Posted by: Indonesian Children | September 5, 2010

Treatment Anti-Immunoglobulin E Antibody (Omalizumab) for Allergy Diseases

Treatment Anti-Immunoglobulin E Antibody (Omalizumab) for Allergy Diseases

Widodo Judarwanto

Children Allergy center, Jakarta Indonesia

Omalizumab (Xolair) is a recombinant humanized monoclonal antibody that blocks the high-affinity Fc receptor of immunoglobulin E (IgE). It is used to treat patients with moderate-persistent to severe-persistent asthma; patients must be older than 12 years, have a positive skin test to a perennial aeroallergen (e.g., dust mites, cats, dogs, and mold), and be symptomatic with inhaled corticosteroids. Omalizumab has a low incidence of side effects, and it is very expensive. The exact dosage of omalizumab dosage is determined by body weight and pretreatment serum total IgE levels. Omalizumab may have a role in the treatment of atopic dermatitis when IgE plays a causal role.

Introduction

Omalizumab (Xolair, Novartis Pharmaceuticals, East Hanover, NJ; Genentech Inc., South San Francisco, CA) is a recombinant humanized monoclonal antibody that blocks immunoglobulin E’s (IgE) high-affinity Fc receptor . Omalizumab stops free-serum IgE from attaching to mast cells and other immune cells and prevents IgE-mediated inflammatory changes.

Omalizumab is used to treat asthma, which is part of the atopic triad with atopic dermatitis and allergic rhinitis. As such, omalizumab is of interest to dermatologists (1) because patients might be taking it; and (2) because of its immunological effects on IgE, it might be a treatment of atopic dermatitis. This review discusses the dosage, indications, effectiveness, immunology, and possible use in dermatology of omalizumab.

Omalizumab

Omalizumab (trade name Xolair, Genentech / Novartis) is a humanized antibody drug approved for patients with moderate-to-severe or severe allergic asthma, which is caused by hypersensitivity reactions to certain harmless environmental substances. Omalizumab’s cost is high ($10,000 to $30,000 per year), as compared to other drugs used for asthma, and hence omalizumab is mainly prescribed for patients with severe, persistent asthma, which cannot be controlled even with high doses of corticosteroids. Like other protein and antibody drugs, omalizumab causes anaphylaxis (a life-threatening systemic allergic reaction) in 1 to 2 patients per 1,000.

Omalizumab is a recombinant DNA-derived humanized IgG1k monoclonal antibody that selectively binds to human immunoglobulin E (IgE). IgE is commonly involved with allergies when present in high amounts in the body.

Tanox, a biopharmaceutical company based in Houston, Texas, started the anti-IgE program, created antibody drug candidates, and filed its first patent application on the anti-IgE therapeutic approach in 1987. In the next year, the company converted one candidate antibody to a chimeric antibody (which was later named CGP51,901 and further developed into a humanized antibody, talizumab). The anti-IgE therapeutic concept was not well received in the early period of the program. In order to seek funding for the anti-IgE program, the two scientist founders of Tanox, Nancy T. Chang, Ph.D. and Tse Wen Chang, Ph.D., visited about 25 pharmaceutical and larger biotech companies in the U.S., Canada, Europe, Japan, and other countries to discuss collaboration throughout 1989. Representatives of Ciba-Geigy (which merged with Sandoz to form Novartis in 1996) thought the anti-IgE program scientifically interesting and executives from Tanox and Ciba-Geigy signed a collaborative agreement in 1990 to develop the anti-IgE program. In 1991-1995, scientists from Tanox and Ciba-Geigy ran a successful Phase I human clinical trial in Southampton, England and a Phase II trial in patients with severe allergic rhinitis in Texas on CGP51,901. In the meantime, representatives of Genentech announced in 1993 that it also had an anti-IgE development program. After a lengthy legal entanglement, Tanox, Novartis, and Genentech formed a tripartite partnership to jointly develop the anti-IgE program in 1996. Omalizumab became the drug of choice for further development, because it had a better developed manufacturing process than TNX-901. Omalizumab, trade-named Xolair, received approval by the U.S. Food and Drug Administration (FDA) in 2003 for treating patients 12 years and older with moderate-to-severe allergic asthma. It has also received approval in many other countries for treating patients 12 years and older with severe allergic asthma. Researchers are also developing Omalizumab for pediatric allergic asthma and several other major allergic diseases, including allergic rhinitis. Major trials have also taken place to evaluate the effects of omalizumab on enhancing the efficacy and safety of allergen-based desensitization immunotherapy. In August 2010, the National Institute for Clinical Excellence in the United Kingdom ruled that Omalizumab should not be prescibed on the NHS to children under 12, causing widespread condemnation from asthma charities. NICE concluded that the high costs of the compound, over £250 per vial, did not represent a sufficiently high increase in quality of life

