Omalizumab for urticaria

Author: Anoma Ranaweera B.V. Sc; PhD (Clinical Biochemistry, University of Liverpool, UK), 2013.


Introduction

Omalizumab is a humanised monoclonal antibody that binds to circulating immunoglobulin E (IgE) and reduces the release of inflammatory mediators from mast cells and basophils.

In New Zealand, it is currently (2018) licensed as add-on therapy for patients with severe, persistent allergic asthma and for patients 12 years of age or older with severe chronic spontaneous urticaria that remain symptomatic despite H1 antihistamine treatment. It is funded by PHARMAC on Special Authority application under certain circumstances.

It is given by subcutaneous injection once every 4 weeks.

The trade name of omalizumab is Xolair™.

What is chronic spontaneous urticaria?

Chronic spontaneous urticaria (also called chronic idiopathic urticaria) is defined as hives or wheals that last for at least 6 weeks, with or without angioedema. Urticaria is often extremely itchy, interfering with sleep, daily activities, social interactions, school and work life.

Symptoms may resolve after a few months; however in about 50% of cases symptoms persist for 3-5 years, and in 20% of cases symptoms can persist for more than 10 years.

Urticaria most often results from the effect of histamine on H1-receptors located on the endothelial cells lining blood vessels. Histamine causes the cells to separate, so that tissue fluid leaks out, forming a wheal. Histamine also affects sensory nerves, resulting in neurogenic flare (red skin) and pruritus (itch).

Chronic urticaria may be refractory to antihistamines and associated with a pronounced cellular infiltrate.

What is the role of omalizumab in treatment of urticaria?

Omalizumab is intended to be used as second-line therapy for the treatment of chronic spontaneous urticaria that is refractory to oral antihistamines. Many patients also fail to respond to a variety of other systemic therapies including systemic steroids and immunomodulating drugs.

Omalizumab is currently in phase III clinical trials in chronic spontaneous urticaria.

How does omalizumab work in urticaria?

The immunoglobulin "E" (IgE) triggers an allergic reaction (e.g. asthma) in response to an allergen (e.g. cat dander). Although chronic spontaneous urticaria is not due to allergy, it occurs through a similar pathway.

Omalizumab has been designed to recognise and attach to a specific structure on circulating human IgE. This prevents IgE binding to high affinity receptors (FcεRI) on the surface of mast cells and basophils, thus reducing receptor expression and the release of inflammatory mediators.

What is the available clinical evidence for the effect of omalizumab?

Results of at least 2 published randomised controlled trials support the efficacy of omalizumab in chronic spontaneous urticaria.

ASTERIA II

  • This global, multicenter, randomised, double-blind, placebo-controlled study was funded by Genentech and Novartis Pharma; ClinicalTrials.gov number, NCT01292473. It has shown that omalizumab reduces symptoms in chronic urticaria.
  • The trial enrolled 323 patients with a history of at least 6 months of chronic idiopathic urticaria resistant to antihistamines.
  • Participants were randomly assigned to receive 3 subcutaneous injections at 4-week intervals of omalizumab: 75 mg, 150 mg, 300 mg, or placebo (a dummy treatment). This was followed by a 16-week observation period.
  • The primary endpoint was change from baseline to week 12 in the weekly itch-severity score; secondary endpoints included safety, oedema, wheals, and quality of life.
  • Throughout the treatment and follow-up period, patients were allowed to remain on antihistamines, and they were also permitted to take rescue antihistamines.
Mean Change from baseline in the weekly itch-severity score
GroupMean ChangeP-Value
Omalizumab 300 mg -9.8 < 0.001
Omalizumab 150 mg -8.1 = 0.001
Omalizumab 75 mg -5.9 = 0.46
Placebo -5.1 Not reported
  • At the end of treatment, 53% of patients receiving the high dose were completely free of hives compared with 23% in the 150-mg group, 18% in the low-dose group, and 10% in the placebo group.
  • The mean change from baseline in weekly rescue diphenhydramine dosing was a decrease of 4.1 tablets in the 300-mg group (P = 0.01), a decrease of 3.7 tablets in the 150-mg group (P = 0.07), a decrease of 2.3 tablets in the 75-mg group (P = 0.91), and a decrease of 2.2 tablets in the placebo group.
  • During the 16-week follow-up period after stopping treatment, patients were permitted to continue anthistamines; however, symptoms slowly returned for most patients.

ClinicalTrials.gov number NCT01264939

  • In this phase III study, 332 patients aged 12-75 years with chronic spontaneous urticaria refractory to antihistamines were randomised to receive 6 subcutaneous injections at 4-week intervals of either 300 mg of omalizumab or placebo, followed by a 16-week observation period.
  • The primary objective was to evaluate the safety of omalizumab compared with placebo. Efficacy was evaluated at weeks 12 and 24 and included itch severity, wheal, and urticaria activity scores.
  • The overall incidence and severity of adverse events and serious adverse events were similar between omalizumab and placebo recipients.
  • At week 12, the mean change from baseline in weekly itch severity score was −8.6 (95% CI, −9.3 to −7.8) in the omalizumab group compared with −4.0 (95% CI, −5.3 to −2.7) in the placebo group ( P < 0.001). These benefits were sustained to week 24.

Omalizumab in chronic urticaria with IgE against thyroperoxidase

  • In a subgroup of patients with chronic spontaneous urticaria, IgE antibodies are directed against autoantigens, such as thyroperoxidase (TPO).
  • A multicenter, randomised, double-blind, placebo-controlled study included patients aged 18-70 years with chronic urticaria with IgE autoantibodies against TPO that had persistent symptoms (wheals and pruritus) despite standard antihistamine therapy. They were randomised to receive either omalizumab (75-375 mg, dose determined by using the approved asthma dosing table) or placebo subcutaneously once every 2 or 4 weeks for 24 weeks.
  • 42 of the 49 randomised patients completed the study (omalizumab, n = 27; placebo, n = 22).
  • The mean weekly urticaria activity score was calcultated after 24 weeks of treatment, using patients' diaries. Patients on omalizumab had a mean reduction of 17.8 and patients on placebo had a reduction of 7.9 (P = 0.0089).
  • Omalizumab has been shown to be effective for patients with chronic urticaria that are refractory to conventional treatment and have IgE autoantibodies against TPO .

Disadvantages of omalizumab

So far, there is no evidence that omalizumab is disease modifying. When patients stopped the study drug, their symptoms recurred. At the end of 16 weeks off treatment, symptoms of urticaria were similar to patients treated with placebo.

What is the risk associated with omalizumab use?

  • Headache and injection site reactions (swelling, redness, pain and itching) affect about 10% of patients treated with omalizumab.
  • Omalizumab should not be used in people that may be hypersensitive (allergic) to the drug or any ingredient in the injection vial.

Omalizumab in inducible-urticaria

Inducible or physical urticaria, such as solar urticaria or cold urticaria, does not always respond well to antihistamines. To date, no randomised placebo-controlled trial of omalizumab has been performed in inducible urticarias.

Future directions

IgE autoantibodies are also detected in a large number of patients with atopic dermatitis and bullous pemphigoid. In case reports, omalizumab treatment has been reported to be effective in some patients with these conditions. It has also been reported effective in chronic recurrent angioedema. Randomised controlled trials are warranted.

 

New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

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References

  • Zuberbier T, Asero R, Bindslev-Jensen C, Walter CG, Church MK, Gimenez-Arnau AM, et al. EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria. Allergy. 2009;64: 1427–1443.
  • Saini S, Rosen KE, Hsieh HJ, Wong DA, Conner E, Kaplan A, et al. A randomized, placebo-controlled, dose-ranging study of single-dose omalizumab in patients with H1-antihistamine-refractory chronic idiopathic urticaria. J Allergy Clin Immunol. 2011;128: 567–573.
  • Maurer M, Altrichter S, Bieber T, Biedermann T, Brautigam M, Seyfried S, et al. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase. J Allergy Clin Immunol. 2011;128: 202–209.
  • Maurer M, Rosen K, Hsieh HJ, Saini S, Grattan C, Gimenez-Arnau A, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013; 368:924–935.
  • Zuberbier T, Asero R, Bindslev-Jensen C, Walter CG, Church MK, Gimenez-Arnau A, et al. EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria. Allergy.2009; 64:1417–1426.
  • Kaplan A, Ledford D, Ashby M, Canvin J et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. Journal of Allergy and Clinical Immunology 2013; 132(1):101-9.

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