van Till J W Olivier, Nojima Hiroyuki, Kameoka Chisato, Hayashi Chieri, Sakatani Taishi, Washburn T Benton, Molitoris Bruce A, Shaw Andrew D, Engelman Daniel T, Kellum John A
Mitobridge Inc., Cambridge, Massachusetts, USA.
Astellas Pharma Global Development Inc., Northbrook, Illinois, USA.
Kidney Int Rep. 2023 Apr 8;8(7):1407-1416. doi: 10.1016/j.ekir.2023.04.004. eCollection 2023 Jul.
Peroxisome proliferator-activated receptor δ (PPARδ) plays a central role in modulating mitochondrial function in ischemia-reperfusion injury. The novel PPARδ modulator, ASP1128, was evaluated.
A randomized, double-blind, placebo-controlled, biomarker assignment-driven, multicenter study was performed in adult patients at risk for acute kidney injury (AKI) following cardiac surgery, examining efficacy and safety of a 3-day, once-daily intravenous dose of 100 mg ASP1128 versus placebo (1:1). AKI risk was based on clinical characteristics and postoperative urinary biomarker (TIMP2)•(IGFBP7). The primary end point was the proportion of patients with AKI based on serum creatinine within 72 hours postsurgery (AKI-SCr72h). Secondary endpoints included the composite end point of major adverse kidney events (MAKE: death, renal replacement therapy, and/or ≥25% reduction of estimated glomerular filtration rate [eGFR]) at days 30 and 90).
A total of 150 patients were randomized and received study medication (81 placebo, 69 ASP1128). Rates of AKI-SCr72h were 21.0% and 24.6% in the placebo and ASP1128 arms, respectively ( = 0.595). Rates of moderate/severe AKI (stage 2/3 AKI-SCr and/or stage 3 AKI-urinary output criteria) within 72 hours postsurgery were 19.8% and 23.2%, respectively ( = 0.609). MAKE occurred within 30 days in 11.1% and 13.0% in the placebo and ASP1128 arms ( = 0.717), respectively; and within 90 days in 9.9% and 15.9% in the placebo and ASP1128 arms ( = 0.266), respectively. No safety issues were identified with ASP1128 treatment, but rates of postoperative atrial fibrillation were lower (11.6%) than in the placebo group (29.6%).
ASP1128 was safe and well-tolerated in patients at risk for AKI following cardiac surgery, but it did not show efficacy in renal endpoints.
过氧化物酶体增殖物激活受体δ（PPARδ）在调节缺血再灌注损伤中的线粒体功能方面发挥着核心作用。对新型PPARδ调节剂ASP1128进行了评估。
在心脏手术后有急性肾损伤（AKI）风险的成年患者中进行了一项随机、双盲、安慰剂对照、生物标志物分配驱动的多中心研究，比较每日一次静脉注射100mg ASP1128与安慰剂（1:1）的疗效和安全性，为期3天。AKI风险基于临床特征和术后尿液生物标志物（TIMP2）•（IGFBP7）。主要终点是术后72小时内基于血清肌酐的AKI患者比例（AKI-SCr72h）。次要终点包括30天和90天时主要不良肾脏事件（MAKE：死亡、肾脏替代治疗和/或估计肾小球滤过率[eGFR]降低≥25%）的复合终点。
共有150名患者被随机分组并接受研究药物治疗（81名接受安慰剂，69名接受ASP1128）。安慰剂组和ASP1128组的AKI-SCr72h发生率分别为21.0%和24.6%（P = 0.595）。术后72小时内中度/重度AKI（2/3期AKI-SCr和/或3期AKI-尿量标准）的发生率分别为19.8%和23.2%（P = 0.609）。安慰剂组和ASP1128组在30天内发生MAKE的比例分别为11.1%和13.0%（P = 0.717）；在90天内分别为9.9%和15.9%（P = 0.266）。未发现ASP1128治疗存在安全问题，但术后房颤发生率低于安慰剂组（11.6%对29.6%）。
ASP1128在心脏手术后有AKI风险的患者中安全且耐受性良好，但在肾脏终点方面未显示出疗效。
