
==== Front
Dermatol Ther (Heidelb)
Dermatol Ther (Heidelb)
Dermatology and Therapy
2193-8210
2190-9172
Springer Healthcare Cheshire

39066978
1231
10.1007/s13555-024-01231-y
Original Research
Dupilumab Reduces Urticaria Activity, Itch, and Hives in Patients with Chronic Spontaneous Urticaria Regardless of Baseline Serum Immunoglobulin E Levels
http://orcid.org/0000-0002-4121-481X
Maurer Marcus marcus.maurer@charite.de

12
Casale Thomas B. 3
Saini Sarbjit S. 4
Ben-Shoshan Moshe 5
Laws Elizabeth 6
Maloney Jennifer 7
Bauer Deborah 6
Radin Allen 7
Makhija Melanie 8
1 grid.6363.0 0000 0001 2218 4662 Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Free University of Berlin and Humboldt-University of Berlin, Hindenburgdamm 27, 12203 Berlin, Germany
2 https://ror.org/01s1h3j07 grid.510864.e Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany
3 https://ror.org/032db5x82 grid.170693.a 0000 0001 2353 285X Division of Allergy and Immunology, University of South Florida, Tampa, FL USA
4 grid.411940.9 0000 0004 0442 9875 Johns Hopkins Asthma and Allergy Center, Baltimore, MD USA
5 https://ror.org/04cpxjv19 grid.63984.30 0000 0000 9064 4811 Division of Allergy/Immunology/Dermatology, Department of Pediatrics, McGill University Health Centre, Montreal, QC Canada
6 grid.417555.7 0000 0000 8814 392X Sanofi, Bridgewater, NJ USA
7 grid.418961.3 0000 0004 0472 2713 Regeneron Pharmaceuticals Inc., Tarrytown, NY USA
8 grid.417555.7 0000 0000 8814 392X Sanofi, Cambridge, MA USA
27 7 2024
27 7 2024
9 2024
14 9 24272441
24 5 2024
3 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Introduction

In chronic spontaneous urticaria (CSU), interleukin (IL)-4 and IL-13 may promote mast cell activation directly via IL-4 receptor expression, or indirectly via upregulated immunoglobulin E (IgE) production. Dupilumab significantly improved CSU signs and symptoms in the phase 3, randomized, placebo-controlled LIBERTY-CSU CUPID Study A. This analysis explores the impact of dupilumab on CSU signs and symptoms and serum IgE levels in patients from LIBERTY-CSU CUPID Study A with serum total IgE above and below 100 IU/mL at baseline.

Methods

Patients with H1-antihistamine-refractory CSU received dupilumab (n = 70) or placebo (n = 68) for 24 weeks. Efficacy endpoints were change from baseline to weeks 12 and 24 in serum total IgE levels, Itch Severity Score over 7 days (ISS7), Urticaria Activity Score over 7 days (UAS7), and Hives Severity Score over 7 days (HSS7) in dupilumab- or placebo-treated patients with serum total IgE above and below 100 IU/mL at baseline.

Results

Dupilumab treatment significantly reduced median (interquartile range) IgE levels at week 12 [dupilumab: −31.9% (−41.9; −22.6); placebo: −6.3% (−21.3; 14.9)] and week 24 [dupilumab: −48.2% (−56.8; − 39.5); placebo: − 6.3% (−34.5; 14.8)]. Similar IgE reductions relative to baseline were observed in dupilumab-treated patients regardless of baseline IgE level. Dupilumab treatment improved ISS7, UAS7, and HSS7 over 12 and 24 weeks, regardless of baseline serum IgE level (interaction p ≥ 0.59 for all treatment by subgroup comparisons), with weak correlations (r < 0.2) observed between IgE level changes and ISS7, UAS7, and HSS7 outcomes.

Conclusions

Dupilumab significantly improved CSU signs and symptoms and reduced serum IgE, regardless of baseline IgE levels. In the current analysis, baseline total IgE had no predictive value as a dupilumab treatment response biomarker in CSU. Downregulation of IgE, a key mediator of mast cell activation and histamine release, may at least partially explain the effectiveness of dupilumab in reducing CSU signs and symptoms.

Trial Registration

ClinicalTrials.gov Identifier: NCT04180488.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-024-01231-y.

