在NASA 2a期试验中，TVB-2640降低了肝脏脂肪，改善了纤维化

StephenW

TVB-2640 Lowers Liver Fat, ImprovesFibrosis, in Phase 2a NASH Trial

EASL 2020, Digital International Liver Congress, August 27-29, 2020

Mark Mascolini

TVB-2640, a fatty acid synthase inhibitor, reduced liver fat in adose-dependent manner and improved adiponectin and fibrosis markers  in a placebo-controlled trial enrollingpeople with nonalcoholic steatohepatitis (NASH) [1]. The novel agent caused nopruritus, thrombocytopenia, or hypertriglyceridemia.

Although NASH remains the most common cause of cirrhosis and the second mostfrequent cause of liver transplantation in the United States, no drugs havebeen licensed to treat this disease. De novo lipogenesis (DNL) and lipotoxicityplay important roles in NASH pathogenesis. TVB-2640 inhibited hepatic DNL up to90% in a phase 1b trial [2].

The phase 2a placebo-controlled trial aimed to evaluate the efficacy ofTVB-2640 in decreasing liver fat measured by magnetic resonance imaging-derivedprotein density fat fraction (MRI-PDFF) in people with NASH.

Participants had at least 8% liver fat and magnetic resonance elastography (MRE)at or above 2.5 kPa or a recent biopsy. The trial excluded people withcirrhosis or other chronic liver disease. Researchers randomized 99participants 1-to-1-to-1 to 25 or 50 mg of TVB-2640 once daily or to placebo.The primary endpoint was liver fat reduction by MRI-PDFF at week 12.

The 25-mg and 50-mg TVB-2640 groups were a little older than the placebo group(median 58 and 55 vs 52), and they had higher proportions of men (54.5% and62.9% vs 45.2%) and marginally higher body mass index (34.0 and 32.8 vs 31.2kg/m2). Baseline liver fat by MRI-PDFF was somewhat lower in the25-mg TVB-2640 group (14.3%) than in the 50-mg group (15.8%) or the placebogroup (15.3%). Proportions of people with type 2 diabetes ranged from 37.1% inthe 50-mg TVB-2640 group to 54.8% in the placebo group and up to 75.8% in the25-mg group.

At week 12 MRI-PDFF showed dose-dependent reductions in mean relative liver fat(-28.2% with 50 mg, -9.6% with 25 mg, and +4.5% with placebo (P <0.005 for 50 mg TVB-2640 vs placebo) and mean absolute liver fat (-5.1% with 50mg, -1.8% with 25 mg, and -0.3% with placebo, P < 0.001 for 50 mgTVB-2640 vs placebo). There were significantly more MRI-PDFF responders (atleast 30% drop in MRI-PDFF from baseline) in the 50-mg TVB-2640 group (61%)than in the placebo group (11%) (P < 0.001).

More people taking 50 mg of TVB-2640 or 25 mg had at least a 17 U/L drop inalanine aminotransferase (ALT) at week 12 than did the placebo group (50% and30% vs 18%), and higher proportions taking the fatty acid synthase inhibitorreached a normal ALT at week 12 (58% and 33% vs 27%).

Compared with the placebo group, LDL cholesterol fell significantly more through12 weeks with 50 mg of TVB-2640 than with placebo (P < 0.005), andadiponectin rose significantly more with 50 mg of TVB-2640 than with placebo(24.1% vs 8.1%, P < 0.05). Fibrosis markers PIIINP and TIMP1 fellmore with TVB-2640, and for TIMP1 the difference was significant betweenTVB-2640 at 50 mg and placebo (P < 0.05).

Rates of grade 1 or grade 2 treatment-emergent adverse events were similar withplacebo and 25 mg or 50 mg of TVB-2640 (grade 1: 45.1%, 54.5%, 31.4%; grade 2:13.0%, 9.0%, 17.1%). Two treatment-emergent adverse events led to drugwithdrawal in the 25-mg TVB-2640 arm, while none did in the 50-mg arm or theplacebo group. No one taking placebo had a grade 2 treatment-emergent adverseevent, compared with 1 person (3%) taking 25 mg of TVB-2640 and 1 (2.9%) taking50 mg of TVB-2640.

No treatment-emergent serious adverse events arose during the trial. Pruritus,thrombocytopenia, or hypertriglyceridemia did not develop in any studyparticipants.

The researchers propose that their findings justify trials of TVB-2640 efficacyin improving NASH resolution and fibrosis in people with biopsy-proved NASH.

References
1. Loomba R, Rinella M, Harrison SA, et al. Novel first-in-class, fatty acidsynthase inhibitor, TVB-2640 versus placebo demonstrates clinically significantreduction in liver fat by MRI-PDFF in NASH: A phase 2 randomized controlledtrial (FASCINATE-1). EASL 2020, Digital International Liver Congress, August27-29, 2020. Abstract AS074.
2. Syed-Abdul MM,  Parks EJ, Gaballah AH,et al. Fatty acid synthase inhibitor TVB-2640 reduces hepatic de novolipogenesis in males with metabolic abnormalities. Hepatology. 2020;72:103-118.doi: 10.1002/hep.31000. Epub 2020 May 7.

