FASN 抑制剂 TVB-2640 在美国/中国 NASH 试验中将肝脂肪减少 28%

StephenW

FASN 抑制剂 TVB-2640 在美国/中国 NASH 试验中将肝脂肪减少 28%

AASLD，肝脏会议，2021 年 11 月 12-15 日

马克·马斯科利尼

TVB-2640 是一种每日一次的口服脂肪酸合成酶 (FASN) 抑制剂，在一项美国/中国安慰剂对照试验中，可使非酒精性脂肪性肝炎 (NASH) 患者的肝脏脂肪减少 28% [1]。在这项 142 人的试验中，用不同剂量的 TVB-2640 治疗 12 周导致 7 次不良事件导致中止，但其中 7 次出现高剂量未开发。所有与药物相关的不良事件均为 1 级或 2 级。

FASN 驱动肝脏中的脂肪生成，而这种从头脂肪生成会刺激脂肪积累，从而导致非酒精性脂肪肝 (NAFLD) 和 NASH。研究表明，抑制 FASN 可降低脂肪变性和炎症，同时禁用活化的星状细胞，否则会促进肝纤维化。

作为一种每日一次的口服药物，TVB-2640 在美国和中国 NASH 患者中具有相似的药代动力学特征，并且在 1b 期试验中将新生脂肪生成减少了 90% [2]。在美国和中国进行的 2a 期随机、安慰剂对照试验 (FASCINATE-1) 旨在评估 TVB-2640 在修剪 NASH 患者肝脏脂肪方面的功效，该试验通过磁共振成像质子密度脂肪分数 (MRI-PDFF) 测量。 NCT03938246) [1,3]。

该试验在美国和中国每天一次测试 50 毫克 TVB-2640，仅在美国测试 25 或 75 毫克。在美国，研究人员将 99 人以 2 比 1 的比例随机分配至每天 25 或 50 毫克 TVB-2640 或安慰剂。另外，美国有 13 人每天服用 75 毫克 TVB-2640 或安慰剂。在中国，该试验将 30 人按 2 比 1 的比例随机分配至每天 50 毫克 TVB-2640 或安慰剂。参与者必须有 8% 或更高的肝脏脂肪和磁共振弹性成像 (MRE) 等于或高于 2.5 kPa 或最近的活检证实 NASH。

在试验的 50 毫克部分的人群中，美国的平均年龄为 53 岁，中国为 33 岁。美国大约 55% 和中国大约 75% 是男性。美国参与者的体重更重（平均 87 公斤 vs 78 公斤），丙氨酸氨基转移酶较低（约 27 比 80 U/L）。中位数 MRI-PDFF 在美国安慰剂组中为 15.3%，在美国 50 毫克组中为 15.8%，在中国安慰剂组中为 20.6%，在中国 50 毫克组中为 16.8%，

TVB-2640 12 周后，MRI-PDFF 肝脏脂肪在 50 毫克美国组（相对变化 -28% 与安慰剂 +4.5%）和 50 毫克中国组（相对变化 = 28% 与 - 11% 安慰剂）（组合相对变化 -28% 与 +0.7%）。在综合分析中，在服用 TVB-2640 12 周后，ALT 下降了 24.3%，而服用安慰剂后则上升了 9.2%。 “不良”低密度脂蛋白胆固醇在美国 50 毫克组中下降，而安慰剂组则上升（-11.0% 对 +9.0%），但在中国，安慰剂组的 LDL 胆固醇比 TVB-2640 下降得更多（-10.6% 对 -2.4%） .

在美国的一个开放标签的 13 人组中，每天 75 毫克的 TVB-2640 剂量并没有显着提高反应率，因此研究人员选择每天 50 毫克作为进一步研究的最佳剂量

安全性分析显示，与安慰剂相比，TVB-2640 没有与剂量相关的显着不良事件。在美国或中国服用 50 毫克剂量的 56 人中，1 人 (1.8%) 有导致退出研究的治疗紧急不良事件，23 人 (43%) 有药物相关不良事件，其中 18它们分别为 1 级和 5 级 2 级。任何剂量下均未出现治疗中出现的严重不良事件。

两个机器学习模型开发并测试了一种算法来预测哪些 NASH 患者会对 TVB-2640 做出反应。预测 PDFF 反应的工具包括几种血清代谢物的组合基线值：1-单醚甘油磷酸乙醇胺、钆酸、硫酸雄酮、硫酸乙二酚、DL-2-氨基辛酸和 D(-)-2-氨基丁酸。

TVB-2640 在活检证实的 NASH 和纤维化患者中进行的一项国际 2b 期双盲、安慰剂对照试验 (FASCINATE-2) 正在进行中 [4]。

参考
1. Loomba R、Harrison SA、Wong VWS 等。新型、一流的脂肪酸合酶 (FASN) 抑制剂 TVB-2640 在美国和中国进行的全球 2 期随机安慰剂对照 NASH 试验 (FASCINATE-1) 中证明了强大的临床疗效和安全性。 AASLD，肝脏会议，2021 年 11 月 12-15 日。摘要 141。
2. Syed-Abdul MM、Parks EJ、Gaballah AH 等。脂肪酸合酶抑制剂 TVB-2640 可减少代谢异常男性的肝脏新生脂肪生成。肝病学。 2020；72:103-118。 doi：10.1002/hep.31000。
3. ClinicalTrials.gov。 TVB 2640 在非酒精性脂肪性肝炎 (NASH) 受试者中的研究。 ClinicalTrials.gov 标识符 NCT03938246。 https://clinicaltrials.gov/ct2/show/NCT03938246?term=NCT03938246
4. ClinicalTrials.gov。 TVB-2640 在非酒精性脂肪性肝炎 (NASH) 受试者中的研究。 ClinicalTrials.gov 标识符 NCT04906421。 https://clinicaltrials.gov/ct2/show/NCT04906421