Keywords

Biomarker
Chronic spontaneous urticaria
CSU
Dupilumab
Immunoglobulin E
IgE
Omalizumab-naïve
Type 2 inflammation
http://dx.doi.org/10.13039/100004339 Sanofi http://dx.doi.org/10.13039/100009857 Regeneron Pharmaceuticals issue-copyright-statement© Springer Healthcare Ltd., part of Springer Nature 2024
==== Body
pmcKey Summary Points

Why carry out this research?	
Key drivers of chronic spontaneous urticaria (CSU) pathophysiology include mast cells, eosinophils, and basophils orchestrated in part by type 2 inflammatory cytokines, such as interleukin (IL)-4 and IL-13, and increased immunoglobulin E (IgE) production. Dupilumab demonstrated significant improvements in the signs and symptoms of CSU in a randomized, placebo-controlled, double-blind phase 3 trial (LIBERTY-CSU CUPID Study A).	
This analysis evaluated the efficacy of dupilumab in patients stratified by baseline serum total IgE levels, and the effect on serum total IgE levels following treatment, to determine whether IgE levels can act as a predictor of dupilumab response.	
What was learned from the study?	
Dupilumab is an effective treatment in H1-antihistamine (H1-AH)-resistant, omalizumab-naïve patients with CSU, regardless of their baseline serum total IgE levels. Dupilumab treatment improves CSU signs and symptoms and reduces serum IgE levels, but these are not strongly correlated.	
These results suggest that the efficacy of dupilumab in CSU may involve IgE downregulation and modulation of additional pathways involving IL-4/IL-13 signaling.	

Introduction

Chronic spontaneous urticaria (CSU) is a chronic inflammatory skin disease characterized by the recurrence of wheals and/or angioedema with associated itch, burning, and pain that can significantly impact quality of life [1–4].

Type 2 inflammatory cytokines such as interleukin (IL)-4 and IL-13, among others, may play a role in CSU pathogenesis through direct and indirect activation of mast cells, basophils, and eosinophils, as well as immune-cell trafficking into the skin and neuronal sensitization promoting itch [5, 6]. Both IL-4 and IL-13 stimulate B-cell immunoglobulin isotype class switching to immunoglobulin E (IgE), which leads to increased IgE production [7]. IgE is involved in the activation and degranulation of mast cells, which leads to the development of hives and itch in CSU. In addition, IgE levels regulate the expression of the high-affinity IgE receptor FcεR1 on mast cells, which is also involved in mast cell activation and degranulation [8]. In a recent review of 141 studies, about 50% of 926 patients with CSU had serum total IgE levels above 100 IU/mL [8]. In a recent meta-analysis including ten interventional studies and 866 patients with CSU, serum total IgE levels were below 100 IU/mL in patients with a poor response to omalizumab [9].

Current therapies for CSU, including H1-antihistamines (H1-AH) and omalizumab (anti-IgE), do not adequately control symptoms in all patients, which leaves a significant unmet need for alternative therapies [1, 10, 11]. Dupilumab is a fully human VelocImmune®-derived monoclonal antibody [12, 13] that blocks the shared receptor component (IL-4Rα) for IL-4 and IL-13, and thus inhibits signaling of these central drivers of type 2 inflammation [14, 15]. LIBERTY-CSU CUPID Study A (NCT04180488) was a randomized, placebo-controlled, double-blind phase 3 trial comparing dupilumab with placebo in omalizumab-naïve patients with CSU who remained symptomatic despite H1-AH therapy. Dupilumab demonstrated significant improvements in the signs and symptoms of CSU, and the overall safety was generally consistent with the known dupilumab safety profile [16].

Previous studies showed a potential link between reduction of serum IgE levels and improvement in signs and symptoms in patients with type 2 inflammatory diseases treated with dupilumab [17–20]. In this subgroup analysis of LIBERTY-CSU CUPID Study A, we hypothesized that dupilumab would similarly decrease serum IgE levels in patients with CSU. As IL-4/IL-13 in CSU may also be involved in direct mast cell activation, immune-cell trafficking, and neuronal sensitization [5, 21–25], we hypothesized that the response to dupilumab would be independent of baseline IgE levels. The current analysis evaluated the effect of dupilumab treatment on CSU signs and symptoms and serum total IgE levels in LIBERTY-CSU CUPID Study A patients stratified by baseline serum total IgE levels.

Methods

Study Design

LIBERTY-CSU CUPID Study A was a 24-week, multicenter, randomized, placebo-controlled, double-blind, phase 3 study conducted in patients with CSU from nine countries. This study was conducted in accordance with the ethical standards of the responsible committees, the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guidelines, and applicable regulatory requirements. All patients or their parents/guardians provided written informed consent before participating in the trial. Regarding pediatric patients, consent was provided according to the Ethics Committee [Institutional Review Board (IRB)/Independent Ethics Committee]-approved standard practice for pediatric patients at each participating center.

Patients and Treatments

Detailed eligibility criteria for LIBERTY-CSU CUPID Study A have been described by Maurer et al. [16]. Briefly, patients participating in LIBERTY-CSU CUPID Study A were aged ≥ 6 years, had had a diagnosis of CSU for more than 6 months prior to the screening visit, presence of itch and hives for > 6 consecutive weeks despite H1-AH use, a Urticaria Activity Score over 7 days (UAS7) ≥ 16 and Itch Severity Score over 7 days (ISS7) ≥ 8, were omalizumab naïve, and had received background therapy of up to fourfold the licensed dose of H1-AH.

