桥接可归因于NASH的纤维化和肝硬化的联合疗法

StephenW

Combination Therapies for Bridging Fibrosis and Cirrhosis Attributable to NASH

Hepatology (Baltimore, Md.)

TAKE-HOME MESSAGE

    This was a phase IIb randomized controlled trial that enrolled patients with cirrhosis or advanced fibrosis to receive placebo, selonsertib, cilofexor, or firsocostat either alone or in combination for 48 weeks. The primary endpoint was at least a one-stage improvement in fibrosis with no worsening of NASH at 48 weeks.
    Overall, 11% of the individuals in the placebo group met the primary endpoint. There was no statistically significant difference among any of the drugs, either alone or in combination. Patients receiving cilofexor and firsocostat in combination did have a significant reduction in the NAFLD Activity Score and serum markers of inflammation. Further study is warranted to see whether this combination can lead to long-term improvements in fibrosis.

– Natasha  VonRoenn, MD
abstract

This abstract is available on the publisher's site.
BACKGROUND AND AIMS

Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease.
APPROACH AND RESULTS

In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients.
CONCLUSIONS

In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH.

StephenW

桥接可归因于NASH的纤维化和肝硬化的联合疗法

肝病学（马里兰州巴尔的摩）

寄回家的消息

    这是一项IIb期随机对照试验，该试验招募了患有肝硬化或晚期纤维化的患者，单独或联合接受安慰剂，selonsertib，cilofexor或fisocostat治疗48周。主要终点指标是纤维化至少改善了一个阶段，而在48周时NASH并未恶化。
    总体而言，安慰剂组中有11％的患者达到了主要终点。单独使用或联合使用的任何一种药物在统计学上均无统计学差异。合并使用cilofexor和fisocostat的患者的NAFLD活性评分和血清炎症标志物的确有明显降低。有必要进行进一步的研究，以查看这种组合是否可以导致纤维化的长期改善。

–医学博士Natasha VonRoenn
抽象的

该摘要可在发布者的网站上找到。
背景与目的

可归因于NASH的晚期纤维化是终末期肝病的主要原因。
方法和结果

在此2b期临床试验中，随机将392例桥接纤维化或代偿性肝硬化（F3-F4）患者随机接受安慰剂，selonsertib 18 mg，cilofexor 30 mg或fisocostat 20 mg单独或以两种药物合用。 48周。根据中央病理学家的审查，主要终点是纤维化≥1阶段改善，而基线至48周之间NASH并未恶化。探索性终点包括NAFLD活动评分（NAS）的变化，使用机器学习（ML）方法评估的肝脏组织学，肝脏生物化学和非侵入性标记物。多数患有肝硬化（56％）和NAS≥5（83％）。主要终点指标在接受安慰剂治疗的患者中达到11％，而西洛法司特/非洛司他（21％; P = 0.17），西洛司匹克/塞洛塞替尼（19％; P = 0.26），非司他司酮/塞洛塞替尼（15％; P = 0.62），司可司他（12％; P = 0.94）和西罗氟沙星（12％; P = 0.96）。通过形态学测定的肝胶原蛋白变化不显着，但西洛法克司/非司他司通导致ML NASH CRN纤维化评分显着降低（P = 0.040），并且活检区域从F3-F4转变为≤F2纤维化模式。与安慰剂相比，西洛法索/非司他司酮患者的NAS减少≥2点的比例更高；减少脂肪变性，小叶炎症和膨胀；并通过瞬时弹性成像显着改善了丙氨酸氨基转移酶（ALT），天冬氨酸氨基转移酶（AST），胆红素，胆汁酸，细胞角蛋白18，胰岛素，估计的肾小球滤过率，ELF评分和肝硬度（所有P≤0.05）。 cilofexor发生瘙痒的比例为20％-29％，而安慰剂治疗的患者为15％。
结论

在具有桥接纤维化和肝硬化的患者中，对48周的cilofexor / firsocostat耐受良好，可改善NASH活性，并可能具有抗纤维化作用。这种组合为患有NASH的晚期纤维化患者提供长期治疗的潜在纤维化消退潜力。