Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy

doi:10.1016/j.jaci.2013.05.013

Journal of Allergy and Clinical Immunology

Volume 132, Issue 1, July 2013, Pages 101-109

https://doi.org/10.1016/j.jaci.2013.05.013 Get rights and content

Background

Patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) often continue to experience symptoms despite receiving standard-of-care therapy with H₁-antihistamines along with 1 or more add-on therapies.

Objectives

We sought to evaluate the safety and efficacy of 24 weeks of treatment with omalizumab in patients with persistent CIU/CSU despite treatment with H₁-antihistamines at up to 4 times the approved dose plus H₂-antihistamines, leukotriene receptor antagonists, or both.

Methods

In this phase III study patients were randomized 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 of the study was to evaluate the overall safety of omalizumab compared with placebo. Efficacy (itch severity, hive, and urticaria activity scores) was evaluated at weeks 12 and 24.

Results

The overall incidence and severity of adverse events and serious adverse events were similar between omalizumab and placebo recipients; the safety profile was consistent with omalizumab in patients with allergic asthma. 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 < .001). Significant improvements were seen for additional efficacy end points at week 12; these benefits were sustained to week 24.

Conclusion

Omalizumab was well tolerated and reduced the signs and symptoms of CIU/CSU 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.

Section snippets

Study design

This global phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study investigated the safety, tolerability, and efficacy of 300 mg of omalizumab in patients aged 12 to 75 years (18-75 years in Germany) with CIU/CSU who remained symptomatic despite treatment with H₁-antihistamines at up to 4 times the approved dose plus H₂-antihistamines, LTRAs, or both. The study involved a 2-week screening period, a 24-week treatment period, and a 16-week follow-up period

Patients

Of 480 patients screened, 336 were randomized to treatment, although 1 patient did not receive the study drug. As a result, safety and efficacy were evaluated in 335 patients (modified intention-to-treat population). In total, 290 (86.3%) completed the study (Fig 1). Mean duration of drug exposure was 22.4 weeks (SD, 4.7 weeks) in the omalizumab-treated group and 20.6 weeks (SD, 6.4 weeks) in the placebo-treated group. Patients in the omalizumab and placebo groups received a mean of 5.6 (SD,

Discussion

The safety and tolerability of omalizumab in patients with CIU/CSU has been observed in this phase III study. Patients with CIU/CSU who remained symptomatic despite treatment with H₁-antihistamines (up to 4 times approved or licensed dose) plus either H₂-antihistamines, LTRAs, or both had 300 mg of omalizumab administered subcutaneously every 4 weeks, and the incidences of AEs and serious AEs were similar in both the omalizumab- and placebo-treated groups. No new safety issues or concerns were

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Cited by (461)

