Metz et al. World Allergy Organization Journal (2022) 15:100716 http://doi.org/10.1016/j.waojou.2022.100716 Open Access Ligelizumab improves angioedema, disease severity and quality-of-life in patients with chronic spontaneous urticaria Martin Metz, MDa,b*, Jonathan A. Bernstein, MDc, Ana M. Giménez-Arnau, MD, PhDd, Michihiro Hide, MD, PhDe,f, Marcus Maurer, MDa,b, Karl Sitz, MDg, Weily Soong, MDh, Gordon Sussman, MDi, Eva Hua, MScj, Avantika Barve, PhDk, Nathalie Barbier, MScl, Maria-Magdalena Balp, MDl and Thomas Severin, MDl ABSTRACT Background: Disease burden is particularly high in Chronic Spontaneous Urticaria (CSU) patients with angioedema, and patients whose signs and symptoms are inadequately controlled by H1-an- tihistamines need new treatment options. Here we report an exploratory analysis, from the ligeli- zumab Phase 2b study, investigating angioedema occurrence in patients with CSU and describe the changes in angioedema following treatment with ligelizumab, omalizumab, or placebo. Methods: Data from the ligelizumab Phase 2b core (ligelizumab 72 mg, 240 mg, omalizumab 300 mg and placebo) and extension study (ligelizumab 240 mg) were used. Changes in Weekly Angioedema Activity Score (AAS7), the Dermatology Life Quality Index (DLQI), and Weekly Urti- caria Activity Score (UAS7) among each time point were analyzed for each treatment arm. Results: From a total of 297 patients analyzed, 165 (55.6%) reported angioedema occurrence at baseline, with mean AAS7 ranging 30.6—42.2 across treatment arms. At Week 12 of the core study 87.5%, 84.6%, 75.0%, and 61.0% of patients were angioedema free for ligelizumab 72 mg, 240 mg, omalizumab 300 mg, and placebo arms, respectively. In CSU patients with angioedema at baseline, the largest change from baseline in AAS7 score was observed with ligelizumab 72 mg (31.9) at week 16 in the core study. Patients with angioedema had a higher mean DLQI at baseline (14.9—16.1) vs. patients without angioedema (10.6—12.0). In patients with angioedema, low AAS7 was significantly associated with complete response on UAS7 (UAS7 ¼ 0) and complete normalization of DLQI (DLQI 0—1). Conclusion: In the Phase 2b study, ligelizumab effectively reduced angioedema and urticaria symptoms, and improve health related quality of life in patients with moderate-to-severe CSU. Clinicaltrails.gov NCT number: NCT02477332; NCT02649218. Keywords: Angioedema, Chronic spontaneous urticaria, Dermatology life quality index, IgE, Ligelizumab a Institute of Allergology, Charité – Universitätsmedizin Berlin, Corporate Received 30 May 2022; Received in revised from 7 September 2022; Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Accepted 19 October 2022 Berlin, Germany Online publication date xxx *Corresponding author. Institute of Allergology, Charité - 1939-4551/© 2022 The Authors. Published by Elsevier Inc. on behalf of Universitätsmedizin Berlin, Germany. E-mail: martin.metz@charite.de World Allergy Organization. This is an open access article under the CC BY Full list of author information is available at the end of the article license (http://creativecommons.org/licenses/by/4.0/). http://doi.org/10.1016/j.waojou.2022.100716 2 Metz et al. World Allergy Organization Journal (2022) 15:100716 http://doi.org/10.1016/j.waojou.2022.100716 INTRODUCTION in the Phase 2b core study (ClinicalTrials.gov number: NCT02477332)18 followed by a one- Studies have indicated that chronic urticaria has year Phase 2b extension study (ClinicalTrials.gov a point prevalence of 0.1—1.4%, depending on the number: NCT02649218).23 The ligelizumab region,1 two thirds of which are chronic clinical Phase 3 studies (NCT03580369 and spontaneous urticaria (CSU).2 Approximately 40% NCT03580356) recruited more than 2000 CSU of patients with CSU experience angioedema,3 patients with or without angioedema, across 48 which is characterized by a sudden pronounced countries worldwide, and met their primary erythematous or painful swelling of the lower endpoints of superiority for ligelizumab vs. dermis and subcutis or mucus membranes, placebo at Week 12, but not vs. omalizumab. occurring mostly on the face and inside the Here, we report the Phase 2b core and extension mouth, but also elsewhere on the body.4,5 A real- exploratory analysis data investigating the world study among inadequately controlled CSU angioedema occurrence in patients with CSU. We patients revealed that angioedema is under- describe the changes in Angioedema Activity reported in medical charts compared to patient Score (AAS) following treatment with ligelizumab, reports.6 omalizumab, or placebo. The assessment of disease activity in affected patients is important Disease burden of