德国柏林夏里特大学Marcus Maurer团队近期取得重要工作进展，他们报道开展了ligelizumab治疗成人和青少年慢性自发性荨麻疹的疗效和安全性研究——两项3期随机对照试验。相关研究成果2023年11月23日在线发表于《柳叶刀》杂志上。

据介绍，许多慢性自发性荨麻疹（CSU）患者在目前可用的治疗方法下无法完全控制其症状。在一项2b期剂量发现研究中，ligelizumab改善了H1-抗组胺药（H1-AH）难治性CSU患者的荨麻疹症状。研究人员报告了两 ligelizumab 3期研究的疗效和安全性结果。

PEARL-1和PEARL-2是相同设计的随机、双盲、活性对照和安慰剂对照平行组研究。从46个国家的347个研究点招募了12岁或12岁以上的中重度H1-AH难治性CSU患者，并通过交互反应技术以3:3:3:1的比例随机分配给72 mg ligelizumab、120 mg ligelizumab、300 mg omalizumab或安慰剂，每4周给药一次，持续52周。分配给安慰剂的患者从第24周开始接受120 mg ligelizumab治疗。主要终点是第12周每周荨麻疹活动评分（UAS7）与基线（CFB）的变化，并根据随机分配的治疗对所有符合条件的成年患者进行分析。在整个研究过程中，对所有至少接受一剂研究药物的患者进行了安全性评估。这些研究在ClinicalTrials.gov、NCT03580369（PEARL-1）和NCT03580356（PEARL-2）上注册。两项试验现已完成。

在2018年10月17日至2021年10月26日期间，2057名成年患者被随机分配到两项研究中（72 mg ligelizumab n=614；120 mg ligelizumab n=616；300 mg omalizumab n=618，安慰剂n=209）。2057人中共有1480人（72%）为女性，577人（28%）为男性。研究组基线时的平均UAS7在29.37到31.10之间。在第12周，CFB-UAS7平均值的估计治疗差异如下：对于72 mg ligelizuma与安慰剂，-8.0（95%CI-10.6至-5.4；PEARL-1），-10.0（-12.6至-7.4；PEARL-2）；72 mg ligelizumab与omalizumab的比较0.7（-1.2至2.5；PEARL-1），0.4（-1.4至2.2；PEARL-2）；120 mg ligelizumab与安慰剂相比–8.0（–10.5至–5.4；PEARL-1），–11.1（–13.7至–8.5；PEARL-2）；120 mg ligelizumab与omalizumab的比较0.7（-1.1至2.5；PEARL-1），-0.7（-2.5至1.1；PEARL-2）。在两项研究中，ligelizumab的两种剂量均优于安慰剂（p＜0.001），但不优于omalizumab。ligelizumab或omalizumab未发现新的安全信号。

总之，在3期PEARL研究中，ligelizumab与安慰剂相比显示出更好的疗效，但不优于omalizumab。ligelizumab的安全性与先前的研究一致。

附：英文原文

Title: Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials

Author: 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, Agondi Rosana, Al Waily Ahmed, Almerigogna Fabio, Alonso Miguel Angel Tejedor, Ammoury Alfred, Anne Goh Eng Kim, Anolik Robert, Ardusso Ledit, Arenberger Petr, AS Nandini, Asefi Mohammad, Astafieva Natalia, Badhwar Anil, Baldrich Esther Serra, Bangert Christine, Barbaud Annick, Bata-Csorgo Zsuzsanna, Bauer Andrea, Berard Frederic, Bergler-Czop Beata, Berman Gary D, Bernstein Jonathan, Bharija Subhash Chandra, Bhat Ramesh M, Boccon-Gibod Isabelle, Botev Ivan, Brockow Knut, Buck Philipp, Busse Paula, Campos Regis, Canonica Giorgio Walter, Carla Irani, Carmen Julia Maria Del, Carpio Jaime Del, Chadalavada Mamatha, Chang Yoon-Seok, Cheema Amarjit, Chen Yi Hsing, Chinuki Yuko, Cho Soyun, Choi Jeong-Hee, Chu Chia-Yu, Confino Ronit, Corren Jonathan, Criado Roberta, Cruz Claudia De La, Cypcar David M, Daftary Pramila, Danilycheva Inna, Dawes Kenneth, De Vera Michelle Joy, Deangelo James, Del Giacco Stefano, Deleanu Diana, Delgado John, DeMera Richard, Denguezli Mohamed, Dickel Heinrich, Doanh Le Huu, Dogan Sinan, Doutre Marie Sylvie, Dupond Anne Sophie, Edin Anton, EDWARD Kent, Ekanayake-Bohling Swarna, Elbirt Daniel, Elkayam David, Ellis Anne, Emanuel Shaunagh, Emeliyanov Alexander

Issue&Volume: 2023-11-23

Abstract: Background

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.

Methods

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.

Findings

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.

Interpretation

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.

DOI: 10.1016/S0140-6736(23)01684-7

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01684-7/abstract