Mapping the intellectual structure of the research of omalizumab in chronic spontaneous urticaria: A bibliometric analysis
2024, Journal of Allergy and Clinical Immunology: Global
The guidelines for treating chronic spontaneous urticaria (CSU) recommend using the IgE-targeted biologic omalizumab in patients with antihistamine-refractory disease.
Our aim was to present a bibliometric review of publications related to omalizumab and CSU over the past 2 decades.
Relevant publications from 2003 to 2022 were extracted from the Science Citation Index-Expanded (SCI-EXPANDED) database in the Web of Science Core Collection database as of January 8, 2023. We utilized CiteSpace (version 6.1.R3), VOSviewer (version 1.6.18), and the R package (version 4.2.1) to analyze and visualize the data. The R package bibliometrix (version 4.2.1) was also used.
Between 2003 and 2022, a total of 566 articles on omalizumab and CSU were published. Since 2014, there has been a rapid increase in publication output. According to the collaboration network, the most influential country, institute, and scholar were the United States, Charité Universitätsmedizin Berlin, and Marcus Maurer, respectively. The study identified the Journal of Allergy and Clinical Immunology: In Practice as the most productive journal and the Journal of Allergy and Clinical Immunology as the most cocited journal. The analysis of key words revealed the presence of high-frequency terms such as angioedema, IgE, treatment, anti-IgE, asthma, and atopic dermatitis. Moreover, recent studies in this area have concentrated mainly on biomarkers, dupilumab, and coronavirus 2019 (COVID-19).
There has been a growing interest in the use of omalizumab in CSU in recent years. The current trending topics in this research are the identification of biomarkers and the development of new mAbs for the treatment of CSU.
Different doses and courses of omalizumab for patients with chronic spontaneous urticaria: A systematic review with meta-analysis and trial sequential analysis
2024, World Allergy Organization Journal
The stability, efficacy, and safety of omalizumab at different doses and regimens for chronic spontaneous urticaria (CSU) are yet to be studied.
A systematic review (SR) with meta-analysis (MA) and trial sequential analysis (TSA) was performed to assess the efficacy and safety of omalizumab in CSU.
Randomised controlled trials (RCTs) of administering omalizumab versus placebo for CSU were searched. Random-effects MAs were performed using planned subgroup analyses. TSA was performed to control for the risk of random errors and assess the stability of our MA results. Publication bias was visually assessed using a contour-enhanced funnel plot and the trim-and-fill method. The quality of RCTs was assessed using the Cochrane Risk of Bias Tool 2.
Twelve studies met the inclusion criteria. Omalizumab had remarkable effects on the patient percentage of the weekly urticaria activity score is zero (UAS = 0) [RR 4.64, 95% CI (3.38, 6.37)], percentage of no angioedema-burdened days [MD 3.15, 95% CI (0.10, 6.19], patient percentage of UAS ≤6 [RR 3.05, 95% CI (2.46, 3.78)], and patient percentage of the weekly itch severity score minimally important difference (ISS7 MID) [RR 1.50, 95% CI (1.36, 1.66)]. Omalizumab was well tolerated across studies [RR 0.98, 95% CI (0.90, 1.08)]. TSA confirmed the above results, except for “the percentage of no angioedema-burdened day”.
Among the different doses and courses assessed, omalizumab (300 mg, 12 weeks) can be recommended as an effective treatment for patients with CSU. However, whether omalizumab improves angioedema requires further investigation. The clinical management of angioedema accompanying CSU requires further attention.
Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials
2024, The Lancet
Many patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies.
PEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The primary endpoint was change-from-baseline (CFB) in weekly Urticaria Activity Score (UAS7) at week 12, and was analysed in all eligible adult patients according to the treatment assigned at random allocation. Safety was assessed throughout the study in all patients who received at least one dose of the study drug. The studies were registered with ClinicalTrials.gov, NCT03580369 (PEARL-1) and NCT03580356 (PEARL-2). Both trials are now complete.
Between Oct 17, 2018, and Oct 26, 2021, 2057 adult patients were randomly allocated across both studies (72 mg ligelizumab n=614; 120 mg ligelizumab n=616; 300 mg omalizumab n=618, and placebo n=209). A total of 1480 (72%) of 2057 were female, and 577 (28%) of 2057 were male. Mean UAS7 at baseline across study groups ranged from 29·37 to 31·10. At week 12, estimated treatment differences in mean CFB-UAS7 were as follows: for 72 mg ligelizumab versus placebo, –8·0 (95% CI –10·6 to –5·4; PEARL-1), –10·0 (–12·6 to –7·4; PEARL-2); 72 mg ligelizumab versus omalizumab 0·7 (–1·2 to 2·5; PEARL-1), 0·4 (–1·4 to 2·2; PEARL-2); 120 mg ligelizumab versus placebo –8·0 (–10·5 to –5·4; PEARL-1), –11·1 (–13·7 to –8·5; PEARL-2); 120 mg ligelizumab versus omalizumab 0·7 (–1·1 to 2·5; PEARL-1), –0·7 (–2·5 to 1·1; PEARL-2). Both doses of ligelizumab were superior to placebo (p<0·0001), but not to omalizumab, in both studies. No new safety signals were identified for ligelizumab or omalizumab.
