■Sparsentan是一部小说,非免疫抑制,单分子,双重内皮素血管紧张素受体拮抗剂(DEARA)在正在进行的2期DUET治疗局灶性节段肾小球硬化(FSGS)试验中进行了检查。在DUET的8周双盲期,与厄贝沙坦相比,sparsentan导致更多的蛋白尿减少。我们报告了sparsentan在开放标签扩展超过4年的长期疗效和安全性。
■患者从第一次服用sparsentan(双盲期或开放标签延长)到4.6年进行检查。
■FSGS患者,不包括二级FSGS。
■Sparsentan(200、400和800mg/d)。
■尿蛋白-肌酐比值,FSGS部分缓解终点(尿蛋白-肌酐比值≤1.5g/g,比基线下降>40%),估计肾小球滤过率,和血压大约每12周。按年份和病例/100患者年划分的治疗紧急不良事件。
■109名患者入组;108名患者接受≥1次剂量的斯帕森坦;103名患者进入开放标签延伸(68斯帕森坦,35厄贝沙坦在双盲期)。45/108例患者(41.7%)接受Sparsentan治疗;治疗终止的中位时间为3.9年(95%CI,2.6-5.2)。通过随访维持从基线的平均蛋白尿减少百分比。在第一剂量的9个月内实现部分缓解(52.8%的患者)与未实现(47.2%)相比,在整个治疗期间(-2.70vs-6.56;P=0.03)和前2年(-1.69vs-6.46;P=0.03),肾小球滤过率下降速率显着降低。最常见的治疗引起的不良事件(>9例/100患者年)是头痛,外周水肿,上呼吸道感染,高钾血症,和低血压。外周水肿和低血压从第1年开始下降(13.9%和15.7%的患者,分别)在≥2年内≤4%。没有心力衰竭病例,也没有患者死亡。
■开放标签扩展不包括比较组。
■长期治疗显示持续的蛋白尿减少和一致的安全性。
对于局灶性节段肾小球硬化(FSGS)的安全有效的治疗方法,临床上存在大量未满足的需求,有多种原因的肾脏病变。Sparsentan正在研究FSGS的治疗方法,并针对导致肾功能丧失的2个重要途径(内皮素-1和血管紧张素II)。在为期8周的随机研究中,FSGS患者的双盲DUET研究,sparsentan比厄贝沙坦(一种常用于治疗FSGS的降压药)更好地降低了尿液中的蛋白质含量。我们检查了在DUET开放标签扩展中使用sparsentan超过4年的长期治疗。我们发现,继续使用sparsentan治疗的患者的蛋白尿持续减少,并且安全性一致,没有新的或意外的不良反应。
UNASSIGNED: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist (DEARA) examined in the ongoing phase 2 DUET trial for focal segmental glomerulosclerosis (FSGS). In the DUET 8-week double-blind period, sparsentan resulted in greater proteinuria reduction versus irbesartan. We report the long-term efficacy and safety of sparsentan during the open-label extension over more than 4 years.
UNASSIGNED: Patients were examined from their first
sparsentan dose (double-blind period or open-label extension) through 4.6 years.
UNASSIGNED: Patients with FSGS, excluding secondary FSGS.
UNASSIGNED: Sparsentan (200, 400, and 800 mg/d).
UNASSIGNED: Urinary protein-creatinine ratio, FSGS partial remission endpoint (urinary protein-creatinine ratio ≤1.5 g/g and >40% reduction from baseline), estimated glomerular filtration rate, and blood pressure approximately every 12 weeks. Treatment-emergent adverse events by year and cases/100 patient-years.
UNASSIGNED: 109 patients were enrolled; 108 received ≥1 sparsentan dose; 103 entered the open-label extension (68
sparsentan, 35 irbesartan during the double-blind period). Sparsentan was ongoing in 45/108 patients (41.7%); median time to treatment discontinuation was 3.9 years (95% CI, 2.6-5.2). Mean percent proteinuria reduction from baseline was sustained through follow-up. Achieving partial remission within 9 months of first sparsentan dose (52.8% of patients) versus not achieving (47.2%) was associated with significantly slower rate of estimated glomerular filtration rate decline over the entire treatment period (-2.70 vs -6.56; P = 0.03) and in the first 2 years (-1.69 vs -6.46; P = 0.03). The most common treatment-emergent adverse events (>9 cases/100 patient-years) were headache, peripheral edema, upper respiratory infection, hyperkalemia, and hypotension. Peripheral edema and hypotension declined from year 1 (13.9% and 15.7% of patients, respectively) to ≤4% in years ≥2. There were no cases of heart failure and no patient deaths.
UNASSIGNED: The open-label extension does not include a comparison group.
UNASSIGNED: Long-term sparsentan treatment showed sustained proteinuria reduction and a consistent safety profile.
There is substantial unmet clinical need for safe and effective treatments for focal segmental glomerulosclerosis (FSGS), a kidney lesion with varied causes. Sparsentan is being studied for treatment of FSGS and targets 2 important pathways (endothelin-1 and angiotensin II) that lead to the loss of kidney function. In the 8-week randomized, double-blind DUET study in patients with FSGS, sparsentan reduced the amount of protein in the urine better than irbesartan (a blood pressure medicine often used to treat FSGS). We examined long-term treatment with
sparsentan over >4 years in the DUET open-label extension. We found sustained proteinuria reduction in patients who continued treatment with sparsentan and a consistent safety profile with no new or unexpected adverse effects.