Mechanism of action

Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor FcεRI by binding to an epitope (a conformational area) on IgE that overlaps with the site to which FcεRI binds. This feature is critical to omalizumab’s pharmacological effects because a typical anti-IgE antibody can cross-link cell surface FcεRI-bound IgE and induce mediator release from basophils and mast cells. The epitope to which omalizumab binds is sterically hindered by the receptor when IgE is bound to the receptor and is therefore not accessible to omalizumab binding, preventing an inadvertent anaphylactic reaction. However, by binding to IgE in solution, omalizumab prevents IgE binding to cell surface receptor. Although the binding peptide sequence on IgE that is used to bind to low affinity IgE receptor (FcεRII) is different from the sequence used to bind to FcεRI, omalizumab, by steric hindrance, also prevents binding of IgE to FcεRII. Reduction in surface bound IgE on FcεRI-bearing cells limits the degree of release of mediators of the allergic response. Treatment with Xolair also reduces the number of FcεRI receptors on basophils in atopic patients.

The primary use of omalizumab is for patients with severe, persistent allergic asthma, uncontrollable with even high doses of corticosteroids. The therapeutic efficacy of omalizumab is more evident among severe patients than among moderately severe patients. The response rates among treated severe “allergic” asthma patients are 60-80%, probably depending on the patient screening procedures used by the various clinical groups of different specialties. Because 30-40% of adult asthma cases are not related to allergy and unresponsive to omalizumab, a reliable way to identify treatable patients has been a subject of considerable research interest. The primary benefits for the responding patients are reduced numbers of exacerbations, improved lung function, reduced numbers of emergency visits to the doctors, reduced days of hospitalization, and increased quality of life measurements. The other major benefit is that most responding patients can reduce or spare entirely the use of corticosteroids.

Due to the lack of sufficient information on the long-term effectiveness and side effects of the drug, omalizumab treatment is not yet very common, and can be expensive. Another barrier to prevalent use is the injectable dosage form, which requires the patient to visit a physician’s office or clinic every 2 to 4 weeks during treatment. Additionally, as IgE could be a natural defense against parasitic diseases, treatment is usually not recommended when living in environments where the presence of parasites is common.

Recent research suggests that IgE might play an important role in the immune system’s recognition of cancer cells, so indiscriminate blocking of IgE / receptor interaction might have unforeseen problems. Clinical studies have indicated a possible small increased risk of cancer in those taking omalizumab. Concerns have also been raised about possible induction of Churg-Strauss syndrome, nasal polyps, and adrenal insufficiency.

A variety of studies have found that omalizumab decreases inflammatory mediators. The result of blocking the immunoglobulin E (IgE) high-affinity Fc receptor are manifold. Omalizumab treatment downregulates dendritic cell FcεRI expression. The combined effect of specific immunotherapy (SIT) and omalizumab is associated with prevention of nasal eosinophilic cationic protein increase and decreased tryptase levels in nasal secretions. Anti-IgE therapy reduces leukotriene release of peripheral leukocytes stimulated with allergen in children with allergic rhinitis undergoing allergen immunotherapy independent of the type of SIT allergen used. In a study assessing the immunologic effects of omalizumab on airway inflammation in allergic asthma, the mean percentage sputum eosinophil count decreased significantly (p < 0.001) from 6.6 percent to 1.7 percent in the omalizumab group, a reduction significantly (p = 0.05) greater than with placebo (8.5 % to 7.0 %); this was associated with a significant reduction in tissue eosinophils, FcεRI+ cells, CD3+, CD4+ and CD8+ T lymphocytes, B lymphocytes, and cells staining for IL-4+, but not with improvement in airway hyperresponsiveness to methacholine. Treatment with omalizumab normalized the number of myeloid dendritic cells during the grass-pollen season.

Omalizumab induces complex changes in interleukin levels and does not decrease all Th-2-related interleukins. In a study of asthmatics, 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 [7]; in addition, IL-13 and s-ICAM were measured before and after 16 weeks of treatment. The results of the aforementioned study were interesting: IL-13 decreased significantly (p < 0.01), IL-5 and IL-8 decreased in the omalizumab group compared to baseline, and other circulating mediators did not change.

