Xolair (Omalizumab)

Number: 0670

Policy

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 (i.e., prick/puncture test) or in-vitro reactivity (e.g., positive radioallergosorbent (RAST) test)) to perennial aeroallergens; 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)Footnotes for Estimated Comparative Daily Dosages for Inhaled Corticosteroids* or leukotriene inhibitors for at least 3 months; and   

   4. Member has exacerbations affecting activity (e.g., exercise) or sleep and/or daily symptoms (e.g., coughing, wheezing, and dyspnea); 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. Member will continue on asthma controller inhalers (e.g., inhaled corticosteroid with or without long-acting beta-2 agonist), unless contraindicated; and

   3. 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

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

4. Aetna considers omalizumab (150 or 300 mg every 4 weeks) medically necessary for adolescents and adults (12 years of age and above) with moderate to severe chronic autoimmune urticaria or chronic idiopathic urticaria who remain symptomatic despite two or more week trials of two or more H1 antihistamines, or one two or more week trial of one H1 antihistamine and one two or more week trial of one 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 with mepolizumab (Nucala) or reslizumab (Cinqair) experimental and investigational because the safety and effectiveness of these combinations has not been established.

7. 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.

   • Allergic broncho-pulmonary aspergillosis
   • Allergic conditions without asthma
   • Allergic rhinitis
   • Atopic dermatitis
   • Aquagenic urticaria
   • Atopic eczema
   • Bullous pemphigoid
   • Cholinergic urticaria and urticaria of other known causes
   • Cutaneous mastocytosis
   • Eosinophilic esophagitis
   • Eosinophilic gastroenteritis
   • Eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome)
   • Eosinophilic pneumonia
   • Food allergy (e.g., peanut allergy)
   • Inhibition of respiratory reaction during aspirin desensitization in individuals with aspirin exacerbated respiratory disease
   • Initial therapy for allergic asthma
   • Insulin allergy
   • Latex allergy
   • Nasal polyposis
   • Non-allergic (non-atopic) asthma
   • Subcutaneous immunotherapy, adjunct
   • Urticarial vasculitis
   • Use as an adjunct in allergen immunotherapy
   • Vibratory angioedema.

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

Background

Omalizumab (Xolair) is a recombinant DNA-derived humanized IgG1k monoclonal antibody that selectively binds to human immunoglobulin E (IgE). Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor (Fc RI) on the surface of mast cells and basophils. Reduction in the surface-bound IgE on the Fc RI-bearing cells limits the degree of release of mediators of the allergic response. Treatment with omalizumab also reduces the number of Fc RI receptors on basophils in atopic patients.

Omalizumab (Xolair) has been approved by the U.S. Food and Drug Administration (FDA) for adults and adolescents (12 years of age and above) with moderate to severe persistent allergic asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen annd whose symptoms are inadequately controlled with inhaled corticosteroids. Omalizumab is also approved for chronic urticaria in adults and adolescents (12 years of age and above) who remain symptomatic despite H1 antihistamine treatment.

Asthma

Asthma is a common chronic disorder of the airways which involves an interaction of airflow obstruction, bronchial hyperresponsiveness and underlying inflammation. Asthma can be highly variable among patients and within the same patient over time. In patients with asthma the walls of the airways are inflammed. The inflammation makes airways very sensitive causing them to react to things that are irritating or allergic. When the airways react, narrowing occurs, leading less air to flow to the lungs. This in turn causes symptoms like wheezing, coughing, chest tightness and difficulty breathing.

Diagnosing asthma should include a thorough review of the patient's medical history. The clinician should determine if symptoms of airflow obstruction and airway hyperresponsiveness are present and that the airflow obstruction is partially reversible. Methods used in diagnosis include physical examination, spirometry, and additional studies necessary to exclude alternative diagnoses.

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 a 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 three randomized, double-blind, placebo-controlled multicenter trials, as well as data from several supportive safety and efficacy studies.  The randomized trials enrolled patients 12 to 76 years of age, with moderate to severe persistent asthma (2--2 NHLBI criteria) for at least one year, and a positive skin test reaction to perennial aeroallergen. Relevant aeroallergens may include dust mite, cockroach, cato ro dog. At screening, patients had a force expiratory volume in one second (FEV1) between 40 percent and 80 percent predicted. In study 3, there was no restriction on screening FEV1. All patients were symptomatic and were being treated with inhaled corticosteroids (ICS) and short-acting beta agonists.

Study 3 allowed the use of long-acting beta-agonists. Patients receiving other concomitant controlled medications were excluded. Initiation of additional controller medicaitons while enrolled in the study were prohibited. All studies included a run-in period to achieve a conversion to a common ICS, followed by randomization to omalizumab or placebo. Patients received omalizumab for 16 weeks with an unchanged corticosteroid dose unless acute exaccerbations necessitated an increase. Omalizumab was doses based upon body weight and basline serum total IgE concentration. All patients were required to have baseline IgE between 30 and 700 IU/ml and body weight not greater than 150 kg. In Studies 1 and 2, the number of exacerbations per patients was significantly reduced in patients treated with omalizumab compared to placebo. In Study 3, the number of exacerbations in patients treated with omalizumab was similar to that in placebo-treated patients. In all three studies, most exacerbations were treated in an outpatient setting with symptomatic corticosteroids.

Overall, hospitalization rates were relatively small and were not signficantly different between omalizumab and placebo-treated patients. In all three studies, a reduction of exacerbations was not observed in omalizumab treated pateints who had an FEV1 greater than 80 percent at the time of randomization. Reductions in exacerbations were also not seen in patients who required oral steroids as maintenance therapy.

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.

Malignancies have been observed in clinical trials while on omalizumab therapy. The observed malignancies in omalizumab-treated patients were a variety of types, with breast, non-melanoma skin, prostate, melanoma, and parotid occurring more than once, and five other types occurring once each. the majority of patients were observed for less than 1 year. The impact of longer exposure to omalizumab in patients at higher risk for malignancy (e.g., elderly, current smokers) is not known.

Xolair carries a boxed warning of its potential to cause anaphylaxis which presents as bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue. Anaphylaxis has occurred as early as after the first dose of omalizumab, but has also occurred beyond one year after beginning regularly administered treatment. Patients should be closely monitored for an appropriate period after administration as well as receive information, prior to treatment, about the signs and symptoms of anaphylaxis and when to see immediate medical care. A medication guide must be issued with each dispensing of Xolair.

Omalizumab has not been shown to alleviate asthma exacerbations acutely and should not be used for the treatment of acute bronchospasm or status asthmaticus.

