Anti-TL1A antibody, afimkibart, in moderately-to-severely active ulcerative colitis (TUSCANY-2): a multicentre, double-blind, treat-through, multi-dose, randomised, placebo-controlled, phase 2b trial.

We evaluated the safety and efficacy of multiple doses of afimkibart, a TL1A-directed antibody, in patients with moderately-to-severely active ulcerative colitis.

我们评估了针对TL1A的抗体药物afimkibart在中度至重度活动性溃疡性结肠炎患者中多次剂量的安全性和有效性。

Methods

The multicentre, double-blind, treat-through, multi-dose, randomised, placebo-controlled, phase 2b, TUSCANY-2 trial was conducted at 114 centres in 23 countries across North America, Europe, Asia, Africa, Australia, and South America.

多中心、双盲、治疗贯穿、多剂量、随机、安慰剂对照的2b期TUSCANY-2试验在北美、欧洲、亚洲、非洲、澳大利亚和南美洲的23个国家的114个中心进行。

Adults (aged 18-75 years) with moderately-to-severely active ulcerative colitis (total Mayo score [tMS] 6-12, endoscopic subscore ≥2) were randomly assigned (2:2:2:2:2:3:1:1:1) to one of nine treatment sequences to receive subcutaneous afimkibart 50 mg, 150 mg, 450 mg, or matched placebo every 4 weeks during the 12-week induction period, and subcutaneous afimkibart 50 mg, 150 mg, or 450 mg during the treat-through 40-week maintenance period.

年龄在18-75岁之间的成人患有中度至重度活动性溃疡性结肠炎（总Mayo评分[tMS]为6-12，内镜下评分≥2）被随机分配（2:2:2:2:2:3:1:1:1）到九种治疗序列之一，以接受皮下注射afimkibart 50 mg、150 mg、450 mg或匹配安慰剂，每4周一次，在12周的诱导期内，以及在治疗贯穿的40周维持期内接受皮下注射afimkibart 50 mg、150 mg或450 mg。

Investigators and patients were masked to treatment.

研究人员和患者对治疗方案进行了盲法处理。

Study drugs were administered by masked site personnel following preparation by an unmasked pharmacist at the investigational site.

研究药物由调查现场的未盲法药剂师准备后，由蒙面的现场人员进行给药。

Efficacy was assessed at weeks 14 and 56 in the intent-to-treat populations.

在第14周和第56周对意向治疗人群进行了疗效评估。

The primary efficacy endpoint of clinical remission at week 14 by tMS (defined as tMS ≤2, with no individual subscore >1) was assessed in those who received at least one dose of drug or placebo during induction, excluding patients who had missing data due to complications resulting from COVID-19.

主要疗效终点是第14周通过tMS（定义为tMS ≤2，且没有单个子分数>1）达到临床缓解，评估对象为在诱导期至少接受过一次药物或安慰剂治疗的患者，排除了因COVID-19并发症导致数据缺失的患者。

Safety endpoints were also analysed in those who were randomly assigned and received at least one dose of assigned treatment.

安全性终点也在那些被随机分配并至少接受了一剂指定治疗的患者中进行了分析。

This study is registered with ClinicalTrials.gov, NCT04090411.

这项研究已在ClinicalTrials.gov上注册，注册号为NCT04090411。

Results

Between Dec 19, 2019, and Oct 25, 2022, 246 patients were randomly assigned treatment, of whom 245 were treated, 228 completed induction, and 178 completed maintenance.

在2019年12月19日至2022年10月25日期间，共有246名患者被随机分配接受治疗，其中245名接受了治疗，228名完成了诱导治疗，178名完成了维持治疗。

Median age was 39 years (IQR 30·0-51·0), 99 (40%) patients were female and 146 (60%) were male; median disease duration was 4·7 years (IQR 2·5-10·2).

中位年龄为39岁（四分位数间距30·0-51·0），99名（40%）患者为女性，146名（60%）为男性；中位疾病持续时间为4·7年（四分位数间距2·5-10·2）。

At week 14, the primary endpoint of clinical remission by tMS was reported in 12 (26%) of 47 patients in the afimkibart 50 mg group (risk difference vs placebo [RD] 13·9% [90% CI -0·2 to 27·7]; p=0·0545), 14 (23%) of 60 patients in the afimkibart 150 mg group (RD 11·7% [-1·7 to 24·1]; p=0·0823), and 21 (24%) of 88 patients in the in the afimkibart 450 mg group (RD 12·2% [-0·6 to 22·9]; p=0·0642) versus five (12%) of 43 patients in the placebo group.