Clinical trials

In approving omalizumab, The FDA considered two 52-week phase-3 trials involving 1,071 asthma patients, along with data from several supportive safety and efficacy studies . When used as add-on therapy to inhaled corticosteroids, omalizumab reduced mean asthma exacerbations per patient by 33-75 percent during the stable-steroid phase and by 33-50 percent during the steroid-reduction phase. In clinical studies of asthma patients, it improved peak response, reduced exacerbations, and improved quality of life scores. Treatment with intravenous and subcutaneous omalizumab resulted in a 98-99 percent reduction in free IgE, reductions that were not observed following placebo treatment.

Side effects

Omalizumab has a low incidence of side effects. Common adverse events in clinical trials included injection-site reaction, viral infection, upper respiratory tract infection, sinusitis, headache, and pharyngitis. The most serious adverse reactions reported in clinical studies were malignancies (0.5  %) and anaphylaxis (0.1  %). The difference in malignancy between patients treated with omalizumab and placebo was not statistically significant. It is unknown whether IgE plays a surveillance role in cancer prevention and whether blocking IgE is associated with an increase in cancer incidence. In one study of 287 subjects, omalizumab was generally well tolerated, but two patients withdrew from treatment because of drug-related adverse events (rash and nausea; facial erythema and edema) .

Dosage range

The exact dosage of omalizumab dosage is determined by body weight and pretreatment serum total IgE levels. Doses greater than 150 mg are to be divided among more than one injection site. Slowly absorbed after subcutaneous administration and with a mean elimination half-life is 26 days, omalizumab (0.016 mg/kg/IgE [IU/mL] per 4 weeks) can be administered fortnightly or monthly. The bioavailability of omalizumab is 62 percent after subcutaneous administration. It reaches a peak concentration within 7-8 days after subcutaneous administration and has a half-life of approximately 26 days. Omalizumab is eliminated by the liver through the reticuloendothelial system . It is a very expensive medication, costing $10,000-15,000 for a course of treatment.

Indications

On the basis of clinical trials, the FDA approved only very specific indications for omalizumab. Patients must have moderate-persistent to severe-persistent asthma, be older than 12 years, have a positive skin test to a perennial aeroallergen (e.g., dust mites, cats, dogs, and mold), and be symptomatic with inhaled corticosteroids . Omalizumab does not have any specific drug interactions and is used with corticosteroids in most cases.

A recent evaluation by the Cochran group involved an evidence-based survey of omalizumab’s utility for asthma . This review found that omalizumab led to a significant reduction in inhaled steroid consumption compared with placebo: -114 mcg/day (95 % CI -150 to -78.13, two trials). Studies seemed to show increased health of patients and decreased steroid need, although the control groups had greater than expected responses. The Cochran reviewers believed the long-term clinical significance of the decrease of IgE induced by omalizumab has to be defined more fully. A variety of off-label uses for omalizumab is being explored. It is being studied for the treatment of allergic rhinitis and peanut allergies. One study suggests it can be used to treat health-care workers with occupational latex allergy.

Treatment For Asthma

Worldwide, 5% to 10% of children suffer from asthma. Atopy, the genetic predisposition to develop IgE-mediated responses to common allergens, and elevated IgE concentrations are the strongest identifiable factors for the development of asthma in young children.The recently developed recombinant humanized monoclonal anti-IgE antibody, omalizumab, has been found to be safe and effective in adult and adolescent patients with seasonal allergic rhinitis  and allergic asthma. The present study was undertaken to assess the safety and steroid-sparing effects of omalizumab in children (aged 6-12 years) with moderate to severe allergic asthma.

Omalizumab  is a recombinant humanized monoclonal anti-IgE antibody that forms complexes with circulating free IgE and prevents it from binding to high-affinity receptors on effector cells, thereby inhibiting allergen-induced activation. It has been reported that subcutaneous treatment with omalizumab reduces the requirement for inhaled corticosteroids while protecting against disease exacerbation in a large placebo-controlled trial in children with moderate-to-severe allergic asthma. Here we report the findings of the effect of omalizumab on asthma-related quality of life (AQoL), which was evaluated during the latter clinical trial.

Omalizumab was well tolerated, with no evidence of clinically significant drug toxicity or serious treatment-related AEs. It is noteworthy that serious asthma exacerbations requiring hospitalization occurred in 5 (4.6%) of 109 placebo patients but in none of the omalizumab group. No immunologic or immune complex-related AEs were noted except for several generally mild or moderate cases of urticaria.

