Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, USA.
Division of Gastroenterology and Hepatology, University of Virginia, USA.
J Hepatol. 2022 Jan;76(1):75-85. doi: 10.1016/j.jhep.2021.08.025. Epub 2021 Sep 4.
BACKGROUND & AIM: Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual agonistic properties (α/γ). Due to a strong mechanistic rationale, we aimed to test the safety and efficacy of saroglitazar in patients with primary biliary cholangitis (PBC) who were either ursodeoxycholic acid (UDCA) resistant or intolerant.
In this double-blind, phase II proof-of-concept trial, 37 patients with PBC were randomized to saroglitazar 4 mg (n = 13), saroglitazar 2 mg (n = 14), or placebo (n = 10) daily for 16 weeks. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at Week 16.
A significant reduction of mean ALP levels was observed at Week 16 relative to baseline in both the saroglitazar 4 mg (least-squares [LS] mean =-163.3 U/L, SE = 25.1, p <0.001) and 2 mg (LS mean =-155.8 U/L, SE = 24.4, p <0.001) groups, compared with placebo (LS mean =-21.1 U/L, SE = 28.9). Treatment with saroglitazar resulted in a rapid reduction of ALP concentration at Week 4 that was sustained through the study duration. At least 1 treatment-emergent adverse event occurred in 11 (84.6%) patients in the saroglitazar 4 mg group, in 12 (85.7%) patients in the 2 mg group and in 8 (80%) patients in the placebo group. Study drug was discontinued in 4 patients (3 patients in the 4 mg group and 1 patient in the 2 mg group) due to aminotransferase increases that promptly returned to baseline values after drug discontinuation.
Saroglitazar at 2 mg and 4 mg daily was tolerated and resulted in rapid and sustained improvements in ALP. Further studies are underway at a daily dose of 2 mg and 1 mg due to the higher incidence of elevated liver enzymes observed with the 4 mg dose. CLINICALTRIALS.
NCT03112681 LAY SUMMARY: Saroglitazar resulted in a rapid and sustained improvement in alkaline phosphatase levels in patients with primary biliary cholangitis. The mean percentage reductions in alkaline phosphatase levels were 49% and 51% in the saroglitazar 4 mg and 2 mg groups compared to 3% in the placebo group.
沙格列汀是一种新型过氧化物酶体增殖物激活受体（PPAR）激动剂，具有双重激动特性（α/γ）。由于有强有力的机制原理，我们旨在测试沙格列汀在原发性胆汁性胆管炎（PBC）患者中的安全性和疗效，这些患者要么对熊去氧胆酸（UDCA）耐药，要么不耐受。
在这项双盲、二期概念验证试验中，37 名 PBC 患者被随机分配至沙格列汀 4 mg（n=13）、沙格列汀 2 mg（n=14）或安慰剂（n=10）组，每日治疗 16 周。主要疗效终点是第 16 周碱性磷酸酶（ALP）水平的降低。
与基线相比，沙格列汀 4 mg 组（最小二乘[LS]均值-163.3 U/L，SE 25.1，p<0.001）和 2 mg 组（LS 均值-155.8 U/L，SE 24.4，p<0.001）的 ALP 水平在第 16 周均显著降低，而安慰剂组（LS 均值-21.1 U/L，SE 28.9）则无显著降低。沙格列汀治疗可在第 4 周迅速降低 ALP 浓度，并持续至研究结束。沙格列汀 4 mg 组有 11 名（84.6%）患者和 2 mg 组有 12 名（85.7%）患者至少出现 1 次治疗中出现的不良事件，而安慰剂组有 8 名（80%）患者出现这种情况。由于转氨酶升高，4 名患者（沙格列汀 4 mg 组 3 名患者，2 mg 组 1 名患者）停止了研究药物治疗，但停药后转氨酶迅速恢复至基线值。
沙格列汀每日 2 mg 和 4 mg 剂量耐受良好，可迅速和持续改善 ALP。由于观察到 4 mg 剂量组肝酶升高的发生率较高，目前正在进行每日 2 mg 和 1 mg 剂量的进一步研究。临床试验。
NCT03112681
沙格列汀可迅速和持续改善原发性胆汁性胆管炎患者的碱性磷酸酶水平。与安慰剂组的 3%相比，沙格列汀 4 mg 和 2 mg 组的碱性磷酸酶水平平均降低了 49%和 51%。