Serum total IgE levels increase following administration of omalizumab due to the formation of omalizumab-IgE complexes. Elevated serum total IgE levels may persist for up to one year following disocntinuation of omalizumab.

The most serious adverse effects occurring during clinical trials with omalizumab were anaphylaxis and malignancies. Other adverse effects observed during clinical trials include: injection site reactions, viral infections, upper respiratory tract infections, sinusitis, headache, and pharyngitis.

Dosages of omalizumab are based on pre-treatment IgE (IU/mL) and body weight (Kg). Doses of more than 150 mg are divided among more than one injection site to limit injections to not more than 150 mg per site.

Omalizumab should not be administered to patients who have experienced a severe hypersensitivity reaction to omalizumab.

On September 26, 2014, Reuters (Clarke, 2014) reported that according to the FDA, Xolair is associated with a higher risk of chest pain, heart attack, mini-stroke as well as blood clots in the lungs and veins, among other problems, though the extent of increased risk is unclear.  The FDA stated that it has added information regarding the increased risk to Xolair’s label after analyzing findings from a 5-year safety study submitted by the drug's manufacturer, Genentech, a unit of Roche Holding AG, and 25 clinical trials comparing Xolair to a placebo.

Omalizuamb in Children

Clinical studies with omalizumab have been completed in pediatric patients 6 to < 12 years of age and updates made to the package labeling in January 2010. Although omalizumab-treated patients had a statistically significant reduction in the rate of exacerbations (exacerbation was defined as worsening of asthma that required treatment with systemic corticosteroids or a doubling of the baseline ICS dose), other efficacy variables such as nocturnal symptoms scores, beta-agonist use, and measures of airflow (FEV1) were not significantly different bwtween omalizumab-treted patients compared to placebo. Considering the risk of anaphylaxis an malignancy seen in omalizumab-treated patients greater than 12 years old and the modest efficay of omalizumab in a pivotal pediatric study, the risk-benefit assessment does not support the use of omalizumab in patients 6 to <12 years of age.

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.

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.

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 less than 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 less than 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 to 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 versus 0.64; rate ratio, 0.69; p = 0.007).  Over a period of 52 weeks, the exacerbation rate was reduced by 43 % versus placebo (p < 0.001).  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.  

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.

Immunoglobulin E levels and Omalizumab

There is limited 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.

Chronic Idiopathic Urticaria

Chronic idiopathic urticaria (CIU) is a severe and distressing skin condition characterized by red, swollen, itchy and sometimes painful hives on the skin that spontaneously present and re-ocur for more than six weeks. Up to 40 percent of CIU patients also experience angioedema, a swelling in the deep layers of the skin.

The prevalence of chronic idiopathic urticaria is up to 1 percent of the world's population, and up to two-thirds of these patients have CIU. In the United States, it is estimated that approximately 1.5 million people suffer from CIU. Women are twice as likely as men to have the condition and most people develop symtpoms between ages of 20 and 40 years.

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.

The FDA has approved Xolair (omalizumab) for chronic idiopathic urticaria in adults and adolescents (12 years of age and above) who remain symptomatic despite H1 antihistamine treatment.

The recommended dose of omalizumab for chronic idiopathic urticaria is 150 mg or 300 mg administered subcutaneously every four weeks. Dosing in CIU is not dependent on serum IgE level or body weight.

Carrillo et al (2014) examined the evidence derived from randomized controlled trials (RCTs) on the safety and effectiveness of omalizumab compared to placebo in controlling symptoms of chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU).  The electronic databases PubMed, Medline, EMBASE, Biomed Central, The Cochrane Central Register of Controlled Trials (CENTRAL), Wiley, OVID, and HighwirePress were reviewed.  The date limit was set to May 31st, but it was extended to September 30th of 2014 due to a new publication.  No language restriction was used.  The articles included were RCTs with placebo in individuals older than 12 years diagnosed with CIU/CSU refractory to conventional treatment, the intervention being, omalizumab at different doses, and the comparison, placebo.  The primary outcome was symptom improvement according to the weekly score of urticaria severity (UAS7), the itch severity score (ISS), the weekly score of number of urticarial lesions, the dermatology life quality index, and the chronic urticaria quality of life questionnaire (CU-QoL).  Databases were searched using the following Mesh or EMTREE key words including as intervention "omalizumab" or "humanized monoclonal antibody," compared to placebo and the disease of interest "urticaria" or "angioedema".  The title, abstract and article were reviewed by 2 independent investigators, according to the selection criteria in each of the databases.  An assessment of the quality of the articles was performed according to the bias tool from the studies of the Cochrane Collaboration.  Information such as author data, date of study, number of participants, interventions, dose and frequency of administration, comparison, time of follow-up, measurements of weekly score of urticaria activity, pruritus severity score, weekly urticarial lesions, percentage of angioedema and post-treatment change were extracted.  Frequency of adverse events and the ones suspected to be caused by the intervention drug were included.  A total of 770 records were identified in all databases described; 720 were eliminated for failing to meet the inclusion criteria in the first review or for duplicate records; 24 articles were reviewed by abstract, 18 additional articles were further removed, leaving 6 records for inclusion.  An experimental study was excluded because it wasn't randomized.  Five studies were finally included, with 1,117 patients, of these 831 received a dose of omalizumab of 75 mg (183 patients, 16.38 %), 150 mg (163 patients, 14.59 %), 300 mg (437 patients, 39.12 %) or 600 mg (21 patients, 1.8 %), as a single dose, or every 4 weeks until 24 weeks maximum.  The average age was 42.07 years, predominantly female gender and white ethnicity.  It was observed that the use of omalizumab 300 mg lowered the weekly scores of urticarial activity in 19.9 versus 6.9 on placebo (p < 0.01), 19 versus 8.5 and 20.7 versus 8.01 in 3 studies, the weekly ISS (-9.2 versus - 3.5, p <0.001, -9.8 versus -5.1 p < 0.01, -8.6 versus -4.0 and -9.4 versus -3.63 p < 0.001 in 4 studies), and the percentage of angioedema-free days (omalizumab 95.5 % versus placebo 89.2 % p < 0.001, and 91.95 % versus 88.1 % p < 0.001 in 2 of the studies, respectively).  The authors concluded that despite the limitations, it is considered that omalizumab 300 mg is effective in treating CIU refractory to H1-antihistamines.  Moreover, they stated that further studies are needed to determine the duration of effective treatment.

