1. Aetna considers the use of Xolair (omalizumab) medically necessary as second line treatment for children 6 years of age and older, adolescents and adults with moderate-to-severe persistent allergic asthma for at least 3 months who meet all of the criteria below:

   1. Member demonstrates atopy (has a positive skin test or in-vitro reactivity (e.g., positive radioallergosorbent (RAST) test)) to a perennial aeroallergen; and
   2. Member's baseline serum IgE level is between 30 and 1500 IU/ml; and 
   3. Member's symptoms are inadequately controlled with a moderate dose of inhaled corticosteroids plus long-acting beta-agonists (LABAs)* or leukotriene inhibitors for at least 3 months; and   
   4. Member has daily symptoms (e.g., coughing, wheezing, and dyspnea) and/or exacerbations affecting activity (e.g., exercise) and sleep; and
   5. Members who smoke are engaged in smoking cessation efforts; and
   6. Member exhibits any of the following signs of poor asthma control:
      1. Daily use of short-acting inhaled beta2-agonists; or
      2. Diurnal variation in peak expiratory flow (PEF) of greater than 30 %; or
      3. Forced expiratory volume in 1 second (FEV1) less than 60 % predicted; or
      4. PEF less than 80 % of personal best; or
      5. A total of at least 3 of the following events within the preceding 12 months due to acute asthma exacerbations while on controller medications:
         1. Hospital admissions ;
         2. Treatments with high-dose injectable or oral corticosteroids;
         3. Visits to the emergency room or urgent care center.

2. For members who meet criteria, dosing of omalizumab is considered medically necesssary according to the FDA-approved labeling of Xolair, presented in Appendix B.

3. Continued treatment with omalizumab beyond 6 months is considered medically necessary for members who met all of the following criteria:

   1. Member had met criteria for omalizumab in section I at initiation of omalizumab therapy; and

   2. Treatment with omalizumab has resulted in clinical improvement as documented by one or more of the following:

      1. Decreased utilization of rescue medications; or
      2. Decreased freqeuency of exacerbations (defined as worsening of asthma that requires increase in inhaled corticosteroid dose or treatment with systemic corticosteroids); or
      3. Increase in percent predicted FEV-1 from pre-treatment baseline; or
      4. Reduction in reported symptoms (decrease in asthma symptom score), as evidenced by decreases in frequency or magnitude of one or more of the following symptoms:
         1. Asthma attacks; or
         2. Chest tightness or heaviness; or
         3. Coughing or clearing throat; or
         4. Difficulty taking deep breath or difficulty breathing out; or
         5. Shortness of breath; or
         6. Sleep disturbance, night wakening, or symptoms upon awakening; or
         7. Tiredness; or
         8. Wheezing/heavy breathing/fighting for air, and

   3. Member has not exhibited symptoms of anaphylaxis (bronchospasm, hypotension, syncope, urticara, and/or angioedema) after administration of omalizumab.

4. Aetna considers omalizumab (300 mg every four weeks) medically necessary for adolescents and adults (12 years of age and above) with moderate to severe chronic idiopathic urticaria who remain symptomatic despite treatment with two or more H1 antihistamines, or one H1 antihistamine and one or more of the following: H2 antihistamines, oral corticosteroids or leukotriene modifiers.

5. Serum IgE levels: Measurement of baseline total serum IgE level is considered medically necessary in persons who are being considered for treatment with omalizumab to determine eligibility for treatment and appropriate dose.  Monitoring of total serum IgE levels during the course of therapy with omalizumab is not considered medically necessary, because these levels will be elevated as a result of the presence of circulating IgE-anti-IgE complexes.

6. Aetna considers the use of omalizumab experimental and investigational for all other indications, including the following (not an all-inclusive list) because omalizumab's safety and effectiveness for these other indications has not been established.

*See Appendix A for “Estimated Comparative Daily Dosages for Inhaled Corticosteroids”.

Allergic asthma is a chronic disorder in which exposure to allergens such as dust, mold and pollen triggers airway inflammation and obstruction.  Bronchodilators (e.g., anti-cholinergic agents and inhaled beta2-agonists), alone or in combination, are used for patients with acute exacerbations.  For patients with chronic symptoms, inhaled corticosteroids are used for those who have frequent exacerbations.  A trial of 6 weeks to 3 months with inhaled corticosteroids to identify patients who may benefit from long-term inhaled corticosteroids therapy is recommended.  On the other hand, chronic treatment with oral corticosteroids is not recommended.

In the step-wise approach to the management of asthma, progression to the next step is indicated when control is not achieved or is lost with the current treatment, and there is assurance that the patient is using medication correctly.  The frequent presence of such symptoms as cough, wheezing, and dyspnea, and the increased use of rapid-acting bronchodilators (e.g., beta-2 agonists), may indicate inadequate control of asthma.  Measurement of peak expiratory flow (PEF) and its variability is helpful in the initial assessment of asthma severity and in monitoring the initial treatment, assessing changes in severity, and preparing for a reduction in therapy.

According to the global strategy for asthma management and prevention of the National Heart, Lung and Blood Institute (NHLBI), patients with moderate persistent asthma exhibit some of the following characteristics:

• Daily use of inhaled short-acting beta2-agonist
• Diurnal PEF variation greater than 30 %
• Exacerbations may affect activity and sleep
• PEF 60 to 80  % of personal best
• Symptoms daily.

For patients with severe persistent asthma, they have some of the following characteristics:

• Diurnal PEF variation greater than 30 %
• Frequent exacerbations
• PEF less than or equal to 60 % of personal best
• Symptoms daily.

The preferred therapy for patients with moderate persistent asthma is regular treatment with a combination of inhaled corticosteroids and a long-acting inhaled beta2-agonist twice-daily. For patients with severe persistent asthma, the primary therapy includes inhaled corticosteroid at higher doses plus a long-acting inhaled beta2-agonist twice-daily.  Furthermore, according to the NHLBI guidelines, control of asthma is defined as:

• (Near) normal PEF
• Minimal (ideally no) chronic symptoms, including nocturnal symptoms
• Minimal (ideally no) use of p.r.n. (as needed) beta2-agonist
• Minimal (infrequent) exacerbations
• Minimal (or no) adverse effects from medicine
• No limitations on activities, including exercise
• No visit to the emergency room
• PEF diurnal variation of less than 20%.

