Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with , . Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m per year versus −3·8 mL/min per 1·73 m per year (difference 1·1 mL/min per 1·73 m per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m per year versus −3·9 mL/min per 1·73 m per year (difference 1·0 mL/min per 1·73 m per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. Travere Therapeutics.

中文翻译：

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Spasentan 与厄贝沙坦治疗 IgA 肾病患者的疗效和安全性 (PROTECT)：随机、主动对照、3 期试验的 2 年结果

Sparsentan 是一种新型非免疫抑制性单分子双重内皮素血管紧张素受体拮抗剂，在 3 期 PROTECT 试验中，与血管紧张素 II 受体阻滞剂厄贝沙坦相比，在 36 周（主要终点）时，可显着降低免疫球蛋白 A 肾病患者的蛋白尿先前报告的中期分析。在这里，我们报告了双盲最终分析 110 周内的肾功能和结果。PROTECT 是一项双盲、随机、主动对照的 3 期研究，在美洲、亚洲和欧洲 18 个国家的 134 个临床实践中心进行。年龄 18 岁或以上、经活检证实患有原发性 IgA 肾病且每天至少 1·0 g 蛋白尿的患者，尽管已最大限度地抑制肾素-血管紧张素系统至少 12 周，但仍被随机分配 (1:1) 接受 Spasentan（目标剂量）治疗基于置换区组随机化方法，每日一次口服 400 毫克斯帕森坦）或厄贝沙坦（每日一次口服厄贝沙坦目标剂量为 300 毫克）。主要终点是 36 周时治疗组之间蛋白尿的变化。次要终点包括估计肾小球滤过率 (eGFR) 的变化率（斜率）、蛋白尿的变化、肾衰竭的综合情况（确认 eGFR 降低 40%、终末期肾病或全因死亡率）和安全性和随机分组后长达 110 周的耐受性。次要疗效结果在完整分析集中进行评估，安全性在安全集中进行评估，这两者都被定义为所有被随机分配并接受至少一剂随机分配的研究药物的患者。该试验已在 , 注册。2018年12月20日至2021年5月26日期间，203名患者被随机分配至sparsentan组，203名患者被随机分配至厄贝沙坦组。每组中都有一名患者未接受研究药物，因此被排除在疗效和安全性分析之外（404 名患者中，282 名 [70%] 为男性，272 名 [67%] 为白人）。与厄贝沙坦组相比，sparsentan 组患者的 eGFR 下降速度较慢。eGFR 慢性 2 年斜率（第 6-110 周）为每年每 1·73 m -2·7 mL/min 与每年每 1·73 m -3·8 mL/min（差异 1·1 mL/min）每年每 1·73 m，95% CI 0·1 至 2·1；p=0·037)；总的 2 年斜率（第 1 天至第 110 周）为每年每 1·73 m -2·9 mL/min，而每年每 1·73 m 为 -3·9 mL/min（差异 1·0 mL/min）每年每 1·73 m，95% CI -0·03 至 1·94；p=0·058）。在整个研究期间，使用sparsentan在第36周时蛋白尿的显着降低得以维持；第 110 周时，稀疏坦组的蛋白尿（根据尿蛋白与肌酐比值相对基线的变化确定）比厄贝沙坦组低 40%（−42·8%，95% CI -49·8 至−35·0，使用sparsentan 对比-4·4%，-15·8 至8·7，使用厄贝沙坦；几何最小二乘平均比0·60，95% CI 0·50 至0·72)。Spasentan 组 202 名患者中有 18 名 (9%) 达到复合肾衰竭终点，而厄贝沙坦组 202 名患者中有 26 名 (13%) 达到复合肾衰竭终点（相对风险 0·7，95% CI 0·4 至 1·2） ）。斯帕生坦和厄贝沙坦之间的治疗引起的不良事件很好地平衡，没有新的安全信号。在 110 周的时间里，IgA 肾病患者的 Spasentan 治疗与最大滴定剂量的厄贝沙坦治疗相比，蛋白尿显着减少，肾功能得以保留。特拉弗雷疗法。