The adverse events reported in the omalizumab group were similar to those in the placebo group. The most frequently reported adverse events in both groups consisted of commonly occurring medical complaints (headache, respiratory infection). Reactions at the injection site occurred infrequently and decreased with continued therapy.

The study was conducted in children whose asthma was well controlled with ICS, and the ability of omalizumab to replace ICS was evaluated to assess the drug efficacy. After 16 weeks of treatment with omalizumab, BDP dose was gradually reduced to the lowest effective dose level. The reduction in BPD dose was significantly greater in the omalizumab group than the placebo group, and a significantly greater percentage of omalizumab treated patients could reduce their BDP dose. BDP could be withdrawn completely in 55% of omalizumab patients. Daily asthma symptom scores, rescue beta -agonist requirement, and pulmonary function assessment showed that asthma control was well maintained despite significant reduction in BDP dose. During the steroid dose-reduction phase, asthma exacerbations requiring doubling of the ICS dose or addition of oral corticosteroid therapy occurred 42% less frequently among omalizumab patients, and 53% fewer patients had 1 or more asthma exacerbations.

Acute asthma exacerbations requiring additional beta -agonist and/or corticosteroid treatment occurred more frequently during the steroid dose-reduction phase compared with stable-steroid phase; the difference in exacerbation rates between the 2 phases was much greater for the placebo group. The increase in exacerbation rate during the steroid dose-reduction phase is related to the loss of anti-inflammatory effects of ICS. The lower exacerbation rate in omalizumab-treated patients reflects its ability to provide similar protection.

Treatment with omalizumab resulted in a reduction from baseline in mean serum free IgE that ranged from 95% to over 99% across all dosing regimens, indicating that the dosing scheme used in the trial effectively reduces serum IgE in patients with initial concentrations as high as 1300 IU/mL. At the same time there was an increase in total IgE, ranging from 167% to 431% of baseline serum IgE level, depending on baseline IgE and omalizumab dose. This increase in total IgE represents the persistence in circulation of biologically inactive omalizumab-IgE complexes. These low molecular weight complexes lack the biological activity of IgE because the Fc portion of the molecule is blocked. They are cleared by low-avidity interaction with the Fc-gamma receptors of leukocytes and the reticuloendothelial system. They do not fix complement or accumulate in renal glomeruli and do not pose a risk for immunopathogenicity.

Overall, the outcome among omalizumab-treated patients was better than the placebo group as evaluated by reduction in BDP dosage, percentage of patients who discontinued BDP, incidence and frequency of asthma exacerbations, participants’ and investigators’ global evaluations of treatment effectiveness, dosage of rescue medication, missed school days, and unscheduled medical contacts attributable to asthma-related medical problems. The frequency and types of all adverse events, judged treatment related or not, were similar in the omalizumab group and the placebo group. The majority of adverse events were mild to moderate in severity. Study-drug-related adverse events occurred more frequently in the omalizumab group than in the placebo group, but were relatively infrequent in both groups. The several cases of urticaria were nearly all mild or moderate.

Early aggressive therapy is needed to maximize control of asthma in all age groups. Despite the effectiveness of ICS, there is a continuing reluctance to use these agents, especially in younger patients. Anti-IgE therapy is a promising alternative treatment for those children who fail to respond to corticosteroid therapy, require unacceptably high doses of ICS or systemic corticosteroids, have frequent exacerbations, or suffer unacceptable side effects of corticosteroid therapy. Because of serious limitations in the adherence to daily ICS therapy, a long-acting treatment is especially desirable. Because imperfect effort or technique limit efficacy of inhaled medication, the introduction of an effective agent that can be administered parenterally at long intervals is a propitious development.

Treatment For Rhinitis

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.

Treatment for Churg-Strauss syndrome (CSS)

Churg-Strauss syndrome (CSS) is a rare, systemic, small-vessel vasculitis belonging to a group of hypereosinophilic syndromes, a heterogeneous collection of disorders characterized by the presence of marked peripheral blood eosinophilia, tissue eosinophilia, or both, often without an identifiable cause. CSS is associated with significant peripheral eosinophilia and constitutional symptoms, but it differs from hypereosinophilic syndrome in that it is characterized by the presence of asthma and eosinophilic vasculitis involving one or more organ systems, including the lungs, sinuses, heart, skin, GI tract, nervous system, and musculoskeletal system.

Although the cause is unknown, CSS has both allergic and autoimmune features. Patients typically have a history of asthma, and the presentation can be subacute or one of severe acute systemic illness. In many cases, CSS is precipitated by withdrawal of inhaled or systemic corticosteroids. When cases of CSS became apparent following the use of novel leukotriene modifiers, Wechsler and colleagues described the emergence of CSS following the initiation of treatment with these new asthma medications. This led to the notion that CSS could be unmasked in patients receiving asthma medications who have an underlying eosinophilic disorder masked by corticosteroid treatment or that delayed onset of corticosteroids by steroid-sparing alternatives for what is perceived to be only asthma may allow for the syndrome to become manifest.

In that regard, the newest class of asthma therapy has also recently been associated with CSS cases; reports of CSS have been received in the postmarketing setting for omalizumab. Omalizumab (Xolair; Genentech Inc; South San Francisco, CA; and Novartis; San Carlos, CA) is a recombinant, humanized monoclonal antibody that selectively binds to human IgE. It is has been approved by the US Food and Drug Administration for the treatment of adults and adolescents with moderate-to-severe persistent allergic asthma. Clinically, omalizumab reduces asthma exacerbations, improves symptom control, decreases rescue medication use, and improves quality of life, allowing a decrease of corticosteroid dosing in patients who remain symptomatic on moderate-to-high doses of inhaled or systemic corticosteroids

There is evidence suggesting that omalizumab therapy may be of benefit to CSS patients. In one report, a man presented with asthma symptoms requiring therapy with high-dose inhaled and systemic corticosteroids. Attempts at tapering the systemic corticosteroids resulted in the worsening of asthma and upper respiratory complications. CSS, which was controlled with systemic corticosteroids and, later, with cyclophosphamide and azathioprine, was diagnosed in the patient. Approximately 17 years later, omalizumab was started as a treatment for the severe asthma. Within 15 days of the initiation of omalizumab therapy, asthma symptoms, lung function, and eosinophilia improved.

In a second report examining a refractory variant of CSS, the unmasking of CSS developed after the withdrawal of steroid therapy in two patients. In these cases, anti-IgE therapy with omalizumab resulted in marked clinical improvement. Given its steroid-sparing effects and its beneficial effect on reduction of eosinophils, omalizumab may provide a benefit to CSS patients. One possibility is that the primary benefit comes from improved pulmonary function, although further studies are needed

Treatment for Dermatitis

The efficacy of omalizumab for the treatment of atopic dermatitis (AD), a disease with significant morbidity. A prospective analysis was performed to assess the efficacy of omalizumab in 21 patients with moderate to severe persistent allergic asthma and AD. Patients were stratified into the following groups: very high IgE (>700 IU/mL), high IgE (186-700 IU/mL), and normal IgE (0-185 IU/mL). AD severity was assessed at 0, 1, 3, 6, and 9 months via an Investigator Global Assessment index. Twenty-one patients (14-64 years old) were evaluated. Pretreatment IgE levels ranged from 18.2 to 8396 IU/mL, (mean IgE level was 1521 IU/mL). All 21 patients showed clinical and statistically significant improvement of their atopic dermatitis (p<0.00052). This study indicates that omalizumab is effective in treating AD in patients with moderate to severe persistent allergic asthma.

Treatment for Food Allergy

An Institutional Review Board-approved prospective pilot study was performed to assess the efficacy of omalizumab in 22 patients with persistent asthma and concomitant IgE-mediated food allergy. All patients showed skin test positivity to foods and experienced allergic food reactions based on history. Patients were interviewed on unintentional and/or unauthorized exposures to sensitized foods. Thirteen female and nine male patients (range, 4-66 years old; mean, 38 years) were evaluated in a private practice setting. Mean IgE level was 1120.74 IU/mL. Sensitized allergens included fish, shellfish, peanuts, tree nuts, egg, soybean, and wheat. All 22 (100%) patients maintained significant improvement as shown by a decrease/lack of clinical symptoms on reexposure to sensitized foods. Clinical improvement by the sixth dosage of omalizumab (150-300 mg q. 2-4 weeks) was noted by history and physical examination. Eight patients noted a decrease in their food-induced atopic dermatitis, 13 patients noted a decrease in their food-induced asthma symptoms, 3 patients noted a decrease in their food-induced urticaria, 6 patients noted a decrease in their food-induced rhinosinusitis symptoms, and 9 patients showed efficacy for angioedema and/or anaphylaxis. While treating asthma patients with omalizumab, patients subjectively observed a reduction in their concomitant IgE-mediated food allergy symptoms.

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