In the phase 3 PEARL studies, ligelizumab demonstrated superior efficacy versus placebo but not versus omalizumab. The safety profile of ligelizumab was consistent with previous studies.
Novartis Pharma.
Omalizumab Drug Survival in Chronic Urticaria: A Retrospective Multicentric French Study
2023, Journal of Allergy and Clinical Immunology: In Practice
Omalizumab (OMA) dramatically improves disease control and quality of life in patients with chronic urticaria (CU).
We aimed to evaluate the discontinuation patterns of OMA and their determinants in a cohort of French patients with CU.
We conducted a retrospective multicenter study in 9 French tertiary referral hospitals. All patients diagnosed with either spontaneous (CSU) and/or inducible (CIndU) CU who received at least 1 injection of OMA between 2009 and 2021 were included. We analyzed OMA drug survival and investigated possible determinants using Kaplan-Meier curves and log-rank tests.
A total of 878 patients were included in this study; 48.8% had CSU, 10.1% CIndU, and 41.1% a combination of both. OMA was discontinued in 408 patients, but the drug was later reintroduced in 50% of them. The main reason for discontinuing treatment was the achievement of a well-controlled disease in 50% of patients. Half of the patients were still being treated with OMA 2.4 years after the initiation of treatment. Drug survival was shorter in patients with CIndU and in those with an autoimmune background. In atopic patients, OMA was discontinued earlier in patients achieving a well-controlled disease. A longer OMA drug survival was observed in patients with a longer disease duration at initiation.
In French patients with CU, the drug survival of OMA appears to be longer than that observed in previous studies conducted elsewhere, highlighting discrepancies in prescription and reimbursement possibilities. Further studies are warranted to develop customized OMA treatment schemes based on individual patterns.
Comparing four immunosuppressive agents for chronic spontaneous urticaria-A network meta-analysis
2023, International Immunopharmacology
Immunosuppression is an integral part of treating chronic spontaneous urticaria (CSU), but there is no literature to evaluate the efficacy of multiple immunosuppressive agents.
The comparison of the efficacy, safety, and incidence of adverse effects of four immunosuppressive medicines (tripterygium glycosides, methotrexate, cyclosporine A, and azathioprine) in combination with antihistamines in treating CSU provides a clinical reference and evidence-based medicine for treating CSU.
PUBMED, The Cochrane Library, EMBASE, WANFANG, CNKI, CBM, and clinical trial registration platform were searched to collect relevant randomized controlled trials (RCT) and cohort studies of four immunosuppressive medicines combined with antihistamines for treating CSU. The primary outcomes were the efficacy of weekly urticaria activity score 7 (UAS7) and adverse effects.
This study pooled data from seven randomized clinical trials with 410 participants. The standardized mean differences for change in UAS7 were 0.10 (95% confidence interval (CI), 0.01 to 0.68) for cyclosporine A plus antihistamine; 0.03 (95% CI, 0.00 to 0.23) for azathioprine plus antihistamine; 0.52 (95% CI, 0.32 to 0.85) for tripterygium glycosides plus antihistamine; and 1.54 (95% CI, 0.64 to 3.67) for methotrexate plus antihistamine. There were no significant differences in side effects between these medicines in the limited number of trials and clinical samples.
Our results indicate that cyclosporine A combined with antihistamine resulted in greater improvements regarding the UAS7 in CSU patients and that tripterygium glycosides are also effective in treating CSU.
Physical urticaria: Clinical features, pathogenesis, diagnostic work-up, and management
2023, Journal of the American Academy of Dermatology
Physical urticaria is a type of urticaria in which recurrent wheals and/or angioedema occur following exposure of the skin to a physical stimulus. It is classified according to its triggers, which may be mechanical (friction, pressure, and vibration), thermal (cold and heat), or solar electromagnetic radiation. Symptoms of different physical urticarias can develop following specific activities that expose patients to an eliciting stimulus and may be variably accompanied by mucosal involvement and systemic symptoms, including nausea, headache, or even anaphylaxis. Differentiation of physical urticaria from other chronic urticarias requires careful clinical assessment and confirmatory provocation testing, which in turn can inform appropriate management. This clinical review provides an evidence-based summary of the epidemiology, clinical features, pathogenesis, diagnostic work-up, and management of physical urticaria.

