虽然缺少终点，但Emricasan降低了肝硬化的门静脉压力

StephenW

Emricasan reduces portal pressure in cirrhosis despite missing endpoint
April 13, 2019

VIENNA — Emricasan missed its primary endpoint of hepatic venous pressure gradient reduction in all patients with nonalcoholic steatohepatitis-related compensated cirrhosis and severe portal hypertension but showed meaningful reductions in portal pressure among patients with high-risk disease, according to a presentation at the International Liver Congress 2019.

“Severe portal hypertension in cirrhosis is a key driver of decompensation and decompensation, in turn, is a key driver of death,” Guadalupe Garcia-Tsao, MD, from Yale University in Connecticut, said during her presentation. “We have recently shown that decreases in [hepatic venous pressure gradient (HVPG)] as small as 1 mmHg have been associated with a reduction in risk for decompensation or death.”

Previously, the oral pan-caspase inhibitor emricasan showed decreases in portal pressure and improved survival in cirrhosis models along with reductions in HVPG in patients with cirrhosis who had HVPG of 12 mmHg or higher.

In this phase 2b study designed to confirm these effects, Garcia-Tsao and colleagues randomly assigned 263 patients to receive 5 mg (n = 65), 25 mg (n = 65) or 50 mg (n = 66) of emricasan or placebo (n = 67) twice daily for 48 weeks. The primary endpoint of HVPG reduction was measured at 24 weeks.

While the endpoint was not met in all patients, a post-hoc analysis showed that HVPG decreased in treated participants with compensated cirrhosis who had HVPG of 16 mmHg or higher compared with placebo.

The mean changes from baseline in the patients with high-risk disease were –1.6 mmHg (5 mg group), –1.7 mmHg (25 mg group), –1.5 mmHg (50 mg group) compared with an increase of 0.5 mmHg in the placebo group (P < .05 for each treatment group vs. placebo).

Additionally, alanine aminotransferase decreased by 3 U/L to 5 U/L and aspartate aminotransferase decreased by 2 U/L to 6 U/L in most treated patients compared with placebo (P < .05).

Treatment-related adverse events were similar between treated groups and placebo. Severe adverse events occurred in 17.9% of treated patients and 11.9% of the placebo group.

“We await completion of the 48-week study for full safety data and clinical outcome events,” Garcia-Tsao said. “These results support additional exploration of emricasan in patients with severe portal hypertension.” – by Talitha Bennett



Reference:

Garcia-Tsao G. Abstract LB-01. Presented at: International Liver Congress; April 10-14, 2019; Vienna, Austria.

StephenW

虽然缺少终点，但Emricasan降低了肝硬化的门静脉压力
2019年4月13日

维也纳 -  Emricasan在所有患有非酒精性脂肪性肝炎相关代偿性肝硬化和严重门静脉高压的患者中错过了其肝静脉压力梯度降低的主要终点，但在高风险疾病患者中显示门静脉压力显着降低，根据国际肝脏的介绍国会2019年。

康涅狄格州耶鲁大学医学博士Guadalupe Garcia-Tsao在她的演讲中表示，“肝硬化严重的门静脉高压是失代偿和失代偿的关键因素，反过来也是导致死亡的关键因素”。 “我们最近表明，[肝静脉压力梯度（HVPG）]降低至1 mmHg与失代偿或死亡风险降低有关。”

此前，口服泛caspase抑制剂emricasan显示肝硬化模型中门静脉压力降低和存活率提高，以及HVPG为12 mmHg或更高的肝硬化患者HVPG降低。

在这项旨在证实这些影响的2b期研究中，Garcia-Tsao及其同事随机分配了263名患者接受5 mg（n = 65），25 mg（n = 65）或50 mg（n = 66）的emricasan或安慰剂（ n = 67）每天两次，持续48周。在24周时测量HVPG降低的主要终点。

虽然所有患者均未达到终点，但事后分析显示，与安慰剂相比，HVPG为16 mmHg或更高的患有代偿性肝硬化的治疗参与者的HVPG降低。

高风险患者的基线平均变化为-1.6 mmHg（5 mg组），-1.7 mmHg（25 mg组），-1.5 mmHg（50 mg组），而安慰剂组增加0.5 mmHg组（每个治疗组与安慰剂组P <.05）。

此外，与安慰剂相比，大多数接受治疗的患者丙氨酸氨基转移酶降低3 U / L至5 U / L，天冬氨酸氨基转移酶降低2 U / L至6 U / L（P <.05）。

治疗组和安慰剂组之间的治疗相关不良事件相似。 17.9％的治疗患者和11.9％的安慰剂组发生严重不良事件。

“我们等待完成48周的完整安全性数据和临床结果事件的研究，”Garcia-Tsao说。 “这些结果支持对患有严重门静脉高压症的患者进行额外的emricasan探查。” - 由Talitha Bennett撰写



参考：

Garcia-Tsao G.摘要LB-01。发表于：国际肝脏大会; 2019年4月10日至14日;维也纳，奥地利。

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