Fc-FGF21融合蛋白可减少肝脏脂肪，改善4臂NASH试验中的纤维化

StephenW

Fc-FGF21 Fusion Protein Cuts Liver Fat, Improves Fibrosis in 4-Arm NASH Trial

AASLD The Liver Meeting Digital Experience, November 13-16, 2020

Mark Mascolini

Efruxifermin (EFX), a once-weekly subcutaneous fibroblast growth factor-21 (FGF21) analog, cut liver fat and improved fibrosis stage in a 16-week 4-arm randomized comparison with placebo in 80 people with nonalcoholic steatohepatitis (NASH) [1]. NASH resolved in about half of study participants biopsied by week 16.

Based on a fusion polypeptide of human IgG1 Fc and FGF21, EFX aims to control NASH by lowering liver fat, inflammation, and fibrosis while restoring healthy lipid metabolism in the liver [2]. By improving lipid function, EFX targets cardiovascular disease, the leading cause of death in people with NASH.

Conducted by US clinical researchers and Akero Therapeutics, this phase 2a trial randomized 80 people with biopsy-confirmed NASH to 28, 50, or 70 mg of subcutaneous EFX weekly or to placebo for 16 weeks. Participants had at least 10% liver fat, a nonalcoholic fatty liver disease (NAFLD) Activity Score of 4 or more, and fibrosis stage F1-3. People with at least a 30% relative drop in liver fat by week 12 underwent end-of-study biopsy to assess changes in fibrosis and NAFLD Activity Score.

While 21 participants received placebo, 19 got 28 mg of EFX subcutaneously once weekly, 20 got 50 mg, and 20 got 70 mg. Average age stood in the low 50s in all four trial arms, and 34 of 80 participants (42.5%) were men. MRI-PDFF-measured liver fat content ranged from 18.3% to 21.4% across the 4 study groups, NAFLD Activity Score from 5.1 to 5.6, and percentage with F2-3 fibrosis from 62% to 65%.

At week 12 all 3 EFX groups had a 12% or greater average absolute reduction in liver fat from baseline, compared with 0% in the placebo group (P < 0.001 for all three EFX groups versus placebo). Proportions with at least a 50% relative reduction in liver fat at week 12 were 69% (n = 16) with 28 mg of EFX, 100% (n = 17) with 50 mg, 93% (n = 19) with 70 mg, and 5% (n = 20) with placebo (all differences between EFX and placebo statistically significant). Respective proportions with at least a 70% relative drop liver fat at week 12 were 50%, 53%, 80%, and 5% (all differences from placebo significant). Proportions with normalized liver fat content by week 12 were 25% with 28 mg of EFX, 53% with 50 mg, 67% with 70 mg, and 5% with placebo (all differences from placebo statistically significant).

Thirteen people getting 28 mg of EFX, 13 getting 50 mg, 14 getting 70 mg, and 2 on placebo had at least a 30% relative reduction in liver fat by week 12 and so became eligible for end-of-study (16-week) assessment of fibrosis and NAFLD Activity Score. At that point 6 of 13 (46%) in the 28-mg EFX group, 7 of 13 (54%) in the 50-mg group, 6 of 14 (43%) in the 70-mg group, and 1 of 2 (50%) in the placebo group had NASH resolution without worsening fibrosis. For the combined EFX arms, 48% had NASH resolution at week 16.

At week 16 fibrosis improved by at least 1 stage without NASH worsening in 6 of 13 people (46%) getting 28 mg of EFX, 8 of 13 (62%) getting 50 mg, 5 of 14 (36%) getting 70 mg, and 0 of 2 getting placebo. Among all 40 EFX-treated people, 55% had improved fibrosis at week 16, 35% had no change, and 10% had worse fibrosis. Among 22 EFX-treated participants with baseline F2-F3 fibrosis, 68% had a 1- or 2-stage fibrosis improvement at week 16, 23% had no change, and 9% had worse fibrosis.

By treatment week 8, both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) dropped about 40% from baseline values in all three EFX arms while remaining unchanged in the placebo group. ALT and AST maintained those levels in all four groups through week 16.