CSU is particularly high in to guide treatment decisions, and patient patients with angioedema.2 Often, patients who reported outcome (PRO) data are essential in experience CSU with concurrent hives and diagnosing and managing CSU. Therefore, to angioedema experience a longer duration of evaluate the efficacy of ligelizumab in patients disease compared with patients who only have with CSU, with and without angioedema, the hives.7,8 Although not life-threatening, angioe- Dermatology Life Quality Index (DLQI) and dema can be disfiguring and painful. Some pa- Urticaria Activity Score (UAS) were also measured. tients fear that swelling episodes will lead to breathing difficulties, which can restrict daily ac- tivities.9,10 Angioedema associated with CSU is METHODS debilitating for affected patients, sometimes Study design leading to unnecessary hospitalizations, and challenging for their treating physicians.11 The study design has been previously reported Angioedema has a significant additional impact in detail.18 Briefly, in the double-blind, active- and on dermatology related quality of life (QoL), placebo-controlled Phase 2b study, adult patients compared to patients without angioedema.6,12 with moderate-to-severe CSU (defined by Weekly Patients with CSU who also experience Urticaria Activity scores [UAS7] 16 on a scale angioedema can suffer a poorer health related from 0 to 42, with higher scores indicating greater QoL (HRQoL) compared to those without disease activity) were randomized to receive lige- angioedema.3,13 lizumab 240 mg, 72 mg, 24 mg, omalizumab 300 mg or placebo every 4 weeks (q4w), or a sin- The global guidelines for treatment of CSU gle dose of ligelizumab 120 mg at randomization recommend the use of omalizumab, the only followed by placebo q4w (2:2:2:1:1:1). All patients licensed anti-immunoglobulin E (IgE) monoclonal received H1 antihistamine background therapy. antibody for clinical use, as an add-on therapy to For the analysis presented in this manuscript, pa- H1-antihistamines for the treatment of CSU.4 tients from the ligelizumab 24 mg (below the Despite ongoing treatment with current standard therapeutic dose-response range) and 120 mg of care, complete control of CSU and single dose (purposed for pharmacokinetic- angioedema remains hard to achieve in some pharmacodynamic assessments) treatment arms patients and additional treatment options are of the core study are not included. However, for needed.14–16 Ligelizumab is a next generation, any analysis regarding the extension study, all high affinity, 97% humanized, monoclonal anti- patients that entered the extension study are IgE antibody which results in rapid, strong, and considered (Supplementary Figure 1). The sustained urticaria control,17–22 as demonstrated institutional review board at each participating Volume 15, No. 11, Month 2022 3 center approved the study protocol. Patients for the extension study. Patients with AAS7 ¼ 0 provided written informed consent to participate were defined as angioedema free. A step-wise in the study. The study was conducted according regression was used to identify potential factors to the ethical principles of the Declaration of influencing the angioedema outcome (AAS7) at Helsinki. Week 20. The least squares (LS) mean for each treatment group was estimated with a repeated Participants measure mixed model using all the selected fac- tors from the stepwise analysis. The number of Adult patients (18 to 75) diagnosed with re- weeks with and without angioedema and the rate fractory CSU who remained symptomatic despite of angioedema and non-angioedema weeks were treatment with H1-anthistamines at approved or also evaluated. Analysis of angioedema status by increased doses, alone or in combination with H2- treatment visit was also conducted. To investigate anthistamines and/or a leukotriene receptor the relationship between AAS7 and UAS7, 2 antagonist, were eligible to enter the core study. repeated measure mixed models, 1 for the core The inclusion and exclusion criteria, and baseline study up to Week 32 and 1 for the extension study demographic and clinical characteristics of the were used on AAS7 scores with UAS7 responder patients, have previously been described in status at each visit, and age, sex, and duration of detail.18 The key inclusion criteria for the extension CSU as fixed effect factors with subject as a study were patients who remained in the follow-up random effect using a compound symmetry period of the core study for at least 12 weeks and covariance matrix. had active disease (UAS712) (Supplementary Figure S1). The mean CFB-UAS7, were evaluated at baseline, and throughout the treatment period. Complete