Study participants were randomized 1:1 to receive either dupilumab or matched placebo. Adults and adolescents ≥ 60 kg received a 600 mg loading dose followed by 300 mg every 2 weeks, adolescents < 60 kg and children ≥ 30 kg received a 400 mg loading dose followed by 200 mg every 2 weeks, and children ≥ 15 kg and < 30 kg received a 600 mg loading dose followed by 300 mg every 4 weeks.

Endpoints

The primary data of LIBERTY-CSU CUPID Study A have been published previously [16]. In this subgroup analysis, efficacy endpoints were change in serum total IgE levels from baseline at week 12 and week 24, and change in ISS7, UAS7, and Hives Severity Score over 7 days (HSS7) from baseline at week 12 and week 24 in patients with serum total IgE above and below 100 IU/mL at baseline.

Safety endpoints included the proportion of patients with at least one treatment-emergent adverse event (TEAE), the proportion of patients with any serious TEAE, deaths, the proportion of patients with TEAEs leading to study discontinuation, and TEAEs reported in ≥ 5% of patients in any treatment group.

Statistical Analyses

Unless otherwise stated, analyses were performed in the intent-to-treat population, consisting of all randomized participants. Analyses were carried out by fitting an analysis of covariance (ANCOVA) model for each imputed complete item of data with the corresponding baseline value, intervention group, presence of angioedema at baseline, and regions as covariates. The analyses were based on the same imputed dataset using worst observation carried forward/multiple imputation that was used in the primary analysis of the primary endpoint of LIBERTY-CSU CUPID Study A. The comparison for the subgroup-by-intervention interaction was also calculated by fitting an ANCOVA model with the corresponding baseline value, intervention group, presence of angioedema at baseline, and regions as covariates, plus the subgroup variable and the subgroup-by-intervention interaction. Analysis was based on the same imputed dataset using worst‐observation carried forward/multiple imputation from the primary analysis of the primary endpoint. Pearson correlation coefficients were calculated for the change from baseline in IgE and change from baseline in ISS7, HSS7, and UAS7 at week 12 and week 24 separately within each treatment group. IgE change from baseline and percent change from baseline at week 12 and week 24 were summarized descriptively. Correlation coefficients were calculated for the overall population and for participants with baseline serum total IgE < 100 IU/mL or ≥ 100 IU/mL.

Results

Patients

Baseline serum total IgE data were available for 65 placebo-treated and 66 dupilumab-treated patients from LIBERTY-CSU CUPID Study A (serum IgE levels at baseline were not available for 3 placebo recipients and 4 dupilumab recipients). Patient demographics and baseline characteristics have been described previously [16].

Due to extreme outliers and skewed data, medians were used in this analysis. In placebo-treated patients, baseline median [interquartile range (IQR)] IgE was 29.0 (14.3; 47.7) and 221.0 (140.0; 693.0) IU/mL in the subgroups with baseline serum total IgE of < 100 and ≥ 100 IU/mL, respectively. In dupilumab-treated patients, baseline median (IQR) IgE was 45.7 (30.3; 64.3) and 305.0 (169.5; 606.0) IU/mL in the subgroups with baseline serum total IgE of < 100 and ≥ 100, respectively (Table 1). Baseline patient demographics (Table 1) and disease characteristics (Table 2) were otherwise generally well balanced between baseline serum total IgE subgroups. In the subgroup with baseline IgE ≥ 100 IU/mL, baseline UAS7 scores were higher in dupilumab- versus placebo-treated patients, and a higher proportion of dupilumab-treated versus placebo-treated patients (85.7% versus 58.1%) had a baseline UAS7 score ≥ 28.Table 1 Baseline demographics

	Baseline IgE < 100 IU/mL (N = 65)	Baseline IgE ≥ 100 IU/mL (N = 66)	Overall	
Placebo (N = 34)a	Dupilumab (N = 31)a	Placebo (N = 31)a	Dupilumab (N = 35)a	Placebo (N = 68)	Dupilumab (N = 70)	
Age (years), mean (SD)	42.4 (14.2)	39.8 (17.2)	41.1 (15.7)	41.8 (15.9)	41.9 (14.8)	40.7 (16.2)	
Age ≥ 18 years, n (%)	34 (100)	29 (93.5)	29 (93.5)	34 (97.1)	66 (97.1)	66 (94.3)	
Age ≥ 12 to < 18 years, n (%)	0	1 (3.2)	2 (6.5)	0	2 (2.9)	2 (2.9)	
Age ≥ 6 to < 12 years n (%)	0	1 (3.2)	0	1 (2.9)	0	2 (2.9)	
Female, n (%)	27 (79.4)	19 (61.3)	21 (67.7)	20 (57.1)	50 (73.5)	41 (58.6)	
Race, n (%)	
 White	28 (82.4)	23 (74.2)	17 (54.8)	21 (60.0)	48 (70.6)	47 (67.1)	
 Black or African American	0	0	2 (6.5)	1 (2.9)	2 (2.9)	1 (1.4)	
 Asian	6 (17.6)	7 (22.6)	10 (32.3)	12 (34.3)	16 (23.5)	19 (27.1)	
 Otherb	0	1 (3.2)	2 (6.4)	1 (2.9)	2 (2.9)	3 (4.3)	
Weight (kg), mean (SD)	75.3 (20.3)	73.3 (20.0)	75.8(16.5)	80.6 (21.5)	75.8 (18.4)	77.2 (21.5)	
BMI (kg/m2), mean (SD)	27.7 (6.8)	26.1 (5.5)	27.9 (5.6)	28.82 (7.6)	27.9 (6.2)	27.4 (6.8)	
Baseline serum total IgE (IU/mL), median (IQR)a	29.0 (14.3; 47.7)	45.7 (30.3; 64.3)	221.0 (140.0; 693.0)	305.0 (169.5; 606.0)	96.5 (27.9; 221.0)	109.4 (49.2; 381.0)	
BMI body mass index, IgE immunoglobulin E, IU international units, IQR interquartile range, n (%) number and percentage of participants, SD standard deviation

