Heerspink Hiddo J L, Cherney David, Gafor Abdul Halim Abdul, Górriz Jose Luis, Pergola Pablo E, Tang Sydney C W, Desch Marc, Iliev Hristo, Sun Zhichao, Steubl Dominik, Nangaku Masaomi
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
The George Institute for Global Health, Sydney, Australia.
J Am Soc Nephrol. 2024 May 25;35(9):1227-39. doi: 10.1681/ASN.0000000000000418.
Despite new treatments for CKD, kidney failure risk remains high, particularly where albuminuria remains. We report a prespecified pooled analysis of two randomized controlled trials assessing a soluble guanylate cyclase activator for CKD. Avenciguat led to improvements in albuminuria in patients with CKD with/without type 2 diabetes mellitus, with acceptable safety.
Avenciguat is a novel, potent soluble guanylate cyclase activator in development for CKD. Two trials investigated avenciguat in diabetic (NCT04750577) and non-diabetic (NCT04736628) CKD.
A prespecified pooled analysis of two randomized, double-blind, placebo-controlled trials of identical design. Adults with CKD (eGFR ≥20 and <90 ml/min per 1.73 m, urine albumin–creatinine ratio [UACR] ≥200 and <3500 mg/g) were randomized to 20 weeks of placebo or avenciguat 1, 2, or 3 mg three times daily (TID), adjunctive to angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. The primary end point was change from baseline in UACR in 10-hour urine at week 20, analyzed per protocol. The secondary end point was UACR change from baseline in first morning void urine at week 20. Safety was monitored throughout.
Overall, 500 patients (mean age 62 years [SD 13]; mean eGFR 44 ml/min per 1.73 m [SD 18] and median 10-hour UACR 719 [interquartile range, 379–1285] mg/g) received placebo (=122) or avenciguat 1 mg (=125), 2 mg (=126), or 3 mg (=127) TID. All 243 patients in study one and 27 of 261 patients in study two had diabetes mellitus. Avenciguat 1, 2, and 3 mg TID reduced UACR in 10-hour and first morning void urine versus placebo throughout the treatment period. At week 20, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UACR in 10-hour urine with avenciguat 1, 2, and 3 mg TID were −15.5% (−26.4 to −3.0), −13.2% (−24.6 to −0.1), and −21.5% (−31.7 to −9.8), respectively, analyzed per protocol. Corresponding changes in first morning void urine were −19.4% (−30.0 to −7.3), −15.5% (−26.9 to −2.5), and −23.4% (−33.5 to −11.8), respectively. Avenciguat was well tolerated; the overall frequency of adverse events was low and similar to placebo. The number of patients who discontinued the study drug because of adverse events with avenciguat 1, 2, and 3 mg TID were five (4%), 11 (9%), and 11 (9%), respectively, compared with four (3%) in the placebo group.
Avenciguat lowered albuminuria and was well tolerated in patients with CKD.
: A Study to Test the Effect of Different Doses of BI 685509 on Kidney Function in People With Diabetic Kidney Disease, NCT04750577, and A Study to Test the Effect of Different Doses of Avenciguat (BI 685509) on Kidney Function in People With Chronic Kidney Disease, NCT04736628.
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尽管慢性肾脏病（CKD）有了新的治疗方法，但肾衰竭风险仍然很高，尤其是在存在蛋白尿的情况下。我们报告了一项预先设定的对两项随机对照试验的汇总分析，该分析评估了一种用于CKD的可溶性鸟苷酸环化酶激活剂。阿万西呱使患有或未患有2型糖尿病的CKD患者的蛋白尿得到改善，且安全性可接受。
阿万西呱是一种正在开发用于CKD的新型强效可溶性鸟苷酸环化酶激活剂。两项试验研究了阿万西呱在糖尿病（NCT04750577）和非糖尿病（NCT04736628）CKD患者中的应用。
对两项设计相同的随机、双盲、安慰剂对照试验进行预先设定的汇总分析。患有CKD的成年人（估算肾小球滤过率[eGFR]≥20且<90 ml/min/1.73 m²，尿白蛋白-肌酐比值[UACR]≥200且<3500 mg/g）被随机分配接受20周的安慰剂或阿万西呱1、2或3 mg，每日三次（TID），作为血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂的辅助治疗。主要终点是第20周时10小时尿液中UACR相对于基线的变化，按方案进行分析。次要终点是第20周时首次晨尿中UACR相对于基线的变化。在整个过程中监测安全性。
总体而言，500例患者（平均年龄62岁[标准差13]；平均eGFR 44 ml/min/1.73 m²[标准差18]，10小时UACR中位数719[四分位间距，379 - 1285]mg/g）接受了安慰剂（n = 122）或阿万西呱1 mg（n = 125）、2 mg（n = 126）或3 mg（n = 127）TID治疗。研究一中的所有243例患者和研究二中261例患者中的27例患有糖尿病。在整个治疗期间，与安慰剂相比，阿万西呱1、2和3 mg TID降低了10小时尿液和首次晨尿中的UACR。在第20周时，按方案分析，阿万西呱1、2和3 mg TID治疗的10小时尿液中UACR相对于基线的安慰剂校正几何平均变化（95%置信区间）分别为-15.5%（-26.4至-3.0）、-13.2%（-24.6至-0.1）和-21.5%（-31.7至-9.8）。首次晨尿中的相应变化分别为-19.4%（-30.0至-7.3）、-15.5%（-26.9至-2.5）和-23.4%（-33.5至-11.8）。阿万西呱耐受性良好；不良事件的总体发生率较低，与安慰剂相似。因不良事件而停用研究药物的患者数量，阿万西呱1、2和3 mg TID组分别为5例（4%）、11例（9%）和11例（9%），而安慰剂组为4例（3%）。
阿万西呱降低了蛋白尿，并且在CKD患者中耐受性良好。
一项测试不同剂量的BI 685509对糖尿病肾病患者肾功能影响的研究，NCT04750577；以及一项测试不同剂量的阿万西呱（BI 685509）对慢性肾病患者肾功能影响的研究，NCT04736628。