Exploratory endpoints and statistical analysis freedom from signs and symptoms of urticaria was indicated by UAS7 ¼ 0. The DLQI, a 10-item The proportion of patients with CSU with and dermatology-specific health-related (HR) QoL mea- without angioedema was recorded at baseline, sure, was completed by all patients at baseline, and and throughout the Phase 2b core and extension every 4 weeks thereafter. A mixed model comparison studies. The baseline characteristics of the patient analysis was conducted between AAS7 and population with and without angioedema are DLQI categories24 (0–1 ¼ no effect, 2–5 ¼ small effect, described with summary statistics. Angioedema 6–10 ¼ moderate effect, 11–20 ¼ very large effect, and occurrence and severity were recorded with the 21–30 ¼ extremely large effect on patient’s life), AAS, a specific PRO that measures disease activity considering DLQI health status at each visit, visit, in patients with recurrent angioedema.9 Episodes age, sex, and duration of CSU as fixed effect factors, of angioedema including duration, severity, and and subject as a random effect factor. impact on daily functioning and appearance were assessed. Angioedema occurrence is reported The implemented statistical analyses had limi- with descriptive statistics. Daily scores were tations. These were exploratory post hoc analyses summed up as the 7-day AAS (AAS7), with total with nominal p-values. No multiplicity adjustments scores ranging between 0 and 105 (a higher score were made, therefore, statistical interpretation on being worse). A patient was considered as having the significance level should be made with caution. angioedema at baseline when there was at least 1 To ensure that the cross arm pooled data were not day during the week prior to baseline visit with an challenged by the confounded treatment effects occurrence of swelling as reported on the AAS7. for these exploratory analyses, not all data from the The mean change from baseline (CFB) in AAS7 Phase 2b study were used. Ligelizumab dose for patients with angioedema at baseline was below the therapeutic dose-response range, and analyzed throughout the studies using a mixed the single dose arm18 were not considered in model analysis with age, IgE at baseline, and these analyses. For the analyses on angioedema, baseline AAS7 as covariates for the core study and the subgroup analyses were only done on with CSU duration and extension baseline AAS7 patients who had angioedema at baseline. This 4 Metz et al. World Allergy Organization Journal (2022) 15:100716 http://doi.org/10.1016/j.waojou.2022.100716 was done to support the conclusion for CSU improvement was sustained until the end of the patients with concomitant angioedema. core study at Week 20, and 87.2%, 86.3%, and 77.8% of patients treated with ligelizumab 72 mg, 240 mg and omalizumab 300 mg, respectively, RESULTS achieved angioedema-free status compared with Participants 65.0% on placebo. Similarly, in the extension study, at Week 12, 88.6% of all patients treated Of the total 382 patients randomized in the core with ligelizumab 240 mg were angioedema-free, study, 88.5% (338) completed the treatment which was sustained at Week 20 (92.3% of all pa- phase; all baseline demographics and clinical tients achieving angioedema-free status). At the characteristics were balanced across treatment end of the extension study treatment period (Week arms.18 For the present analysis, data of 297 52), 92.5% of all patients were angioedema-free. patients from the ligelizumab 72 mg and 240 mg, omalizumab 300 mg and placebo arms of the core study were considered. From the Changes in AAS7 over time core study population that entered the treatment- The LS mean change from baseline (CFB) in free follow-up period (n ¼ 320), 70.6% (226) of AAS7 evaluated for patients with angioedema, by patients were included, after the 12-week washout treatment groups is shown in Fig. 1b and c. The period (at Week 32), to receive ligelizumab greatest LS mean  standard error (SE) CFB- 240 mg in the one-year open-label extension AAS7 was observed for patients treated with lige- study. Baseline demographics, disease character- lizumab 72 mg at Week 16 (31.9  2.9). At Week istics, patient disposition and safety during the 12, CFB-AAS7 for ligelizumab 72 mg, 240 mg, core and extension study have been reported omalizumab and placebo was 31.6  2.9, previously.18 A summary of patient demographics 28.6  2.8, 25.5  2.9 and 21.2  3.6, and disease characteristics of patients considered respectively. For patients in the extension study, for this analysis is provided in Table 1. ligelizumab 240 mg showed an LS mean  SE CFB in AAS7 of 24.8  1.7 at