Saini and associates (2015) noted that ASTERIA I was a 40-week, randomized, double-blind, placebo-controlled study to evaluate the safety and effectiveness of subcutaneous omalizumab as add-on therapy for 24 weeks in patients with CIU/CSU who remained symptomatic despite H1-antihistamine treatment at licensed doses.  Patients aged 12 to 75 years with CIU/CSU who remained symptomatic despite treatment with approved doses of H1-antihistamines were randomized (1:1:1:1) in a double-blind manner to subcutaneous omalizumab 75 mg, 150 mg, or 300 mg or placebo every 4 weeks for 24 weeks followed by 16 weeks of follow-up.  The primary end-point was change from baseline in weekly ISS at week 12.  Among randomized patients (n = 319: placebo n = 80, omalizumab 75 mg n = 78, 150 mg n = 80, 300 mg n = 81), 262 (82.1 %) completed the study.  Compared with placebo (n = 80), mean weekly ISS was reduced from baseline to week 12 by an additional 2.96 points (95 % confidence interval [CI]: -4.71 to -1.21; p = 0.0010), 2.95 points (95 % CI: -4.72 to -1.18; p = 0.0012), and 5.80 points (95 % CI: -7.49 to -4.10; p < 0.0001) in the omalizumab 75-mg (n = 77), 150-mg (n = 80), and 300-mg groups (n = 81), respectively.  The omalizumab 300-mg group met all 9 secondary end-points, including a significant decrease in the duration of time to reach minimally important difference response (greater than or equal to 5-point decrease) in weekly ISS (p < 0.0001) and higher percentages of patients with well-controlled symptoms (UAS7 less than or equal to 6: 51.9 % versus 11.3 %; p < 0.0001) and complete response (UAS7 = 0: 35.8 % versus 8.8 %; p < 0.0001) versus placebo.  During the 24-week treatment period, 2 (2.9 %), 3 (3.4 %), 0, and 4 (5.0 %) patients in the omalizumab 75-mg, 150-mg, 300-mg, and placebo groups, respectively, experienced a serious adverse event.  The authors concluded that omalizumab 300 mg administered subcutaneously every 4 weeks reduced weekly ISS and other symptom scores versus placebo in CIU/CSU patients who remained symptomatic despite treatment with approved doses of H1-antihistamines.

Urgert and colleagues (2015) stated that CSU is characterized by the occurrence of hives, angioedema or both for a period of at least 6 weeks.  Many patients remain symptomatic despite treatment with H1-antihistamines, even at higher doses.  These researchers assessed the quality of the evidence for the effects of omalizumab as treatment in patients with CSU.  They searched PubMed, the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials up to August 7, 2014.  Three review authors independently carried out study selection, risk of bias assessment and data extraction; 2 review authors analyzed the data; 5 RCTs that included 1,116 participants were evaluated.  All of the RCTs were judged as low risk of bias.  There was a statistically significant improvement in measures of disease activity and quality of life following treatment with omalizumab when compared to placebo (mean difference (MD) -11.58, 95 % CI: -13.39 to -9.77 and MD -13.12, 95 % CI: -16.30 to -9.95, respectively).  Complete response and partial response was more frequent after treatment with omalizumab (risk ratio (RR) 6.44, 95 % CI: 3.95 to 10.49 and RR 4.08, 95 % CI: 2.98 to 5.60, respectively).  There was no difference in the proportion of participants reporting adverse events between the omalizumab and placebo treatment groups (RR 1.05, 95 % CI: 0.96 to 1.16).  The authors concluded that there was high quality evidence to support the safety and effectiveness of omalizumab 300 mg per month for the treatment of CSU for up to 6 months.

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).  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.

Occupational Rhinitis

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.

Allergic Bronchopulmonary Aspergillosis

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.

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.

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

In a Cochrane review, Jat and colleagues (2018) evaluated the efficacy and adverse effects (AEs) of anti-IgE therapy for ABPA in people with CF.  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 carried out on September 29, 2017.  They searched 2 ongoing trial registries (Clinicaltrials.gov and the WHO trials platform).  Date of latest search was January 24, 2018; RCTs and quasi-RCTs comparing anti-IgE therapy to placebo or other therapies for ABPA in people with CF.  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.  Only 1 study enrolling 14 subjects was eligible for inclusion in the review.  The double-blind study compared a daily dose of 600-mg omalizumab or placebo along with twice-daily itraconazole and oral corticosteroids, with a maximum daily dose of 400 mg.  Treatment lasted 6 months but 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 participants into the study despite all reasonable attempts.  One or more serious AEs were encountered in 6 of 9 (66.67 %) and 1 of 5 (20 %) subjects in omalizumab group and placebo group, respectively.  The authors concluded that there is lack of evidence for the safety and efficacy of anti-IgE (omalizumab) therapy in people with CF and ABPA.  They stated that there is a need for large, prospective RCTs of anti-IgE therapy in people with CF and ABPA with both clinical and laboratory outcome measures such as steroid requirement, allergic bronchopulmonary aspergillosis exacerbations and lung function.

Food Allergies

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.

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.

Atopic Dermatitis

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.

Holm and colleagues (2017) presented a case series of 9 patients with AD treated off-label with omalizumab and a systematic review of the existing literature.  Patients were selected consecutively from a tertiary dermatological referral center during a 5-year period.  All patients were treated with omalizumab at a starting dose of 300 mg subcutaneously every 4 weeks.  Systematic literature searches were performed in PubMed, Web of Science, Embase, and ClinicalTrials.gov to identify any study (case reports, case series, and controlled trials) evaluating the effect of treatment with omalizumab in AD.  Based on physicians' assessment, 50 % of the patients had a good or excellent response to treatment with omalizumab; a further 12.5 % had a moderate response, while 37.5 % experienced no response or deterioration of symptoms during treatment.  Treatment was generally well-tolerated.  A total of 26 studies with a median of 4 patients each (range of 1 to 21), comprising 174 patients, were included in the systematic review.  Summed over all studies, a total of 129 patients (74.1 %) experienced a beneficial effect of treatment ranging from little to complete response.  The authors concluded that omalizumab appeared to be a safe and well-tolerated, however expensive, treatment with some clinical benefit in patients with severe recalcitrant AD.  Moreover, they stated that recommendation for use in clinical practice awaits evidence from larger RCTs.

Insulin Allergy

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.

