizumab in children with asthma. This was a 28-week, double-blind, randomized, placebo-controlled trial with a 24-week open-label extension. In the core trial 225 children (ages 6 to 12 years) with moderate-to-severe allergic asthma requiring inhaled beclomethasone dipropionate (BDP) received omalizumab every 2 or 4 weeks, and 109 received placebo. BDP dosage was stable for weeks 1 to 16, then reduced during weeks 17 to 24 using strict safety criteria. The lowest dose for optimal asthma control was maintained for 4 more weeks. During the 24-week extension, all patients (n = 309) received open-label omalizumab in addition to other asthma medications. One-year safety data were analyzed. The incidence of adverse events in patients treated with omalizumab for 52 weeks was similar to those treated for 28 weeks in the core trial, which was generally comparable with placebo. In the 52-week omalizumab group, upper respiratory tract infection and headache were the most frequently reported adverse events (47.1% and 42.7%, respectively). Eleven patients (4.9%) reported urticaria, which resolved spontaneously or with antihistamine, except for 1 patient who was discontinued because of severe urticaria. No anaphylactic reactions or adverse events suggestive of serum sickness or immune complex formation occurred. No anti-omalizumab antibodies were detected in any of the children. There is no evidence that new or more serious adverse events occur with long-term omalizumab treatment. Long-term treatment with omalizumab is safe and well tolerated in children with allergic asthma.

EFFECT OF OMALIZUMAB ON SYMPTOMS OF SEASONAL ALLERGIC RHINITIS: A RANDOMIZED, CONTROLLED TRIAL

Casale TB, Condemi J, LaForce C, et al. JAMA. 2001;286:2956–2967Seasonal allergic rhinitis is a common immunoglobulin E (IgE)-mediated disorder that produces troublesome symptoms. A recombinant humanized monoclonal anti-IgE antibody (omalizumab) forms complexes with free IgE, blocking its interaction with mast cells and basophils and lowering free IgE levels in the circulation. This study specifically seeks to assess the efficacy and safety of omalizumab for prophylaxis of symptoms in patients with seasonal allergic rhinitis.Patients 12 to 75 years old with no or mild symptoms during the preceding month but with at least a 2-year history of moderate-to-severe seasonal allergic rhinitis attributable to ragweed were considered eligible for the study. The history of moderate to severe ragweed-induced allergic rhinitis was defined as having a score of 2 or more on a 0- to 3-point scale (0 = no symptoms; 3 = severe symptoms), in 4 of 8 symptom categories (sneezing, itchy nose, runny nose, stuffy nose, watery eyes, red eyes, itchy eyes, or itchy throat) based on patient recall of the previous ragweed pollen season. Skin test sensitivity to ragweed pollen and a baseline total IgE level of between 30 and 700 IU/mL also were required.This randomized, double-blind, dose-ranging, placebo-controlled trial assigned patients to receive omalizumab, 50 mg (n = 137), 150 mg (n = 134), or 300 mg (n = 129), or placebo (n = 136) subcutaneously just before ragweed season and repeated during the pollen season every 3 weeks in patients with baseline IgE levels of 151 to 700 IU/mL (4 total treatments) and every 4 weeks in patients with baseline IgE levels of 30 to 150 IU/mL (3 total treatments). Main outcome measures were self-assessed daily nasal symptom severity scores (range: 0–3), rescue antihistamine use, and rhinitis-specific quality of life during the 12 weeks from the start of the treatment.Nasal symptom severity scores were significantly lower in patients who received 300 mg omalizumab than in those who received placebo (P = .002). A significant association was observed between IgE reduction and nasal symptoms and rescue antihistamine use. A linear dose-response relationship was observed for average daily nasal symptom scores and omalizumab dose. Patients in the 300-mg and the 150-mg omalizumab groups had significantly greater percentage of days with minimal nasal symptoms versus those in the placebo group. Rhinitis-specific quality of life scores were consistently better in patients who received 300 mg of omalizumab than in those who received lower dosages or placebo and did not decline during the peak season. A dose-dependent decrease in serum-free IgE levels occurred after omalizumab treatment. The frequency of adverse events was not significantly different among the omalizumab and placebo groups.Omalizumab decreased serum-free IgE levels and provided clinical benefit in a dose-dependent fashion in patients with seasonal allergic rhinitis. This was demonstrated by decreased average daily nasal symptom scores, daily nasal and ocular symptom severity and duration scores, and assessment of quality of life scores. Patients receiving 300 mg omalizumab also experienced profound reductions in serum-free IgE levels after the first dosing interval, when 63% of patients had serum-free IgE levels <10.4 IU/mL.This well-designed study thoroughly assesses the impact that omalizumab can have on the treatment of allergic rhinitis. There are, however, several limitations to this study. According to the article, only two thirds of patients were exposed to the severe pollen season. Therefore, variability in ragweed exposure across different sites in the United States is one factor that must be considered. It should also be known that patients entering the study were not completely asymptomatic, which could be attributable to a lingering effect from allergic rhinitis symptoms from the spring allergy season. However, this 12-week study of patients with seasonal allergic rhinitis did demonstrate that omalizumab therapy decreased serum-free IgE levels and provided clinical benefits, improving rhinitis-specific quality of life and reducing rescue medication use. Additional studies are necessary to pinpoint the exact placement of this agent in the therapeutic regimen for treatment of seasonal allergic rhinitis.

