Heerspink Hiddo J L, Du Xiaoying, Xu Yan, Zhang Yanning, Liu Bin, Bi Guangyu, Xu Chengyun, Luo Qun, Wu Henglan, Wan Jianxin, Cao Liou, Wang Rong, Fan Qiuling, Cheng Hong, Xu Lixia, Huang Jiyi, Zhong Aimin, Peng Qingfeng, Hei Yongjiang, Wang Yiwei, Zhou Bo, Zhang Liqin, Chen Jianghua
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
The George Institute for Global Health, Sydney, New South Wales, Australia.
J Am Soc Nephrol. 2025 Apr 1;36(4):657-667. doi: 10.1681/ASN.0000000538. Epub 2024 Oct 26.
Patients with IgA nephropathy and significant proteinuria are at high risk of progressive kidney function loss and kidney failure. We report the results of a clinical trial assessing the selective endothelin receptor antagonist SC0062 for the treatment of IgA nephropathy. SC0062 led to clinically meaningful improvements in proteinuria and did not increase risk of peripheral edema at higher doses.
Endothelin receptor type A activation contributes to kidney injury in patients with IgA nephropathy. SC0062 is a novel selective endothelin receptor type A antagonist. We report the results of a phase 2 dose-finding trial to characterize the efficacy and safety of SC0062 in patients with IgA nephropathy.
We conducted a randomized, placebo-controlled, double-blind, clinical trial in adults with biopsy-proven IgA nephropathy and eGFR ≥30 ml/min per 1.73 m with urine protein-creatinine ratio (UPCR) ≥0.75 g/g or proteinuria ≥1 g/24 hour despite using maximum tolerated doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were randomized 1:1:1:1 to 24-week treatment with SC0062 5, 10, and 20 mg or matching placebo once daily. The primary efficacy outcome was percent change from baseline in UPCR in 24-hour urine samples after 12 weeks of treatment. Secondary end points included changes in eGFR. Safety outcomes including treatment-emergent adverse events and serious adverse events were recorded.
Overall, 131 patients (mean age 42 years [SD 11]; mean eGFR 72 ml/min per 1.73 m [SD 24] and median 24-hour UPCR 1.2 g/g [25th–75th percentile, 0.9–1.5 g/g]) were randomized to placebo (=34) or SC0062 5 mg (=33), 10 mg (=32), or 20 mg (=32). All SC0062 doses reduced UPCR versus placebo throughout treatment. At week 12, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UPCR with SC0062 5, 10, and 20 mg were−27.6% (−43.0 to −8.2), −20.5% (−37.4 to 1.0), and −38.1% (−51.4 to −21.0), respectively, and at week 24 they were−22.4% (−42.2 to 4.3), −30.9% (−48.6 to −7.0), and −51.6% (−64.2 to −34.6), respectively. No differences in eGFR were observed among treatment groups. The proportion of participants with treatment-emergent adverse events or serious adverse events was balanced among treatment groups. Peripheral edema was reported by two (6%), one (3%), one (3%) participants in the 5, 10, and 20 mg SC0062-treated groups, respectively, compared with five (15%) in the placebo group.
In patients with IgA nephropathy, SC0062 reduced proteinuria and did not increase risk of peripheral edema.
: A Study to Evaluate the Efficacy and Safety of SC0062 in the Treatment of CKD, NCT05687890.
This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_10_26_KTS_October2024.mp3
患有IgA肾病且蛋白尿显著的患者有肾功能进行性丧失和肾衰竭的高风险。我们报告了一项评估选择性内皮素受体拮抗剂SC0062治疗IgA肾病的临床试验结果。SC0062使蛋白尿有临床意义的改善，且在较高剂量时未增加外周水肿风险。
A型内皮素受体激活在IgA肾病患者的肾损伤中起作用。SC0062是一种新型的选择性A型内皮素受体拮抗剂。我们报告一项2期剂量探索试验的结果，以确定SC0062在IgA肾病患者中的疗效和安全性。
我们对经活检证实为IgA肾病且估算肾小球滤过率（eGFR）≥30 ml/（min·1.73 m²）、尿蛋白肌酐比（UPCR）≥0.75 g/g或蛋白尿≥1 g/24小时的成年人进行了一项随机、安慰剂对照、双盲临床试验，尽管已使用最大耐受剂量的血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂。患者按1:1:1:1随机分组，接受SC0062 5 mg、10 mg和20 mg或匹配安慰剂治疗24周，每日一次。主要疗效指标是治疗12周后24小时尿样中UPCR相对于基线的变化百分比。次要终点包括eGFR的变化。记录安全性指标，包括治疗中出现的不良事件和严重不良事件。
总体而言，131例患者（平均年龄42岁[标准差11]；平均eGFR 72 ml/（min·1.73 m²）[标准差24]，24小时UPCR中位数1.2 g/g[第25 - 75百分位数，0.9 - 1.5 g/g]）被随机分配至安慰剂组（n = 34）或SC0062 5 mg组（n = 33）、10 mg组（n = 32）或20 mg组（n = 32）。在整个治疗过程中，所有SC0062剂量组的UPCR相对于安慰剂组均降低。在第12周时，SC0062 5 mg、10 mg和20 mg组相对于基线的安慰剂校正几何平均变化（95%置信区间）的UPCR分别为 - 27.6%（- 43.0至 - 8.2）、- 20.5%（- 37.4至1.0）和 - 38.1%（- 51.4至 - 21.0），在第24周时分别为 - 22.4%（- 42.2至4.3）、- 30.9%（- 48.6至 - 7.0）和 - 51.6%（- 64.2至 - 34.6）。各治疗组之间未观察到eGFR的差异。治疗中出现不良事件或严重不良事件的参与者比例在各治疗组之间是平衡的。SC0062 5 mg、10 mg和20 mg治疗组分别有2例（6%）、1例（3%）、1例（3%）参与者报告有外周水肿，而安慰剂组有5例（15%）。
在IgA肾病患者中，SC0062降低了蛋白尿且未增加外周水肿风险。
一项评估SC0062治疗慢性肾脏病疗效和安全性的研究，NCT05687890。
本文包含一个播客，链接为https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_10_26_KTS_October2024.mp3
