近80％对NASH的新生长因子作出反应

StephenW

Nearly 80% respond to novel growth factor for NASH
April 22, 2017

AMSTERDAM — With 12 weeks of treatment, more than one-third of biopsy-diagnosed non-alcoholic steatohepatitis patients who received novel growth factor NGM282 achieved normal liver fat content, according to data at the International Liver Congress.

“There were significant and rapid reductions in multiple markers that are relevant to the resolution of NASH and improvement in fibrosis, although more work needs to be done to define this histopathologically,” Stephen A. Harrison, MD, medical director at Pinnacle Clinical Research and visiting professor of hepatology at the Radcliffe Department of Medicine at University of Oxford, U.K., said during his late breaker presentation. “The data strongly support continued development in non-alcoholic steatohepatitis.”

Harrison explained that NGM282 (NGM Bio) is an engineered variant of human fibroblast growth factor 19 (FGF19). The researchers in the randomized, double-blinded, placebo controlled trial looked to test its safety and efficacy in treating NASH.

The study group included 82 individuals across 18 sites in Australia and the United States. Subjects had biopsy-confirmed NASH and a NASH activity score greater than 4, stage 1, 2 or 3 fibrosis, a minimum of 8% absolute liver fat content by MRI-PDFF and abnormal ALT.

Harrison and colleagues randomized patients to placebo, NGM282 3 mg or NGM282 6 mg for 12 weeks. All three groups were similarly matched at baseline. Response was defined as greater than a 5% decrease in fat content at 12 weeks and normalization was defined as absolute liver fat content less than 5% at 12 weeks.

Primary endpoints

No placebo-treated participants normalized at 12 weeks, but 25.9% in the 3-mg group and 42.3% in the 6-mg group normalized by that time frame. In the 3-mg group, 74% of participants responded, while 85% of those in the 6-mg group responded for an overall response of 79%.

“Importantly, 34% of the treated cohort achieved normal liver fat content. This wasn’t limited to minimal fat content in the liver. ... Significant fat reductions were seen with patients with high levels of fat content,” Harrison said.

He showed that the placebo group had a 0.9% decrease in absolute liver fat while the 3-mg group had a 9.7% decrease (P < .001) and the 6-mg group had an 11.9% decrease (P < .001). Patients in the placebo group experienced a 1% relative decrease in liver fat, as compared to a 47% relative decrease in the 3 mg group (P <.001) and a 61% relative decrease in the 6 mg group (P < .001), according to Harrison.

“Importantly, 89% of subjects achieved a clinically meaningful, greater than 30% relative change in fat,” Harrison said. “Also, the decreases in liver fat strongly correlated with reductions in ALT, AST and serum C4 levels.”


In those with baseline MRI-PDFF greater than 20%, the participants who received 3 mg of NGM282 dropped from 26.1% liver fat content to 13.2% liver fat content (P = .002), while those who received 6 mg dropped from 26.8% liver fat content to 7.9% liver fat content (P < .001) at 12 weeks.

Other metrics

Harrison said the decreases in ALT also support the overall reductions in inflammation.

“Overall, 36% of subjects normalized the ALT, the majority of those by week 2,” he said. It was “a rapid and profound reduction of ALT by week 2. This was sustained throughout the course of therapy.”

He showed that triglycerides decreased slightly, while LDL increased, though data also presented at the meeting showed addition of a statin normalized these outcomes. Further studies will be conducted, according to Harrison.

“Ultimately, there was significant absolute and percentage change in total ELF score for 3 mg NGM282 cohort with numeric decreases observed with 6 mg cohort and no significant changes observed in hyaluronic acid,” he said.

In the safety report, Harrison said there were mostly “mild and general” adverse events and only one severe adverse event — pancreatitis — was possibly related.

Lastly, Harrison reported significant weight reduction with 6-mg NGM282 vs. placebo (–2.6 kg vs –0.7, P = 0.023), but not at the 3-mg dose.

“The decrease in liver fat content appears independent of weight loss,” he said. – by Katrina Altersitz

Reference:

Harrison SA. LBO-08. Presented at: International Liver Congress; April 19-24, 2017; Amsterdam.

Disclosures: Harrison reports being on the speakers’ bureaus of Alexion and Gilead Sciences; acting as a consultant or advisory board member for Allergan, Chronic Liver Disease Foundation, Cirius, Echosens, Fibrogen, Galmed, Genfit, Gilead, Intercept, Madrigal, NGM Bio, Novartis, Perspectum and Pfizer; and receiving grant or research support from Allergan, Conatus, Galectin, Galmed, Genfit, Gilead, Immuron, Intercept, Madrigal, NGM Bio and Taiwan J.