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 µg), 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 β₂-agonist use in daily diaries and spirometry was performed at each visit. β₂-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 FEV₁ (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.

The Anti-IgE Antibody Omalizumab Reduces Exacerbations and Steroid Requirement in Sallergic Asthmatics

Purpose of the Study. To demonstrate the clinical benefit and steroid-sparing effect of treatment with anti-immunoglobulin E (IgE) antibody, omalizumab, in patients with moderate-to-severe asthma.Study Population. A total of 546 allergic asthmatics (aged 12–76 years), symptomatic despite inhaled corticosteroids (500–1200 μg daily of beclomethasone dipropionate) and demonstrating a positive skin prick test to dust mites, dog, or cat and a serum total IgE level of >30 and <700 international units (IU).Methods. After a run-in period of 4 to 6 weeks, patients were randomized to receive either placebo or omalizumab subcutaneously every 2 to 4 weeks for 7 months. The interval was determined on dosing based on body weight and baseline IgE level. During the run-in period, patients were switched to inhaled beclomethasone using the dose at which they were stable. Dose was maintained during the first 16 weeks of the study. In the next 12 weeks, patients were seen every 2 weeks and inhaled steroid dose was decreased based on clinical symptoms and forced expiratory volume in 1 second (FEV1). Lowest inhaled steroid dose was held for the remaining 4 weeks of the study. IgE levels were determined pre- and poststudy.Results. There was a reduction in serum-free IgE from baseline by 89% to 99% for those patients on omalizumab. The number of asthma exacerbations per patient were statistically different in favor of omalizumab for both stable steroid and steroid reduction phases (P < .001). Percentage of patients with at least 1 asthma exacerbation was significantly lower in the omalizumab group (P < .001). During the steroid reduction phase, there were 52% fewer exacerbations in the omalizumab group versus the placebo group (P < .001) despite the greater reduction of the beclomethasone dosage on omalizumab (P < .001). There were also statistically significant differences in asthma symptom scores and number of puffs of rescue medication in favor of omalizumab. Incidence of adverse effects were similar in placebo and omalizumab groups.Conclusion. These results indicate that omalizumab therapy safely improves asthma control in allergic asthmatics who remain symptomatic despite regular use of inhaled corticosteroids and simultaneous reduction in corticosteroid requirement.Reviewer’s Comments. The role of immunomodulating therapies in the treatment of allergic disease and asthma has become an exciting area of investigation in recent years. This study provides promising results in that anti-IgE therapy may have a role in controlling asthmatics who remain symptomatic despite regular use of inhaled corticosteroids. This therapy also appears to have a steroid-sparing effect, which is desirable. However, I would be interested in seeing more studies comparing anti-IgE with some of the other inhaled steroid compounds, such as fluticasone and budesonide, as long-term follow-up, especially because this therapy would require shots every 2 to 4 weeks indefinitely. Practicality and compliance will be important factors, as well as efficacy and safety, as we continue to study these new therapies.