背景:Nemolizumab,白细胞介素(IL)-31受体亚基α拮抗剂,在特应性皮炎中抑制瘙痒和皮肤炎症的IL-31途径。进行了两项国际3期研究,以评估奈莫珠单抗在特应性皮炎中的疗效和安全性。在本文中,我们报告了两项试验的16周初始治疗期的结果。
方法:ARCADIA1和ARCADIA2是相同的48周随机分组,双盲,在患有中度至重度特应性皮炎的成人和青少年参与者(年龄≥12岁)中的安慰剂对照3期试验,相关瘙痒,对局部类固醇的反应不足。参与者来自281个诊所,医院,以及两项试验在22个国家的学术中心,并被随机分配(2:1),每4周一次皮下接受nemolizumab30mg(基线负荷剂量60mg)或匹配的安慰剂,背景外用皮质类固醇(TCS),有或没有外用钙调磷酸酶抑制剂(TCI;即,TCS-TCI背景处理)。通过交互式反应技术进行随机化,并根据基线疾病和瘙痒严重程度进行分层。研究人员和参与者在整个研究过程中都被蒙上了面具,结果评估员被屏蔽,直到数据库锁定。基线后第16周的共同主要终点是研究者的全球评估(IGA)成功(评分为0[透明皮肤]或1[几乎透明皮肤],与基线相比改善≥2分)和至少75%改善湿疹面积和严重程度指数评分(EASI-75反应)。采用Cochran-Mantel-Haenszel检验对随机化分层进行调整,比较各组间的结果率。关键的次要终点是在第1、2、4和16周,皮肤瘙痒峰值数字评定量表(PP-NRS)得分提高至少4分的参与者比例;在第4周和第16周,PP-NRS得分低于2分;在第16周,睡眠障碍数字评定量表得分提高至少4分;在第16周,EASI-75反应加PP-NRS得分提高至少4分;在第16周,在意向治疗的基础上进行疗效分析;安全性分析包括所有接受一剂奈莫珠单抗或安慰剂的参与者。两项研究均已完成(ClinicalTrials.gov:ARCADIA1,NCT03985943和ARCADIA2,NCT03989349)。
结果:在2019年8月9日至2022年11月2日之间,两项试验均招募了1728名参与者:1142人被分配给nemolizumab加TCS-TCI(ARCADIA1中620人,ARCADIA2中522人)和586人被分配给安慰剂加TCS-TCI(ARCADIA1中321人和2ARCADIA1包括500名(53%)男性参与者和441名(47%)女性参与者,ARCADIA2包括381名(48%)男性参与者和406名(52%)女性参与者.治疗组的平均年龄为33·3(SD15·6)至35·2(17·0)岁。两项试验均达到共同主要终点;在第16周,与安慰剂加TCS-TCI相比,接受奈莫珠单抗加TCS-TCI的参与者中有更大比例的IGA成功(ARCADIA1:620中的221[36%]对321中的79[25%],调整后的百分比差异为11·5%[97·5%CI4·7-18·3],p=0·0003;ARCADIA2:522中的197[38%]与265中的69[26%],调整后的差异为12·2%[4·6-19·8],p=0·0006)和EASI-75响应(ARCADIA1:270[44%]vs93[29%],调整后的差异14·9%[7·8-22·0],p<0·0001;ARCADIA2:220[42%]对80[30%],调整后的差异12·5%[4·6-20·3],p=0·0006)。nemolizumab对所有关键次要终点均有显著益处,包括瘙痒改善,早在第1周,并在第16周改善睡眠。奈莫珠单抗加TCS-TCI和安慰剂加TCS-TCI之间的安全性相似。在安全装置中,接受奈莫珠单抗加TCS-TCI的616名参与者(ARCADIA1)中的306名(50%)和519名参与者(ARCADIA2)中的215名(41%)至少发生了一次因治疗引起的不良事件(严重的因治疗引起的不良事件分别为6[1%]和13[3%],分别);接受安慰剂加TCS-TCI的321(ARCADIA1)中的146(45%)和263(ARCADIA2)中的117(44%)至少发生了一次因治疗引起的不良事件(严重的因治疗引起的不良事件分别为4[1%]和3[1%],分别)。在ARCADIA2的5名(1%)参与者中报告了10起可能与nemolizumab相关的严重治疗引起的不良事件。没有死亡发生。
结论:Nemolizumab联合TCS-TCI对患有中度至重度特应性皮炎的成人和青少年的炎症和瘙痒有统计学和临床意义的改善。如果获得批准,尼莫珠单抗可能会提供当前疗法的有价值的扩展。
背景:Galderma.
BACKGROUND: Nemolizumab, an interleukin (IL)-31 receptor subunit α antagonist, inhibits the IL-31 pathway of itch and skin inflammation in atopic dermatitis. Two international phase 3 studies were done to assess the efficacy and safety of nemolizumab in atopic dermatitis. In this Article we report results for the 16-week initial treatment period of both trials.
METHODS: ARCADIA 1 and ARCADIA 2 were identical 48-week randomised, double-blind, placebo-controlled phase 3 trials in adult and adolescent participants (aged ≥12 years) with moderate-to-severe atopic dermatitis, associated pruritus, and inadequate response to topical steroids. Participants were enrolled from 281 clinics, hospitals, and academic centres in 22 countries across both trials, and were randomly assigned (2:1) to receive nemolizumab 30 mg subcutaneously (baseline loading dose 60 mg) or matching placebo once every 4 weeks with background topical corticosteroids (TCS) with or without topical calcineurin inhibitors (TCI; ie, TCS-TCI background treatment). Randomisation was done via interactive response technology and stratified by baseline disease and pruritus severity. Study staff and participants were masked throughout the study, with outcome assessors masked until database lock. Coprimary endpoints at week 16 post-baseline were Investigator\'s Global Assessment (IGA) success (score of 0 [clear skin] or 1 [almost clear skin] with a ≥2-point improvement from baseline) and at least 75% improvement in Eczema Area and Severity Index score from baseline (EASI-75 response). Outcome rates were compared between groups with the Cochran-Mantel-Haenszel test adjusting for randomisation strata. The key secondary endpoints were the proportion of participants with Peak Pruritus Numerical Rating Scale (PP-NRS) score improvement of at least 4 points at weeks 1, 2, 4, and 16; PP-NRS score below 2 at weeks 4 and 16; Sleep Disturbance Numerical Rating Scale score improvement of at least 4 points at week 16; EASI-75 response plus PP-NRS score improvement of at least 4 points at week 16; and IGA success plus PP-NRS score improvement of at least 4 points at week 16. Efficacy analyses were done on an intention-to-treat basis; safety analyses included all participants who received one dose of nemolizumab or placebo. Both studies are completed (ClinicalTrials.gov: ARCADIA 1, NCT03985943 and ARCADIA 2, NCT03989349).
RESULTS: Between Aug 9, 2019, and Nov 2, 2022, 1728 participants were enrolled across both trials: 1142 were allocated to nemolizumab plus TCS-TCI (620 in ARCADIA 1 and 522 in ARCADIA 2) and 586 to placebo plus TCS-TCI (321 in ARCADIA 1 and 265 in ARCADIA 2). ARCADIA 1 included 500 (53%) male participants and 441 (47%) female participants, and ARCADIA 2 included 381 (48%) male participants and 406 (52%) female participants. Mean age ranged from 33·3 (SD 15·6) years to 35·2 (17·0) years across the treatment groups. Both trials met the coprimary endpoints; at week 16, a greater proportion of participants receiving nemolizumab plus TCS-TCI versus placebo plus TCS-TCI had IGA success (ARCADIA 1: 221 [36%] of 620 vs 79 [25%] of 321, adjusted percentage difference 11·5% [97·5% CI 4·7-18·3], p=0·0003; ARCADIA 2: 197 [38%] of 522 vs 69 [26%] of 265, adjusted difference 12·2% [4·6-19·8], p=0·0006) and an EASI-75 response (ARCADIA 1: 270 [44%] vs 93 [29%], adjusted difference 14·9% [7·8-22·0], p<0·0001; ARCADIA 2: 220 [42%] vs 80 [30%], adjusted difference 12·5% [4·6-20·3], p=0·0006). Significant benefits were observed with nemolizumab for all key secondary endpoints including improvement in itch, as early as week 1, and sleep improvement by week 16. The safety profile was similar between nemolizumab plus TCS-TCI and placebo plus TCS-TCI. In the safety sets, 306 (50%) of 616 participants (ARCADIA 1) and 215 (41%) of 519 participants (ARCADIA 2) who received nemolizumab plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in six [1%] and 13 [3%], respectively); and 146 (45%) of 321 (ARCADIA 1) and 117 (44%) of 263 (ARCADIA 2) who received placebo plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in four [1%] and three [1%], respectively). Ten serious treatment-emergent adverse events possibly related to nemolizumab were reported in five (1%) participants in ARCADIA 2. No deaths occurred.
CONCLUSIONS: Nemolizumab plus TCS-TCI was efficacious and showed statistically and clinically significant improvements in inflammation and itch in adults and adolescents with moderate-to-severe atopic dermatitis. Nemolizumab might offer a valuable extension of current therapies if approved.
BACKGROUND: Galderma.