Enpatoran, a Toll-like receptor 7/8 inhibitor, in moderate-to-severe systemic lupus erythematosus: findings from Cohort B of a multicentre, international, double-blind, placebo-controlled dose-finding phase 2 trial.

In Cohort B of WILLOW, a phase 2, randomised, placebo-controlled, double-blind, basket, dose-finding study, enpatoran, an oral small molecule inhibitor of TLR7/8, was evaluated in participants with active systemic lupus erythematosus (SLE).

在WILLOW研究的B队列中，这是一项2期、随机、安慰剂对照、双盲、篮子式、剂量探索性研究，评估了TLR7/8的口服小分子抑制剂enpatoran，在活动性系统性红斑狼疮（SLE）患者中的效果。

Methods

Participants were eligible if they were aged 18-75 years with moderate-to-severe SLE, with or without cutaneous manifestations, had a disease duration of at least 6 months, and were receiving a stable dose of medication before the screening period.

参与者符合条件，如果他们年龄在18-75岁之间，患有中度至重度系统性红斑狼疮，无论是否有皮肤表现，疾病持续时间至少为6个月，并在筛选期前接受稳定剂量的药物治疗。

Participants were recruited from 132 centres in 22 countries.

参与者是从22个国家的132个中心招募的。

In Part 1, participants were randomly allocated in a 1:2 ratio to receive either placebo or 100 mg enpatoran, both twice-daily.

在第一部分，参与者以1:2的比例随机分配接受安慰剂或100 mg的enpatoran，均为每日两次。

Following the enrolment of 60 participants, Part 2 was activated and additional participants were randomly allocated in a 1:1:1:1 ratio to 25 mg, 50 mg, or 100 mg of enpatoran or placebo, all twice-daily, for 24 weeks.

在招募了60名参与者后，激活了第二部分，并且额外的参与者以1:1:1:1的比例随机分配接受25 mg、50 mg或100 mg的enpatoran或安慰剂，均为每日两次，为期24周。

Random allocation was stratified by region, biomarker status, and hybrid Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index score.

随机分配按地区、生物标志物状态和混合的狼疮活动性评估-系统性红斑狼疮疾病活动指数评分进行分层。

The primary objective was to evaluate the dose-response relationship of enpatoran, using British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rate at week 24, based on multiple comparison procedure-modelling analysis.

主要目标是评估enpatoran的剂量反应关系，使用基于英国群岛狼疮评估组的复合狼疮评估(BICLA)响应率在第24周，基于多重比较程序-建模分析。

Study visits were scheduled from week 0 to week 24, followed by a 2-week safety follow-up period for participants who chose not to enter the long-term extension.

研究访问从第0周安排到第24周，随后为选择不进入长期扩展期的参与者安排了为期2周的安全随访期。

From weeks 2 to 12, glucocorticoid doses were tapered to a prednisone-equivalent dose of no more than 5 mg/day, as clinically tolerated.

从第2周到第12周，糖皮质激素剂量逐渐减少至相当于不超过5 mg/天的泼尼松等效剂量，根据临床耐受情况调整。

Adverse events were monitored continuously throughout the study; safety parameters (including physical examination, vital signs, and routine chemistry and haematology) were assessed at all study visits.

在整个研究期间持续监测不良事件；在所有研究访问时评估安全参数（包括体格检查、生命体征以及常规的生化和血液学检查）。

The trial was registered at ClinicalTrials.gov (NCT05162586) and a long-term extension study is ongoing.

该试验已在ClinicalTrials.gov上注册（NCT05162586），并且正在进行一项长期扩展研究。

Results

Between May 4, 2022, and Feb 6, 2024, participants were screened for eligibility for WILLOW cohorts A and B; 715 participants were screened and 354 were randomly allocated and included in the Cohort B safety population (95 to placebo, 71 to 25 mg enpatoran, 74 to 50 mg enpatoran, and 114 to 100 mg enpatoran).

2022年5月4日至2024年2月6日期间，对WILLOW队列A和B的参与者进行了资格筛查；共筛查了715名参与者，其中354名被随机分配并纳入队列B的安全性人群（95名接受安慰剂，71名接受25毫克的enpatoran，74名接受50毫克的enpatoran，以及114名接受100毫克的enpatoran）。

One patient allocated to the placebo group was found to be ineligible and was excluded from the full analysis set for the efficacy analyses. 335 (95%) of 353 participants were female, 18 (5%) were male, and median age was 41 years (IQR 33-51).

被分配到安慰剂组的一名患者被发现不符合资格，并从疗效分析的完整分析集中排除。353名参与者中有335名（95%）为女性，18名（5%）为男性，中位年龄为41岁（四分位数间距33-51岁）。

At week 24, the study did not meet its primary objective of identifying a statistically significant dose-response relationship for enpatoran in BICLA response rate (p=0·14).

在第24周时，该研究未能达到其主要目标，即识别出enpatoran在BICLA反应率中具有统计学意义的剂量-反应关系（p=0.14）。

BICLA response rates at week 24 were higher with all doses of enpatoran (25 mg: 41 [58%] of 71; odds ratio [OR] vs placebo 2·2 [95% CI 1·1-4·0], 50 mg: 36 [49%] of 74; OR 1·5 [95% CI 0·8-2·8], and 100 mg: 56 [49%] of 114; OR 1·6 [95% CI 0·9-2·8]) versus placebo (37 [39%] of 94).

在第24周时，所有剂量的enpatoran的BICLA反应率均高于安慰剂组（25毫克：71人中有41人[58%]；与安慰剂相比的比值比[OR]为2.2 [95%置信区间1.1-4.0]，50毫克：74人中有36人[49%]；OR为1.5 [95%置信区间0.8-2.8]，以及100毫克：114人中有56人[49%]；OR为1.6 [95%置信区间0.9-2.8]）与94名安慰剂组中的37人[39%]相比。

The most common treatment-emergent adverse eventwas diarrhoea, in four (6%) of 71, two (3%) of 74, and two (2%) of 114 participants in the 25 mg, 50 mg, and 100 mg enpatoran groups, respectively, and seven (7%) of 95 participants in the placebo group.

最常见的治疗后不良事件是腹泻，在25 mg、50 mg和100 mg enpatoran组的71名、74名和114名参与者中，分别有4人（6%）、2人（3%）和2人（2%）出现腹泻，而在安慰剂组的95名参与者中有7人（7%）出现腹泻。

Serious adverse events were reported in one (1%) of 71, three (4%) of 74, five (4%) of 114, and three (3%) of 95 participants treated with 25 mg, 50 mg, and 100 mg enpatoran and placebo, respectively.

在分别接受25 mg、50 mg和100 mg enpatoran以及安慰剂治疗的71名、74名、114名和95名参与者中，分别有1人（1%）、3人（4%）、5人（4%）和3人（3%）报告了严重不良事件。

interpretation

In this study of participants with moderate-to-severe SLE, enpatoran improved BICLA response rates versus placebo; however, the primary objective of a statistically significant dose-dependent effect on disease activity based on BICLA response was not met.

在这项针对中度至重度系统性红斑狼疮患者的临床研究中，enpatoran 改善了基于 BICLA 反应率的疗效，与安慰剂相比有显著提升；然而，基于 BICLA 反应的疾病活动度的统计学上有显著的剂量依赖性效果的主要研究目标并未达成。

Enpatoran was well tolerated across all dose groups.

在所有剂量组中，enpatoran 的耐受性良好。

funding

Merck Healthcare (Darmstadt, Germany).

默克医疗保健（德国达姆施塔特）