Week 12, Angioedema occurrence 25.4  1.7 at Week 20, and 26.8  1.7 at Week 52. The rate of angioedema free weeks during the In the core study, a total of 165/297 (55.6%) treatment period was higher in the ligelizumab patients reported to have angioedema at baseline, and omalizumab arms vs. placebo (Fig. 1d). comprising of 51.2% and 54.1% of patients in the ligelizumab 72 mg and 240 mg groups, respec- tively, 56.5% for omalizumab 300 mg, and 65.1% Changes in UAS7 for placebo. In the extension study, 84/226 (37.2%) In the core study, mean  SD UAS7 at baseline of patients had angioedema at extension study for all patients with angioedema (31.2  7.5) was baseline (Table 1). Patients in the present analysis similar to that observed in patients without had a numerically higher mean  SD AAS7 score angioedema at baseline (29.7  7.3). Similarly, in of 35.7  25.5 at baseline in the Phase 2b core the extension study, mean  SD UAS7 at baseline study compared with 30.9  24.8 in the for all patients with angioedema (29.2  8.2) was extension study. The Baseline AAS7 among comparable to that observed in patients without patients with angioedema in the core study was angioedema (27.7  9.6; Table 1 and Fig. 2a). 42.2, 32.8, 30.6 and 39.5 for ligelizumab 72 mg, Improvements in mean CFB in UAS7 in patients 240 mg, omalizumab 300 mg and placebo arms, with angioedema were observed across all treat- respectively (Table 1 and Fig. 1a). ment groups. For patients with angioedema, the For all patients in the core study, at Week 12, LS mean  SE CFB-UAS7 at Weeks 4, 12 and 20 87.5%, 84.6%, and 75.0% of patients treated with were higher (better) for ligelizumab 72 mg ligelizumab 72 mg, 240 mg, and omalizumab (20.9  2.0, 21.4  2.1 and 22.5  2.1), lige- 300 mg, respectively, were angioedema-free, lizumab 240 mg (18.1  2.1, 20.5  2.1 compared with 61.0% on placebo. This and 20.1  2.1) and omalizumab 300 mg Corea Extension Volume 15, No. 11, Month 2022 Ligelizumab Ligelizumab Omalizumab Placebo Total Ligelizumab 72 mg (N ¼ 84) 240 mg (N ¼ 85) 300 mg (N ¼ 85) (N ¼ 43) (N ¼ 297) 240 mg (N ¼ 226) Presence of 43 (51.2) 46 (54.1) 48 (56.5) 28 (65.1) 165 (55.6) 84 (37.2) angioedemab n (%) Age (years) 44.3  12.4 42.9  10.5 41.8  13.1 45.4  11.2 43.4  11.9 44.5  12.7 Angioedema 46.7  13.4 42.8  11.0 42.3  13.1 47.1  10.7 44.4  12.3 45.4  11.8 No angioedema 41.8  10.8 43.1  10.0 41.2  13.1 42.2  11.8 42.1  11.3 44.0  13.2 Female sex, n (%) 61 (72.6) 67 (78.8) 66 (77.6) 31 (72.1) 225 (75.8) 170 (75.2) Angioedema 32 (74.4) 41 (89.1) 37 (77.1) 19 (67.9) 129 (78.2) 65 (77.4) No angioedema 29 (70.7) 26 (66.7) 29 (78.4) 12 (80.0) 96 (72.2) 105 (73.9) BMI 28.5  7.1 27.9  6.1 28.1  6.4 27.4  6.5 28.1  6.5 28.8  7.2 Angioedema 29.0  6.8 27.9  6.1 28.8  7.2 28.9  7.0 28.6  6.7 30.2  7.3 No angioedema 28.1  7.5 27.9  6.2 27.2  5.3 24.7  4.7 27.4  6.3 27.9  7.1 Duration of CSU (years) 3.9  5.4 4.1  5.6 5.1  7.5 3.6  3.5 4.2  5.9 4.8  6.2 Angioedema 4.9  6.1 5.0  6.5 5.7  8.9 3.2  2.9 4.9  6.8 4.6  6.7 No angioedema 2.7  4.3 3.1  4.1 4.3  5.3 4.4  4.5 3.5  4.6 4.8  5.9 AAS7c score 42.2  25.0 32.8  28.1 30.6  22.8 39.5  24.9 35.7  25.5 30.9  24.8 UAS7 Angioedema 33.1  6.7 29.8  7.5 30.2  8.5 32.0  6.5 31.2  7.5 29.2  8.2 No angioedema 30.2  7.8 30.9  7.1 28.1  7.0 29.4  7.3 29.7  7.3 27.7  9.6 DLQI Angioedema 16.1  8.0 15.2  7.9 15.0  6.9 14.9  5.9 15.4  7.3 15.7  6.8 No angioedema 10.9  6.7 12.0  7.1 11.9  6.6 10.6  5.7 11.5  6.6 12.6  7.3 Table 1. Baseline demographics and disease characteristics of patients in the Phase 2b core and extension studies All data are expressed as mean  standard deviation or n (%).AAS7, weekly angioedema activity score; BMI, body mass index; CSU, chronic spontaneous urticaria; DLQI, dermatology life quality index; N, full analysis set; n, number of patients; QoL, quality of life; UAS7, weekly urticaria activity score. aOnly data from four treatment groups from the core study are presented. bPercentage of patients with angioedema non missing evaluation at baseline are presented. cAAS7 of patients with angioedema at baseline are presented. All patients had a baseline DLQI score >13 suggesting a severe impact on QoL. 5 6 Metz et al. World Allergy Organization Journal (2022) 15:100716 http://doi.org/10.1016/j.waojou.2022.100716 Fig. 1 Angioedema status of patients in the ligelizumab Phase 2b studies: (a) median (IQ range), mean  SD of AAS7 at baseline in the core and extension studies, (b) LS mean CFB AAS7 in the core Phase 2b study, (c) LS mean CFB AAS7 in the extension study, (d) mean rate of weeks with or without angioedema in the core and extension studies. Presented at EAACI 2022: https://www.urticariaknowledgecenter. novartis.com/EAACI/presentations/2022/Posters/EAACI_2022_Angioedema_control_Poster.pdf. Box-and-whisker plot shows medians (horizontal line) with Q1-Q3 range (edges of box), error bars represent SD, with a diamond marker within the box depicting mean. LS means from Mixed model of repeated measures (MMRM model): CFB in AAS7 score, considering treatment, visit, baseline total IgE, baseline AAS7 score, age as covariates for core study, and visit and extension baseline AAS7 score as covariates for the extension. Only patients with angioedema at baseline were considered for this analysis. Rate of angioedema is defined as (number of weeks with angioedema in core treatment phase)/(number of completed weeks in core treatment phase). Rate of non-angioedema is defined as: (number of weeks without angioedema in core treatment phase)/(number of completed weeks in core treatment phase). Blue dotted line indicates primary endpoint. Red dotted line indicates the end of the treatment period of the core study. AAS7, weekly angioedema activity score; CFB, change from baseline; Ext., extension; LIG, ligelizumab; LS Mean, least squares mean; n, number of patients; OMA, omalizumab; Q1-Q3, 1st to 3rd interquartile range; SD, standard deviation. (14.9  1.9, 16.4  2.0 and 16.8  2.0) vs. treatment arms, and higher compared with pla- placebo (6.1  2.4, 13.3  2.6 and 13.8  2.5; cebo (Fig. 2c). In the extension study, the LS Fig. 2b). For patients without angioedema at mean  SE CFB-UAS7 scores, at Weeks 4, 12, 20 baseline the CFB-UAS7 was similar between and 52 was 19.0  1.4, 19.7  1.3, 21.3  1.2 Volume 15, No. 11, Month 2022 7 and 22.4  1.2, respectively, for patients with identified in the extension study where all angioedema. (Fig. 2d). patients received the highest dose (240 mg) of ligelizumab.23 In the core study, the comparison by UAS7 responder status (pooled data up to Week 32) demonstrated that patients who were free from DISCUSSION urticaria signs and symptoms (complete response: UAS7 ¼ 0) had a lower LS mean  SE AAS7 vs. Angioedema is a common symptom, albeit patients with well-controlled urticaria (0.4  1.4 vs. fluctuating and unpredictable, that may co-occur 2.5  1.4, p ¼ 0.062; Fig. 2e). Similarly, in 52 weeks with hives and itch in patients with CSU. Even pooled data from the extension study, the though angioedema is not considered life- comparison by UAS7 responder status threatening in CSU patients, it increases the demonstrated that patients achieving UAS7 ¼ 0 burden of disease and severely impacts patient’s had significantly lower LS mean  SE AAS7 vs. QoL. Chronic spontaneous urticaria patients with patients with well controlled urticaria (1.7  1.4 angioedema, whose signs and symptoms are vs. 5.3  1.4, p < 0.0001; Fig. 2f). inadequately controlled by H1-antihistamines, need new treatment options. In the ligelizumab Phase 2b core study, the patient inclusion criteria Impact of angioedema on DLQI were not dependent on co-occurrence of angioe- In the core study, across arms the mean (14.9— dema with CSU, but patients were assessed for 16.1) and median (14.0—16.0) baseline DLQI score occurrence of angioedema at baseline as any for patients with angioedema was higher positive value of AAS7 in the week prior to compared to patients without angioedema (mean randomization. This is in contrast to the angioe- 10.6—12.0; median 10.0–12.0), indicating a more dema focused X-ACT study in which history of severe impact on life; Table 1 and Fig. 3a. angioedema with 4 episodes within the last 6 Similarly, in the extension study, overall, patients months was the inclusion criteria.10 Despite this, with angioedema had a higher mean DLQI score more than 56% of patients in this post-hoc anal- at baseline (15.7) compared with patients without ysis of the ligelizumab Phase 2b core study had angioedema (12.6; Table 1 and Fig. 3a). In the angioedema at baseline. In addition, the studies pooled data up to Week 32 from the core study, enrolled patients with moderate-to-severe disease the comparison by DLQI categories activity regardless of presence or absence of demonstrated that patients with DLQI 0–1 had a angioedema at baseline. A greater proportion of significantly lower LS mean  SE AAS7 vs. patients in the core study had angioedema at patients with DLQI 2–5 (0.46  1.43 vs. baseline compared to the extension study, 6.51  1.75, p ¼ 0.0006; Fig. 3b). Similarly, in 52 although the baseline angioedema scores were weeks pooled data from the extension study, the comparable between the studies. This further comparison by DLQI categories status highlights the fluctuating nature and unpredict- demonstrated that patients achieving DLQI 0–1 ability of angioedema in patients with CSU, espe- had