aData on serum total IgE at baseline were not available for three patients in the placebo arm and four in the dupilumab arm

bIncludes Native Hawaiian or other Pacific Islander, American Indian or Alaska Native, and unknown

Table 2 Baseline disease characteristics

	Baseline IgE < 100 IU/mL (N = 65)	Baseline IgE ≥ 100 IU/mL (N = 66)	Overall (N = 138)	
Placebo (N = 34)a	Dupilumab (N = 31)a	Placebo (N = 31)a	Dupilumab (N = 35)a	Placebo (N = 68)	Dupilumab (N = 70)	
Age at onset of CSU (years), mean (SD)	36.6 (15.6)	32.7 (17.1)	36.7 (17.0)	38.1 (16.4)	36.7 (16.0)	35.5 (16.6)	
Time since first diagnosis of CSU (years), mean (SD)	6.3 (8.6)	7.7 (12.1)	5.0 (7.0)	4.3 (6.4)	5.7 (7.7)	5.8 (9.3)	
Baseline ISS7 score, mean (SD)	16.5 (4.1)	15.5 (4.3)	15.3 (4.1)	16.7 (3.8)	15.7 (4.1)	16.1 (4.0)	
Baseline UAS7 score, mean (SD)	31.7 (8.3)	30.1 (8.2)	30.0 (8.3)	33.6 (6.0)	30.8 (8.2)	31.9 (7.2)	
Baseline UAS7 score < 28, n (%)	9 (26.5)	10 (32.3)	13 (41.9)	5 (14.3)	24 (35.3)	17 (24.3)	
Baseline UAS7 score ≥ 28, n (%)	25 (73.5)	21 (67.7)	18 (58.1)	30 (85.7)	44 (64.7)	53 (75.7)	
Baseline HSS7 score, mean (SD)	15.2 (5.1)	14.6 (4.3)	14.7 (4.6)	16.9 (3.1)	15.0 (4.8)	15.8 (3.8)	
Presence of angioedema at baseline, n (%)b	18 (52.9)	13.0 (41.9)	15 (48.4)	14 (40.0)	34 (50.0)	28 (40.0)	
Baseline AAS7 score for participants with angioedema, mean (SD)	38.5 (27.9)	34.5 (27.6)	32.7 (27.8)	29.6 (20.0)	35.3 (27.4)	32.1 (23.2)	
Baseline UCT score, mean (SD)	3.4 (2.3)	3.5 (2.0)	3.8 (2.2)	3.9 (2.5)	3.6 (2.3)	3.8 (2.3)	
Baseline DLQI score,c mean (SD)	15.8 (5.5)	13.0 (5.7)	15.2 (7.3)	13.9 (6.2)	15.3 (6.7)	13.5 (5.9)	
Baseline PGIS score, mean (SD)	3.4 (0.6)	3.4 (0.5)	3.5 (0.5)	3.4 (0.7)	3.5 (0.6)	3.4 (0.6)	
Baseline H1-AH, n (%)	
 Standard dosed	19 (55.9)	13 (41.9)	21 (67.7)	16 (45.7)	41 (60.3)	31 (44.3)	
 2–3-fold standard dosed	10 (29.4)	10 (32.3)	5 (16.1)	15 (42.9)	16 (23.5)	27 (38.6)	
 Fourfold standard dosed	5 (14.7)	8 (25.8)	5 (16.1)	4 (11.4)	11 (16.2)	12 (17.1)	
Unless otherwise indicated, data are presented for all participants in the intention-to-treat population, which included all randomized participants. Higher scores indicate worse disease activity/outcomes, except for the UCT, where higher scores indicate higher disease control

