Liver Institute Northwest, Seattle, WA, USA.
Indiana University School of Medicine, Indianapolis, IN, USA.
J Hepatol. 2020 Jul;73(1):94-101. doi: 10.1016/j.jhep.2020.02.033. Epub 2020 Mar 10.
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC.
AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5-3.0 mg, or OCA 5-10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety.
The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5-3.0 mg (n = 25), and OCA 5-10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5-10 mg vs. placebo (least-square [LS] mean difference = -83.4 [SE = 40.3] U/L; 95% CI -164.28 to -2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5-3.0 mg vs. placebo at week 24 (LS mean [SE] difference = -78.29 [41.81] U/L; 95% CI -162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5-3.0 mg 60%; OCA 5-10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged.
Treatment with OCA 5-10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event.
ClinicalTrials.gov: NCT02177136; EudraCT: 2014-002205-38.
Primary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies.
原发性硬化性胆管炎（PSC）是一种罕见的胆汁淤积性肝病，目前尚无批准的治疗方法。奥贝胆酸（OCA）是一种有效的法尼醇 X 受体（FXR）激动剂，已被批准用于治疗原发性胆汁性胆管炎。我们研究了 OCA 在 PSC 患者中的疗效和安全性。
AESOP 是一项 II 期、随机、双盲、安慰剂对照、剂量发现研究。符合条件的患者为年龄在 18 至 75 岁之间、诊断为 PSC 且血清碱性磷酸酶（ALP）≥正常上限（ULN）的 2 倍和总胆红素<2.5×ULN 的患者。患者按 1:1:1 的比例随机分为安慰剂组、OCA 1.5-3.0mg 组和 OCA 5-10mg 组，每天一次，进行 24 周的双盲期，随后进行 2 年的长期安全性扩展（LTSE）。主要终点是从基线到第 24 周时 ALP 的变化，以及安全性。
意向治疗人群包括 76 名随机分配至安慰剂（n=25）、OCA 1.5-3.0mg（n=25）和 OCA 5-10mg（n=26）的患者。第 24 周时，OCA 5-10mg 与安慰剂相比，血清 ALP 显著降低（最小二乘[LS]均值差异=-83.4[SE=40.3]U/L；95%CI-164.28 至-2.57；p=0.043）。第 24 周时，OCA 1.5-3.0mg 与安慰剂相比，血清 ALP 无显著降低（LS 均值[SE]差异=-78.29[41.81]U/L；95%CI-162.08 至 5.50；p=0.067）。所有组的总胆红素均与基线相比保持不变。最常见的治疗相关不良反应是剂量相关的瘙痒（安慰剂 46%；OCA 1.5-3.0mg 组 60%；OCA 5-10mg 组 67%）。在 LTSE 期间，ALP 的降低得以维持，并且没有出现新的安全性信号。
OCA 5-10mg 治疗可降低 PSC 患者的血清 ALP。轻度至中度剂量相关瘙痒是最常见的不良反应。
ClinicalTrials.gov：NCT02177136；EudraCT：2014-002205-38。
原发性硬化性胆管炎（PSC）是一种长期疾病，随着时间的推移会损害肝脏中的胆管。在 PSC 患者的 AESOP 临床研究中，奥贝胆酸在最初的 24 周治疗期间降低了血清碱性磷酸酶（一种潜在的疾病严重程度标志物）。该结果在研究的 2 年长期扩展期间得以维持。奥贝胆酸在研究中的最常见副作用是皮肤瘙痒，这与早期的临床研究一致。
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