StephenW

近80％对NASH的新生长因子作出反应
2017年4月22日

AMSTERDAM - 根据国际肝脏大会的数据，经过12周的治疗，接受新生长因子NGM282的活检诊断非酒精性脂肪性肝炎患者的三分之一以上达到正常的肝脏脂肪含量。

Pinnacle临床研究医学总监Stephen A. Harrison博士说：“与NASH的分辨率和纤维化改善相关的多重标记物有显着和快速的减少，尽管需要做更多的工作来确定组织病理学。”英国牛津大学拉德克利夫医学系肝病学访问教授在他迟到的演讲中表示。 “数据大力支持非酒精性脂肪性肝炎的持续发展。”

哈里森解释说，NGM282（NGM Bio）是人类成纤维细胞生长因子19（FGF19）的工程变体。随机，双盲，安慰剂对照试验的研究人员试图测试其治疗NASH的安全性和疗效。

研究组在澳大利亚和美国的18个地点共有82人。受试者具有活检证实的NASH和NASH活动评分大于4，1级，2级或3级纤维化，MRI-PDFF和ALT异常至少为8％的绝对肝脏脂肪含量。

Harrison和同事将患者随机分为安慰剂，NGM282 3 mg或NGM282 6 mg，持续12周。所有三组在基线时相似。反应定义为在12周时脂肪含量降低5％，正常化定义为12周时绝对肝脏脂肪含量低于5％。

主要端点

没有安慰剂治疗的参与者在12周时归一化，但3 mg组为25.9％，6 mg组为42.3％。在3mg组中，74％的受试者作出反应，而6mg组中85％的患者反应总体反应为79％。

“重要的是，34％的治疗队列达到了正常的肝脏脂肪含量。这不仅限于肝脏中最小的脂肪含量。哈里森说：“脂肪含量高的患者，脂肪减少显着。

他表明，安慰剂组绝对肝脏脂肪减少0.9％，而3-mg组下降9.7％（P <0.001），6 mg组下降11.9％（P <0.001）。安慰剂组患者肝脏脂肪相对减少1％，而3mg组相对降低47％（P <0.001），6mg组相对降低61％（P <0.001） ），根据哈里森。
“重要的是，89％的受试者获得了临床上有意义的，超过30％的脂肪相对变化，”哈里森说。 “而且，肝脏脂肪减少与ALT，AST和血清C4水平的降低密切相关。”


在基线MRI-PDFF大于20％的患者中，接受3mg的NGM282的参与者从肝脏脂肪含量的26.1％下降到13.2％的肝脏脂肪含量（P = .002），而6mg的患者从26.8％肝脏脂肪含量在12周时达到7.9％的肝脏脂肪含量（P <0.001）。

其他指标

哈里森说，ALT的减少也支持炎症的总体减少。

他说：“总体而言，36％的受试者对ALT进行标准化，其中绝大多数是第2周。这是“在第2周急剧减少ALT。这在治疗过程中是持续的。”

他表明甘油三酸酯略有下降，而低密度脂蛋白增加，尽管在会议上提供的数据显示，加入他汀类药物使这些结果标准化。哈里森将进一步研究。

“最终，3 mg NGM282队列的总ELF评分有绝对百分比和百分比变化，其中6毫克队列观察到数字下降，透明质酸无明显变化。”他说。

在安全报告中，哈里森说，大多数“轻度和一般”不良事件，只有一个严重的不良事件 - 胰腺炎可能相关。

最后，哈里森报道6-mg NGM282与安慰剂相比显着降低（-2.6 kg vs -0.7，P = 0.023），但不是3 mg剂量。

他说：“肝脏脂肪含量的下降与减肥有关。 - 由Katrina Altersitz

参考：

哈里森LBO-08。主讲：国际肝会; 2017年4月19日至24日阿姆斯特丹

披露：哈里森报告是在亚历山大和吉利德科学院的发言人的局;担任Allergan，慢性肝病基金会，Cirius，Echosens，Fibrogen，Galmed，Gen​​fit，Gilead，Intercept，Madrigal，NGM Bio，Novartis，Perspectum和辉瑞的顾问或咨询委员会成员;并获得Allergan，Conatus，Galectin，Galmed，Gen​​fit，Gilead，Immuron，Intercept，Madrigal，NGM Bio和Taiwan J.的资助或研究支持。