TRPC6 inhibition for the treatment of focal segmental glomerulosclerosis: a randomised, placebo-controlled, phase 2 trial of BI 764198.

This exploratory study assessed the safety and efficacy of a novel once-daily oral selective TRPC6 inhibitor, BI 764198.

这项探索性研究评估了一种新型每日一次口服选择性TRPC6抑制剂BI 764198的安全性和有效性。

Methods

This multicentre phase 2, double-blind, placebo-controlled, randomised controlled trialassessed BI 764198 (20 mg, 40 mg, or 80 mg once daily) versus placebo over 12 weeks in participants aged 18-75 years with biopsy-confirmed primary FSGS (based on the absence of clinical evidence of secondary cause) or with a disease-causing TRPC6 variant.

这项多中心II期、双盲、安慰剂对照、随机对照试验评估了BI 764198（每日一次20毫克、40毫克或80毫克）与安慰剂在12周内对18-75岁经活检证实的原发性FSGS患者（基于无继发性原因的临床证据）或携带致病性TRPC6变异的患者的效果。

The study took place in 31 sites in ten countries, and random allocation was performed centrally in blocks in a 1:1:1:1 ratio and was stratified according to use of corticosteroids.

该研究在十个国的31个地点进行，随机分配以1:1:1:1的比例进行分层，根据是否使用皮质类固醇进行分层。

Participants were receiving stable conservative and immunosuppressive therapy, with screening urine protein-creatinine ratio (UPCR) at 1·0 g/g or greater and estimated glomerular filtration rate at 30 mL/min per 1·73 m2 or greater.

参与者正在接受稳定的保守和免疫抑制治疗，筛选时尿蛋白-肌酐比值（UPCR）为1.0 g/g或更高，估算的肾小球滤过率（eGFR）为30 mL/min/1.73 m2或更高。

The primary endpoint was the proportion of participants with proteinuria response (≥25% UPCR reduction from baseline) at week 12.

主要终点是第12周时蛋白尿反应（基线UPCR降低≥25%）的参与者比例。

Other key outcomes were safety and tolerability.

其他关键结果包括安全性和耐受性。

The study was registered with ClinicalTrials.gov on Jan 27, 2022 (NCT05213624) and is complete as of Jan 3, 2025.

该研究于2022年1月27日在美国临床试验注册处注册（NCT05213624），截至2025年1月3日研究已完成。

Results

From March 10, 2022, to Sept 3, 2024, 139 participants were screened and 67 were randomly assigned to receive placebo or BI 764198 at doses of 20 mg, 40 mg, or 80 mg (five participants were randomly assigned in error and were not treated). 62 participants received treatment, two of whom had missing baseline or post-baseline UPCR measurements and were not included in the full analysis set.

从2022年3月10日至2024年9月3日，共筛选了139名参与者，其中67名被随机分配接受安慰剂或BI 764198 20 mg、40 mg或80 mg剂量治疗（五名参与者被随机分配错误且未接受治疗）。62名参与者接受了治疗，其中两名因缺失基线或基线后UPCR测量值而未被纳入全分析集。

Overall, 37 participants (60%) were male and 25 participants (40%) were female; the mean age was 40·7 years (SD 12·6); and the majority of the trial cohort were White (39 [63%] of 62).

总体而言，37名参与者（60%）为男性，25名参与者（40%）为女性；平均年龄为40.7岁（标准差12.6）；试验队列中的大多数为白人（62名中的39名，占63%）。

Proteinuria responses were observed in eight (44%) of 18, two (14%) of 14, and six (43%) of 14 participants receiving BI 764198 20 mg, 40 mg, and 80 mg, respectively (16 [35%] of 46 for all BI 764198 doses) versus one (7%) of 14 receiving placebo; corresponding odds ratios (ORs) versus placebo were OR 10·0 (95% CI 1·6-118·1), 1·5 (0·2-19·5), and 6·0 (0·9-73·6) for the three doses of BI 764198, and 4·9 (1·0-48·8) for all doses combined.

在接受BI 764198 20 mg、40 mg和80 mg治疗的18名、14名和14名参与者中，分别观察到8名（44%）、2名（14%）和6名（43%）出现蛋白尿反应（所有BI 764198剂量的16名[35%]中的46名），与接受安慰剂的14名参与者中的1名（7%）相比；相应地，与安慰剂相比，三种剂量的BI 764198的比值比（ORs）分别为10.0（95%置信区间1.6-118.1）、1.5（0.2-19.5）和6.0（0.9-73.6），所有剂量合并后的比值比为4.9（1.0-48.8）。

BI 764198 was well tolerated with no meaningful differences in adverse eventfrequencies across treatment arms; treatment-emergent adverse events were reported by 44 (71%) of 62 participants, with similar frequencies of adverse events observed in the placebo group (ten [71%] of 14) and BI 764198 groups (34 [71%] of 48).

BI 764198的耐受性良好，治疗组之间不良事件发生频率没有显著差异；62名参与者中有44名（71%）报告了治疗后出现的不良事件，安慰剂组（14名中的10名，71%）和BI 764198组（48名中的34名，71%）观察到的不良事件频率相似。

interpretation

BI 764198 lowered proteinuria and was well tolerated by participants in this trial. This is the first evidence of efficacy with a podocyte-targeted therapy in FSGS.

BI 764198 降低了蛋白尿，并且在本试验中受试者对其耐受性良好。这是首次有证据显示针对足细胞的治疗在局灶节段性肾小球硬化症（FSGS）中有效。

Larger randomised controlled trials over longer treatment durations, enabling meaningful subgroup analyses, are planned to evaluate the safety and efficacy of BI 764198 treatment in FSGS and other conditions affected by podocytopathy.

计划进行更大规模的随机对照试验，持续更长时间的治疗，以便进行有意义的亚组分析，以评估 BI 764198 治疗在 FSGS 及其他受足细胞病变影响的疾病中的安全性和有效性。

funding

Boehringer Ingelheim.

勃林格殷格翰。