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Key clinical-trial evidence for omalizumab

Author: Anoma Ranaweera, Medical Writer, Auckland, New Zealand. DermNet Chief Editor in Chief: Adjunct A/Prof Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand. First published December 2013; updated April 2020. Copy edited by Gus Mitchell/Maria McGivern.


Introduction

Omalizumab (trade name Xolair™) is a humanised monoclonal antibody that binds to circulating immunoglobulin E (IgE) and reduces the release of inflammatory mediators from mast cells and basophils. It is given by subcutaneous injection once every 4 weeks.

Omalizumab was licensed in New Zealand as an 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.

What is the available clinical evidence to support omalizumab for urticaria?

Results of three several phase III trials ASTERIA I, ASTERIA II, and GLACIAL 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 [1].
  • 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 changed from baseline to Week 12 in the weekly itch-severity score; secondary endpoints included safety, oedema, weals, 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

Group Mean Change P-Value
Omalizumab 300 mg -9.8 p < 0.001
Omalizumab 150 mg -8.1 p = 0.001
Omalizumab 75 mg -5.9 p = 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.
  • 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 antihistamines; however, symptoms slowly returned for most patients.

ASTERIA I

  • ASTERIA I was a 40-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous omalizumab as add-on therapy for 24 weeks in patients with chronic idiopathic urticaria/spontaneous urticaria (CIU/CSU) who remained symptomatic despite H1 antihistamine treatment at licensed doses.
  • Patients aged 12–75 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 [2].
  • The primary end point was change from baseline in weekly itch severity score (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 nine secondary end points, including a significant decrease in the duration of time to reach minimally important difference response (⩾ 5-point decrease) in weekly ISS and higher percentages of patients with well-controlled symptoms (urticaria activity score over 7 days (UAS7) ⩽ 6: 51.9% vs. 11.3%; p < 0.0001) and complete response (UAS7 = 0: 35.8% vs. 8.8%; p < 0.0001) versus placebo.
  • During the 24-week treatment period, the proportions of patients who experienced one or more treatment-emergent adverse events (AEs) ranged from 57–69% in the omalizumab groups versus 51% in the placebo group. Headaches, arthralgia, and injection-site reactions were more common in the omalizumab groups than in the placebo group. The majority of AEs were mild or moderate in intensity.
  • Thus, 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.
  • Efficacy and safety results were consistent with those of ASTERIA II.
  • A return of symptoms was observed in both the current study and ASTERIA II during follow-up, reaching mean values similar to those in the placebo group but not returning to baseline values.

GLACIAL (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 [3].
  • 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.
  • It was concluded that omalizumab was well tolerated and reduced the signs and symptoms of chronic idiopathic urticaria/chronic spontaneous urticaria in patients who remained symptomatic despite the use of H1-antihistamines (up to 4 times the approved dose) plus H2-antihistamines, leukotriene receptor antagonists, or both.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 multicentre, randomised, double-blind, placebo-controlled study included patients aged 18–70 years with chronic urticaria with IgE autoantibodies against TPO that had persistent symptoms (weals 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 [4].
  • 42 of the 49 randomised patients completed the study (omalizumab, n = 27; placebo, n = 22).
  • The mean weekly urticaria activity score was calculated 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.

Omalizumab and Quality of Life – X-ACT study

The X‐ACT study aimed to examine the effect of omalizumab treatment on quality of life (QoL) in chronic spontaneous urticaria (CSU) patients with angioedema refractory to high doses of H1‐antihistamines [5].

In this phase III double-blind randomised study patients were randomised 1:1 to receive omalizumab 300 mg SC or placebo every 4 weeks for 28 weeks. 68 patients (omalizumab, n = 35; placebo, n = 33) completed the 28‐week treatment period. All were chronic spontaneous urticaria patients (18–75 years) with ≥ 4 angioedema episodes during the 6 months before inclusion.

Angioedema‐related quality of life (QoL), skin‐related QoL impairment, and psychological well‐being were assessed. At baseline, the mean (SD) total Angioedema QoL (AE‐QoL; 56.2 [18.7] and 59.9 [19.2]) and Dermatology Life Quality Index (DLQI; 14.6 [5.7] and 16.6 [7.3]) score were high in the omalizumab and placebo groups, respectively.