AAS7 Angioedema Activity Score over 7 days (0–105), CDLQI Children’s Dermatology Life Quality Index (0–30), CSU chronic spontaneous urticaria, DLQI Dermatology Life Quality Index (0–30), H1-AH H1-antihistamines,

HSS7 Hives Severity Score over 7 days (0–21), IgE immunoglobulin E, IU international units, ISS7 Itch Severity Score over 7 days (0–21), n (%) number and percentage of participants, PGIS Patient Global Impression of Severity (1–4), SD standard deviation, UAS7 Urticaria Activity Score over 7 days (0–42), UCT urticaria control test (0–16)

aData on serum total IgE at baseline were not available for three patients in the placebo arm and four in the dupilumab arm

bParticipants with an AAS7 baseline score > 0

cExcludes adolescents/children who completed the CDLQI, one adult who incorrectly completed the CDLQI, and one child who incorrectly completed the DLQI

dStandard dose is the locally approved dose of H1-AH

Treatment with Dupilumab Reduced Serum Total IgE Levels over 12 and 24 Weeks Regardless of Baseline Serum IgE Level

Treatment with dupilumab resulted in a greater reduction from baseline in median serum total IgE versus treatment with placebo, both at week 12 (dupilumab: −31.9%; placebo: −6.3%) and at week 24 (dupilumab: −48.2%; placebo: −6.3%) [16] (See Fig S1 in the electronic supplementary material for details and Fig. 1). Similar degrees of IgE reduction relative to baseline were observed in dupilumab-treated patients at week 12 and week 24 regardless of their baseline IgE levels, with more pronounced reductions in serum total IgE observed for dupilumab-treated patients at week 24 versus week 12 (Fig. 1).Fig. 1 Median percent change in serum total IgE at a week 12 and b week 24 in dupilumab- or placebo-treated patients with baseline IgE levels < 100 IU/mL or ≥ 100 IU/mL. IgE immunoglobulin E

Treatment with Dupilumab Improved ISS7, UAS7, and HSS7 over 12 and 24 Weeks Regardless of Baseline Serum IgE Level

In LIBERTY-CSU CUPID Study A, patients treated with dupilumab (versus placebo) achieved a significantly greater improvement in ISS7 score at week 12 (p = 0.038) and week 24 (p = 0.0005) [16]. In dupilumab-treated patients, improvement in ISS7 score was independent of baseline serum total IgE levels at week 12 (< 100 subgroup: −8.8, ≥ 100 subgroup: −8.5, interaction p = 0.80) and week 24 (< 100 subgroup: −9.8, ≥ 100 subgroup: −11.2, interaction p = 0.98) (Fig. 2a,b).Fig. 2 LS mean (SE) change from baseline at weeks 12 and 24 in ISS7 (a, b), UAS7 (c, d), and HSS7 (e, f) in dupilumab- or placebo-treated patients with baseline serum total IgE levels < 100 IU/mL or ≥ 100 IU/mL. *p-values in blue are for testing the treatment-by-baseline IgE. HSS7 Hives Severity Score over 7 days, IgE immunoglobulin E, ISS7 Itch Severity Score over 7 days, LS least squares, SE standard error, UAS7 Urticaria Activity Score over 7 days

Similarly, significant improvements were observed in UAS7 scores in dupilumab-treated patients versus placebo-treated patients at both week 12 (p = 0.022) and week 24 (p = 0.0003) [16]. These improvements were also independent of baseline serum total IgE levels in dupilumab-treated patients at both week 12 (< 100 subgroup: −17.4, ≥ 100 subgroup: −17.1, interaction p = 0.70) and at week 24 (< 100 subgroup: −19.5, ≥ 100 subgroup: −22.6, interaction p = 0.77) (Fig. 2c,d).

Improvements were also observed in HSS7 scores in dupilumab-treated patients versus placebo-treated patients at both week 12 (nominal p = 0.016) and at week 24 (p = 0.0003) [16], and these improvements were also independent of baseline serum total IgE levels in dupilumab-treated patients at both week 12 (< 100 subgroup: −8.7, ≥ 100 subgroup: −8.5, interaction p = 0.64) and at week 24 (< 100 subgroup: −9.7, ≥ 100 subgroup: −11.3, interaction p = 0.59) (Fig. 2e,f).

Weak Correlations between IgE Reduction and ISS7, UAS7, and HSS7 Outcomes at Week 12 and Week 24

Weak correlations (r < 0.2) were observed between change in IgE levels and changes in ISS7, UAS7, and HSS7 at week 12 and week 24 (Table 3).Table 3 Correlation between serum total IgE reduction and changes in ISS7, UAS7, and HSS7 from baseline at week 12 and week 24