After 12 weeks ALT absolute change from baseline fell 24 U/L in the 28-mg EFX group, 30 U/L in the 50-mg group, 32 U/L in the 70-mg group, and 5.9 U/L in the placebo group. Respective week-16 absolute changes in HbA1c, a diabetes marker, were -0.1%, -0.4%, -0.5%, and +0.1%. “Good” high-density lipoprotein cholesterol rose by 34%, 39%, 41%, and 4% from baseline to week 16. Over that period triglycerides fell 39%, 48%, and 46% in the 3 EFX groups and rose 6% in the placebo group. Through 16 weeks average “bad” low-density lipoprotein cholesterol fell 16%, 2%, and 6% in the 3 EFX arms and did not change in the placebo arm.

Two people receiving 28 mg of EFX, 4 receiving 70 mg of EFX, and 1 receiving placebo had a treatment-emergent adverse event leading them to stop treatment. One person in the 28-mg EFX group and 1 in the 70-mg group had a serious adverse event. Transient mild or moderate gastrointestinal distress was the most frequent adverse event.

EFX joins lanifibranor [3] as one of the first two agents that both improved fibrosis and resolved NASH in a randomized trial.

References
1. Harrison SA, Ruane PJ, Freilich BL, et al. Efruxifermin (EFX), a long-acting Fc-FGF21 fusion protein, administered for 16 weeks to patients with NASH substantially reduces liver fat and ALT, and improves liver histology: analysis of a randomized, placebo-controlled, phase 2a study (BALANCED). AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 8.
2. Akero. Efruxifermin (EFX): a multi-modal drug. https://akerotx.com/efruxifermin/
3. Francque S, Bedossa P, Ratziu V, et al. The panPPAR agonist lanifibranor induces both resolution of NASH and regression of fibrosis after 24 weeks of treatment in non-cirrhotic NASH: results of the native phase 2b trial. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 12. (Reported separately by NATATP at the AAFLD Liver Meeting.)

StephenW

Fc-FGF21融合蛋白可减少肝脏脂肪，改善4臂NASH试验中的纤维化

AASLD肝脏会议数字体验，2020年11月13日至16日

马克·马斯科利尼

Efruxifermin（EFX），每周一次的皮下成纤维细胞生长因子21（FGF21）类似物，在80周的非酒精性脂肪性肝炎（NASH）患者中与安慰剂进行16周4组随机比较，减少了肝脏脂肪并改善了纤维化阶段[1 ]。到第16周时，约有一半的研究参与者完成了NASH的治疗。

EFX基于人IgG1 Fc和FGF21的融合多肽，旨在通过降低肝脏脂肪，炎症和纤维化同时恢复肝脏中健康的脂质代谢来控制NASH [2]。通过改善脂质功能，EFX靶向心血管疾病，这是NASH患者死亡的主要原因。

由美国临床研究人员和Akero Therapeutics进行的这项2a期试验每周将80例经活检证实的NASH患者随机分配至28、50或70 mg皮下EFX或安慰剂治疗16周。参与者的肝脂肪至少为10％，非酒精性脂肪肝疾病（NAFLD）活动得分为4或更高，并且纤维化阶段为F1-3。到第12周肝脂肪相对下降至少30％的人接受研究结束后的活检，以评估纤维化和NAFLD活动评分的变化。

21名参与者接受了安慰剂，其中19名参与者每周一次皮下注射28毫克EFX，20名参与者获得50毫克，20名参与者获得70毫克。在所有四个试验组中，平均年龄均处于50岁以下的低位，在80名参与者中，有34名（42.5％）是男性。在四个研究组中，MRI-PDFF测量的肝脂肪含量范围从18.3％到21.4％，NAFLD活动评分从5.1到5.6，F2-3纤维化的百分比从62％到65％。