在第14周，主要终点临床缓解通过tMS报告在50毫克组的47名患者中有12名（26%）（与安慰剂相比风险差异[RD] 13·9% [90% 置信区间 -0·2至27·7]；p=0·0545），在150毫克组的60名患者中有14名（23%）（RD 11·7% [-1·7至24·1]；p=0·0823），以及在450毫克组的88名患者中有21名（24%）（RD 12·2% [-0·6至22·9]；p=0·0642），相比之下，安慰剂组的43名患者中有5名（12%）。

In alignment with updated US Food and Drug Administration guidance, clinical remission using the modified Mayo score at week 14 was reported in 14 (30%) of 47 patients in the afimkibart 50 mg group (RD 18·2% [90% CI 3·3 to 32·2]), 21 (35%) of 60 patients in the in the afimkibart 150 mg group (RD 23·4% [6·2 to 36·3]), and 28 (32%) of 88 patients in the in the afimkibart 450 mg group (RD 20·2% [3·2 to 31·3]) versus five (12%) of 43 patients in the placebo group.

与美国食品药品监督管理局更新的指导方针一致，使用改良的Mayo评分在第14周报告的临床缓解在50毫克组的47名患者中有14名（30%）（与安慰剂相比风险差异[RD] 18·2% [90% 置信区间 3·3至32·2]），在150毫克组的60名患者中有21名（35%）（RD 23·4% [6·2至36·3]），以及在450毫克组的88名患者中有28名（32%）（RD 20·2% [3·2至31·3]），相比之下，安慰剂组的43名患者中有5名（12%）。

Overall, 117 (48%) of 245 patients in the induction phase and 132 (59%) of 224 patients in the maintenance phase reported at least one treatment-emergent adverse event; incidences of treatment-emergent adverse events during induction were similar with placebo and afimkibart.

总体而言，245名诱导期患者中有117名（48%），以及224名维持期患者中有132名（59%）报告至少出现了一种治疗相关不良事件；诱导期期间，与安慰剂相比，接受afimkibart治疗的患者治疗相关不良事件的发生率相似。

The most common treatment-emergent adverse events (occurring in ≥5% of patients) during induction were nausea, urinary tract infection, ulcerative colitis, anaemia, fatigue, headache, and pyrexia.

诱导期间最常见的治疗相关不良事件（发生率≥5%的患者）包括恶心、尿路感染、溃疡性结肠炎、贫血、疲劳、头痛和发热。

Six serious adverse events were reported during induction in the active treatment groups and four in the placebo group.

在活性治疗组中，诱导期间报告了六起严重不良事件，而安慰剂组报告了四起。

Two patients who completed induction and did not receive the study drug during maintenance had serious adverse events during safety follow-up.

两名完成诱导治疗且在维持治疗期间未接受研究药物的患者，在安全随访期间发生了严重不良事件。

During the maintenance period, 12 (5%) of 224 patients had 13 serious adverse events.

在维持治疗期间，224名患者中有12名（5%）发生了13起严重不良事件。

No deaths occurred.

没有发生死亡事件。

interpretation

Differences in the primary endpoint of clinical remission by tMS were not significantly different for any dose of afimkibart compared with placebo.

使用 tMS 作为主要终点的临床缓解差异对于任何剂量的 afimkibart 与安慰剂相比均无显著差异。

However, secondary endpoints suggest that afimkibart was associated with a favourable benefit-risk profile, with clinically meaningful improvements in clinical remission with the modified Mayo score for patients with moderately-to-severely active ulcerative colitis.

然而，次要终点表明 afimkibart 与有利的风险-效益比相关，对于中度至重度活动性溃疡性结肠炎患者，使用改良的 Mayo 评分在临床缓解方面有临床上有意义的改善。

These results support the continued development of afimkibart.

这些结果支持afimkibart的持续开发。

funding

Pfizer, Roivant Sciences, and F Hoffmann-La Roche.

辉瑞、罗伊万特科学和F.霍夫曼-拉罗切公司。