Mishra and colleagues (2018) stated that insulin allergy is a rare yet severe side effect of exogenous insulin use.  Management typically involves use of alternative anti-hyperglycemic agents, symptom control with anti-histamines, use of different insulin formulations, and induction of tolerance with incremental doses of insulin.  This treatment regimen is not always successful, and the use of omalizumab has been used to induce tolerance to insulin.  These investigators reported the case of a 62-year old man with type 2 diabetes mellitus.  His condition was not optimized on oral agents, and insulin therapy was required.  He had anaphylaxis to insulin NPH, and subsequent skin-prick testing was positive to insulin aspart, insulin NPH, insulin glulisine, insulin detemir, regular insulin, insulin glargine 100 units/ml and insulin glargine 300 units/ml.  He received incremental doses of several insulin formulations; however, he experienced diffuse urticaria preventing optimal glycemic control.  Since 3 successful cases have been described in the literature of omalizumab inducing tolerance to exogenous insulin; thus, the patient was started on omalizumab.  He subsequently tolerated treatment doses of insulin glulisine and insulin detemir with no allergic reactions and with improvement in glycemic control.  The authors concluded that this was the first described case of allergy to insulin glargine 300 units/ml and reiterated the potential use of omalizumab in insulin allergy.  Moreover, they stated that further research is needed to determine if omalizumab should be considered standard of care in difficult-to-treat insulin hypersensitivity.

Bullous Pemphigoid

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.

Angioedema

Pressler et al (2013) 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. 

Eosinophilic Esophagitis

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.

Eosinophilic Pneumonia

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.

Nasal Polyposis

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.

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.

Other Indications

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. 

Aquagenic Urticaria

An UpToDate review on “Physical urticarias” (Dice and Gonzalez-Reye, 2017) does not mention omalizumab as a therapeutic option for aquagenic urticarial.

Atopic Eczema

Chan and colleagues (2017) stated that the evidence for systemic treatments for severe childhood eczema is limited and largely based on extrapolation of data from adult studies.  Current therapies are often immunosuppressant and may be associated with both short- and long-term side effects.  There is increasing in-vitro and murine-model evidence for the role of IgE in the immunopathogenesis of atopic eczema.  These researchers  examine if anti-IgE treatment (omalizumab) improves eczema, compared to placebo.  The Atopic Dermatitis Anti-IgE Pediatric Trial (ADAPT) is a randomized, double-blind, placebo-controlled study evaluating the role of anti-IgE in the management of severe pediatric eczema.  Children with severe atopic eczema, with an objective SCORing Atopic Dermatitis (SCORAD) score of over 40 will be recruited.  These children are candidates for systemic therapy, have failed systemic therapy or have experienced side effects from systemic therapy.  A total of 62 patients aged between 4 and 19 years will receive anti-IgE for 6 months.  The primary outcome measure will be the validated eczema score, the objective SCORAD at 24 weeks.  This study has 90 % power to detect a 33 % relative reduction in SCORAD between active and placebo groups, with 5 % significance.  The authors noted that IgE may have a role to play in eczema, particularly in childhood.  This forms the basis for the hypothesis that anti-IgE may be an effective treatment in this patient population.  This will be the largest study to evaluate the effectiveness of omalizumab versus placebo in children with severe eczema.  The findings will help to clarify the role of anti-IgE as a potential therapeutic option in patients with severe childhood eczema.

Chronic Autoimmune Urticaria

Kaplan et al (2008) stated that approximately 45 % of patients with chronic urticaria have an IgG autoantibody directed to the alpha-subunit of the high-affinity IgE receptor (chronic autoimmune urticaria, CAU) leading to cutaneous mast cell and basophil activation.  Treatment of allergic asthma with omalizumab produces rapid reduction in free IgE levels and subsequent decrease in Fc epsilon RI expression on mast cells and basophils.  If this occurs in CAU, cross-linking of IgE receptors by autoantibody would be less likely, reducing cell activation and urticaria/angioedema.  These researchers examined the effectiveness of omalizumab in patients with CAU symptomatic despite anti-histamine therapy.  A total of 12 patients with CAU, identified by basophil histamine release assay and autologous skin test, with persistent symptoms for at least 6 weeks despite anti-histamines, were treated with placebo for 4 weeks followed by omalizumab (greater than or equal to 0.016 mg/kg/IU mL(-1) IgE per month) every 2 or 4 weeks for 16 weeks.  Primary efficacy variable was change from baseline to the final 4 weeks of omalizumab treatment in mean Urticaria Activity Score (UAS, 0 to 9 scale).  Changes in rescue medication use and quality of life (QOL) were assessed.  Mean UAS declined significantly from baseline to the final 4 weeks of omalizumab treatment (7.50 +/- 1.78 to 2.66 +/- 3.31, -4.84 +/- 2.86, p = 0.0002); 7 patients achieved complete symptom resolution.  In 4 patients, mean UAS decreased, but urticaria persisted; 1 patient did not respond.  Rescue medication use was reduced significantly, and QOL improved.  No adverse effects were reported or observed.  The authors concluded that this exploratory proof of concept study suggested omalizumab is an effective therapy for CAU resistant to anti-histamines.

Maspero et al (2009) reported the case of a child with diagnosis of CAU/angioedema and its evolution upon omalizumab treatment.  The patient was a 12-years old female who suffered for 14 months severe CAU/angioedema.  She had a poor response to the highest doses of combined therapy with 3 anti-histamines, steroids and anti-leukotrienes and great impairment of her QOL.  An autologous serum skin test was positive until 1:100 dilutions, leading to the diagnosis of CAU.  Due to the lack of response to treatment, therapy with omalizumab was administered.  A notable reduction in symptoms toward the 3rd dose was observed.  After 12 months of this treatment, the patient is asymptomatic and has a negative autologous serum test.  The authors concluded that omalizumab could be a therapeutic option for patients with autoimmune urticaria unresponsive to other treatments.

Al-Ahmad (2010) noted that chronic urticaria is a common skin disease.  In about 45 % of patients the cause is an autoantibody directed at the α-subunit of the high-affinity IgE receptor (CAU).  Omalizumab is a monoclonal anti-IgE antibody that has a proven role in the treatment of various allergic diseases.  These investigators gave omalizumab once-monthly for 16 weeks to 3 patients that were refractory to standard treatment, including high doses of anti-histamines, leukotriene receptor antagonist, and corticosteroid.  There was dramatic improvement in the primary efficacy variable -- the change in mean UAS from baseline (i.e., the average over the first 4-week period before omalizumab) to the final 4-week period of omalizumab treatment.  There was improvement in the secondary efficacy variables, which included change from baseline in interference with sleep, interference with daily activities, daily diary record of urticaria signs and symptoms based on a scoring system, and rescue medication use.  These improvements persisted for 12 weeks after discontinuation of the drug.  The authors concluded that omalizumab may have a role in treating refractory cases of CAU.