在第12周时，所有3个EFX组的肝脏脂肪平均绝对减少量均较基线水平高12％，而安慰剂组为0％（与安慰剂相比，所有3个EFX组的P <0.001）。在第12周时，肝脏脂肪相对减少至少50％的比例为：EFX 28 mg时为69％（n = 16），50 mg时为100％（n = 17），70 mg时为93％（n = 19） ，以及使用安慰剂的5％（n = 20）（EFX和安慰剂之间的所有差异均具有统计学意义）。在第12周，相对脂肪含量下降至少70％的相应比例分别为50％，53％，80％和5％（与安慰剂的所有差异均显着）。到12周时，具有正常肝脂肪含量的比例分别为：使用EFX 28 mg时为25％，使用50 mg时为53％，使用70 mg时为67％，使用安慰剂时为5％（与安慰剂相比所有差异均具有统计学意义）。

服用安慰剂的13人获得EFX 28 mg，13人获得50 mg，14人获得70 mg，其中2人在第12周时肝脂肪相对减少至少30％，因此有资格接受研究结束（16周）评估纤维化和NAFLD活动评分。此时，28 mg EFX组中有13人中有6人（46％），50 mg组中有7人中有13人（54％），70 mg组中有14人中有6人（43％），2组中有1人安慰剂组（50％）的NASH缓解率并未恶化纤维化。对于合并的EFX部门，第16周有48％的人具有NASH分辨率。

在第16周，纤维化至少改善了1个阶段，而NASH却没有恶化，其中13人中有6人（46％）得到28 mg EFX，13人中有8人（62％）得到50 mg，14人中5人（36％）得到70 mg，还有2人中有0人获得安慰剂。在接受EFX治疗的所有40位患者中，第16周有55％的患者纤维化改善，其中35％的患者无变化，而10％的患者纤维化更严重。在22名接受FFX-F3基线纤维化治疗的参与者中，有68％的患者在第16周出现了1或2期纤维化改善，23％的患者无变化，9％的患者的纤维化更严重。

到第8周治疗时，所有三个EFX组的丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）均较基线值下降了约40％，而安慰剂组保持不变。到第16周，ALT和AST在所有四个组中均保持这些水平。

12周后，ALT相对于基线的绝对变化在28 mg EFX组下降了24 U / L，在50 mg组下降了30 U / L，在70 mg组下降了32 U / L，而在5.9 mg / L下降了5.9 U / L。安慰剂组。第16周糖尿病指标HbA1c的绝对变化分别为-0.1％，-0.4％，-0.5％和+ 0.1％。从基线到第16周，“良好”的高密度脂蛋白胆固醇分别上升了34％，39％，41％和4％。在此期间，三个EFX组中的甘油三酸酯下降了39％，48％和46％，上升了6个安慰剂组中的百分比。在16周内，三个EFX组的平均“坏”低密度脂蛋白胆固醇分别下降了16％，2％和6％，而安慰剂组没有变化。

接受28毫克EFX的两个人，接受70毫克EFX的4个人和接受安慰剂的1个人出现了治疗紧急不良事件，导致他们停止治疗。 28 mg EFX组中的1人和70 mg组中的1人有严重不良事件。短暂的轻度或中度胃肠道不适是最常见的不良事件。

在一项随机试验中，EFX与lanifibranor [3]一起成为首批同时改善纤维化和解决NASH的两种药物之一。
参考文献
1. Harrison SA，Ruane PJ，Freilich BL等。 Efruxifermin（EFX）是一种长效Fc-FGF21融合蛋白，向NASH患者给药16周可显着降低肝脏脂肪和ALT，并改善肝脏组织学：一项随机，安慰剂对照的2a期研究的分析（平衡） 。 AASLD肝脏会议数字体验，2020年11月13日至16日。摘要8。
2. Akero。 Efruxifermin（EFX）：一种多模式药物。 https://akerotx.com/efruxifermin/
3.弗朗克·S，贝多萨·P，拉齐乌·V等。 在非肝硬化性NASH中治疗24周后，panPPAR激动剂Lanifibranor既诱导了NASH的分解，又诱导了纤维化的消退：天然2b期试验的结果。 AASLD肝脏会议数字体验，2020年11月13日至16日。摘要12.（由NATATP在AAFLD肝脏会议上另行报告。）