StephenW

FASN Inhibitor TVB-2640 Cuts Liver Fat 28% in US/China NASH Trial

AASLD, The Liver Meeting, November 12-15, 2021

Mark Mascolini

TVB-2640, a once-daily oral fatty acid synthase (FASN) inhibitor, reduced liver fat 28% in people with nonalcoholic steatohepatitis (NASH) in a US/China placebo-controlled trial [1]. Twelve weeks of treatment with various doses of TVB-2640 caused 7 adverse events leading to discontinuation in this 142-person trial, but 4 of those 7 came with a high dose not being developed. All drug-related adverse events were grade 1 or 2.

FASN drives fat production in the liver, and that de novo lipogenesis spurs fat accumulation that can lead to nonalcoholic fatty liver disease (NAFLD) and NASH. Research shows that inhibiting FASN lowers steatosis and inflammation while disabling activated stellate cells, which otherwise promote liver fibrosis.

As a once-daily oral drug, TVB-2640 had a similar pharmacokinetic profile in US and Chinese people with NASH and cut de novo lipogenesis up to 90% in a phase 1b trial [2]. The phase 2a randomized, placebo-controlled trial in the United States and China (FASCINATE-1) aimed to assess TVB-2640 efficacy in trimming liver fat measured as magnetic resonance imaging proton density fat fraction (MRI-PDFF) in people with NASH (NCT03938246) [1,3].

The trial tested 50 mg of TVB-2640 once daily in both the US and China and 25 or 75 mg only in the US. In the US researchers randomized 99 people in a 2-to-1 ratio to 25 or 50 mg of TVB-2640 daily or to placebo. Separately, 13 people in the US took 75 mg of TVB-2640 daily or placebo. In China the trial randomized 30 people in a 2-to-1 ratio to 50 mg of TVB-2640 daily or placebo. Participants had to have 8% or greater liver fat and magnetic resonance elastography (MRE) at or above 2.5 kPa or a recent biopsy confirming NASH.

Among people in the 50-mg part of the trial, ages averaged 53 in the US and 33 in China. About 55% in the US and 75% in China were men. US participants weighed more (average 87 vs 78 kg) and had lower alanine aminotransferase (about 27 vs 80 U/L). Median MRI-PDFF measured 15.3% in the US placebo group, 15.8% in the US 50-mg group, 20.6% in the Chinese placebo group, and 16.8% in the Chinese 50-mg group,

MRI-PDFF liver fat dropped significantly after 12 weeks of TVB-2640 in the 50-mg US group (relative change -28% vs +4.5% with placebo) and in the 50-mg Chinese group (relative change =28% vs -11% with placebo) (combined relative change -28% vs +0.7%). In the combined analysis ALT fell 24.3% after 12 weeks of TVB-2640 while rising 9.2% with placebo. “Bad” LDL cholesterol fell in the US 50-mg group while rising with placebo (-11.0% vs +9.0%), but in China LDL cholesterol fell more with placebo than with TVB-2640 (-10.6% vs -2.4%).

In an open-label 13-person group in the US, a TVB-2640 dose of 75 mg daily did not improve response rates much, so the investigators picked 50 mg once daily as the optimal dose for further study

The safety analysis disclosed no dose-related significant adverse events with TVB-2640 versus placebo. Among 56 people who took the 50-mg dose in the US or China, 1 (1.8%) had a treatment-emergent adverse event leading to withdrawal from the study and 23 (43%) had a drug-related adverse event, 18 of them grade 1 and 5 grade 2. There were no treatment-emergent serious adverse events at any dose.

Two machine-learning models developed and tested an algorithm to predict which people with NASH will respond to TVB-2640. A tool that foretold PDFF response included combined baseline values of several serum metabolites: 1-monoetherglycerophosphoethanolamine, gadoleic acid, androsterone sulfate, etiocholanolone sulfate, DL-2-aminocaprylic acid, and D(-)-2-aminobutyric acid.

An international phase 2b double-blind, placebo-controlled trial of TVB-2640 in people with biopsy-confirmed NASH and fibrosis (FASCINATE-2) is underway [4].

References
1. Loomba R, Harrison SA, Wong VWS, et al. Novel, first-in-class, fatty acid synthase (FASN) inhibitor TVB-2640 demonstrates robust clinical efficacy and safety in a global phase 2 randomized placebo-controlled NASH trial (FASCINATE-1) conducted in the US and China. AASLD, The Liver Meeting, November 12-15, 2021. Abstract 141.
2. Syed-Abdul MM, Parks EJ, Gaballah AH, et al. Fatty acid synthase inhibitor TVB-2640 reduces hepatic de novo lipogenesis in males with metabolic abnormalities. Hepatology. 2020;72:103-118. doi: 10.1002/hep.31000.
3. ClinicalTrials.gov. Study of TVB 2640 in subjects with non-alcoholic steatohepatitis (NASH). ClinicalTrials.gov identifier NCT03938246. https://clinicaltrials.gov/ct2/show/NCT03938246?term=NCT03938246
4. ClinicalTrials.gov. Study of TVB-2640 in subjects with nonalcoholic steatohepatitis (NASH). ClinicalTrials.gov identifier NCT04906421. https://clinicaltrials.gov/ct2/show/NCT04906421