Viswanathan et al (2013) stated that omalizumab has been shown to be effective in chronic urticaria (CU) patients in numerous reports.  However, it remains unknown whether there are specific phenotypes of CU that are more responsive to omalizumab therapy.  These researchers identified CU phenotypes responsive to treatment with omalizumab by characterizing patients and their response patterns.  A retrospective chart review analysis of refractory CU patients unresponsive to high-dose H1-blockers and immunomodulators and subsequently treated with omalizumab at the University of Wisconsin Allergy Clinic was performed with particular focus on their autoimmune characteristics, response to therapy, and dosing parameters.  These investigators analyzed 19 refractory CU patients (16 patients failed or had toxic side effects to immunomodulators) treated with omalizumab with an overall response rate of 89 % (17/19).  Of these 19 patients, 9 patients (47 %) had a complete response, 8 patients (42 %) had a partial response, and 2 patients (11 %) had no response.  In comparing the response patterns to omalizumab, these researchers found no statistically significant differences among "autoimmune positive" versus "autoimmune negative" patients.  No statistically significant differences in responses were observed when comparing demographic parameters including age, gender, IgE levels, or dosing regimen.  The authors concluded that the findings of this study showed that omalizumab had robust efficacy in refractory CU patients regardless of their autoimmune status, age, gender, IgE levels, or dosing protocol.

Sanjuan et al (2016) noted that there is accumulating evidence to suggest that IgE plays a significant role in autoimmunity.  The presence of circulating self-reactive IgE in patients with autoimmune disorders has been long known but, at the same time, largely understudied.  However, studies have shown that the increased IgE concentration is not associated with higher prevalence for atopy and allergy in patients with autoimmune diseases, such as systemic lupus erythematosus.  IgE-mediated mechanisms are conventionally known to facilitate degranulation of mast cells and basophils and promote TH2 immunity, mechanisms that are not only central to mounting an appropriate defense against parasitic worms, noxious substances, toxins, venoms, and environmental irritants but that also trigger exuberant allergic reactions in patients with allergies.  More recently, IgE autoantibodies have been recognized to participate in the self-inflicted damaging immune responses that characterize autoimmunity.  Such autoimmune responses include direct damage on tissue-containing autoantigens, activation and migration of basophils to lymph nodes, and, as observed most recently, induction of type 1 interferon responses from plasmacytoid dendritic cells.  The importance of IgE as a central pathogenic mechanism in autoimmunity has now been clinically validated by the approval of omalizumab, an anti-IgE mAb, for patients with chronic spontaneous urticaria and for the clinical benefit of patients with bullous pemphigoid.  The authors summarized recent reports describing the prevalence of self-reactive IgE and discussed novel findings that incriminate IgE as central in the pathogenesis of inflammatory autoimmune disorders.

Poddighe et al (2016) noted that the etiologic diagnosis of pediatric CU is quite challenging, as a minority of cases can be associated to specific triggers.  Thus, more than 50 % of CU in children are labeled as idiopathic.  Several evidences supported an autoimmune pathogenesis in 30 to 40 % of patients with idiopathic (or spontaneous) CU in adults, where the diagnosis of autoimmune chronic urticaria should include in-vivo and in-vitro tests, revealing the presence of autoantibodies against high-affinity IgE receptors mainly, as stated by the majority of guidelines.  in this review, these investigators collected and analyzed all the available evidences on the diagnosis and treatment of CAU in children, including most recent development and patents.  Most pediatric studies relied on autologous serum skin test only, in order to evidence autoimmune urticaria, which make such a diagnosis be incomplete.  A complete diagnostic assessment of pediatric CAU, demonstrating an antibody-mediated mechanism, could ameliorate the therapeutic management, supporting the use of omalizumab rather than other immuno-suppressive therapy in cases resistant to the first-line treatments.

Also, an UpToDate review on “Chronic urticaria: Treatment of refractory symptoms” (Khan, 2017) states that “Omalizumab, a monoclonal antibody directed against immunoglobulin E (IgE), has been shown in randomized trials to be effective for chronic urticaria (CU).  Omalizumab was approved in the United States in 2014 for the treatment of patients 12 years of age and older with CU that is not controlled with H1 antihistamine therapy … For patients with CU who have significant symptoms despite maximal doses of non-sedating H1 antihistamines in combination with other standard therapies, we suggest adding omalizumab therapy over other anti-inflammatory or immunosuppressant drugs, with the understanding that the cost of this medication may be prohibitive in many settings”.

Urticarial Vasculitis

Ghazanfar and Thomsen (2015) stated that urticarial vasculitis (UV) is characterized by inflamed itching or burning red patches or wheals that resemble urticaria but persist for greater than 24 hours.  It is often idiopathic but is sometimes associated with collagen-vascular disease, particularly systemic lupus erythematosus (SLE).  Therapeutic options include oral anti-histamines, oral corticosteroids, dapsone, colchicine or hydroxychloroquine.  These investigators described a male patient with UV who was treated with omalizumab with convincing results and provided a review of previous reports of patients with UV treated with omalizumab.  The authors concluded that clinical trials with a greater number of patients with UV that compare standard treatment with omalizumab are needed.

Fueyo-Casado and colleagues (2017) noted that UV is a eucocytoclastic vasculitis with urticarial plaques.  Treating patients with UV is challenging as the available treatments have poor efficacy.  Oral corticosteroids are considered the 1st-line treatment, but H1 anti-histamines, dapsone, colchicine, anti-malarials, cyclosporine and anti-leukotrienes have also been tried.  However, because of their adverse effects and/or lack of efficacy, new agents are still needed.  Omalizumab has been shown to be effective in treating chronic spontaneous urticaria, and might also be a good treatment for angioedema and UV.  The authors noted that to their knowledge, there have been only 7 relevant case reports published in the English literature.  They added a new case of severe chronic recurrent UV refractory to all of the afore-mentioned drugs.  These investigators started the patient on subcutaneous omalizumab 300 mg every 4 weeks that produced clinical improvement within the 1st month and total remission in the 5th month; the patient has remained stable for 23 months, and follow-up is ongoing.

Seasonal Allergens

Omalizumab is marketed for chronic severe asthma patients who are allergic to perennial allergens. Evidence for use of omalizumab in asthma due to seasonal allergens is limited.

