National Institute for Health Research, Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
Shire Plc, a Takeda company, Lexington, MA, USA.
J Hepatol. 2020 Aug;73(2):231-240. doi: 10.1016/j.jhep.2020.03.024. Epub 2020 Mar 29.
BACKGROUND & AIMS: Volixibat is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that has been hypothesized to improve non-alcoholic steatohepatitis (NASH) by blocking bile acid reuptake and stimulating hepatic bile acid production. We studied the safety, tolerability and efficacy of volixibat in patients with NASH.
In this double-blind, phase II dose-finding study, adults with ≥5% steatosis and NASH without cirrhosis (N = 197) were randomized to receive volixibat (5, 10 or 20 mg) or placebo once daily for 48 weeks. The endpoints of a predefined interim analysis (n = 80), at week 24, were: ≥5% reduction in MRI-proton density fat fraction and ≥20% reduction in serum alanine aminotransferase levels. The primary endpoint was a ≥2-point reduction in non-alcoholic fatty liver disease activity score without worsening fibrosis at week 48.
Volixibat did not meet either interim endpoint; the study was terminated owing to lack of efficacy. In participants receiving any volixibat dose, mean serum 7-alpha-hydroxy-4-cholesten-3-one (C4; a biomarker of bile acid synthesis) increased from baseline to week 24 (+38.5 ng/ml [SD 53.18]), with concomitant decreases in serum total cholesterol (-14.5 mg/dl [SD 28.32]) and low-density lipoprotein cholesterol (-16.1 mg/dl [SD 25.31]). These changes were generally dose-dependent. On histological analysis, a greater proportion of participants receiving placebo (38.5%, n = 5/13) than volixibat (30.0%, n = 9/30) met the primary endpoint. Treatment-emergent adverse events (TEAEs) were mainly mild or moderate. No serious TEAEs were related to volixibat. Diarrhoea was the most common TEAE overall and the most common TEAE leading to discontinuation.
Increased serum C4 and decreased serum cholesterol levels provide evidence of target engagement. However, inhibition of ASBT by volixibat did not elicit a liver-related therapeutic benefit in adults with NASH.
A medicine called volixibat has previously been shown to reduce cholesterol levels in the blood. This study investigated whether volixibat could reduce the amount of fat in the liver and reduce liver injury in adults with an advanced form of non-alcoholic fatty liver disease. Volixibat did not reduce the amount of fat in the liver, nor did it have any other beneficial effect on liver injury. Participants in the study generally tolerated the side effects of volixibat and, as in previous studies, the main side effect was diarrhoea. These results show that volixibat is not an effective treatment for people with fatty liver disease.
NCT02787304.
Volixibat 是一种顶端钠依赖性胆汁酸转运蛋白（ASBT）抑制剂，据推测它可以通过阻断胆汁酸重吸收和刺激肝胆汁酸生成来改善非酒精性脂肪性肝炎（NASH）。我们研究了 NASH 患者使用 Volixibat 的安全性、耐受性和疗效。
在这项双盲、Ⅱ期剂量探索研究中，≥5%的脂肪变性和非肝硬化 NASH 患者（N=197）随机接受每日一次 Volixibat（5、10 或 20mg）或安慰剂治疗 48 周。在第 24 周（n=80）进行的预先设定的中期分析的终点为：MRI-质子密度脂肪分数降低≥5%和血清丙氨酸氨基转移酶水平降低≥20%。主要终点为第 48 周时非酒精性脂肪性肝病活动评分降低≥2 分且纤维化无恶化。
Volixibat 均未达到上述任何中期终点，由于疗效不佳，该研究提前终止。在接受任何 Volixibat 剂量的参与者中，血清 7-α-羟基-4-胆甾烯-3-酮（C4；胆汁酸合成的生物标志物）从基线至第 24 周增加（+38.5ng/ml[SD53.18]），同时血清总胆固醇（-14.5mg/dl[SD28.32]）和低密度脂蛋白胆固醇（-16.1mg/dl[SD25.31]）降低。这些变化通常与剂量相关。在组织学分析中，接受安慰剂（38.5%，n=5/13）的参与者比例高于接受 Volixibat（30.0%，n=9/30）的参与者，达到主要终点。治疗期出现的不良事件（TEAEs）主要为轻度或中度。没有与 Volixibat 相关的严重 TEAEs。腹泻总体上是最常见的 TEAEs，也是最常见导致停药的 TEAEs。
血清 C4 的增加和血清胆固醇水平的降低提供了靶标结合的证据。然而，Volixibat 抑制 ASBT 并未在患有 NASH 的成年人中引起与肝脏相关的治疗益处。
NCT02787304
