Inhibition of IL-33 in Diabetic Kidney Disease: A Randomized, Placebo-Controlled Phase 2b Trial.

IL-33 signaling was blocked at all doses, eosinophil counts decreased, and urinary CC-chemokine ligand 2 decreased at the high dose versus placebo.

所有剂量下均阻断了IL-33信号传导，嗜酸性粒细胞计数减少，并且与安慰剂相比，高剂量下尿液CC趋化因子配体2减少。

No significant differences in urinary albumin-creatinine ratio were observed between placebo and tozorakimab on top of standard of care.

在安慰剂和托佐拉单抗加标准治疗之间，未观察到尿液白蛋白-肌酐比值有显著差异。

Background

In patients with type 2 diabetes and CKD, elevated inflammatory biomarkers are associated with adverse kidney outcomes.

在2型糖尿病和慢性肾脏病患者中，升高的炎症生物标志物与不良肾脏结果相关。

IL-33 contributes to glomerular endothelial inflammation in diabetic kidney disease (DKD).

IL-33在糖尿病肾病（DKD）的肾小球内皮炎症中起作用。

This study evaluated the therapeutic potential of tozorakimab, an IL-33-neutralizing mAb, in DKD.

本研究评估了IL-33中和性单克隆抗体tozorakimab在糖尿病肾病（DKD）中的治疗潜力。

Methods

FRONTIER-1 ( NCT04170543 ) was a phase 2b, randomized, double-blind, placebo-controlledtrial including adults with type 2 diabetes, an eGFR of 25-75 ml/min per 1.73 m 2 , urinary albumin-creatinine ratio (UACR) of 100-3000 mg/g, and maximally tolerated renin-angiotensin-aldosterone system blocker therapy.

FRONTIER-1 (NCT04170543) 是一项2b期、随机、双盲、安慰剂对照试验，纳入了成年2型糖尿病患者，eGFR为25-75 ml/min/1.73 m²，尿白蛋白-肌酐比值(UACR)为100-3000 mg/g，并且接受了最大耐受剂量的肾素-血管紧张素-醛固酮系统阻断剂治疗。

Participants received tozorakimab (30, 60, 120, or 300 mg) or placebo every 28 days for 168 days.

参与者每28天接受一次托佐拉单抗（30、60、120或300毫克）或安慰剂，持续168天。

All participants received dapagliflozin during days 85-168.

所有参与者在第85天至第168天期间接受了达格列净治疗。

The primary end point was UACR change on treatment from baseline to day 169 (per-protocol population).

主要终点是治疗前后（意向治疗人群）第169天的尿白蛋白/肌酐比值（UACR）变化。

Exploratory end points included inflammatory biomarkers linked to IL-33 activity.

探索性终点包括与IL-33活性相关的炎症生物标志物。

Results

Among 558 randomized participants (mean [SD] age 67 [10] years, 30% female, mean [SD] eGFR 48 [15] ml/min per 1.73 m 2 , geometric mean UACR 460 mg/g), tozorakimab ( N =425) was well tolerated with no safety concerns identified.

在558名随机参与者中（平均年龄67[10]岁，30%为女性，平均eGFR为48[15] ml/min/1.73 m2，几何平均UACR为460 mg/g），托扎利单抗（N=425）耐受性良好，未发现安全问题。

In the per-protocol population ( N =465), IL-33 signaling was inhibited by >95% across all doses, eosinophil counts decreased by >19%, and urinary CC-chemokine ligand 2 levels were significantly decreased by 29% with the 300 mg dose (two-sided 90% confidence intervals, 14% to 42%) versus placebo.

在符合方案分析的人群（N=465）中，所有剂量组的IL-33信号传导被抑制超过95%，嗜酸性粒细胞计数减少了超过19%，并且在300 mg剂量下，尿液CC-趋化因子配体2水平显著下降了29%（双侧90%置信区间，14%至42%）与安慰剂相比。

However, no statistically significant differences in UACR were observed between placebo (-22%) and treatment (-23% to -25%).

然而，在安慰剂（-22%）和治疗组（-23%至-25%）之间，未观察到统计学上显著的尿白蛋白/肌酐比值（UACR）差异。

Conclusions

Tozorakimab effectively inhibited IL-33 signaling but did not reduce UACR compared with placebo in patients with DKD over 24 weeks.

Tozorakimab有效地抑制了IL-33信号传导，但在24周内与安慰剂相比，并未降低DKD患者的UACR。

clinical_trial_registry_name_and

ClinicalTrials.gov, NCT04170543.

ClinicalTrials.gov, NCT04170543号。