significantly lower LS mean  SE AAS7 vs. cially considering the overall baseline UAS7 was patients with DLQI 2–5 (1.27  1.31 vs. similar between the two studies. However, it was 4.84  1.75, p ¼ 0.0218; Fig. 3c). Overall, lower evident from the data that patients with angioe- AAS7 were significantly associated with better dema had a higher impact on dermatology related dermatology-QoL outcomes (Fig. 3 b and c). QoL compared with patients without angioedema. The reported exploratory analysis showed that Safety CSU patients with angioedema who were treated Safety results for the core study and the exten- with ligelizumab experienced significant improve- sion study have been previously reported. Briefly, ments in AAS7 and UAS7. A large number of pa- all tested doses of ligelizumab showed a safety tients were angioedema-free by Week 12 of both profile comparable to omalizumab. No adverse studies, and patients treated with ligelizumab and events of clinical relevance were observed during omalizumab experienced a greater CFB in AAS7 the core study,18 and no new safety signals were scores over time compared with placebo. In the 8 Metz et al. World Allergy Organization Journal (2022) 15:100716 http://doi.org/10.1016/j.waojou.2022.100716 Fig. 2 Urticaria activity and co-occurrence of angioedema: (a) median (IQ range), mean  SD UAS7 at baseline in the Phase 2b and studies; mean CFB UAS7 in patients (b) with angioedema and (c) without angioedema in the core Phase 2b study, and (d) with or without angioedema in the extension study; AAS7 by UAS7 responder status among patient with angioedema at baseline in (e) core study, and (f) extension study. Presented at AAD 2022: https://www.urticariaknowledgecenter.novartis.com/AAD/presentations/2022/AAD_2022_ Patients_treated_Poster.pdf. Box-and-whisker plot shows medians (horizontal line) with Q1-Q3 range (edges of box). Error bars represent SD. Diamond marker within the box depicts mean. Blue and red dotted line indicates primary endpoint (Week 12) and end of the treatment period (Week 20), respectively. Patients who remained in the follow-up period for at least 12 weeks and had active disease (UAS712), could enter the extension study from Week 32 onwards for the core study. UAS7 disease activity categories; complete response (UAS7 ¼ 0); well-controlled (UAS7 ¼ 1–6); mild (UAS7 ¼ 7–15); moderate (UAS7 ¼ 16–27); severe (UAS7 ¼ 28–42). AAS7, Weekly Angioedema Activity score; BL, baseline; CFB, change from baseline; Ext., extension; LIG, ligelizumab; LS mean, least squares mean; n, number of patients; OMA, omalizumab; SD, standard deviation; SE, standard error; UAS7, weekly urticaria activity score. Volume 15, No. 11, Month 2022 9 Fig. 3 Dermatology-QoL by angioedema status at baseline: (a) Median (IQ range), mean  SD in the Phase 2b core and extension studies. AAS7 comparison by DLQI categories among patient with angioedema at baseline (b) in the Phase 2b core study, and (c) in the extension study. Presented at EAACI 2022: https://www.urticariaknowledgecenter.novartis.com/EAACI/presentations/2022/Posters/EAACI_2022_ Angioedema_control_Poster.pdf. Box-and-whisker plot shows medians (horizontal line) with Q1-Q3 range (edges of box), error bars represent SD, with a diamond marker within the box depicting mean. DLQI categories for effect on QoL (DLQI score 0–1: no effect; 2–5: small effect; 6–10: moderate effect; 11–20: very large effect; and 21–30: extremely large effect). AAS7, weekly angioedema activity score; BL, baseline; DLQI, Dermatology Life Quality Index; Ext., extension; LIG, ligelizumab; OMA, omalizumab; QoL, quality of life; SE, standard error; SD, standard deviation core study, all patients with CSU and angioedema that were sustained over time. In agreement with that received ligelizumab or omalizumab treat- the previously reported ligelizumab dose response ments, achieved improvements in AAS7 and UAS7 relationship in terms of complete response on 10 Metz et al. World Allergy Organization Journal (2022) 15:100716 http://doi.org/10.1016/j.waojou.2022.100716 hives,18 the efficacy of ligelizumab on angioedema that lower rates of angioedema occurrence in was similar between the 72 mg and 120 mg doses. patients moving from the core to the extension Improvements in mean CFB AAS7 scores were study warrant further studies on whether the ef- observed throughout the treatment phase of the fect of anti-IgE treatment on angioedema may be core study and follow-up periods. Similarly, in the more sustained in comparison to its effect on extension study, re-treatment with ligelizumab urticaria in patients with CSU. It will also be 240 mg was effective in reducing AAS7 for all interesting to explore the efficacy of anti-IgE patients who were included from the core study. therapy as an early intervention for patients with The efficacy of re-treatment with ligelizumab new onset CSU and concomitant angioedema. 