法国索邦大学V. Ratziu研究团队揭示了Aramchol 治疗非酒精性脂肪性肝炎(NASH) 的2b期试验结果。2021年10月7日，国际学术期刊《自然-医学》发表了这一成果。

ARREST是一项为期52周的双盲、安慰剂对照、2b期试验，将247名NASH患者进行随机分配（在Aramchol 400 mg、600 mg和安慰剂组中，n分别= 101、 98和48）。主要终点是使用600 mg  Aramchol的个体在52周时通过磁共振波谱显示肝脏甘油三酯降低。关键的次要终点包括肝脏组织学和丙氨酸氨基转移酶(ALT)。在用安慰剂校正后，Aramchol 600 mg可降低肝脏甘油三酯，但未达到预先设定的显著性（-3.1，95%置信区间(CI) -6.4至0.2，P=0.066），排除进一步的正式统计分析。在Aramchol 600 mg组中，16.7%（78名中的13名）出现NASH消退，而安慰剂组为5%（40名中的2名）（比值比 (OR) = 4.74，95% CI=0.99至22）。纤维化改善≥1且NASH没有恶化，分别为29.5%和17.5%（OR = 1.88，95% CI = 0.7至5.0）。600 mg组在安慰剂校正后ALT降低至-29.1 IU l-1（95% CI=-41.6 至 -16.5）。

由于不良事件(AE)导致的提前终止<5%，且Aramchol 600和400 mg是安全的、耐受性良好且两组之间的严重或超严重AE没有失衡。尽管 Aramchol 600 mg减少肝脏脂肪的主要终点未达到预先指定的显著水平，但观察到的安全性以及肝脏组织学和酶的变化为SCD1调节作为NASH和纤维化潜在治疗方法提供了依据，并且正在接受3期临床实验的评估。 

据悉，非酒精性脂肪性肝炎是一种不具有获批治疗方案的慢性肝病，与脂毒性和胰岛素抵抗有关，是造成肝硬化和肝细胞癌的主要原因。Aramchol是肝硬脂酰辅酶A去饱和酶(SCD1)的部分抑制剂，在早期临床试验中可改善啮齿动物的脂肪性肝炎和纤维化，并减少脂肪变性。

附：英文原文

Title: Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial

Author: Ratziu, V., de Guevara, L., Safadi, R., Poordad, F., Fuster, F., Flores-Figueroa, J., Arrese, M., Fracanzani, Anna L., Ben Bashat, D., Lackner, K., Gorfine, T., Kadosh, S., Oren, R., Halperin, M., Hayardeny, L., Loomba, R., Friedman, S., Sanyal, Arun J.

Issue&Volume: 2021-10-07

Abstract: Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n=101, n=98 and n=48 in the Aramchol 400mg, 600mg and placebo arms, respectively; NCT02279524). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (3.1, 95% confidence interval (CI) 6.4 to 0.2, P=0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR)=4.74, 95% CI=0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR=1.88, 95% CI=0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600mg was 29.1IUl1 (95% CI=41.6 to 16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program.

DOI: 10.1038/s41591-021-01495-3

Source: https://www.nature.com/articles/s41591-021-01495-3