	Week 12	Week 24	
Baseline IgE subgroupa	Placebo	Dupilumab	Placebo	Dupilumab	
Correlation between ISS7 and IgE changes from baseline at week 12 and week 24	
 Overall	−0.18	0.12	−0.13	0.12	
 < 100 IU/mL	−0.23	−0.08	0.29	−0.05	
 ≥ 100 IU/mL	−0.16	0.18	−0.16	0.14	
Correlation between UAS7 and IgE changes from baseline at week 12 and week 24	
 Overall	−0.17	0.11	−0.13	0.10	
 < 100 IU/mL	− 0.25	− 0.05	0.29	0.02	
 ≥ 100 IU/mL	−0.13	0.15	−0.15	0.11	
Correlation between HSS7 and IgE changes from baseline at week 12 and week 24	
 Overall	−0.15	0.07	−0.12	0.08	
 < 100 IU/mL	−0.25	−0.01	0.27	0.08	
 ≥ 100 IU/mL	−0.10	0.10	−0.12	0.06	
HSS7 Hives Severity Score over 7 days, IgE immunoglobulin E, ISS7 Itch Severity Score over 7 days, IU international units, UAS7 Urticaria Activity Score over 7 days

aData on serum total IgE at baseline were not available for three patients in the placebo arm and four patients in the dupilumab arm

Safety

Safety analyses were performed for all patients from LIBERTY-CSU CUPID Study A [dupilumab (n = 70) versus placebo (n = 68)]. In addition, safety analyses were performed for patients in the stratified subgroups included in this analysis [< 100 subgroup: dupilumab (n = 31) versus placebo (n = 34); ≥ 100 subgroup: dupilumab (n = 35) versus placebo (n = 31)]. TEAEs were observed in 58.8% of placebo-treated patients and 54.3% of dupilumab-treated patients (Table 4).Table 4 Safety outcomes

	Baseline IgE < 100 IU/mL	Baseline IgE ≥ 100 IU/mL	Overall	
Placebo (n = 34)a	Dupilumab (n = 31)a	Placebo (n = 31)a	Dupilumab (n = 35)a	Placebo (N = 68)	Dupilumab (N = 70)	
Participants with any TEAE, n (%)	21 (61.8)	17 (54.8)	16 (51.6)	18 (51.4)	40 (58.8)	38 (54.3)	
Participants with any severe TEAE, n (%)	3 (8.8)	2 (6.5)	1 (3.2)	0	4 (5.9)	2 (2.9)	
Participants with any treatment-emergent SAE, n (%)	4 (11.8)	1 (3.2)	1 (3.2)	1 (2.9)	5 (7.4)	2 (2.9)	
Participants with any TEAE leading to death, n (%)	0	0	1 (3.2)	0	1 (1.5)	0	
Participants with any TEAE leading to permanent study treatment discontinuation, n (%)	1 (2.9)	2 (6.5)	3 (9.7)	0	4 (5.9)	2 (2.9)	
Participants with TEAEs that occurred with a frequency ≥ 5% in any treatment group, n (%)	
 Chronic spontaneous urticaria	3 (8.8)	1 (3.2)	3 (9.7)	1 (2.9)	6 (8.8)	3 (4.3)	
 Angioedema	3 (8.8)	1 (3.2)	2 (6.5)	0	5 (7.4)	1 (1.4)	
 Injection-site reaction	1 (2.9)	3 (9.7)	0	0	2 (2.9)	4 (5.7)	
 Injection-site erythema	3 (8.8)	2 (6.5)	0	0	4 (5.9)	3 (4.3)	
 Headache	2 (5.9)	0	0	2 (5.7)	3 (4.4)	2 (2.9)	
 Nasopharyngitis	3 (8.8)	0	0	1 (2.9)	3 (4.4)	1 (1.4)	
 Abdominal pain upper	2 (5.9)	0	0	0	2 (2.9)	0	
 Back pain	0	0	3 (9.7)	0	3 (4.4)	0	
 Dermatitis contact	0	0	3 (9.7)	1 (2.9)	3 (4.4)	1 (1.4)	
IgE immunoglobulin E, IU international units, SAE serious adverse event, TEAE treatment-emergent adverse event

aData on serum total IgE at baseline were not available for three patients in the placebo arm and four in the dupilumab arm

Discussion

This analysis of LIBERTY-CSU CUPID Study A demonstrated that dupilumab was associated with a decrease in serum total IgE over 24 weeks in patients with H1-AH-resistant CSU, regardless of baseline serum total IgE levels. The reduction in serum total IgE with dupilumab treatment in patients with CSU is consistent with studies reporting reductions in IgE in patients with atopic dermatitis, chronic rhinosinusitis with nasal polyps, allergic rhinitis, or uncontrolled asthma who were treated with dupilumab [17–20, 26, 27]. The observed reduction in serum total IgE in patients treated with dupilumab may result from inhibition of IL-4/IL-13-mediated B-cell proliferation and IgE isotype switching [28].

