Background & Aims

Primary sclerosing cholangitis (PSC) is a major unmet medical need in clinical hepatology. Cilofexor is a nonsteroidal farnesoid X receptor agonist being evaluated for the treatment of PSC. Here, we describe the safety and preliminary efficacy of cilofexor in a 96-week, open-label extension (OLE) of a phase II trial.

Methods

Noncirrhotic subjects with large-duct PSC who completed the 12-week, blinded phase of a phase II study (NCT02943460) were eligible, after a 4-week washout period, for a 96-week OLE with cilofexor 100 mg daily. Safety, liver biochemistry, and serum markers of fibrosis, cellular injury, and pharmacodynamic effects of cilofexor (fibroblast growth factor 19, C4, and bile acids [BAs]) were evaluated.

Results

Among 52 subjects enrolled in the phase II study, 47 (90%) continued in the OLE phase (median age, 44 years; 60% male patients, 60% with inflammatory bowel disease, and 45% on ursodeoxycholic acid [UDCA]). At OLE baseline (BL), the median serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were 368 U/L (interquartile range [IQR], 277–468 U/L) and 417 U/L (IQR, 196–801 U/L), respectively. Of the 47 subjects enrolled, 15 (32%) discontinued treatment prematurely (pruritus [n = 5], other adverse events [n = 5], subject decision/investigator discretion [n = 5]). At week 96, reductions in liver biochemistry parameters occurred, including serum ALP (median, −8.3% [IQR, −25.9% to 11.0%]; P = .066), GGT (−29.8% [IQR, −42.3% to −13.9%]; P < .001), alanine aminotransaminase (ALT) (−29.8% [IQR, −43.7% to −6.6%]; P = .002), and aspartate aminotransaminase (AST) (−16.7% [IQR, −35.3% to 1.0%]; P = .010), and rebounded after 4 weeks of untreated follow-up. ALP response (≥20% reduction from BL to week 96) was similar in the presence or absence of UDCA therapy (29% vs 39%; P = .71). At week 96, cilofexor treatment was associated with a significant reduction in serum 7α-hydroxy-4-cholesten-3-one (C4) (−29.8% [IQR, −64.3% to −8.5%]; P = .001). In subjects with detectable serum BAs at BL (n = 40), BAs decreased −23.9% (IQR, −44.4% to −0.6%; P = .006) at week 48 (n = 28) and −25.7% (IQR, −35.9% to 53.7%; P = .91) at week 96 (n = 26). Serum cytokeratin 18 (CK18) M30 and M65 were reduced throughout the OLE; significant reductions were observed at week 72 (CK18 M30, −17.3% [IQR, −39.3% to 8.8%]; P = .018; CK18 M65, −43.5% [IQR, −54.9% to 15.3%]; P = .096). At week 96, a small, but statistically significant absolute increase of 0.15 units in Enhanced Liver Fibrosis score was observed compared with BL (median, 9.34 vs 9.53; P = .028).

Conclusions

In this 96-week OLE of a phase II study of PSC, cilofexor was safe and improved liver biochemistry and biomarkers of cholestasis and cellular injury. ClinicalTrials.gov identifier: NCT02943460

中文翻译：

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法尼醇 X 受体 (FXR) 激动剂 Cilofexor 在 PSC 患者中为期 96 周的开放标签延长期的安全性和持续疗效

背景与目标

原发性硬化性胆管炎 (PSC) 是临床肝病学中未满足的主要医疗需求。Cilofexor 是一种非甾体类法尼醇 X 受体激动剂，正在评估用于治疗 PSC。在这里，我们描述了 cilofexor 在为期 96 周的开放标签扩展 (OLE) II 期试验中的安全性和初步疗效。

方法

完成 12 周盲法 II 期研究 (NCT02943460) 的大胆管 PSC 非肝硬化受试者在 4 周清除期后有资格接受为期 96 周的 OLE，每日服用 100 mg cilofexor。评估了 cilofexor（成纤维细胞生长因子 19、C4 和胆汁酸 [BAs]）的安全性、肝脏生化和纤维化血清标志物、细胞损伤和药效学效应。

结果

在参加 II 期研究的 52 名受试者中，47 名 (90%) 继续处于 OLE 阶段（中位年龄，44 岁；60% 为男性患者，60% 患有炎症性肠病，45% 接受熊去氧胆酸 [UDCA]）。在 OLE 基线 (BL) 时，中位血清碱性磷酸酶 (ALP) 和 γ-谷氨酰转移酶 (GGT) 分别为 368 U/L（四分位数间距 [IQR]，277–468 U/L）和 417 U/L（IQR， 196–801 U/L)，分别。在登记的 47 名受试者中，15 名 (32%) 提前停止治疗（瘙痒症 [n = 5]、其他不良事件 [n = 5]、受试者决定/研究者判断 [n = 5]）。第 96 周时，肝脏生化参数降低，包括血清 ALP（中位数，-8.3% [IQR，-25.9% 至 11.0%]；P = .066）、GGT（-29.8% [ IQR  ，-42.3% 至 - 13.9%]；P< .001)、丙氨酸转氨酶 (ALT)（-29.8% [IQR，-43.7% 至 -6.6%]；P  = .002）和天冬氨酸转氨酶 (AST)（-16.7% [IQR，-35.3% 至 1.0 %]；P  = .010)，并在 4 周未治疗的随访后反弹。ALP 反应（从 BL 到第 96 周减少 ≥ 20%）在存在或不存在 UDCA 治疗的情况下相似（29% 对 39%；P  = .71）。在第 96 周，cilofexor 治疗与血清 7α-hydroxy-4-cholesten-3-one (C4) 的显着降低相关（-29.8% [IQR，-64.3% 至 -8.5%]；P = .001 ）  。在 BL 时可检测到血清 BA 的受试者（n = 40）中，BA 在第 48 周（n = 28）和 -25.7 %（IQR，-44.4% 至 -0.6%； P = .006）下降了 -23.9%（IQR，-44.4% 至 -0.6%；P = .006） -35.9% 至 53.7%；P = .91) 在第 96 周 (n = 26)。血清细胞角蛋白 18 (CK18) M30 和 M65 在整个 OLE 期间减少；在第 72 周观察到显着降低（CK18 M30，-17.3% [IQR，-39.3% 至 8.8%]；P  = .018；CK18 M65，-43.5% [IQR，-54.9% 至 15.3%]；P  = . 096). 在第 96 周，与 BL 相比，增强型肝纤维化评分有 0.15 个单位的小幅但具有统计学意义的绝对增加（中位数，9.34 对 9.53；P  = .028）。

结论

在这项为期 96 周的 PSC II 期 OLE 研究中，cilofexor 是安全的，并且改善了肝脏生物化学以及胆汁淤积和细胞损伤的生物标志物。ClinicalTrials.gov 标识符：NCT02943460