240 mg could be indicative of sustained response The CFB in urticaria activity in the present data on continued therapy, as over 92.5% of patients was congruous with the CFB in AAS7 throughout reached angioedema-free status by the end of the the core study. extension study treatment period. Angioedema can be a debilitating condition CONCLUSION and is frustrating for both patients and physicians. In patients presenting with CSU it is estimated that Overall, the best outcomes on angioedema ac- 33–67% of cases will have associated angioe- tivity were significantly associated with complete dema.3,10 Similarly, in our study,18 based on the response on patients’ disease activity status and AAS7 score, over 50% of patients reported dermatology-QoL. This emphasizes the need and having angioedema at baseline. The results of the the importance to achieve freedom from signs and ASSURE study showed that CSU patients with symptoms of urticaria and treating the disease angioedema are underdiagnosed, have high until it is completely controlled. Together with the disease severity, and are significantly impacted increased disease severity reported in patients on their HRQoL outcomes.6 Nearly one-third of with CSU and angioedema, these findings high- patients with CSU in the ASSURE study reported light the efficacy of ligelizumab in reducing having experienced angioedema in the past 12 symptoms in moderate-to-severely affected pa- months but did not have physician-reported tients with CSU. CSU patients with angioedema angioedema and that mean DLQI scores were experience a higher disease activity and worse significantly higher (indicating worse HRQoL) for HRQoL than those without angioedema. Well patients with angioedema vs. no angioedema. tolerated and effective therapies will lead to better These patients are often overlooked, therefore clinical outcomes for patients with CSU and asso- increased awareness and education to promote ciated angioedema. best practice in primary and secondary healthcare is urgently required. The high numbers of Abbreviations angioedema cases reported in the CSU population AAS; Angioedema Activity Score, AAS7; Weekly highlights the need for CSU treatment options that Angioedema Activity Score, CFB; change from baseline, also improve angioedema. In the present analysis, CSU; chronic spontaneous urticaria, DLQI; dermatology life patients with angioedema had higher mean DLQI quality index, HR; health-related, HRQoL; health related quality of life, IgE; immunoglobulin E, LS; least squares, scores at baseline. This finding is comparable to PRO; patient reported outcome, q4w; every 4 weeks, QoL; the ASSURE-CSU study,6 however, the impact on quality of life, SD; standard deviation, SE; standard error, patients’ dermatology-QoL was higher in the pre- UAS; Urticaria Activity Score, UAS7; Weekly Urticaria sent analysis. The significant association of AAS7 Activity scores score with DLQI categories clearly shows that pa- tients that demonstrate better response on AAS7 Acknowledgments are more likely to achieve the better dermatology- The authors thank Bharat Suryawanshi of IQVIA India Ltd. QoL outcomes, though there may also be other for statistical analysis support, Hayley Furlong, Ph.D., Gillian active confounders. Brodie MSc of Novartis Ireland, and Mohammad Fahad Haroon, Ph.D. of Novartis Healthcare Pvt. Ltd. India, for The rapid onset of action and therapeutic ef- providing medical writing assistance in accordance with fects in the Phase 2b study indicate that effective Good Publication Practice guidelines (www.ismpp.org/ treatments can improve QoL. The observation gpp3). Volume 15, No. 11, Month 2022 11 Funding activities for Uriach Pharma, Novartis, Genentech, Menarini, This work was supported by the Novartis Pharma AG, LEO- PHARMA, GSK, MSD, Almirall, AVENE and Sanofi. Switzerland. Michihiro Hide has received lecture and/or consultation fees from Kaken Pharmaceutical, Kyowa Kirin, Mitsubishi Tanabe Pharma, MSD, Novartis, Sanofi, TAIHO Ethics statements Pharmaceutical, and Teikoku Seiyaku. The institutional review board at each participating center Marcus Maurer is or recently was a speaker and/or advisor approved the protocol. Patients provided written informed for and/or has received research funding from Amgen, consent to participate in the study. The study was Allakos, Aralez, AstraZeneca, Celldex, FAES, Genentech, GI conducted according to the ethical principles of the Innovation, Kyowa Kirin, Leo