Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands; The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
Division of Nephrology, Columbia University, New York, NY, USA.
Lancet. 2023 May 13;401(10388):1584-1594. doi: 10.1016/S0140-6736(23)00569-X. Epub 2023 Apr 1.
Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety.
PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to <60 mL/min per 1·73 m and ≥60 mL/min per 1·73 m) and urine protein excretion at screening (≤1·75 g/day and >1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850.
Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups.
Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan.
Travere Therapeutics.
Sparsentan 是一种新型非免疫抑制单分子双重内皮素和血管紧张素受体拮抗剂，目前正在一项针对 IgA 肾病成人患者的 3 期临床试验中进行研究。我们报告了主要蛋白尿疗效终点的预先指定中期分析结果和安全性。
PROTECT 是一项国际性、随机、双盲、阳性对照研究，在 18 个国家的 134 个临床实践点进行。该研究比较了 sparsentan 与厄贝沙坦在活检证实的 IgA 肾病和蛋白尿 1.0 g/天或更高的成人患者中的疗效，这些患者在至少 12 周的最大肾素-血管紧张素系统抑制剂治疗后仍未得到改善。参与者以 1:1 的比例随机分配接受 sparsentan 400 mg 每日一次或厄贝沙坦 300 mg 每日一次治疗，根据筛选时的估计肾小球滤过率（30 至<60 mL/min/1.73 m 和≥60 mL/min/1.73 m）和筛选时的尿蛋白排泄量（≤1.75 g/天和>1.75 g/天）进行分层。主要疗效终点是基于 24 小时尿液样本的尿液蛋白-肌酐比值自基线至 36 周的变化，使用混合模型重复测量进行评估。治疗出现的不良事件（TEAEs）是安全性终点。所有终点均在至少接受一次随机治疗的所有参与者中进行评估。该研究正在进行中，并在 ClinicalTrials.gov 注册，NCT03762850。
在 2018 年 12 月 20 日至 2021 年 5 月 26 日期间，404 名参与者被随机分配至 sparsentan（n=202）或厄贝沙坦（n=202）组，并接受了治疗。在 36 周时，sparsentan 组尿液蛋白-肌酐比值自基线的几何均数最小平方百分比变化在统计学上显著大于厄贝沙坦组（-49.8% vs. -15.1%），组间相对减少 41%（最小平方均值比=0.59；95%CI 0.51-0.69；p<0.0001）。sparsentan 的治疗相关不良事件与厄贝沙坦相似。无严重水肿、心力衰竭、肝毒性或与水肿相关的停药病例。sparsentan 和厄贝沙坦组自基线的体重变化无差异。
与厄贝沙坦相比，sparsentan 每日一次治疗可显著降低 IgA 肾病成人患者的蛋白尿。sparsentan 的安全性与厄贝沙坦相似。在完成 2 年双盲期后，未来的分析将显示这些有益效果是否转化为 sparsentan 的长期肾脏保护潜力。
Travere Therapeutics。