Domingo et al (2017) investigated whether omalizumab is effective in persistent severe asthma due to seasonal allergens. Investigators treated 30 patients with oral corticosteroid-dependent asthma with omalizumab according to the dosing table. For each patient with asthma due to seasonal allergens, investigators recruited the next two consecutive patients with asthma due to perennial allergens. The dose of oral methyl prednisolone was tapered at a rate of 2 mg every two weeks after the start of treatment with omalizumab depending on tolerance. At each monthly visit, a forced spirometry and fractional exhaled nitric oxide (FeNO) measurement were performed and the accumulated monthly methyl prednisolone dose was calculated. At entry, there were no differences between groups in terms of gender, body mass index or obesity, year exacerbation rate, monthly dose of methyl-prednisolone (MP), FeNO and blood immunoglobuline E (IgE) MP, FeNO and IgE values, or spirometry (perennial: FVC: 76%; FEV₁: 62%; seasonal: FVC: 79%; FEV₁: 70%). The follow-up lasted 76 weeks. One patient in each group was considered a non-responder. Spirometry did not worsen in either group. There was a significant intragroup reduction in annual exacerbation rate and methyl prednisolone consumption but no differences were detected in the intergroup comparison. The investigators concluded that omalizumab offered the same clinical benefits in the two cohorts regardless of whether the asthma was caused by a seasonal or a perennial allergen. The investigators posited that these results suggest that allergens are the trigger in chronic asthma but that it is the persistent exposure to IgE that causes the chronicity.

Kopp et al (2009) studied the effect of omalizumab in combination with specific immunotherapy (SIT) in patients with seasonal allergic rhinoconjunctivitis (SAR) and co-morbid seasonal allergic asthma (SAA) incompletely controlled by conventional pharmacotherapy. The investigators performed a randomized, double-blind, placebo-controlled, multi-center trial to assess the efficacy and safety of omalizumab versus placebo in combination with depigmented SIT (Depigoid) during the grass pollen season. Omalizumab or placebo was started 2 weeks before SIT; the whole treatment lasted 18 weeks. Primary endpoint was daily 'symptom load', the sum of daily scores for symptom severity and rescue medication use. A total of 140 patients (age 11-46 years) were randomized; and a total of 130 finished the study. Combination therapy reduced the symptom load by 39% (P=0.0464, Wilcoxon test) over SIT monotherapy. This difference was mainly due to reduced symptom severity (P=0.0044), while rescue medication use did not change significantly. Combination therapy also improved asthma control (Asthma Control Questionnaire, P=0.0295) and quality of life in the case of asthma (Asthma Quality of Life Questionnaire, P=0.0293) and rhinoconjunctivitis (Rhinoconjunctivitis Quality of Life Questionnaire, P=0.0537). Numbers of patients with 'excellent or good' treatment efficacy according to ratings of investigators (75.0% vs. 36.9%) or patients (78.5% vs. 46.1%) were markedly higher in the combination group than under SIT alone.

Cutaneous Mastocytosis

Lieberoth and colleagues (2015) noted that the pathogenesis of mastocytosis is not well-defined and thus treatment remains challenging and remains on a palliative basis.  These researchers presented 2 cases (a 48-year old woman and a 57-year old man) with indolent systemic mastocytosis in whom omalizumab reduced gastro-intestinal and cutaneous symptoms significantly.  The authors concluded that this observation provided additional insight into the effects of omalizumab on systemic mastocytosis.  This was a small case-series study (n = 2); its findings need to be validated by well-designed studies.

Hughes and associates (2018) stated that omalizumab  is an anti-IgE monoclonal antibody, which may benefit adults with systemic mastocytosis.  These investigators reported effective treatment with omalizumab in 2 toddlers with severe diffuse cutaneous mastocytosis.  The authors concluded that these 2 cases offered preliminary evidence to support the use of omalizumab in pediatric patients with cutaneous mastocytosis.

Furthermore ,an UpToDate review on “Treatment and prognosis of cutaneous mastocytosis” (Castells and Akin, 2018) does not mention omalizumab as a therapeutic option.

Eosinophilic Granulomatosis with Polyangiitis (formerly Churg-Strauss Syndrome)

Raffray and Guillevin (2018) stated that eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome) is a rare type of anti-neutrophil cytoplasm antibody-associated vasculitis.  Nevertheless, eosinophilic granulomatosis with polyangiitis stands apart because it has features of vasculitis and eosinophilic disorders that require targeted therapies somewhat different from those used for other anti-neutrophil cytoplasm antibody-associated vasculitides.  Considerable advances have been made in understanding the underlying pathophysiology of eosinophilic granulomatosis with polyangiitis that have highlighted the key role of eosinophils and opened new therapeutic opportunities.  Its conventional treatment relies mainly on agents that decrease inflammation: corticosteroids and immunosuppressant adjunction for severe manifestations.  New therapeutic approaches are needed for refractory disease, relapses and issues associated with corticosteroid dependence, especially for asthma manifestations.  Drugs under evaluation mostly target eosinophils and B cells.  Results of low-evidence-based trials suggested possible efficacies of biologicals: B-cell-blocking rituximab and anti-immunoglobulin E omalizumab.  Recently, the 1st large-scale RCT on eosinophilic granulomatosis with polyangiitis proved the efficacy of anti-interleukin-5 mepolizumab.  That finding opens a new era in eosinophilic granulomatosis with polyangiitis management, with mepolizumab approval but also in future drug evaluations and trial designs for eosinophilic granulomatosis with polyangiitis.  The authors concluded that additional studies are needed to determine which patients would benefit most from targeted therapies and achieve personalized treatment for patients with eosinophilic granulomatosis with polyangiitis.

Inhibition of Respiratory Reaction during Aspirin Desensitization

Lang and colleagues (2018) stated that aspirin desensitization has been associated with benefit in management of aspirin exacerbated respiratory disease (AERD).  An intervention that would encourage aspirin desensitization to be performed more frequently has substantial potential for improving outcomes and QOL in patients with AERD.  These investigators examined if omalizumab administration would be associated with attenuation of aspirin-provoked bronchospasm in patients with AERD undergoing aspirin desensitization.  They performed a randomized, double-blind, placebo-controlled study in which subjects with AERD who fulfilled label criteria for omalizumab received omalizumab or placebo for 16 weeks, and then underwent aspirin desensitization.  A total of 11 subjects completed aspirin desensitization.  Of the 7 who were randomized to omalizumab, 5 had no respiratory reaction during aspirin desensitization.  Compared with placebo, omalizumab was associated with a significantly greater likelihood for subjects with AERD to have no respiratory reaction during desensitization (p = 0.04, Fisher Exact Test).  There was an overall difference in urinary LTE4 levels in subjects who received omalizumab and did not have respiratory reaction during desensitization compared to subjects randomized to placebo (p = 0.035, mixed model with interaction).  Urinary LTE4 levels were significantly higher with respiratory reaction in placebo subjects compared with levels obtained after the 100-mg dose in AERD subjects who had no respiratory reaction (p < 0.001, mixed model with interaction).  The authors concluded that in atopic AERD subjects, omalizumab administration for 16 weeks was associated with "clinically silent" desensitization.  Moreover, they stated that further studies to investigate the therapeutic utility of omalizumab in patients with AERD who are candidates for aspirin desensitization are needed based on these findings.