Pharma, Menarini, Novartis, Declaration of Helsinki. Data were collected by the trial Moxie, MSD, Roche, Sanofi, Third Harmonic, UCB, and investigators according to Good Clinical Practice Uriach. guidelines and were analyzed by the sponsor. Karl Sitz has received research grants from AstraZeneca, ClinicalTrials.gov NCT number: NCT02477332; Bellus, BioCryst, CSL Behring, Evidera, GlaxoSmithKline, NCT02649218. Novartis Teva, KalVista, and has provided consultancy to BioCryst Pharmaceuticals Inc. Weily Soong has been an advisor and/or clinical Author contribution investigator and/or received speaker’s honoraria and/or MMr, EH, AB and MMB participated in the conception and received consulting fee and/or grants and/or participated design of the study, MMz, JAB, AMG, MH, MMr, KS, WS and as a clinical investigator for/from the following companies: GS contributed to the acquisition of data, and EH and NB AbbVie, Aimmune Therapeutics, Amgen, AstraZeneca, contributed to the analysis of the data. All authors Genentech, GlaxoSmithKline, Novartis, Pfizer, Regeneron, contributed to the interpretation of the data, participated in Sanofi and Teva. the drafting and revisions of the manuscript and approved Gordon Sussman has received research support from the final version of the manuscript. Aimmune, Amgen, Astra Zeneca, DBV technologies, Genentech, Kedrion S.p.A, Leo Pharma Inc., Novartis, Nuvo Pharmaceuticals Inc., Sanofi, Stallergenes, Merck, Schering Authors’ consent for publication Plough, Regeneron and ALK; is a medical advisor and/or All authors agree to publish this work. All authors confirm has received payment for lectures from Merck, Novartis, and agree to the editorial policy. Authors confirm that their CSL Behring, Pfizer, Anaphylaxis Canada, the Allergy manuscript is original, has not been published before, is Asthma and Immunology Society of Ontario and the not currently being considered for publication elsewhere, Canadian Hereditary Angioedema Network. and has not been posted to a preprint server. Eva Hua is an employee of Novartis Institutes for Biomedical Research Co. Ltd., China. Avantika Barve is an employee of Novartis Data availability statement Pharmaceuticals Corporation, East Hanover, New Jersey, Novartis is committed to sharing with qualified external United States. researchers, access to data and supporting clinical Maria-Magdalena Balp, Nathalie Barbier and Thomas documents from eligible studies. These requests are Severin are employees of Novartis Pharma AG, Basel, reviewed and approved by an independent review panel Switzerland. on the basis of scientific merit. All data provided will be anonymized to respect the privacy of patients participating in the trial in line with applicable laws and regulations. Appendix A. Supplementary data Supplementary data to this article can be found online at Declaration of competing interest https://doi.org/10.1016/j.waojou.2022.100716. Martin Metz reports personal fees from Amgen, personal fees from Aralez, personal fees from Argenx, personal fees Author details from Moxie, personal fees from Novartis, personal fees a Institute of Allergology, Charité – Universitätsmedizin from Roche, personal fees from Sanofi, personal fees from Berlin, Corporate Member of Freie Universität Berlin and Uriach, outside the submitted work. Humboldt-Universität zu Berlin, Berlin, Germany. b Jonathan A. Bernstein reports grants and personal fees Fraunhofer Institute for Translational Medicine and from Novartis, Astra Zeneca, Sanofi-Regeneron, Amgen, Pharmacology ITMP, Allergology and Immunology, Berlin, Roche, Allakos, Celldex, CSL Behring, Takeda/Shire, Germany. cUniversity of Cincinnati College of Medicine and Biocryst, Pharming, Ionis, Biomarin and Genentech outside Bernstein Clinical Research Center, Cincinnati, OH, United the submitted work. States. dDermatology Department, Hospital Del Mar-Parc Ana M Giménez-Arnau reports roles as a medical advisor de Salut Mar, IMIM Universitat Autònoma and Universitat for Uriach Pharma, Sanofi and Genentech, Novartis, FAES, Pompeu Fabra, Barcelona, Spain. eDepartment of GSK, AMGEN, Thermo Fisher, Almirall and has research Dermatology, Hiroshima University, Hiroshima, Japan. f grants supported by Uriach Pharma, Novartis, and Instituto Department of Dermatology, Hiroshima City Hospital, Carlos III- FEDER; she also participates in educational Hiroshima, Japan. gLittle Rock Allergy and Asthma Clinic, 12 Metz et al. World Allergy Organization Journal (2022) 15:100716 http://doi.org/10.1016/j.waojou.2022.100716 Little Rock, AR, United States. hAllerVie Health-Alabama 12. Weller K, Maurer M, Grattan C, et al. 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