用于治疗免疫球蛋白 A 肾病的双重内皮素 A 型和血管紧张素 II 亚型 1 受体拮抗剂 Sparsentan:最新试验结果、药代动力学考虑因素和结合概况

Eleanor Roberts
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摘要

免疫球蛋白 A 肾病(IgAN)是原发性肾小球肾炎中最常见的一种。有些患者病情发展迅速,可导致蛋白尿、肾衰竭和死亡。传统的标准治疗方法是使用血管紧张素转换酶抑制剂(ACEi)或血管紧张素 II(Ang II)受体阻滞剂(ARB)。最近,由于内皮素 1(ET-1)和血管紧张素 II 受体的过度激活与 IgAN 有关,针对这两种受体的药物应运而生。Sparsentan 是一种 A 型 ET(ETAR)和 Ang II 1 亚型受体(AT1R)双重拮抗剂。PROTECT研究比较了斯帕生坦和ARB厄贝沙坦对IgAN患者的治疗效果,这些患者在使用稳定剂量的ACEi/ARB≥90天后仍出现蛋白尿≥1克/天。在2023年美国肾脏病学会(ASN)肾脏周上公布的数据显示,与厄贝沙坦相比,使用司帕生坦可持续(>110周)减少蛋白尿,并显著提高肾功能保护水平。目前正在进行的 SPARTAN 研究正在调查斯帕生坦在新近确诊、治疗无效的 IgAN 患者中的应用情况。12例患者的初步数据显示,患者的蛋白尿迅速而持续地减少,但在第36周时,患者的估计肾小球滤过率(eGFR)、体重或体内总水分平均值与基线相比变化不大。在这两项研究中,斯帕生坦的耐受性普遍良好,在PROTECT研究中,其安全性与厄贝沙坦相当。大会上公布的数据还显示,斯帕生坦对AT1R的占用水平一直超过ETAR的占用水平。据推测,这种平衡有助于斯帕生坦降低体液潴留的风险。
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Sparsentan, a Dual Endothelin Type A and Angiotensin II Subtype 1 Receptor Antagonist for the Treatment of Immunoglobulin A Nephropathy: Latest Trial Results, Pharmacokinetic Considerations, and Binding Profile
Immunoglobulin A nephropathy (IgAN) is one of the most common forms of primary glomerulonephritis. In some patients, it can progress rapidly, leading to proteinuria, kidney failure, and death. Standard of care is traditionally with an angiotensin converting enzyme inhibitor (ACEi), or an angiotensin II (Ang II) receptor blocker (ARB). More recently, drugs targeting both endothelin 1 (ET-1) and Ang II receptors have been developed, as overactivation of such is implicated in IgAN. Sparsentan is a dual ET Type A (ETAR) and Ang II subtype 1 receptor (AT1R) antagonist. The PROTECT study compared sparsentan with the ARB irbesartan, in patients with IgAN and with proteinuria of ≥1 g/day despite stable dose of ACEi/ARB for ≥90 days. Data presented at the 2023 American Society of Nephrology (ASN) Kidney Week showed that use of sparsentan led to sustained (>110 weeks) decreases in proteinuria, and a significantly greater preservation of kidney function, compared with irbesartan. The ongoing SPARTAN study is investigating the use of sparsentan in recently diagnosed, treatment-naïve patients with IgAN. Preliminary data in 12 patients showed rapid and sustained proteinuria reductions, with little change from baseline in estimated glomerular filtration rate (eGFR), body weight, or total body water mean at Week 36. In both studies, sparsentan was generally well-tolerated with, in PROTECT, a comparable safety profile to irbesartan. Data presented at the congress also showed that sparsentan consistently occupies AT1R at levels exceeding ETAR occupancy. This balance is hypothesised to contribute to sparsentan’s limited risk of fluid retention.
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