• Marcus Maurer, Luis Felipe Ensina, Ana Maria Gimenez-Arnau, Gordon Sussman, Michihiro Hide, Sarbjit Saini, Clive Grattan, Daria Fomina, Dimitrios Rigopoulos, Frederic Berard, Giorgio Walter Canonica, Heike Rockmann, Carla Irani, Jacek C Szepietowski, Jeffrey Leflein, Jonathan A Bernstein, Jonny G Peter, Kanokvalai Kulthanan, Kiran Godse, Ledit Ardusso, Olga Ukhanova, Petra Staubach, Rodney Sinclair, Shaila Gogate, Simon Francis Thomsen, Tonny Tanus, Young Min Ye, Alis Burciu, Avantika Barve, Darshna Modi, Emil Scosyrev, Eva Hua, Kerstin Letzelter, Vineeth Varanasi, Manmath Patekar, Thomas Severin, and PEARL-1 and PEARL-2 trial investigators.
• Urticaria Center of Reference and Excellence (UCARE), Institute of Allergology, Charité-Universitätsmedizin Berlin, Germany; Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany. Electronic address: marcus.maurer@charite.de.
• Lancet. 2024 Jan 13; 403 (10422): 147159147-159.

BackgroundMany 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.MethodsPEARL-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.FindingsBetween 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.InterpretationIn 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.FundingNovartis Pharma.Copyright © 2024 Elsevier Ltd. All rights reserved.

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