StephenW

在NASA 2a期试验中，TVB-2640降低了肝脏脂肪，改善了纤维化

EASL 2020，数字国际肝脏大会，2020年8月27日至29日

马克·马斯科利尼

TVB-2640是一种脂肪酸合酶抑制剂，在一项安慰剂对照试验中招募了非酒精性脂肪性肝炎（NASH）的人，该药以剂量依赖性方式减少了肝脏脂肪，并改善了脂联素和纤维化指标[1]。该新型药物未引起瘙痒，血小板减少或高甘油三酯血症。

尽管在美国，NASH仍是肝硬化的最常见原因，也是肝移植的第二最常见原因，但尚未获得用于治疗这种疾病的任何药物的许可。从头脂肪形成（DNL）和脂毒性在NASH发病机理中起重要作用。在1b期临床试验中，TVB-2640抑制肝DNL的作用高达90％[2]。

2a期安慰剂对照试验旨在评估TVB-2640在通过磁共振成像衍生的蛋白质密度脂肪分数（MRI-PDFF）降低NASH患者肝脂肪中的功效。

参与者至少有8％的肝脏脂肪和磁共振弹性成像（MRE）在2.5 kPa或以上或近期活检。该试验排除了患有肝硬化或其他慢性肝病的人。研究人员每天一次或安慰剂将99名参与者按1比1比1至25或50毫克的TVB-2640进行随机分组。主要终点是在第12周时通过MRI-PDFF减少肝脏脂肪。

25 mg和50 mg TVB-2640组比安慰剂组稍大一点（中位数58和55 vs 52），他们的男性比例更高（54.5％和62.9％vs 45.2％），并且身体略高质量指数（34.0和32.8 vs 31.2千克/平方米）。 MRI-PDFF检测的基线肝脂肪在25 mg TVB-2640组（14.3％）比50 mg组（15.8％）或安慰剂组（15.3％）低。 2型糖尿病患者的比例范围从50 mg TVB-2640组的37.1％到安慰剂组的54.8％，以及25 mg组的75.8％。

在第12周时，MRI-PDFF显示平均相对肝脂肪呈剂量依赖性降低（50 mg为-28.2％，25 mg为-9.6％，安慰剂为+ 4.5％（TVB-2640与安慰剂相比P <0.005）和平均绝对肝脏脂肪（TVB-2640与安慰剂相比，50 mg为-5.1％，25 mg为-1.8％，安慰剂为-0.3％，P <0.001，相对于安慰剂，P <0.001）。 50 mg TVB-2640组（61％）的MRI-PDFF与基线相比下降至少30％（61％），比安慰剂组（11％）下降（P <0.001）。

与安慰剂组相比，服用50 mg TVB-2640或25 mg的人在第12周的丙氨酸转氨酶（ALT）下降至少17 U / L（50％和30％vs 18％），并且服用的比例更高脂肪酸合酶抑制剂在第12周达到了正常的ALT（58％和33％比27％）。

与安慰剂组相比，TVB-2640 50 mg组的LDL胆固醇在12周内的下降明显高于安慰剂组（P <0.005），TVB-2640 50 mg脂联素的升高明显高于安慰剂组（24.1％vs 8.1） ％，P ＜0.05）。纤维化标记物PIIINP和TIMP1在TVB-2640上下降更多，对于TIMP1，TVB-2640在50 mg和安慰剂之间有显着差异（P <0.05）。

发生1级或2级治疗紧急不良事件的发生率与安慰剂和25 mg或50 mg TVB-2640相似（1级：45.1％，54.5％，31.4％; 2级：13.0％，9.0％，17.1％ ）。在25毫克的TVB-2640组中出现了两个紧急治疗不良事件，导致药物停药，而在50毫克的组或安慰剂组中没有撤药。没有人服用安慰剂发生2级治疗紧急不良事件，相比之下，服用25 mg TVB-2640的1人（3％）和服用50 mg TVB-2640的1人（2.9％）。

在试验过程中没有出现治疗紧急的严重不良事件。任何研究参与者均未出现瘙痒，血小板减少或高甘油三酯血症。

研究人员认为，他们的发现证明了TVB-2640在改善经活检证实的NASH患者的NASH分辨率和纤维化方面的功效的试验是正确的。

参考文献
1. Loomba R，Rinella M，Harrison SA等。与安慰剂相比，新型一流的脂肪酸合酶抑制剂TVB-2640证明了MRI-PDFF在NASH中可显着降低肝脏脂肪：一项2期随机对照试验（FASCINATE-1）。 EASL 2020，数字国际肝脏大会，2020年8月27日至29日。摘要AS074。
2. Syed-Abdul MM，Parks EJ，Gaballah AH等。脂肪酸合酶抑制剂TVB-2640可减少患有代谢异常的男性的肝脏新生脂肪形成。肝病学。 2020; 72：103-118。 doi：10.1002 / hep.31000。 Epub 2020年5月7日。