Furthermore, dupilumab demonstrated significant improvements in the signs and symptoms of CSU, as measured by ISS7, UAS7, and HSS7, regardless of baseline IgE level. Additionally, a weak correlation (r < 0.2) was observed between IgE reduction and ISS7, UAS7, and HSS7 outcomes, suggesting that the efficacy of dupilumab in CSU is only partially mediated by modulation of IgE-dependent pathways. Safety findings were generally consistent with the known dupilumab safety profile [16]. On the basis of these findings using the 100 IU/mL cutoff, baseline total IgE appears to have no predictive value as a dupilumab treatment response biomarker in CSU.

The pathophysiology of CSU is thought to include both type I autoimmunity (autoallergy; IgE autoantibodies against thyroid peroxidase, thyroglobulin, tissue factor, double-stranded DNA, IL-24) and type IIb autoimmunity [IgG or immunoglobulin M (IgM) autoantibodies against IgE and/or its high-affinity receptor, FcεRI] [29–32]. Many studies have defined elevated IgE as a serum total IgE > 100 IU/mL [8]. However, IgE levels are known to vary with age, sex, genetic background, and environmental exposure. Higher-than-normal total IgE levels have been reported in up to 82% of patients with CSU, with the highest levels of IgE found in atopic patients with CSU, indicating that atopic status may influence serum total IgE levels in patients with CSU [8]. High total IgE in patients with CSU is associated with high disease activity, long disease duration, increased probability of responding to omalizumab, rapid relapse after omalizumab treatment termination, and low chance of responding to cyclosporine [8, 9].

In CSU, IL-4/IL-13 may promote B-cell proliferation and isotype switching, leading to increased IgE production and mast cell activation. However, IL-4/IL-13 may also be involved in direct mast cell activation (via IL4Ra expression on mast cells), immune-cell trafficking into the skin, and neuronal sensitization leading to itch [5, 21–25]. Given that IL-4/IL-13 may make multiple IgE-independent contributions to CSU pathogenesis, it should not be surprising that the response to dupilumab is independent of baseline IgE levels and only weakly correlated with a dupilumab-mediated reduction in serum IgE levels. Indeed, other agents investigated for CSU, such as quilizumab, a monoclonal antibody that binds membrane IgE at the M1-prime segment, reduced IgE levels compared with placebo but did not result in clinically meaningful improvements in patients with CSU [33].

Study limitations include small cohort sizes, including the limited number of enrolled pediatric and adolescent patients aged 6 years and older, and the definition of study subgroups based on baseline serum total IgE levels, which may not have accounted for inherent variations in serum total IgE levels. This study was only 24 weeks in duration, which limited assessment of patient response after an extended period of treatment.

Conclusions

Dupilumab was well tolerated and demonstrated significant improvements in the signs and symptoms of CSU in patients who were omalizumab naïve, regardless of baseline serum total IgE levels. Serum total IgE decreased over time in patients with H1-AH-resistant CSU receiving dupilumab, regardless of baseline serum total IgE levels. In the current analysis, baseline serum total IgE has no predictive value as a dupilumab treatment response biomarker in patients with CSU.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (PDF 235 KB)

Acknowledgements

We thank the participants of the study.

Medical Writing/Editorial Assistance

Medical writing/editorial assistance was provided by Moataz Badawi, PhD, of Excerpta Medica, and was funded by Sanofi and Regeneron Pharmaceuticals Inc., according to the Good Publication Practice guidelines.

Author Contributions

Conceptualization: Marcus Maurer, Thomas B. Casale, Sarbjit S. Saini, Moshe Ben-Shoshan, Elizabeth Laws, Jennifer Maloney, Deborah Bauer, Allen Radin, Melanie Makhija. Data curation: Elizabeth Laws, Jennifer Maloney, Deborah Bauer, Allen Radin, Melanie Makhija. Formal analysis: Elizabeth Laws, Jennifer Maloney, Deborah Bauer, Allen Radin, Melanie Makhija. Investigation: Marcus Maurer, Thomas B. Casale, Sarbjit S. Saini. Writing review and editing: Marcus Maurer, Thomas B. Casale, Sarbjit S. Saini, Moshe Ben-Shoshan, Elizabeth Laws, Jennifer Maloney, Deborah Bauer, Allen Radin, Melanie Makhija.

Funding

LIBERTY-CSU CUPID Study A was sponsored by Sanofi and Regeneron Pharmaceuticals Inc., ClinicalTrials.gov Identifier: NCT04180488. The journal's Rapid Service Fee was also funded by Sanofi and Regeneron Pharmaceuticals Inc.

Data Availability

Qualified researchers may request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, and statistical analysis plan) that support the methods and findings reported in this manuscript. Individual de-identified participant data will be made available once the indication has been approved by a regulatory body if there is participant consent and there is not a reasonable likelihood of participant reidentification.