Following omalizumab treatment initiation, the mean angio-oedema activity scores (AAS7); consisting of an opening question (Have you had a swelling episode in the last 24 hours?), followed by the five specific AAS questions to determine the severity and impact of the angioedema episode, decreased rapidly with significant differences observed as early as Week 4 through to Week 28.

The mean (SD) AAS7 scores increased to placebo levels (omalizumab, 10.2 [19.6]; placebo, 9.8 [12.0]) after discontinuation of omalizumab at Week 36.The most severely affected subdomains of the AE‐QoL were fears/shame, fatigue/mood, and functioning.

The most severely affected subdomains of the DLQI score included daily activities and leisure. General psychological and well-being improved with omalizumab treatment. In the omalizumab group, the mean (SD) WHO‐5 score (The World Health Organisation -5 Well-Being Index) was 10.0 (5.5) at baseline and increased above the depression threshold to 18.6 (5.1) by the end of the treatment period. The corresponding results in the placebo group were 7.7 (5.3) at baseline and 11.5 (5.8) at Week 28 (least square mean difference between groups at Week 28, p < 0.001).

Omalizumab in Paediatric Atopic dermatitis – ADAPT TRIAL

This study attempted to determine the effectiveness of omalizumab in treating severe atopic dermatitis in children.

  • This was a 24-week single-center, double-blind, placebo-controlled randomized clinical trial with a 24-week follow-up and patients were randomised to omalizumab or placebo [6].
  • Eligible participants (n = 62) were aged 4 to 19 years and had severe eczema (with objective Scoring Atopic Dermatitis [SCORAD] index > 40) that was unresponsive to optimum therapy.
  • Interventions: consisted of subcutaneous omalizumab or placebo for 24 weeks and the drug manufacturer's dosing tables were used to determine the dosage based on total IgE (30-1500 IU/mL) and body weight (in kilograms) at randomization.
  • The main outcome was the objective SCORAD index after 24 weeks of treatment.
  • At Week 24 the mean difference in objective SCORAD index improvement between groups was -6.9 (95% CI, -12.2 to -1.5; p = 0.01), significantly favouring omalizumab therapy.
  • Improved quality-of-life scores were seen in the omalizumab group, as measured by the Children's Dermatology Life Quality Index/Dermatology Life Quality Index (-3.5; 95% CI, -6.4 to -0.5) and Pediatric Allergic Disease Quality of Life Questionnaire score (-0.5; 95% CI, -0.9 to -0.0)
  • This randomized clinical trial found that omalizumab significantly reduced atopic dermatitis severity and improved quality of life in a pediatric population with atopy and severe eczema despite highly elevated total IgE levels at baseline.

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. When omalizumab was restarted in patients that had previously responded, the omalizumab was again effective.

Future directions

IgE autoantibodies are also detected in a large number of patients with atopic dermatitis and bullous pemphigoid. In individual 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.

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If you are not based in New Zealand, we suggest you refer to your national drug approval agency for further information about medicines (eg, the Australian Therapeutic Goods Administration and the US Food and Drug Administration) or a national or state-approved formulary (eg, the New Zealand Formulary and New Zealand Formulary for Children and the British National Formulary and British National Formulary for Children).

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References

  1. Maurer M, Rosen K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013; 368: 924–35. DOI: 10.1056/NEJMoa1215372. PubMed
  2. Saini SS, Bindslev-Jensen C, Maurer M, et al. Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 antihistamines: a randomized, placebo-controlled study. J Invest Dermatol 2015; 135: 67–75. DOI: 10.1038/jid.2014.306. PubMed Central
  3. Kaplan A, Ledford D, Ashby M, et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin Immunol 2013; 132: 101–9. DOI: 10.1016/j.jaci.2013.05.013. PubMed
  4. Maurer M, Altrichter S, Bieber T, et al. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase. J Allergy Clin Immunol 2011; 128: 202–9. DOI: 10.1016/j.jaci.2011.04.038. PubMed
  5. P Staubach, M Metz, N Chapman‐Rothe, et al. Omalizumab rapidly improves angioedema‐related quality of life in adult patients with chronic spontaneous urticaria: X‐ACT study data. Allergy 2018; 73: 576–84. DOI: 10.1111/all.13339. PubMed
  6. Chan S, Cornelius V, Cro S, Harper JI, Lack G. Treatment effect of omalizumab in severe pediatric atopic dermatitis: the ADAPT randomized clinical trial. JAMA Pediatr 2020; 174: 29–37. DOI: 10.1001/jamapediatrics.2019.4476. PubMed

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