Xolair (omalizumab) is the first biotechnology treatment for allergy related asthma.  According to the labeling, it is indicated for adults and adolescents (12 years of age and older) with moderate-to-severe persistent asthma who have a positive skin test or in-vitro reactivity to a perennial aero-allergen and whose symptoms are inadequately controlled with inhaled corticosteroids.  Xolair, a recombinant humanized monoclonal anti-immunoglobulin E (IgE) antibody, is directed against the receptor-binding domain of IgE.  This binding is specific towards free IgE, thus preventing it from attaching to the mast cell and its subsequent activation.  Xolair is administered subcutaneously once- or twice-monthly, and in some cases more than one injection at a time.  Clinical studies have shown that omalizumab improves the control of allergic asthma while lowering steroid consumption, and enhances long-term disease control in patients with recurrent symptoms.

The Food and Drug Administraion (FDA) approved Xolair based on the findings of 2 clinical trials that included over 1,000 asthma patients, as well as data from several supportive safety and efficacy studies.  Although the FDA found Xolair to be generally safe, a few patients suffered severe allergic reactions that responded to medical treatment.  The most commonly observed side effects associated with Xolair include injection site reaction (45 %), viral infections (23 %), upper respiratory infections (20 %), sinusitis (16 %), headaches (15 %), and pharyngitis (11 %).  Moreover, the FDA is requiring the manufacturer to study an unexplained increase in the rate of cancer for patients taking the drug.  Cancers observed in Xolair-treated patients were a variety of types, including breast, non-melanoma skin, prostate, melanoma, and parotid.  Cancers developed in 0.5 % of those on Xolair, compared with 0.2 % on a placebo.

The FDA-approved indication for omalizumab is moderate-to-severe persistent asthma of an allergic nature, not controlled with the use of inhaled corticosteroids.  In addition, the patient should have an IgE level between 30 IU and 700 IU and not weigh more than 150 kg (330 lbs).  An IgE level of 2.5 ng/ml corresponds to 1 IU/ml.  The patient should also demonstrate allergies to common perennial allergens either via skin testing (in- vivo) or radioallergosorbent testing (in-vitro).  The FDA-approved prescribing information states that omalizumab 150 to 375 mg is administered subcutaneously every 2 or 4 weeks.  Doses and dosing frequency are determined by serum total IgE level, measured before the start of treatment, and body weight (see Appendix B).  A total serum IgE level should be measured in all patients who are being considered for treatment with omalizumab, because the dose of omalizumab is determined on the basis of the IgE level and body weight (Strunk and Bloomberg, 2006).  The recommended dose is 0.016 mg/kg body weight/IU of IgE every 4 weeks, administered subcutaneously at either 2-week or 4-week intervals.  This dose is based on the estimated amount of the drug that is required to reduce circulating free IgE levels to less than 10 IU/ml.  The total dose should not exceed 375 mg and this will require multiple injections, as no single injection should exceed 150 mg.  Monitoring of total serum IgE levels during the course of therapy with omalizumab is not indicated, because these levels will be elevated as a result of the presence of circulating IgE-anti-IgE complexes.  No other laboratory tests seem to be necessary, since there have been no clinically significant laboratory abnormalities noted during treatment.

In a Cochrane review on the use of anti-IgE antibody for chronic asthma in adults and children, Walker et al (2006) concluded that omalizumab was significantly more effective than placebo at increasing the numbers of patients who were able to reduce or withdraw their inhaled steroids, but the clinical value of the reduction in steroid consumption has to be considered in the light of the high cost of omalizumab.  The impressive placebo effects observed in control groups bring into question the true effect of omalizumab.  Omalizumab was effective in reducing asthma exacerbations as an adjunctive therapy to inhaled steroids, and during steroid tapering phases of clinical trials.  Omalizumab was generally well-tolerated, although there were more injection site reactions with omalizumab.  Patient and physician assessments of the drug were positive. 

Some current guidelines recommend use of omalizumab only in persons age 12 and older (NAEPP, 2007; NICE, 2007; and NICE, 2010).  The authors of the Cochrane review (Walker et al, 2006) stated that further assessment in pediatric populations is necessary, as is direct double-dummy comparison with inhaled steroid.  This is in agreement with the observation of Hadj (2004) who stated that further evaluation on omalizumab needs to be done in the pediatric (less than 12 years of age) population. The Global Initiative for Asthma (GINA, 2012) guidelines state that omalizumab has proven efficacy in children ages 6 to 12 years with moderate to severe and severe persistent allergic (IgE mediated) asthma. The GINA guidelines note that trials involving these children have shown similar efficacy to adolescents and adults. European Medicines Agency (EMEA) labeling for Xolair indicates omalizumab for children ages 6 years older, as well as for adolescents and adults, with IgE mediated asthma.

Milgrom et al (2001) evaluated omalizumab therapy in 6- to 12-year old children with moderate-to-severe allergic asthma.  The primary end point was the measurement of omalizumab's steroid-sparing effects.  Eligibility criteria included: stable asthma that was well-controlled with low-dose inhaled corticosteroids, a positive skin prick test to at least 1 common allergen, total serum IgE 30 to 1,300 IU/ml, and a baseline FEV₁ greater than or equal to 60 % of predicted.  A total of 334 patients were enrolled; the mean FEV₁ was approximately 85 % of predicted.  After 28 weeks of therapy (12 in the steroid-stable and 16 in the steroid-reduction phases), the median inhaled beclamethasone diproprionate dose reduction in omalizumab recipients was 100 % (versus 66.7 % among placebo recipients, p = 0.001).  A significantly greater proportion of omalizumab recipients reduced their inhaled corticosteroid dose, and more were able to withdraw inhaled corticosteroid therapy (55 % versus 39 %, p = 0.004).  Regarding secondary end points, during the steroid-reduction phase, a smaller proportion of omalizumab recipients experienced an exacerbation (18.2 % versus 38.5 %, p < 0.001), and the exacerbation frequency was significantly lower.  With omalizumab treatment, there were fewer urgent, unscheduled outpatient physician visits (12.9 % versus 30.3 %, p = 0.001), less variability in the morning peak expiratory flow rates, fewer 2- or 3-consecutive-night awakenings requiring rescue medications (11.6 % versus 21.1 %, p = 0.002), fewer requirements for rescue beta-agonist therapy, and fewer school days missed (0.65 days versus 1.21 days, p = 0.04).  Inhaled beclamethasone diproprionate dose requirements and asthma control measurements were similar during the subsequent 24-week extension phase (Berger et al, 2003).

In a review on omalizumab for asthma published in the New England Jounal of Medicine, Strunk and Bloomberg (2006) stated that "[s]ince asthma is a chronic disease, long-term studies, especially in children, are needed to evaluate the effect of serum IgE suppression throughout development; adverse effects may become apparent only with follow-up into adulthood.   We know of only one study to date that has been performed exclusively in the pediatric group (Milgrom et al, 2001).  Efficacy and safety studies are also needed for geriatric and nonwhite patients".

Lanier, et al. (2009) reported that add-on omalizumab is effective and well tolerated as maintenance therapy in children (6 to <12 years) with moderate-to-severe persistent allergic (IgE-mediated) asthma whose symptoms are inadequately controlled despite medium to high doses of inhaled corticosteroids.  The investigators conducted a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of omalizumab in children with moderate-to-severe persistent allergic asthma that was inadequately controlled despite treatment with medium-dose or high-dose inhaled corticosteroids (ICS) with or without other controller medications. The trial enrolled children age 6 to <12 years with perennial allergen sensitivity and history of exacerbations and asthma symptoms despite at least medium-dose ICSs. Patients were randomized 2:1 to receive omalizumab (75-375 mg sc, q2 or q4 wk) or placebo over a period of 52 weeks (24-week fixed-steroid phase followed by a 28-week adjustable-steroid phase). A total of 627 patients (omalizumab, n = 421; placebo, n = 206) were randomized, with efficacy analyzed in 576 (omalizumab, n = 384; placebo, n = 192). Over the 24-week fixed-steroid phase, omalizumab reduced the rate of clinically significant asthma exacerbations (worsening symptoms requiring doubling of baseline ICS dose and/or systemic steroids) by 31% versus placebo (0.45 vs 0.64; rate ratio, 0.69; P = .007). Over a period of 52 weeks, the exacerbation rate was reduced by 43% versus placebo (P < .001). The investigators reported that omalizumab significantly reduced severe exacerbations. They noted that, over a period of 52 weeks, omalizumab had an acceptable safety profile, with no difference in overall incidence of adverse events compared with placebo.  

The effectiveness of omalizumab in the treatment of occupational rhinitis has not been evaluated.  Occupational rhinitis is a heterogeneous group of inflammatory conditions in the nose, caused by exposure to airborne irritants as well as sensitizers in the occupational environment.  The mechanism can be allergic, neurogenic or toxic.  Animal dander, organic dusts, latex and chemicals can cause occupational rhinitis, but because of methodological problems as well as weaknesses in the definition of occupational rhinitis, occupational exposure is probably an underestimated cause of rhinitis.  In a review on the management options of occupational rhinitis, Hellgren et al (2003) stated that avoidance of exposure, protective measures at the workplace and medical treatment, with agents such as second generation anti-histamines and nasal corticosteroids, can make it possible to avoid progress of the disease from rhinitis to asthma.

Zirbes and Milla (2008) stated that allergic broncho-pulmonary aspergillosis (ABPA) is a complication commonly encountered in patients with cystic fibrosis (CF) that produces significant respiratory morbidity.  Chronic airway colonization with Aspergillus induces strong inflammatory responses with high IgE levels.  Current guidelines for therapy include prolonged courses of systemic corticosteroids as the main therapeutic strategy.  However this has the potential to induce significant detrimental side effects in children.  Omalizumab is a humanized monoclonal antibody directed against IgE that prevents its binding to high- and low-affinity receptors on effector cells.  It has been shown to be effective in improving asthma control in patients with a strong allergic component.  These investigators presented their long-term experience with the use of anti-IgE therapy in 3 children with CF and ABPA (mean age at start of therapy = 14.2 years) who were steroid-dependent.  All 3 were already experiencing significant side effects from chronic steroid therapy.  After the start of omalizumab, these children experienced significant and sustained clinical improvements at the same time that they were discontinued from chronic systemic steroids.  The authors concluded that these findings suggested that IgE blockade has tremendous potential as a strategy to control this disease in steroid-dependent patients.

Recent reviews on the management of ABPA (Meza Brítez et al, 2008; Schubert, 2009) did not mention the use of omalizumab as a therapeutic option.

Chehade (2007) noted that food allergies can be classified into those that are IgE-mediated and those that are non-IgE-mediated.  Various advances have been made in treating IgE-mediated food allergies.  A phase II clinical trial of omalizumab was recently initiated in subjects with peanut allergy, but was stopped as a result of safety concerns after severe reactions occurred during initial oral challenges.  Oral immunotherapy is showing promise in various studies on patients with IgE-mediated food allergies.  Gastro-intestinal food allergic disorders involving non-IgE-mediated food allergies have recently received attention, particularly eosinophilic esophagitis.  Although amino acid-based formula therapy remains the most successful in controlling inflammation and symptoms in these disorders, other therapeutic options including various dietary elimination protocols and swallowed fluticasone are showing success.  Anti-IL-5 therapy may prove to be a promising future therapeutic option for refractory patients.  The author stated that although there are no specific therapeutic recommendations for many IgE-mediated and non-IgE-mediated food allergic disorders besides allergen avoidance, various novel approaches are currently being investigated and may influence treatment approaches in the future.

Ricci et al (2009) stated that atopic dermatitis (AD) is a common disease in childhood.  Most AD is mild and can be managed with the use of emollients and standard therapy consisting of topical corticosteroids or topical calcineurin inhibitors.  However, in a subgroup of patients with moderate-to-severe AD, the disease is recalcitrant to topical therapy and systemic treatments become necessary.  Short courses of systemic corticosteroids are often used in clinical practice, but their use is controversial.  International guidelines suggest that in the case of acute flare-ups, patients might benefit from a short course of systemic corticosteroids, but long-term use and use in children should be avoided.  Ciclosporin is an immunosuppressant agent that acts directly on cells of the immune system, with an inhibitory effect on T cells.  When AD can not be controlled by standard topical therapies, ciclosporin significantly decreases symptom scores, disease extent, pruritus and sleep deprivation, and improves quality of life.  The most frequent side effects associated with the use of ciclosporin are hypertension and renal dysfunction, but they are usually reversible after drug discontinuation.  Ciclosporin has been found to be safely used, effective and well-tolerated in children with severe AD.  However, studies to assess the long-term effectiveness and safety of ciclosporin in AD are lacking.  In patients for whom ciclosporin is not suitable, or when there is a lack of response, alternative drugs should be considered, such as azathioprine or interferon-gamma.  Intravenous immunoglobulins and infliximab only have a place in the systemic therapy of AD when other drugs have failed.  Mycophenolate mofetil has recently been introduced in the treatment of recalcitrant AD.  Efalizumab and omalizumab are monoclonal antibodies with a possible future role in the treatment of AD, but further studies are needed.

Heil and colleagues (2010) examined if blocking free IgE would alter the course of AD.  These investigators administered either omalizumab or placebo subcutaneously for 16 weeks to 20 AD patients and measured immunological and clinical disease parameters.  Omalizumab (i) reduced free serum IgE, (ii) lowered surface IgE and high-affinity IgE receptor (FceRI) expression on different peripheral blood mononuclear cells, (iii) reduced the saturation of FceRI with IgE, (iv) increased the number of free FceRI and (v) lowered the number of IgE+, but not of FceRI+ cells in skin.  The in-vivo relevance of these results is evidenced by the increase in the threshold allergen concentration required to give a type I hypersensitivity reaction in the titrated skin test.  While not significantly altering the clinical disease parameters, omalizumab treatment led to an improvement of the atopy patch test results in single patients, i.e., an eczematous reaction upon epicutaneous allergen challenge.  The authors concluded that the interference with immediate and delayed type skin tests may imply that a therapeutic benefit of omalizumab treatment, if present at all, would be seen in patients with acute rather than chronic forms of AD.

Fonacier et al (2010) noted that chronic urticaria is characterized by recurrent pruritic wheals with surrounding erythema for greater than 6 weeks.  It is associated with a significant health care burden and affects patient quality of life.  The etiology of chronic urticaria is often difficult to elucidate; however, known etiologies include autoimmune urticaria, physical urticarias (e.g., cold, cholinergic, and delayed pressure urticaria), and idiopathic urticaria.  The etiology is unknown in many patients, leading to a diagnosis of chronic idiopathic urticaria.  The diagnosis of chronic idiopathic urticaria can be challenging for the primary care physician because of the disease's chronic symptoms.  Diagnosis requires a detailed patient history and comprehensive physical examination, with additional testing tailored to the patient's history.  Effective treatments include anti-histamines, leukotriene receptor antagonists in combination with anti-histamines, and oral immunomodulatory drugs, including corticosteroids, cyclosporine, dapsone, hydroxychloroquine, and sulfasalazine.  Newer experimental therapies include intravenous immunoglobulin and omalizumab.

Walker et al (2011) presented a summary of the evidence review group report into the clinical effectiveness and cost-effectiveness of omalizumab for the treatment of severe persistent asthma in children aged 6 to 11 years, based upon the evidence submission from Novartis Pharmaceutical UK Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process.  The manufacturer's submission was generally considered to be of good quality.  The submission was based primarily on a pre-planned subgroup IA-05 EUP (European Union Population) from the IA-05 trial, with outcomes including the number of clinically significant (CS) and clinically significant severe (CSS) exacerbations.  Omalizumab therapy was associated with a statistically significant reduction in the rate of CS exacerbations, but the reduction in the rate of CSS exacerbations was not statistically significant.  The benefit in terms of CS exacerbations was achieved mainly in patients with more than 3 exacerbations per year at baseline.  The manufacturer found no previous published cost-effectiveness studies of omalizumab in children aged 6 to 11 years, so their de novo economic evaluation formed the basis of the submitted economic evidence.  The economic model was considered appropriate for the decision problem.  The results from the model indicated that omalizumab in addition to standard therapy compared with standard therapy alone did not appear cost-effective in either the overall population or a subgroup of patients hospitalized in the year prior to enrollment, with incremental cost-effectiveness ratios of £ 91,169 and £ 65,911 per quality-adjusted life-year, respectively.  These findings were found to be robust across a wide range of alternative assumptions through 1-way sensitivity analyses.  The guidance issued by NICE states that omalizumab is not recommended for the treatment of severe persistent allergic asthma in children aged 6 to 11 years.

Koroscil et al (2011) described the clinical manifestations of insulin allergy and explained a systematic management approach.  These investigators presented the clinical, laboratory, and pathologic findings of a type 1 diabetic patient with allergy to subcutaneous insulin and briefly reviewed the related literature.  An 18-year old woman with type 1 diabetes mellitus had an insulin allergy and developed subcutaneous nodules after insulin administration.  Human and analog insulins were used, but painful nodule formation persisted.  Treatment with anti-histamines, steroids, and omalizumab and insulin desensitization were ineffective.  The patient required pancreatic transplant because glycemic control could not be achieved due to the insulin allergy.

Messingham et al (2012) stated that bullous pemphigoid (BP) is an autoimmune blistering disorder that is characterized by elevated total serum IgE and both IgG and IgE class autoantibodies directed against the hemidesmosomal proteins BP180 and BP230.  In BP, IgE is found at the basement membrane zone and coating mast cells in lesional skin.  IgE binding to immune cells is mediated through its high affinity receptor, FcεRI on the surface of mast cells, basophils and eosinophils.  In BP lesions, IgE binding is thought to be a critical step in the activation of these cells.  Models of the disease have demonstrated that BP IgE can replicate the early stages of BP lesion formation.  These findings suggested that IgE inhibition may be a therapeutic approach for BP.  Omalizumab is a humanized monoclonal antibody that inhibits IgE binding to FcεRI and is currently FDA-approved for the treatment of severe allergic asthma.  To date, 2 case reports have each described the efficacy of omalizumab in a patient with severe recalcitrant BP.  These studies were the first to provide clear evidence of the contribution of IgE autoantibodies in the pathogenesis of human BP and suggested that omalizumab may provide an additional therapeutic tool for treatment.

Pressler et al (2012) noted that vibratory angioedema is a rare form of physical urticaria characterized by pruriginous weals and angioedema at the site of exposure to vibration.  Severe treatment-resistant disease can occur, and is associated with significant disability.  These researchers reported a patient with vibratory angioedema for whom all standard treatments for urticaria, including omalizumab, failed to show a clinical benefit.  Finally, ketotifen was tried, and unexpectedly reduced symptoms significantly.  Ketotifen may thus represent a therapeutic option in patients with treatment-resistant vibratory angioedema. 

There is insufficient reliable evidence to support use of Xolair in persons with high IgE levels greater than 700 IU/ml. Most of the literature on use in persons with higher IgE levels are to case reports and uncontrolled case series, and most come from unpublished abstracts rather than full-length publications in the peer-reviewed published medical literature. 

An unpublished study by the manufacturer (Genentech, undated) included asthmatic subjects with up to IgE levels up to 1600 IU/ml but the results of subjects with high IgE levels were not reported separately. It also should be noted that the mean IgE level at screening was 193 IU/mL.

Asai et al (2011) reported in a letter reporting on 2 cases of subjects with asthma treated with omalizumab, 1 patient with high IgE and 1 with low IgE.

Boulet et al (1997) reported on 20 patients with asthma who were randomized to omalizumab or placebo.  Among the 13 subjects assigned to omalizumab, 4 had IgE levels above 700.  Results were not reported separately for subjects with high IgE levels.

Selection criteria for a study of omalizumab by Busse et al (2001) required subjects to have a baseline IgE between 30 to 700 IU/ml.

Inclusion criteria for a study of 19 subjects with asthma treated with omalizumab by Fahey et al (1997) required a baseline IgE level of 500 IU/ml or less.

An abstract and poster from Gillssen et al (2007) described the same case reports on the use of omalizumab in six patients with IgE levels between 729 to 5,000.

An abstract from Hirdt (2008) was also case reports, involving 7 omalizumab-treated patients with mean IgE levels of 2,000.  Only the mean IgE was reported and not the range.

An abstract from Katz (2005) was also case reports, involving 7 omalizumab-treated patients with a meant IgE level of 3,000, with no range reported.

A study from Krathen (2005) is of 3 cases with IgE ranging between 5,440 and 24,400, examining the effect of omalizumab on atopic dermatitis.  The abstract stated that 1 patient had improvement in asthma symptoms, and no improvement in atopic dermatitis symptoms in any subject.

An abstract by Vigo (2006) was case reports involving 7 patients treated with omalizumab who had baseline IgE between 265 and 2,020.

A study by Stukus et al (2008) involved 49 subjects, 10 of whom had IgE levels greater than 700.  The paper reported that subjects with IgE levels greater than 700 had similar subjective improvements and reductions in inhaler usage as subjects with IgE levels less than 700.  However, the study was difficult to interpret because 50 % of study subjects discontinued omalizumab for a variety of reasons.

A poster by Peters et al (2011) reported on a retrospective case-control study involving 26 subjects with an IgE level greater than 700 and 26 matched subjects with an IgE level less than 700.  The authors reported that both groups of subjects improved on omalizumab.  As this was not a clinical study, it is not known whether the clinical improvements in both groups are attributable to omalizumab versus other concurrent interventions for asthma that patients were receiving. 

A report by Vennera et al (2012) was a post-marketing observational study of 266 subjects treated with omalizumab, 46 of whom had a baseline IgE level greater than 700.  Because of the observational nature of this study, one cannot attribute any improvements that are observed to omalizumab treatment or other concurrent interventions.

Entry criteria for a study of omalizumab by Soler et al (2001) required baseline IgE between 30 and 700 Iu/ml.

A study by Kwong (2006) reported on results of omalizumab dosing in 2 asthma patients who fell out of the recommended dosing range due to obesity, not due to baseline IgE levels.  Baseline IgE levels were 459 in 1 patient and 677 in another patient.

An abstract by Maqbool et al (2005) was looking at the efficacy of omalizumab in 6 patients with atopic dermatitis, and it not relevant to the treatment of asthma. 

A reference to Kommann et al (2010) was to another unpublished abstract looking at the pharmacokinetics, pharmacodynamics and adverse events from 2 injections of omalizumab over a 2-week period.  Although the authors reported that the patients had IgE levels greater than 700 Iu/ml, no further details on the specific IgE levels and weights were reported in the abstract.  Twenty-six of the 32 patients reported 69 adverse events, but the authors stated that they determined that only 6 of the 26 patients adverse events were related to omalizumab (it is not described how this was determined).  This small, open-label, short-term study did not report on the efficacy of omalizumab.

A reference to Lanier (2008) was to an oral presentation.  The reports of this oral presentation stated that these were results from a double-blind, randomized, phase III study that evaluated omalizumab in pediatric patients 6 to 12 years old with moderate or severe allergic asthma whose symptoms were inadequately controlled on ICS.  Eligible patients had weights between 20 to 150 kg.  Although this study included patients with a body weight below 30 kg, no specific details were provided about that subgroup of patients.  The report also indicated that serum IgE greater than or equal to 30 to 1,300 IU/mL, but no specific details were provided on the subgroup of patients with IgE levels greater than 700 Iu/ml. 

A study by Vennera et al (2012) was the report of a registry with 266 patients, 46 of whom had IgE levels greater than 700 Iu/ml.  Patients were included in the registry if they received as little as one dose of omalizumab.  The authors stated that patients included in the registry met criteria set forth in the EU labeling of Xolair, but that some physicians deviated from this requirement by prescribing omalizumab to patients with IgE levels outside of the recommended ranges.  Since this was a registry study, it was unclear whether any improvements were due to omalizumab or other concurrent interventions.  Limitations of this study included the fact that it is a registry, which is considered low quality evidence, and that baseline data were collected retrospectively.  In addition, there were relatively few patients with IgE greater than 700, and no clear criteria for determining which patients with IgE levels greater than 700 would be entered into the registry.  

The study by Zielen et al (2013) was a randomized controlled trial comparing 18 persons with low IgE (30 to 300) to 16 persons with high IgE (700 to 2,000).  The primary study end-point was a measure called the early-phase allergic response (EAR), defined as the maximum percentage drop in forced expiratory volume in 1 second during the first 30 minutes after allergen broncho-provocation (ABP) testing.  A search of PubMed failed to identify other studies that have used the EAR as a primary end-point; thus there is insufficient information to determine whether this surrogate endpoint has been validated.  Other limitations of this study included its small size and short duration. 

Garcia et al (2013) examined if omalizumab has biological and clinical effects in patients with refractory non-atopic asthma.  A total of 41 adult patients with severe non-atopic refractory asthma despite daily treatment according to GINA step 4 with or without maintenance oral corticosteroids were randomized to receive omalizumab or placebo in a 1:1 ratio.  The primary end-point was the change in expression of high-affinity IgE receptor (FcεRI) on blood basophils and plasmacytoid dendritic cells after 16 weeks.  The impact of omalizumab on lung function and clinical variables was also examined.  Compared to placebo, omalizumab resulted in a statistically significant reduction in FcεRI expression on basophils and plasmacytoid dendritic cells.  The omalizumab group also showed an overall increase in FEV1 compared to baseline (+ 250 ml; p = 0.032, +9.9 %; p = 0.029).  A trend toward improvement in global evaluation of treatment effectiveness and asthma exacerbation rate was also observed.  The authors concluded that omalizumab negatively regulates FcεRI expression in patients with severe non-atopic asthma as it does in severe atopic asthma.  Omalizumab may have a therapeutic role in severe non-atopic asthma.  Moreover, they stated that these preliminary findings support further investigation to better assess the clinical efficacy of omalizumab.

Maselli et al (2013) reported on a retrospective case-control study comparing the efficacy of omalizumab  in patients with IgE levels above 700 IU/mL (n = 26 patients) versus less than or equal to700 IU/mL (n = 26 patients).  The range of IgE greater than 700 was 786 to 10,9791 IU/mL, and the mean was 2,371 IU/mL.  There was no significant change in mean FEV1 in either group after treatment.  The study authors concluded that treatment with omalizumab was as effective in reducing asthma symptoms, corticosteroid requirements, and ED visits in asthmatic patients with IgE levels greater than 700 IU/mL compared with similar patients with levels of 30 to 700 IU/mL.  In addition, the average highest FEV1 improved after therapy in patients with IgE levels greater than 700 lU/mL.  The investigators reported that the incidence of adverse reactions was not different among the groups.  The authors concluded that these studies suggested that additional studies of omalizumab in persons with baseline IgE levels above 700 IU/mL are needed.  The authors stated: "Future prospective studies are needed to confirm these findings before recommending omalizumab for poorly controlled asthma with IgE levels above 700 IU/mL".  Limitations of the study included its retrospective nature and small sample size.

Barthwa et al (2013) presented a poster reporting on an open-label, non-comparative, non-interventional study of patients (age greater than 12 years) with moderate-to-severe persistent allergic asthma, inadequately controlled despite inhaled corticosteroids plus long-acting beta agonists (GINA step 4) treatment.  All patients were receiving OMA at baseline.  Mean changes in (D) FEV1 and asthma control (measured using ACQ5 and ACT) versus baseline were assessed.  Patients were stratified according to baseline serum IgE level: group 1 (30 to 75 IU/mL) (n = 10), group 2 (76 to 700 IU/mL) (n = 65) and group 3 (701 to 1,500 IU/mL) (n = 25).  Data were analyzed using chi-squared and paired t-tests.  All parameters were compared between baseline and Week 28 post-OMA treatment.  The investigators reported that to date, 100 patients have completed 28 weeks of follow-up.  The proportion of patients with greater than or equal to 1 exacerbation decreased from 22.2 % at baseline to 0 % in group 1, from 19 % to 1.7 % in group 2, and from 59.1 % to 0 % in group 3.

NICE guidelines (2010) recommended the use of omalizumab as add-on therapy to optimized standard therapy only in patients 12 years of age and older with severe persistent (IgE mediated) asthma who have been identified as having severe unstable disease.  Optimized standard therapy is defined as a full trial of, and documented compliance with, inhaled high dose corticosteroids and long acting beta2 agonists in addition to leukotriene receptor antagonists, theophyllines, oral corticosteroids and beta-2 agonist tablets and smoking cessation where clinically appropriate.  Furthermore, in the clinical studies submitted to the FDA for approval of omalizumab (Xolair), patients currently smoking were excluded.

In a Cochrane review, Jat and colleagues (2013) evaluated the effectiveness and adverse effects of anti-IgE therapy for allergic broncho-pulmonary aspergillosis in people with cystic fibrosis.  These investigators searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and hand-searching of journals and conference abstract books.  They also searched the reference lists of relevant articles and reviews; last search was January 21, 2013.  They also searched the ongoing trial registry clinicaltrials.gov for any ongoing trials.  Latest search for clinicaltrials.gov was February 22, 2013.  Randomized and quasi-randomized controlled trials comparing anti-IgE therapy to placebo or other therapies for allergic broncho-pulmonary aspergillosis in people with cystic fibrosis were selected for analysis.  Two review authors independently extracted data and assessed the risk of bias in the included study.  They planned to perform data analysis using Review Manager 5.1.  Only 1 trial enrolling 14 patients was eligible for inclusion in the review.  The study was terminated prematurely and complete data were not available.  These researchers contacted the study investigator and were told that the study was terminated due to the inability to recruit patients into the study despite all reasonable attempts.  One or more serious side effects were encountered in 6 out of 9 (66.67 %) and 1 out of 5 (20 %) patients in omalizumab group and placebo group respectively.  The authors concluded that there is lack of evidence for the safety and effectiveness of anti-IgE (omalizumab) therapy in patients with cystic fibrosis and allergic broncho-pulmonary aspergillosis.  They noted that there is a need for large prospective randomized controlled trials of anti-IgE therapy in people with cystic fibrosis and allergic broncho-pulmonary aspergillosis with both clinical and laboratory outcome measures such as steroid requirement, allergic broncho-pulmonary aspergillosis exacerbations and lung function.

Maurer and colleagues (2013) noted that at the end of 2012, more than 300 participants discussed and agreed on the update of the international guidelines on urticaria at the 4th International Consensus Meeting (URTICARIA 2012).  Currently, the recommendations are in the final process of international coordination.  In preparation for the update, questions were prepared by an expert panel; this was followed by a systematic literature search.  The questions and the resulting recommendations were discussed by the participants and decided upon in an open vote.  Consensus was defined as at least 75 % agreement.  The updated guidelines will modify and improve the currently available guidelines in various areas, especially in therapy.  For the treatment of chronic urticaria, the new algorithm recommends a 3-step process starting with a standard dose of a non-sedating H1 anti-histamine.  If there is an insufficient treatment response, the dosage should be increased up to 4 times. In therapy- refractory patients, omalizumab, cyclosporine A, or montelukast are advised in the 3rd step.  Short-term corticosteroid treatment for a maximum of 10 days may be considered; H2 anti-histamines and dapsone, which were included in the previous version of the guidelines, are absent in the updated and revised version because of changes in the evidence level.

Clayton and associates (2014) stated that eosinophilic esophagitis (EoE) is usually induced by foods, by unclear mechanisms.  These researchers evaluated the roles of IgE and IgG4 in development of EoE.  These investigators performed a prospective, randomized, double-blind, placebo-controlled trial of adults with EoE given an antibody against IgE (omalizumab, n = 16) or placebo (n = 14) every 2 to 4 weeks for 16 weeks, based on weight and serum level of IgE.  Endoscopy was performed, esophageal biopsies were collected, and symptoms were assessed at baseline and 16 weeks.  Maximum numbers of eosinophils/high-power field were determined.  Homogenates of esophageal biopsies from 11 subjects with EoE and 8 without (controls) were assessed for IgM, IgA, and IgG subclasses.  In a retrospective analysis, these researchers measured levels of IgG4 in fixed esophageal tissues from 2 patients with EoE who underwent esophagectomy and 47 consecutive autopsies (controls).  They performed immunofluorescence analysis of IgG4 in esophageal mucosal biopsies from 24 subjects with EoE and 9 without (controls).  Finally, sera were collected from 15 subjects with EoE and 41 without (controls), and assayed for total and food-reactive IgG4.  Omalizumab did not alter symptoms of EoE or eosinophil counts in biopsy samples, compared with placebo.  Homogenates of esophageal tissues from patients with EoE had a 45-fold increase in IgG4 compared with controls (p < 3x10-5), but no significant increases in other IgG subclasses, IgM, or IgA.  Sparse stromal deposits resembling immune complexes were found in 2/5 EoE biopsies, based on ultra-structural analysis.  Esophagectomy samples from 2 patients with EoE contained 180 and 300 IgG4 plasma cells/maximal high-power field, mainly in the deep lamina propria; these levels were greater than tissues from controls.  Fibrosis was essentially exclusive to the lamina propria.  Granular extracellular IgG4 was detected in biopsies from 21/24 patients with EoE, but 0/9 controls (p = 6x10-6).  Total serum level of IgG4 increased only slightly in patients with EoE, compared with controls.  Subjects with EoE had increased serum levels of IgG4 that reacted with milk, wheat, egg, and nuts-the 4 foods that most commonly trigger this condition (p ≤ 3x10-4 for each food).  The authors concluded that in a prospective trial, omalizumab did not reduce symptoms of EoE or tissue eosinophil counts, compared with placebo.  This finding, along with observed granular deposits of IgG4, abundant IgG4-containing plasma cells, and serum levels of IgG4 reactive to specific foods indicated that in adults, EoE is IgG4-associated, and not an IgE-induced allergy.

Kaya et al (2012) noted that chronic eosinophilic pneumonia (CEP) is an idiopathic eosinophilic pulmonary disease characterized by an abnormal and marked accumulation of eosinophils in the lung.  Common presenting complaints include cough, fever, dyspnea, wheezing, and night sweats.  Common laboratory abnormalities are peripheral blood and BAL eosinophilia.  The pathognomonic radiographic finding is bilateral peripheral infiltrates.  Corticosteroids are the mainstay of therapy, and dramatic improvement follows treatment.  Relapses are common, and most patients require prolonged therapy.  Side effects associated with chronic corticosteroid therapy must be monitored.  These researchers presented the case of a 36-year old woman who had characteristic clinical and radiologic features.  She was treated with corticosteroids but she needed prolonged therapy, and side effects occurred.  Because the patient had high IgE levels and a positive skin prick test result, these investigators used omalizumab for the treatment.  The patient responded well.  To the authors’ knowledge, this was the first CEP case in the literature successfully treated with omalizumab.

Furthermore, an UpToDate review on “Treatment of chronic eosinophilic pneumonia” (Brown and King, 2014) does not mention the use of omalizumab as a therapeutic option.

Lieberman and Chehade (2013) stated that omalizumab is currently FDA-approved for allergic asthma.  Given its mechanism of action, recent reports have suggested its possible clinical use for food allergy and some forms of anaphylaxis.  Omalizumab exerts its action by binding to circulating IgE, reducing IgE receptor expression, and decreasing mediator release from mast cells and basophils.  Clinical trials using omalizumab in patients with food allergy resulted in achieving tolerance to higher amounts of the allergen in some patients.  When used as an adjunct therapy during immunotherapy trials in patients with food allergy and anaphylaxis, omalizumab allowed more rapid and higher doses of immunotherapy to be given.  Omalizumab has also been reported to be effective in a few patients with idiopathic anaphylaxis and mast cell disorders.  Moreover, the authors concluded that large multi-center trials are needed to confirm these findings, and to identify subsets of patients that would benefit the most from omalizumab.

In a pilot study, Penn et al (2007) stated that although the etiology of nasal polyposis (NP) remains unknown, emerging evidence showing elevated local IgE levels and eosinophilic infiltration suggests an allergic etiology.  These researchers examined if anti-IgE therapy is effective in the treatment of NP.  Data were retrospectively collected on 2 groups of patients with atopic asthma and NP who underwent endoscopic sinus surgery (ESS), including a control group (n = 4) and an anti-IgE treatment group (n = 4), who received omalizumab post-operatively.  Both groups were evaluated by sinus computed tomography (CT) and nasal endoscopic examination, and comparisons were made between the groups with respect to differences in the recurrence of NP after ESS.  Collectively, the subjects showed a direct relationship between NP severity and pre-treatment total serum IgE levels.  Pre-operatively, there were no differences between the groups with regard to their total serum IgE levels, sinus CT scores, and endoscopically determined NP scores.  Relative to corresponding pre-operative values, there was no significant improvement in the sinus CT scores in either treatment group post-operatively.  In contrast, relative to pre-operative values, the nasal polyp scores significantly improved in the anti-IgE group, whereas the control group showed no significant improvement.  The authors concluded that this pilot study provided new evidence establishing that (i) endoscopic NP severity directly correlates to total serum IgE levels and (ii) inclusion of anti-IgE therapy in the post-polypectomy management of atopic asthmatic individuals may reduce the severity of NP recurrence.  The findings of this small, pilot study need to be validated by well-designed studies.

Gevaert et al (2013) noted that adult patients with nasal polyps often have co-morbid asthma, adding to the serious effect on the quality of life of these patients.  Nasal polyps and asthma might represent a therapeutic challenge; inflammation in both diseases shares many features, such as airway eosinophilia, local IgE formation, and a T(H)2 cytokine profile.  Omalizumab could be a treatment option for patients with nasal polyps and asthma.  In a randomized, double-blind, placebo-controlled study, these researchers investigated the clinical effectiveness of omalizumab in patients with nasal polyps and co-morbid asthma.  A total of 24 allergic and non-allergic patients with nasal polyps and co-morbid asthma were enrolled in this study.  Subjects received 4 to 8 (subcutaneous) doses of omalizumab (n = 16) or placebo (n = 8).  The primary end-point was reduction in total nasal endoscopic polyp scores after 16 weeks.  Secondary end-points included a change in sinus computed tomographic scans, nasal and asthma symptoms, results of validated questionnaires (Short-Form Health Questionnaire, 31-item Rhinosinusitis Outcome Measuring Instrument, and Asthma Quality of Life Questionnaire), and serum/nasal secretion biomarker levels.  There was a significant decrease in total nasal endoscopic polyp scores after 16 weeks in the omalizumab-treated group (-2.67, p = 0.001), which was confirmed by means of computed tomographic scanning (Lund-Mackay score).  Omalizumab had a beneficial effect on airway symptoms (nasal congestion, anterior rhinorrhea, loss of sense of smell, wheezing, and dyspnea) and on quality-of-life scores, irrespective of the presence of allergy.  The authors concluded that omalizumab demonstrated clinical effectiveness in the treatment of nasal polyps with co-morbid asthma, supporting the importance and functionality of local IgE formation in the airways.  Please note that the reference by Gevaert et al (2013) is the citation noted by the provider below.  The study population (16 patients in the experimental group and 8 patients in the control group) is insufficient to provide robust statistical power for analysis.  The results of this study need to be validated in well-designed studies.

Yalcin et al (2013) reported that the historic triad of nasal polyposis, asthma and intolerance to aspirin and related chemicals, recently designated as Samter's syndrome, is an inflammatory condition of unknown pathogenesis.  These researchers surveyed the levels of chosen serum eosinophil cationic peptide, soluble CD200 (SCD200), interleukin (IL)-1β, high sensitive C-reactive protein (hs-CRP) and 25-hydroxyvitamin-D (25(OH)D) in the aspirin-induced asthmatic patients treated with anti-IgE therapy to examine their roles in the pathogenesis of disease perpetuation and anti-IgE therapy's impact on them.  Medical history, lung function tests and measurement of fractional exhale nitric oxide concentrations were performed on the same day.  Concentrations of IL-1β and SCD200 in the serum samples were quantified using ELISA kits.  Total and specific IgE and hs-CRP levels were enumerated by fluoroenzyme immunoassay.  Serum levels of 25(OH)D were quantified by a radioimmunoassay.  There were 3 patients of severe persistent allergic asthma with Samter's syndrome.  Levels of total IgE, ECP, fractional exhale nitric oxide concentrations, SCD200, IL-1β and hs-CRP were decreased while 25(OH)D was increased after starting the treatment of anti-IgE.  The authors concluded that to their best knowledge, this was the first time an association between omalizumab use and Samter's syndrome has been documented.  They noted that allergic nasal symptoms (sneezing, post-nasal drip) and asthma symptoms were decreased in patients, but no change was seen on nasal polyposis development after omalizumab treatment.

Babu et al (2013) noted that omalizumab has been licensed for use in severe allergic asthma.  A search on the website clinicaltrials.gov revealed there are currently 109 clinical trials with omalizumab of which 46 are for conditions other than asthma.  In addition to asthma, omalizumab has been investigated in various conditions including perennial and seasonal allergic rhinitis (AR), peanut allergy, latex allergy, atopic dermatitis, chronic urticaria , idiopathic anaphylaxis, mastocytosis, eosinophilic gastroenteritis and nasal polyposis. 

Furthermore, an UpToDate review on “Clinical presentation, diagnosis, and treatment of nasal obstruction” (Bhattacharyya, 2014) does not mention the use of omalizumab as a therapeutic option.

Appendix A

Estimated Comparative Daily Dosages for Inhaled Corticosteroids

Appendix B

Dosing Schedule for Subcutaneously Administered Omalizumab for Asthma