Declarations

Conflict of Interest

Marcus Maurer reports speaker and/or consultant and/or institutional research support from Allakos, Alexion, Alvotech, Almirall, Amgen, Aquestive, ArgenX, AstraZeneca, Celldex Therapeutics, Celltrion, Clinuvel Pharmaceuticals, Escient Pharmaceuticals, Evommune, Excellergy Therapeutics, GSK, Incyte, Jasper Therapeutics, Kashiv BioSciences, Kyowa Kirin, LEO Pharma, Lilly, Menarini, Mitsubishi Tanabe Pharma, Moxie Pharmaceutical, Noucor, Novartis, Orion Pharma, Resonance Medicine, Sanofi-Regeneron Pharmaceuticals Inc., Santa Ana Bio, Septerna, Servier, Third Harmonic Bio, ValenzaBio, Vitalli Bio, Yuhan Corporation, and Zura Bio. Thomas B. Casale reports research support from Aimmune Therapeutics, Alladapt Immunotherapeutics, Allergy Therapeutics, ARS Pharma, Genentech, NIH, PCORI, Pfizer, Regeneron Pharmaceuticals Inc., and Sanofi; is a consultant for Aimmune Therapeutics, ARS Pharma, AstraZeneca, Genentech, Novartis, and Regeneron Pharmaceuticals Inc.; is on the speakers bureau for Genentech and Sanofi; and is the chief medical advisor for Food Allergy Research & Education (FARE). Sarbjit S. Saini reports receiving grants and/or research/clinical trial support from Amgen, Allakos, Escient Pharmaceuticals, NIH, Novartis, Sanofi, Regeneron Pharmaceuticals Inc., and served as a consultant or on advisory boards for Allakos, Aquestive, Celltrion, Escient Pharmaceuticals, Innate Therapies, Granular Therapeutics, Novartis, Regeneron Pharmaceuticals Inc., and Sanofi. Moshe Ben-Shoshan is a consultant with Bausch Health, Medexus Pharmaceuticals, Miravo, Novartis, Sanofi, and Stallergenes Greer. Elizabeth Laws, Deborah Bauer, and Melanie Makhija are employees of Sanofi and may hold stock and/or stock options in the company. Jennifer Maloney and Allen Radin are employees and shareholders of Regeneron Pharmaceuticals Inc.

Ethical Approval

This study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guidelines, and applicable regulatory requirements. All patients or their parents/guardians provided written informed consent before participating in the trial. Pediatric patients provided assent according to the Ethics Committee (Institutional Review Board [IRB]/Independent Ethics Committee)-approved standard practice for pediatric patients at each participating center.

Prior Presentation: (1) Maurer M, Casale T, Saini S, et al. Dupilumab significantly reduces itch in patients with chronic spontaneous urticaria: results from a phase 3 Trial (LIBERTY-CSU CUPID Study A). (Poster) presented at the European Academy of Allergy and Clinical Immunology meeting; Prague, Czech Republic; 1–3 July 2022; poster 001593. Abstract published in: Abstracts Poster. Allergy, 2023. 78; 56–716. (2) Maurer M, Casale T, Saini R, et al. Dupilumab significantly reduces itch and hives in patients with chronic spontaneous urticaria irrespective of baseline IgE level: results from a phase 3 trial (LIBERTY- CSU CUPID Study A). (Poster) presented at the 31st Congress of the European Academy of Dermatology and Venereology in Milan, Italy; 7–10 September 2022; abstract 2907. (3) Maurer M, Casale TB, Campos Galán A, et al. Eficacia de dupilumab en pacientes con urticaria crónica espontánea según el nivel de IgE y la IgE a lo largo del tiempo: estudio A de LIBERTY-CSU CUPID. (Poster) presented at the 34º Congreso Nacional de la Sociedad Española de Alergología e Inmunología Clínica 2023 in Santiago de Compostela, Spain Santiago de Compostela, Spain; 25–28 October 2023. (4) Maurer M, Casale T, Saini S, et al. Dupilumab efficacy in patients with chronic spontaneous urticaria by IgE level: LIBERTY-CSU CUPID Study A. (Oral Presentation) presented at the 2022 Annual American College of Allergy, Asthma, and Immunology Scientific Meeting in Louisville, KY, USA; 10–14 November 2022. Published in: Annals of Allergy, Asthma & Immunology. 2022;129(5):S11. (5) Maurer M, Casale T, Saini SS, et al. Dupilumab efficacy in patients with chronic spontaneous urticaria by IgE level and IgE over time: LIBERTY-CSU CUPID Study A. (Oral Presentation) presented at the European Allergy and Clinical Immunology Hybrid Congress in Hamburg, Germany; 9–11 June 2023. Published in: Oral abstracts (OAS). Allergy, 2023. 78: 167–282. The primary data of LIBERTY-CSU CUPID Study A have been published previously. (6) Maurer M, Casale TB, Saini SS, et al. Dupilumab in patients with chronic spontaneous urticaria (LIBERTY-CSU CUPID): two randomized, double-blind, placebo-controlled, phase 3 trials. J Allergy Clin Immunol. 2024;S0091-6749(24)00196–9. 10.1016/j.jaci.2024.01.028.
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