View all citing articles on Scopus

: Supported by Genentech, Inc, South San Francisco, Calif, and Novartis Pharma AG, Basel, Switzerland. Genentech, Inc also provided support for the preparation of this manuscript.

: Disclosure of potential conflict of interest: A. Kaplan has received travel support and fees for participation in review activities from Genentech, Inc. D. Ledford has received a grant and consulting fees or honoraria from Genentech, Inc; has consultant arrangements with Shook Bacon Hardy, Saieva and Stine, and AstraZeneca; has received grants from Teva, Forest, Merck, and Viropharma; and has received payment for lectures from South Carolina Allergy and Immunology Society and Meda Pharmaceutical. M. Ashby and J. L. Zazzali are employed by and have stock/stock options with Genentech, Inc. J. Vieth is employed by and received stock/stock options from Genentech, Inc. N. Kamath is employed by Roche Products Ltd. T. Jakob has received grants from Genentech, Inc, Novartis, Allergopharma, and Thermo Fischer Scientific; has received consulting fees from Novartis, Allergopharma, Novartis, and Jansen Cilag; has received travel support from Novartis; and has received payment for lectures from Thermo Fischer Scientific, Stallergenes, ALK-Abelló, Allergies Therapeutics, and Novartis. P. Kuna has board memberships with Boehringer Ingelheim, Merck Sharpe & Dohme, Chiesi, ALK-Abelló, FAES, AstraZeneca, Almirall, and Novartis; has received payment for lectures from Novartis Poland, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Teva, Adamed, Allergopharma, Hal, FAES, and Chiesi; and has received travel expenses from Novartis Poland, Boehringer Ingelheim, Merck Sharp and Dohme, and Astra Zeneca. W. Berger has board memberships with Alcon, AstraZeneca, Novartis, Meda, Sepracor, GlaxoSmithKline, Teva, ORA, and Schering-Plough; has consultant arrangements with Alcon, AstraZeneca, Novartis, Meda, GlaxoSmithKline, Teva, ORA, Mylan, Allergan, Genentech, Inc, and Merck; is employed by Allergy & Asthma Associates of Southern California and the University of California–Irvine; has provided expert testimony on behalf of Sunovion; has received grants from Alcon, AstraZeneca, Novartis, Meda, GlaxoSmithKline, Teva, and Merck; has received payment for lectures from Alcon, Allergan, Meda, Teva, Sunovion, AstraZeneca, GlaxoSmithKline, and Merck. M. Maurer has received consulting fees, travel support, and payment for lectures from and is a board member for Genentech, Inc and Novartis. K. Rosén is employed by Genentech, Inc and receives stock/stock options from Genentech, Inc. The rest of the authors declare that they have no relevant conflicts of interest.

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Atopic dermatitis and skin diseaseOmalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy

Background

Objectives

Methods

Results

Conclusion

Section snippets

Study design

Patients

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

Ann Allergy Asthma Immunol

Curr Opin Immunol

J Allergy Clin Immunol

EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria

Allergy

Chronic unremitting urticaria: is the use of antihistamines above the licensed dose effective? A preliminary study of cetirizine at licensed and above-licensed doses

Clin Exp Dermatol

Unmet clinical needs in chronic spontaneous urticaria. A GA(2)LEN task force report

Allergy

Atopic dermatitis and skin disease
Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy