Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials.

IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Lancet Neurology Pub Date : 2024-11-01 Epub Date: 2024-09-19 DOI:10.1016/S1474-4422(24)00328-4
Xavier Montalban, Patrick Vermersch, Douglas L Arnold, Amit Bar-Or, Bruce A C Cree, Anne H Cross, Eva Kubala Havrdova, Ludwig Kappos, Olaf Stuve, Heinz Wiendl, Jerry S Wolinsky, Frank Dahlke, Claire Le Bolay, Li Shen Loo, Sathej Gopalakrishnan, Yann Hyvert, Andrija Javor, Hans Guehring, Nadia Tenenbaum, Davorka Tomic
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引用次数: 0

Abstract

Background: Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown preliminary efficacy in people with relapsing multiple sclerosis in a phase 2 trial. Here, we aimed to compare the safety and efficacy of evobrutinib with the active comparator teriflunomide in people with relapsing multiple sclerosis.

Methods: EvolutionRMS1 and evolutionRMS2 were two multicentre, randomised, double-blind, double-dummy, active-controlled, phase 3 trials conducted at 701 multiple sclerosis centres and neurology clinics in 52 countries. Adults aged 18-55 years with relapsing multiple sclerosis (Expanded Disability Status Scale [EDSS] score of 0·0-5·5) were included. Participants were randomly assigned (1:1) using a central interactive web response system to receive either evobrutinib (45 mg twice per day with placebo once per day) or teriflunomide (14 mg once per day with placebo twice per day), all taken orally and in an unfasted state, with randomisation stratified by geographical region and baseline EDSS. All study staff and participants were masked to the study interventions. The primary endpoint for each study was annualised relapse rate based on adjudicated qualified relapses up to 156 weeks, assessed in the full analysis set (defined as all randomly assigned participants) with a negative binomial model. These studies are registered with ClinicalTrials.gov (NCT04338022 for evolutionRMS1 and NCT04338061 for evolutionRMS2, both are terminated).

Findings: The primary analysis was done using data for 2290 randomly assigned participants collected from June 12, 2020, to Oct 2, 2023. 1124 participants were included in the full analysis set in evolutionRMS1 (560 in the evobrutinib group and 564 in the teriflunomide group) and 1166 in evolutionRMS2 (583 in each group). 751 (66·8%) participants were female and 373 (33·1%) were male in evolutionRMS1, whereas 783 (67·2%) were female and 383 (32·8%) were male in evolutionRMS2. Annualised relapse rate was 0·15 (95% CI 0·12-0·18 with evobrutinib vs 0·14 [0·11-0·18] with teriflunomide (adjusted RR 1·02 [0·75-1·39]; p=0·55) in evolutionRMS1 and 0·11 (0·09-0·13 vs 0·11 [0·09-0·13]; adjusted RR 1·00 [0·74-1·35]; p=0·51) in evolutionRMS2. The pooled proportion of participants with any treatment-emergent adverse event (TEAE) was similar between treatment groups (976 [85·6%] of 1140 with evobrutinib vs 999 [87·2%] of 1146 with teriflunomide). The most frequently reported TEAEs were COVID-19 (223 [19·6%] with evobrutinib vs 223 [19·5%] with teriflunomide), alanine aminotransferase increased (173 [15·2%] vs 204 [17·8%]), aspartate aminotransferase increased (110 [9·6%] vs 131 [11·4%]), and headache (175 [15·4%] vs 176 [15·4%]). Serious TEAE incidence rates were higher with evobrutinib than teriflunomide (86 [7·5%] vs 64 [5·6%]). Liver enzyme elevations at least 5 × upper limit of normal were more common with evobrutinib than with teriflunomide, particularly in the first 12 weeks (55 [5·0%] vs nine [<1%]). Three people who received evobrutinib and one who received teriflunomide met the biochemical definition of Hy's law; all cases resolved after discontinuation of treatment. There were two deaths (one in each group), neither related to study treatment.

Interpretation: The efficacy of evobrutinib was not superior to that of teriflunomide. Together, efficacy and liver-related safety findings do not support the use of evobrutinib in people with relapsing multiple sclerosis.

Funding: Merck.

