Texas Liver Institute and University of Texas Health San Antonio, San Antonio, Texas.
Texas Liver Institute and University of Texas Health San Antonio, San Antonio, Texas.
Clin Gastroenterol Hepatol. 2018 Dec;16(12):1983-1991.e3. doi: 10.1016/j.cgh.2018.04.042. Epub 2018 Apr 26.
BACKGROUND & AIMS: Increased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS-0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH.
In an open-label prospective study, patients with NASH (n = 10) received GS-0976 20 mg orally once daily for 12 weeks. NASH was diagnosed based on a proton density fat fraction estimated by magnetic resonance imaging (MRI-PDFF) ≥10% and liver stiffness by magnetic resonance elastography (MRE) ≥2.88 kPa. The contribution from hepatic DNL to plasma palmitate was measured by 14 days of heavy water labeling before and at the end of treatment. We performed the same labelling protocol in an analysis of healthy volunteers who were not given DNL (controls, n = 10). MRI-PDFF and MRE at baseline, and at weeks 4 and 12 of GS-0976 administration, were measured. We analyzed markers of liver injury and serum markers of fibrosis.
The contribution of hepatic DNL to plasma palmitate was significantly greater in patients with NASH compared with controls (43% vs 18%) (P = .003). After 12 weeks administration of GS-0976, the median hepatic DNL was reduced 22% from baseline in patients with NASH (P = .004). Compared with baseline, reductions in MRI-PDFF at week 12 (15.7% vs 9.1% at baseline; P = .006), liver stiffness by MRE (3.4 kPa vs 3.1 kPa at baseline; P = .049), TIMP metallopeptidase inhibitor 1 (275 ng/mL vs 244 ng/mL at baseline; P = .049), and serum level of alanine aminotransferase (101 U/L vs 57 U/L at baseline; P = .23) were consistent with decreased hepatic lipid content and liver injury. At week 12, 7 patients (70%) had a ≥30% decrease in MRI-PDFF.
In an open-label study, patients with NASH given GS-0976 for 12 weeks had reduced hepatic DNL, steatosis, and markers of liver injury. ClinicalTrials.gov no: NCT02856555.
从头合成的脂肪酸（DNL）增加导致非酒精性脂肪性肝炎（NASH）的发病机制。乙酰辅酶 A 羧化酶催化 DNL 的限速步骤。我们评估了小分子乙酰辅酶 A 羧化酶抑制剂 GS-0976 治疗 NASH 患者的安全性和疗效。
在一项开放标签前瞻性研究中，10 名 NASH 患者（n=10）接受 GS-0976 20mg 口服，每日 1 次，持续 12 周。通过磁共振成像（MRI）估计的质子密度脂肪分数（MRI-PDFF）≥10%和磁共振弹性成像（MRE）≥2.88kPa 诊断 NASH。通过治疗前和治疗结束时的 14 天重水标记，测量肝内 DNL 对血浆棕榈酸的贡献。我们对未给予 DNL 的健康志愿者（对照组，n=10）进行了相同的标记方案分析。在 GS-0976 给药的基线、第 4 周和第 12 周，测量 MRI-PDFF 和 MRE。我们分析了肝损伤标志物和血清纤维化标志物。
与对照组相比，NASH 患者肝内 DNL 对血浆棕榈酸的贡献明显更大（43%比 18%）（P=0.003）。在接受 GS-0976 治疗 12 周后，NASH 患者的肝内 DNL 中位数从基线下降 22%（P=0.004）。与基线相比，第 12 周时 MRI-PDFF 的降低（15.7%比基线时的 9.1%；P=0.006）、MRE 测量的肝硬度（3.4kPa 比基线时的 3.1kPa；P=0.049）、金属蛋白酶抑制剂 1（TIMP1）（275ng/mL 比基线时的 244ng/mL；P=0.049）和血清丙氨酸氨基转移酶水平（101U/L 比基线时的 57U/L；P=0.23）与肝内脂质含量和肝损伤的减少一致。第 12 周时，7 名患者（70%）的 MRI-PDFF 下降≥30%。
在一项开放标签研究中，接受 GS-0976 治疗 12 周的 NASH 患者肝内 DNL、脂肪变性和肝损伤标志物减少。临床试验.gov 编号：NCT02856555。