Use as an Adjunct to Allergen Immunotherapy

Dantzer and Wood (2018) noted that although omalizumab is currently only approved for the treatment of asthma and chronic idiopathic urticaria, it has also been studied as an off-label treatment for numerous allergic conditions, including use as an adjunct to allergen immunotherapy in the treatment of allergic rhinitis, asthma, venom hypersensitivity and food allergy.  These investigators conducted a review of publications involving the use of omalizumab with allergen immunotherapy, by searching PubMed with key search terms of "omalizumab" and "immunotherapy".  Omalizumab has been used in combination with inhalant allergen immunotherapy for the treatment of seasonal allergic rhinitis and co-morbid asthma.  While there have been no RCTs evaluating the addition of omalizumab to venom IT, several case reports and small patient series have been published on the use of omalizumab with venom IT.  Omalizumab has been used in conjunction with oral immunotherapy for the treatment of milk, peanut and egg, as well as other foods in multi-allergen protocols.  The authors concluded that omalizumab used in conjunction with immunotherapy has shown promising results, especially in the reduction of adverse reactions.  At this stage, larger, randomized, placebo-controlled trials are needed to better identify those patients who would benefit the most from the addition of omalizumab to immunotherapy, as well as optimal dosing strategies and duration of treatment.

Appendix A

Table: Estimated Comparative Daily Dosages for Inhaled Corticosteroids

In Adults and Youths Aged 12 Years and Older
Drug	Low Daily Dose		Medium Daily Dose		High Daily Dose
Beclomethasone HFA 40 or 80 mcg/puff	80-240 mcg (2-6 puffs - 40 mcg) (1-3 puffs - 80 mcg)		> 240-480 mcg (6-12 puffs - 40 mcg) (3-6 puffs - 80 mcg)		> 480 mcg (> 12 puffs - 40 mcg) (> 6 puffs - 80 mcg)
Budesonide DPI: 90, 180, or 200 mcg/inhalation	180-600 mcg (2-6 inhalations - 90 mcg) (1-3 inhalations -180 mcg) (1-3 inhalations - 200 mcg)		> 600 mcg-1,200 mcg (3-6 inhalations -- 200 mcg)		> 1,200 mcg (> 6 inhalations -- 200 mcg)
Flunisolide 250 mcg/puff	500-1,000 mcg (2-4 puffs)		> 1,000-2,000 mcg (4-8 puffs)		> 2,000 mcg (> 8 puffs)
Flunisolide HFA 80 mcg/puff	320 mcg (4 puffs)		> 320-640 mcg (4-8 puffs)		> 640 mcg (> 8 puffs)
Fluticasone HFA/MDI: 44, 110, 220 mcg/puff	88-264 mcg (2-6 puffs -- 44 mcg)		> 264-440 mcg (4-10 puffs -- 44 mcg) (2-4 puffs -- 110 mcg) (2 puffs -- 220 mcg)		(> 440 mcg (> 4 puffs - 110 mcg) (> 2 puffs -  220 mcg)
Fluticasone DPI: 50, 100, 250 mcg/inhalation	100-300 mcg (2-6 puffs - 50 mcg) (1-3 puffs - 100 mcg)		> 300-500 mcg (3-5 puffs - 100 mcg) (2 puffs - 250 mcg)		> 500 mcg (> 5 puffs - 100 mcg) (> 2 puffs - 250 mcg)
Mometasone Furoate 100 or 200 mcg/inhalation	200 mcg (2 puffs - 100 mcg) (1 puff - 200 mcg)		400 mcg (4 puffs - 100 mcg) (2 puffs - 200 mcg)		> 400 mcg (> 4 puffs - 100 mcg) (> 2 puffs - 200 mcg)
Triamcinolone acetonide 75 mcg/puff	300-750 mcg (4-10 puffs)		> 750-1,500 mcg (10 - 20 puffs)		> 1500 mcg (> 20 puffs)
In Children:  0-4 Years;  5-11 Years
Drug	Low Dose		Medium Dose		High Dose
Range of Child Age	Child 0-4	Child 5-11	Child 0-4	Child 5-11	Child 0-4	Child 5-11
Beclomethasone HFA 40 or 80 mcg/puff	N/A	80-160 mcg (2-4 puffs - 40 mcg) (1-2 puffs - 80 mcg)	N/A	> 160-320 mcg (4-8 puffs - 40  mcg) (2-4 puffs - 80 mcg)	N/A	> 320 mcg (> 4 puffs -80 mcg)
Budesonide DPI: 90,180, or 200 mcg/inhalation	N/A	180 - 400 mcg (2-4 puffs -90 mcg) (1-2 puffs -180 mcg) (2 puffs - 200 mcg)	N/A	> 400 - 800 mcg (2-4 puffs - 200 mg)	N/A	> 800 mcg (> 4 puffs -200 mcg)
Budesonide  Inhalation suspension for nebulization (child dose 0.25 mg/2ml; 0.5 mg/2ml; 1 mg/2ml)	0.25 - 0.5 mg (1-2 respules - 0.25 mg)	0.5 mg (2 resp - 0.25 mg) (1 resp - 0.5 mg)	> 0.5 - 1.0 mg (1 - 2 resp.- 0.5 mg)	1.0 mg (2 resp-0.5 mg) (1 resp - 1.0 mg)	> 1.0 mg (>2 resp-0.5 mg) (> 1 resp - 1.0 mg)	2.0 mg (2 resp. - 1.0 mg)
Flunisolide 250 mcg/puff	N/A	500-750 mcg (2-3 puffs)	N/A	1,000-1,250 mcg (4-5 puffs)	N/A	> 1,250 mcg (> 5 puffs)
Fluticasone HFA 80 mcg/puff	N/A	160 mcg (2 puffs)	N/A	320 mcg (4 puffs)	N/A	³ 640mcg (³  8 puffs)
Fluticasone HFA/MDI 44,110, or 220 mcg/puff	176 mcg (4 puffs - 44 mcg)	88 - 176 mcg (2-4 puffs-44 mcg)	> 176-352 mcg (4-8 puffs - 44 mcg)	> 176 - 352 mcg (4-8 puffs - 44 mcg)	> 352 mcg (> 8 puffs - 44 mcg) (> 3 puffs-110 mcg) (> 2 puffs-220 mcg)	> 352 mcg (> 8 puffs - 44 mcg) (> 3 puffs-110 mcg) (> 2 puffs-220 mcg)
Fluticasone DPI 50, 100, or 250 mcg/inhalation	N/A	100 - 200 mcg (2-4 puffs - 50 mcg) (1-2 puffs-100 mg)	N/A	> 200 - 400 mcg (2-4 puffs -100 mg	N/A	> 400 mcg (> 4 puffs-100 mcg) (> 2 puffs- 250 mcg)
Mometasone Furoate 100 or 200 mcg/inhalation	N//A	N//A	N//A	N//A	N//A	N//A
Triamcinolone Acetonide 75 mcg/puff	N/A	300 - 600 mcg (4-8 puffs)	N/A	> 600 - 900 mcg (8 - 12 puffs)	N/A	> 900 mcg (> 12 puffs)
Key: HFA, hydrofluoroalkane; NA, not approved and no data available for this age group.  MDI (metered-dose inhaler) dosages are expressed as the actuator dose (the amount of the drug leaving the actuator and delivered to the patient), which is the labeling required in the United States.  DPI (dry powder inhaler) doses are expressed as the amount of drug in the inhaler following actuation.
Adapted from: National Asthma Educational Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma.  Full Report 2007.  Available at: EPR 3 Guidelines on Asthma by National Asthma Education and Prevention Program (NAEPP) opens a dialog

