Key clinical-trial evidence for omalizumab

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 is 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 New Zealand's Pharmaceutical Management Agency (PHARMAC) on special authority application under certain circumstances.

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

Results of three phase III trials ASTERIA I, ASTERIA II, and GLACIAL trials support the efficacy of omalizumab in chronic spontaneous urticaria.

ASTERIA II

This global, multicentre, 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 aged 12-75 years with a history of at least 6 months of chronic idiopathic urticaria resistant to antihistamines.
• Participants were randomly assigned to receive three subcutaneous injections of omalizumab at 4-week intervals: 75 mg, 150 mg, or 300 mg; or placebo (a dummy treatment). This was followed by a 16-week observation period.
• The primary endpoint was the change in the weekly itch-severity score from baseline to Week 12; 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 were also permitted to take rescue antihistamines.

Mean change from baseline in the weekly itch-severity score

• At the end of treatment, 53% of patients receiving the highest 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.
• Most serious adverse events occurred in the 300mg group.
• Angioedema-free days reached significance only in the 300mg group.

ASTERIA I

• ASTERIA I was a 40-week, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous omalizumab as an 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.
• 318 patients aged 12–75 years were randomised (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 endpoint was change from baseline in weekly itch severity score (ISS) at Week 12.
• Of the 319 randomised patients (placebo [n = 80]; omalizumab 75 mg [n = 78], 150 mg [n = 80], and 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 endpoints, 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.
• It was concluded that omalizumab 300 mg administered subcutaneously every 4 weeks reduced weekly ISS and other symptom scores compared to 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 ASTERIA I and II trials 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.
• 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 four times the approved dose) plus H2-antihistamines, leukotriene receptor antagonists, or both.

Omalizumab in chronic urticaria with IgE against thyroperoxidase

• A subgroup of patients with chronic spontaneous urticaria have IgE antibodies directed against autoantigens, such as thyroperoxidase (TPO).
• A multicentre, randomised, double-blind, placebo-controlled study included patients aged 18–70 years with chronic urticaria and IgE autoantibodies against TPO with 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.
• A total of 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 patient 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 and IgE antibodies against thyroperoxidase who are refractory to conventional antihistamine treatment.

Omalizumab and quality of life – the 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.

In this phase III double-blind randomised study patients aged 18-75 years, were randomised 1:1 to receive subcutaneous omalizumab 300 mg or placebo every 4 weeks for 28 weeks. 68 of the 91 patients randomised (omalizumab, n = 35; placebo, n = 33) completed the 28‐week treatment period. All had chronic spontaneous urticaria with at least 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]) in the omalizumab and placebo groups, respectively.

Following omalizumab treatment initiation, the mean angioedema 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 at Week 36 (omalizumab, 10.2 [19.6]; placebo, 9.8 [12.0]) after discontinuation of omalizumab. 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 Organization -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 studied the effectiveness of omalizumab in treating severe atopic dermatitis in children.

• This was a 24-week single-centre, double-blind, placebo-controlled randomised clinical trial and a 24-week follow-up and patients were randomised to omalizumab or placebo.
• Eligible participants (n = 62) were aged 4 to 19 years and had severe eczema (with objective Scoring Atopic Dermatitis [SCORAD] index > 40) 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 randomisation.
• 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), favouring omalizumab therapy.
• Improved quality-of-life scores were seen in the omalizumab group, as measured by the Children’s Dermatology Life Quality Index (CDLQI)/Dermatology Life Quality Index (−3.5; 95% CI: −6.4 to −0.5) and Paediatric Allergic Disease Quality of Life Questionnaire score (−0.5; 95% CI: −0.9 to −0.0).
• This randomised clinical trial found that omalizumab significantly reduced atopic dermatitis severity and improved quality of life in a paediatric population with atopy, severe eczema, and 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.

Omalizumab is administered by subcutaneous injection.

Future directions

IgE autoantibodies are detected in some patients with bullous pemphigoid. In small numbers of individual case reports, omalizumab treatment has been reported to be effective in most patients, although recurrence is more common and occurs more rapidly compared to rituximab.

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