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evobrutinib治疗复发性多发性硬化症的安全性和疗效(evolutionRMS1和evolutionRMS2):两项多中心、随机、双盲、主动对照、3期试验。
背景埃沃布替尼是一种布鲁顿酪氨酸激酶(BTK)抑制剂,在一项二期试验中显示出对复发性多发性硬化症患者的初步疗效。在此,我们旨在比较 evobrutinib 与特立氟胺(teriflunomide)在复发性多发性硬化症患者中的安全性和有效性:EvolutionRMS1和evolutionRMS2是两项多中心、随机、双盲、双假、活性对照的3期试验,在52个国家的701个多发性硬化症中心和神经病学诊所进行。研究对象包括 18-55 岁的复发性多发性硬化症成人患者(扩展残疾状态量表 [EDSS] 评分为 0-0-5-5)。参与者通过中央交互式网络响应系统被随机分配(1:1)到埃沃布鲁替尼(45 毫克,每天两次,安慰剂每天一次)或特利福罗米(14 毫克,每天一次,安慰剂每天两次)治疗方案中,所有药物均在非禁食状态下口服,并按地理区域和基线 EDSS 进行分层。所有研究人员和参与者都对研究干预措施进行了蒙蔽。每项研究的主要终点均为年化复发率,以156周内判定的合格复发为基础,采用负二项模型对全部分析集(定义为所有随机分配的参与者)进行评估。这些研究已在 ClinicalTrials.gov 注册(evolutionRMS1 为 NCT04338022,evolutionRMS2 为 NCT04338061,两项研究均已终止):主要分析使用了从 2020 年 6 月 12 日至 2023 年 10 月 2 日收集的 2290 名随机分配参与者的数据。1124名参与者被纳入evolutionRMS1的完整分析集(evobrutinib组560人,特立氟胺组564人),1166名参与者被纳入evolutionRMS2的完整分析集(每组583人)。evolutionRMS1组有751人(66-8%)为女性,373人(33-1%)为男性;evolutionRMS2组有783人(67-2%)为女性,383人(32-8%)为男性。evobrutinib的年复发率为0-15(95% CI 0-12-0-18 vs 0-14 [0-11-0-18] teriflunomide(调整后RR 1-02 [0-75-1-39]; p=0-55),evolutionRMS1的年复发率为0-11(0-09-0-13 vs 0-11 [0-09-0-13]; 调整后RR 1-00 [0-74-1-35]; p=0-51),evolutionRMS2的年复发率为0-11(0-09-0-13 vs 0-11 [0-09-0-13]; 调整后RR 1-00 [0-74-1-35]; p=0-51)。各治疗组中出现任何治疗突发不良事件(TEAE)的总人数比例相似(埃沃布替尼治疗组1140人中有976人[85-6%],特立氟胺治疗组1146人中有999人[87-2%])。最常报告的TEAE为COVID-19(埃沃布替尼223 [19-6%] vs 特立氟胺223 [19-5%])、丙氨酸氨基转移酶升高(173 [15-2%] vs 204 [17-8%])、天冬氨酸氨基转移酶升高(110 [9-6%] vs 131 [11-4%])和头痛(175 [15-4%] vs 176 [15-4%])。evobrutinib的严重TEAE发生率高于特立氟胺(86 [7-5%] vs 64 [5-6%])。evobrutinib的肝酶升高至少为正常值上限的5倍,比特立氟胺更常见,尤其是在前12周(55 [5-0%] vs 9 [解释:evobrutinib的疗效比特立氟胺好,但肝酶升高至少为正常值上限的5倍:evobrutinib的疗效并不优于特立氟胺。总之,疗效和肝脏相关安全性研究结果均不支持在复发性多发性硬化症患者中使用evobrutinib:默克公司。
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来源期刊
Lancet Neurology
Lancet Neurology 医学-临床神经学
CiteScore
58.70
自引率
1.00%
发文量
572
审稿时长
6-12 weeks
期刊介绍: The Lancet Neurology is the world-leading clinical neurology journal. It publishes original research that advocates for change in, or sheds light on, neurological clinical practice. The topics covered include cerebrovascular disease, Alzheimer's disease and other dementias, epilepsy, migraine, neurological infections, movement disorders, multiple sclerosis, neuromuscular disorders, peripheral nerve disorders, pediatric neurology, sleep disorders, and traumatic brain injury. The journal publishes a range of article types, including Articles (including randomized clinical trials and meta-analyses), Review, Rapid Review, Comment, Correspondence, and Personal View. It also publishes Series and Commissions that aim to shape and drive positive change in clinical practice and health policy in areas of need in neurology. The Lancet Neurology is an internationally trusted source of clinical, public health, and global health knowledge. It has an Impact Factor of 48.0, making it the top-ranked clinical neurology journal out of 212 journals worldwide.
期刊最新文献
On how a brain beholds beauty. Equitable access to levetiracetam for people with epilepsy. Evobrutinib in multiple sclerosis: challenges and unmet goals. Frailty for neurologists: perspectives on how frailty influences care planning. Learning to be an adult with a disability.
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