Department of Internal Medicine, University of California, Davis, Davis, California, United States.
Digestive Healthcare of Georgia P.C., Piedmont Atlanta Hospital, Atlanta, Georgia, United States.
J Hepatol. 2022 Aug;77(2):353-364. doi: 10.1016/j.jhep.2022.02.033. Epub 2022 Mar 30.
BACKGROUND & AIMS: We examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ≥1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid.
In this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5 mg/day (n = 53) or 10 mg/day (n = 55) or assigned to 2 mg/day (n = 11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10 mg/day. The primary efficacy endpoint was ALP change from baseline to Week 8.
Mean baseline ALP was 300, 345, and 295 U/L in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Twenty-one percent of patients had cirrhosis, 71% had pruritus. At Week 8, mean ± standard error ALP reductions from baseline were 26 ± 2.8%, 33 ± 2.6%, and 41 ± 1.8% in the 2 mg (n = 11), 5 mg (n = 49), and 10 mg (n = 52) cohorts (all p ≤0.005), respectively. Responses were maintained or improved at Week 52, after dose escalation in 91% and 80% of the 2 mg and 5 mg cohorts, respectively. At Week 52, composite response (ALP <1.67xULN, ≥15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5 mg and 10 mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events.
Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus.
NCT02955602 CLINICALTRIALSREGISTER.
2016-002996-91 LAY SUMMARY: Current treatment options for patients living with primary biliary cholangitis (PBC) are not optimal due to inadequate effectiveness or undesirable side effects. Patients with PBC who took seladelpar, a new treatment being developed for PBC, at increasing doses (2, 5, or 10 mg/day) for 1 year had clinically significant, dose-dependent improvements in key liver tests. Treatment appeared safe and was not associated with any worsening in patient self-reported itch scores.
我们研究了选择性过氧化物酶体增殖物激活受体-δ激动剂 seladelpar 在有疾病进展风险（碱性磷酸酶[ALP]≥1.67x 正常值上限[ULN]）的原发性胆汁性胆管炎（PBC）成人患者中的疗效和安全性，这些患者正在接受熊去氧胆酸治疗或不耐受熊去氧胆酸。
在这项为期 52 周、2 期、剂量范围、开放标签研究中，患者按 1:1 随机分配（n=53）接受 seladelpar 5mg/天或 10mg/天，或分配至 2mg/天（n=11；英国在中期分析后分配）治疗 12 周。然后可以将剂量增加至 10mg/天。主要疗效终点是基线至第 8 周时 ALP 的变化。
2mg、5mg 和 10mg 队列的患者基线 ALP 平均值分别为 300、345 和 295U/L。21%的患者患有肝硬化，71%的患者有瘙痒。在第 8 周时，2mg（n=11）、5mg（n=49）和 10mg（n=52）队列的平均±标准误差 ALP 降低分别为 26%±2.8%、33%±2.6%和 41%±1.8%（均 p≤0.005）。在 91%和 80%的 2mg 和 5mg 队列中分别在第 52 周时剂量增加后，应答得到维持或改善。在第 52 周时，复合应答（ALP<1.67xULN，≥15%的 ALP 下降和总胆红素正常）率分别为 64%、53%和 67%，ALP 正常率分别为 9%、13%和 33%在 2mg、5mg 和 10mg 队列中。5mg 和 10mg 队列的瘙痒视觉模拟量表评分降低。没有与治疗相关的严重不良事件，有 4 名患者因不良事件而停药。
在有疾病进展风险的 PBC 患者中，seladelpar 显示出强大的、剂量依赖性的、临床显著的和持久的改善，这些患者的胆汁淤积和炎症的生化标志物得到改善。Seladelpar 似乎安全且耐受良好，与瘙痒加重无关。
NCT02955602 临床试验注册处。
2016-002996-91 总结：目前，对于原发性胆汁性胆管炎（PBC）患者的治疗选择并不理想，因为疗效不足或副作用不理想。接受新开发的 PBC 治疗药物 seladelpar 治疗的 PBC 患者，以递增剂量（2、5 或 10mg/天）治疗 1 年，其关键肝脏检测指标有显著的、剂量依赖性的改善。治疗似乎是安全的，并且没有与患者自我报告的瘙痒评分恶化相关。
