Q:

2/28/2012
10 yo M with severe persistent asthma uncontrolled, on Advair 500 bid, requiring 3 courses of oral steroids last year and 2 hospitalizations for asthma. This is despite sinus surgery 5/2011 for chronic sinusitis and adenoidal hypertrophy. Allergies to pets dog and cat > 100 ku/L, dust mites 2 ku/L, total IgE 2100 ku/L, eosinophilia 1100. Moved out of home with dog 3 weeks ago and still with exacerbation and recurrence of sinusitis. Upper respiratory symptoms precede asthma flares, and is on nasal steroid and nasal antihistamine, cannot tolerate Singulair. CXR negative x 2. His total IgE is high for Xolair and cannot build immunotherapy due to asthma. Elevated eosinophilia but no evidence of aspergillus on skin test. Please advise if Xolair would be worth trial despite young age and total IGE or other options?

A:

Thank you for your inquiry.

As you can see from the abstract copied below, omalizumab has been clearly shown to be helpful in children with severe persistent asthma who have not responded to "standard" therapy.

Therefore, in my opinion, it would be worthwhile to try omalizumab in your patient. However, I am going to ask Dr. Bob Lanier, who, as you can see, is the lead author on one of the articles mentioned below, to share his thoughts with us in this regard. Dr. Lanier has vast experience with omalizumab and has published extensively in this area. As soon as I receive Dr. Lanier's response, I will forward it to you.

Thank you again for your inquiry.

A review of anti-IgE monoclonal antibody (omalizumab) as add on therapy for severe allergic (IgE-mediated) asthma
Gennaro D’Amato, Antonello Salzillo, Amedeo Piccolo,Maria D’Amato, Gennaro Liccardi in Therapeutics And Clinical Risk Management (2007)
Abstract
Background: Many children with severe persistent allergic (IgE-mediated) asthma remain inadequately controlled despite treatment with high-dose inhaled corticosteroids (ICS) plus a long-acting beta(2)-agonist (LABA).
Research and Design Methods: This pre-specified analysis of a randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of omalizumab in children (6-or=500 microg x day(-1) or equivalent) plus a LABA. Patients received omalizumab (75-375 mg once or twice a month by subcutaneous injection, as determined from dosing tables) or placebo over 52 weeks (24-week fixed-steroid then 28-week adjustable-steroid phases).
Results: Out of 246 randomized patients (omalizumab, n = 166; placebo, n = 80), efficacy was analysed in 235 (omalizumab, n = 159; placebo, n = 76). 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 34% versus placebo (0.42 vs 0.63, rate ratio 0.662; P = 0.047). Over 52 weeks, the exacerbation rate was reduced by 50% (P < 0.001). Omalizumab had an acceptable safety profile, with no statistically significant (P < 0.05) differences in adverse events observed between omalizumab and placebo. CONCLUSION: Add-on omalizumab is well-tolerated and reduces exacerbations in children (6-<12 years) with severe persistent allergic asthma, inadequately controlled despite high-dose ICS plus a LABA. It should be noted that the sample size was not based on providing statistical power in the severe subgroup, and no corrections were made for multiple comparisons; however, outcomes consistently favoured omalizumab

Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma.
by Bob Lanier, Tracy Bridges, Marek Kulus, Angel Fowler Taylor, Indrias Berhane, Carlos Fernandez Vidaurre
The Journal of Allergy and Clinical Immunology (2009)
Volume: 124, Issue: 6, Publisher: Elsevier Ltd, Pages: 1210-1216
Abstract
Background: Many children with asthma continue to experience symptoms despite available therapies.
Objective: This study evaluated the efficacy and safety of omalizumab, a humanized anti-IgE mAb, in children with moderate-to-severe persistent allergic (IgE-mediated) asthma that was inadequately controlled despite treatment with medium-dose or high-dose inhaled corticosteroids (ICSs) with or without other controller medications.
Methods: A randomized, double-blind, placebo-controlled trial enrolled children age 6 to <12 years with perennial allergen sensitivity and history of exacerbations and asthma symptoms despite at least medium-dose ICSs. Patients were randomized 2:1 to receive omalizumab (75-375 mg sc, q2 or q4 wk) or placebo over a period of 52 weeks (24-week fixed-steroid phase followed by a 28-week adjustable-steroid phase).
Results: A total of 627 patients (omalizumab, n = 421; placebo, n = 206) were randomized, with efficacy analyzed in 576 (omalizumab, n = 384; placebo, n = 192). Over the 24-week fixed-steroid phase, omalizumab reduced the rate of clinically significant asthma exacerbations (worsening symptoms requiring doubling of baseline ICS dose and/or systemic steroids) by 31% versus placebo (0.45 vs 0.64; rate ratio, 0.69; P = .007). Over a period of 52 weeks, the exacerbation rate was reduced by 43% versus placebo (P < .001). Omalizumab significantly reduced severe exacerbations. Over a period of 52 weeks, omalizumab had an acceptable safety profile, with no difference in overall incidence of adverse events compared with placebo.
Conclusion: Add-on omalizumab is effective and well tolerated as maintenance therapy in children (6 to <12 years) with moderate-to-severe persistent allergic (IgE-mediated) asthma whose symptoms are inadequately controlled despite medium to high doses of ICSs.

Sincerely,
Phil Lieberman, M.D.

We received a response from Dr. Bob Lanier. Thank you again for your inquiry and we hope this response is helpful to you.

Sincerely,
Phil Lieberman, M.D.

Response from Dr. Bob Lanier:
The short answer is YES- I would consider a 3-6 month trial of omalizumab in this severe, brittle asthmatic with perennial sensitivity. I base this opinion on both safety and efficacy.

Safety:
One consideration for high levels of omalizumab in the presence of a high level of IgE might be the development of immune complex disease. There develops a dense blood buffer state of IgE-IgG with therapy, raising the total level of IgE in therapy 3-5x baseline. In other words, repeating an IgE level in a month or two post omalizumab might reveal a total IgE of 3000- 6000 ku/l. The majority of these complexes are trimers, but even in the case larger complexes, they do not approach the size of the IgM molecule which is the generally accepted cut off for size concern and immune complex disease. No immune complex disease has been reported in clinical trials or in the published literature.

While there were artifactual signals early in trials for neoplasia, seven year studies (EXCEL- in publication) find no evidence of that concern, particularly in the case of a short 3-6 month trial. If the trial is not efficacious, long term considerations become moot as the drug is discontinued. Anaphylaxis and anaphylactoid reactions have been reported, but not correlated to the dose of anti-IgE to my knowledge.

Efficacy:
The high level of IgE in this patient are often found in children with eczema, sometimes not associated with antigen specific IgE. This is sometimes called "nonsense" IgE. Even if this level doesn't reflect pertinent IgE, it must occupy the energy of monoclonal anti-IgE.

The original basic mechanism of this drug is that anti-IgE reduced the number of antigen receptors on the mast cell making it more difficult for antigen to crosslink IgE. That goal was achieved by tying up free IgE which was well shown to reduce receptor density.

Working backwards, the dosage of anti-IgE was computed as a function of the vascular department (using weight as the surrogate parameter) against the level of IgE. The original table was produced using a formula of 0.015mgm of Omalizumab / kg of patient body weight merely for investigators computing a dose inside the framework of the study. The table used a scale of IgE of 30-700 for exclusion / inclusion criteria for these clinical trials. The "table" was accepted by FDA and became an artifact embedded in the product information. You could compute a "dose" regardless of the level of IgE versus enormous weight. The only risk would be costs, comfort, and the poorly studied super doses with respect to immune complex disease issues.

Many investigators theorize that the true effect of anti-IgE may be wholly different than simply tying up free IgE, including actual IgE B cell modification. In my own studies I have noted 16 patients with IgE of >2000 (up to 7000) complete initial treatment. In 10 of 16, the total IgE (the only commonly available tool to study this) actually decreased after six months of therapy, dropping in most cases into the 300-500 range, but certainly not sustained at the very high levels I had feared. To me, that suggests an action on the IgE B cell itself, a frequent discussion topic between the compound originator, Tse Wen Chang and I. Those individuals with high IgE that did not drop I have found no evidence of clinical disease.

When I see a child like the you describe, I use the "maximum" allowable anti-IgE (375/mgm month) if it exceeds the normal table dosage, and watch them carefully over 3-6 months clinically, in addition to monthly IgE levels. If I see clinical improvement, I sustain treatment and with no improvement (as with all patients) discontinue it.

Unfortunately we sail in uncharted waters, but at this point, I have no reason to withhold what might be a disease modifying drug from a severely affected child.

• Lanier BQ, Chang TW, Will Anti-IgE therapy Compromise Normal Immune Functions?, Allergy & Clinical Immunology International, Nov/Dec 2004

• Lanier, Bob Q.  Unanswered questions and speculations about the role of anti-immunoglobulin E in atopic and nontoxic disease, Allergy Asthma Proceedings Vol. 27, No. 2 March-April 2006, Supplement No.1

• Lanier, Bob Q. Unanswered Questions and Warnings Involving Anti-Immunoglobulin E Therapy Based on 2-Year Observation of Clinical Experience Proceedings of Allergy Asthma and Immunology Volume 26, Number 6, November-December 2005 pp. 435-439(5)

• 2008 Abstract European Respiratory Association, Efficacy and Safety of Omalizumab Added to Optimize Asthma Care in Children

Bob Lanier

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