Appendix B

Table: Dosing Schedule for Subcutaneously Administered Omalizumab for Asthma

Body Weight
kg	>20-25	>25-30	>30-40	>40-50	>50-60	>60-70	>70-80	>80-90	>90-125	>125-150
lbs	>44-55	>55-66	>66-88	>88-110	>110-132	>132-154	>154-176	>176-198	>198-275	>275-331
Baseline Serum IgE Level (IU/ml)	Dose in milligrams
>30-100	75	75	75	150	150	150	150	150	300	300
>100-200	150	150	150	300	300	300	300	300	225	300
>200-300	150	150	225	300	300	225	225	225	300	375
>300-400	225	225	300	225	225	225	300	300	450	525
>400-500	225	300	300	300	300	300	375	375	525	600
>500-600	300	300	300	300	300	375	450	450	600
>600-700	300	225	375	375	375	450	450	525
>700-800	225	225	300	375	450	450	525	600
>800-900	225	225	300	375	450	525	600
>900-1000	225	300	375	450	525	600
>1000-1100	225	300	375	450	600
>1100-1200	300	300	450	525	600	DO NOT ADMINISTER
>1200-1300	300	375	450	525		data unavailable for dose recommendation
>1300-1500	300	375	525	600
Every 4 Week Dosing
Every 2 Week Dosing
Adapted from: Genentech USA, Inc. Xolair® (Omalizumab) for Injection, for subcutaneous Use.  Prescribing Information. South San Francisco, CA: Genentech USA;Revised June 2017; Novartis Pharma GmBH. Xolair Solution for Injection. Omalizumab. Annex I. Summary of Product Characteristics. Nuremberg, Germany: Novartis; September 9, 2016.

See: Xolair Prescribing Information - FDA; Xolair - EMA Product Information

Appendix C

Dosing of Xolair (Omalizumab) for chronic idiopathic urticaria

The recommended dose of Xolair (omalizumab) is 150 mg to 300 mg administered subcutaneously every 4 weeks. Dosing in CIU is not dependent on serum IgE level or body weight.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
95004 - 95079	Allergy Testing
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96401 - 96549	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J2357	Injection, omalizumab, 5 mg
Other HCPCS codes related to the CPB:
J2182	Injection, mepolizumab, 1 mg [not covered in combination with omalizumab]
J2786	Injection, reslizumab, 1 mg [not covered in combination with omalizumab]
J7622	Beclomethasone, inhalation solution, compounded product, administered through DME, unit dose form, per milligram
J7626	Budesonide, inhalation solution, FDA-approved final product, noncompounded, administered through DME, unit dose form, up to 0.5 mg
J7627	Budesonide, inhalation solution, compounded product, administered through DME, unit dose form, up to 0.5 mg
J7633	Budesonide, inhalation solution, FDA-approved final product, noncompounded, administered through DME, concentrated form, per 0.25 mg
J7634	Budesonide, inhalation solution, compounded product, administered through DME, concentrated form, per 0.25 mg
J7640	Formoterol, inhalation solution, compounded product, administered through DME, unit dose form, 12 mcg
J7641	Flunisolide, inhalation solution, compounded product, administered through DME, unit dose form, per mg
Xolair (omalizumab) [6-11 age group]:
ICD-10 codes covered if selection criteria are met:
J45.40 - J45.52	Asthma [moderate to severe persistent allergic]
Xolair (omalizumab) [adolescent and adult age group (age 12 and over)]:
ICD-10 codes covered if selection criteria are met:
J45.40 - J45.52	Asthma [moderate to severe persistent allergic]
L50.1	Idiopathic urticaria
L50.8	Other urticaria [covered for chronic autoimmune urticaria only] [not covered for aquagenic urticaria]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
B44.81	Allergic bronchopulmonary aspergillosis
D47.01	Cutaneous mastocytosis
J30.1 - J30.9	Allergic rhinitis
J33.0 - J33.9	Nasal polyps
J82	Pulmonary eosinophilia, not elsewhere classified
K20.0	Eosinophilic esophagitis
K52.81	Eosinophilic gastritis or gastroenteritis
L12.0 - L12.9	Pemphigoid
L20.0 - L20.89	Atopic dermatitis
L27.2	Dermatitis due to ingested food
L50.0, L50.2 – L50.6, L50.9	Urticaria [cholinergic urticaria and urticaria of other known causes]
L95.8	Other vasculitis limited to the skin [urticarial vasculitis]
M30.1	Polyarteritis with lung involvement [Churg-Strauss] [eosinophilic granulomatosis with polyangiitis]
Q82.2	Congenital cutaneous mastocytosis
Z51.89	Encounter for other specified aftercare [need for desensitization to allergens]
Z88.6	Allergy status to analgesic agent status [inhibition of respiratory reaction during aspirin desensitization in individuals with aspirin exacerbated respiratory disease]
Z91.010 - Z91.038	Food and insect allergy status
Z91.040	Latex allergy status
Z91.049, Z91.09	Other allergy, other than to medicinal agents [atopy to perennial aeroallergen with positive skin test or in vitro reactivity]

The above policy is based on the following references: