地那非司他治疗代谢相关脂肪性肝炎：一项多中心、双盲、随机、安慰剂对照、2b 期临床试验。

Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial.

机构信息

MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, CA, USA.

Liverpat, Paris, France.

出版信息

Lancet Gastroenterol Hepatol. 2024 Dec;9(12):1090-1100. doi: 10.1016/S2468-1253(24)00246-2. Epub 2024 Oct 11.

DOI:10.1016/S2468-1253(24)00246-2

PMID:39396529

Abstract

BACKGROUND

Denifanstat, an oral fatty acid synthase (FASN) inhibitor, blocks de-novo lipogenesis, a key pathway driving progressive lipotoxicity, inflammation, and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to examine the safety and efficacy of denifanstat for improving liver histology in individuals with MASH and moderate to advanced fibrosis.

METHODS

This multicentre, double-blind, randomised, placebo-controlled, phase 2b trial was conducted at 100 clinical sites in the USA, Canada, and Poland. After a screening period of up to 90 days, participants aged 18 years and older with biopsy-confirmed MASH and stage F2 or F3 fibrosis were randomly assigned (2:1) to receive either 50 mg oral denifanstat or placebo once per day for 52 weeks. Participants were dynamically allocated to treatment groups via a centrally administered interactive web-based response system and stratified by type 2 diabetes, region, and fibrosis stage. Investigators, patients, and the sponsor were masked to group allocation until database lock. The primary efficacy endpoints were a 2-point or greater improvement in non-alcoholic fatty liver disease activity score (NAS) without a worsening of fibrosis or MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis at week 52, assessed by intention to treat. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04906421, and is closed for enrolment.

FINDINGS

Of the 1087 individuals screened between June 2, 2021, and June 28, 2022, 168 eligible participants were randomly assigned to receive a dose of 50 mg denifanstat once per day (n=112) or placebo (n=56). All 168 participants (100 female, 68 male) received at least one dose of study treatment. In the ITT population, 42 (38%) of 112 participants in the denifanstat group had a 2-point or greater improvement in NAS without a worsening of fibrosis versus nine (16%) of 56 participants in the placebo group (common risk difference 21·0%, 95% CI 8·1-33·9; p=0·0035). 29 (26%) of 112 participants in the denifanstat group showed MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis compared with six (11%) of 56 participants in the placebo group (common risk difference 13·0%, 0·7-25·3; p=0·0173). The most common treatment-emergent adverse events were COVID-19 (19 [17%] of 112 in the denifanstat group vs six [11%] of 56) in the placebo group, dry eye symptoms (ten [9%] of 112 vs eight [14%] of 56), and alopecia (21 [19%] of 112 vs two [4%] of 56). All adverse events considered to be related to the study drug were of grade 1 or grade 2. None of the serious adverse events (13 [12%] of 112 participants in the denifanstat group vs three [5%] of 56 in the placebo group) were considered drug-related.

INTERPRETATION

Treatment with denifanstat resulted in statistically significant and clinically meaningful improvements in disease activity, MASH resolution, and fibrosis. The results of this phase 2b trial support the advancement of denifanstat to phase 3 development.

FUNDING

Sagimet Biosciences.

摘要

背景

Denifanstat 是一种口服脂肪酸合酶（FASN）抑制剂，可阻断从头合成脂肪，这是代谢功能相关脂肪性肝炎（MASH）中导致进行性脂肪毒性、炎症和纤维化的关键途径。本研究旨在研究 denifanstat 改善代谢功能相关脂肪性肝炎合并中重度纤维化患者肝组织学的安全性和有效性。

方法

这项多中心、双盲、随机、安慰剂对照、2b 期临床试验在美国、加拿大和波兰的 100 个临床中心进行。在长达 90 天的筛选期后，年龄在 18 岁及以上、经活检证实为 MASH 且纤维化分期为 F2 或 F3 的患者被随机分为 denifanstat 50mg 组或安慰剂组，每天口服一次，持续 52 周。通过中央管理的交互式网络响应系统对参与者进行动态分组，并根据 2 型糖尿病、地区和纤维化分期进行分层。研究者、患者和赞助商在数据库锁定前对分组情况不知情。主要疗效终点为非酒精性脂肪性肝病活动评分（NAS）改善 2 分或以上且无纤维化恶化或 MASH 改善 2 分或以上且无纤维化恶化，52 周时通过意向治疗进行评估。在接受至少一剂研究药物的所有参与者中评估安全性。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT04906421，现已关闭入组。

结果

在 2021 年 6 月 2 日至 2022 年 6 月 28 日期间筛选的 1087 名患者中，有 168 名符合条件的患者被随机分配接受 50mg denifanstat 每日一次（n=112）或安慰剂（n=56）。所有 168 名患者（100 名女性，68 名男性）均接受了至少一剂研究治疗。在 ITT 人群中，denifanstat 组 112 名患者中有 42 名（38%）的 NAS 改善 2 分或以上且无纤维化恶化，安慰剂组 56 名患者中有 9 名（16%）（常见风险差 21.0%，95%CI 8.1-33.9；p=0.0035）。与安慰剂组 56 名患者中的 6 名（11%）相比，denifanstat 组 112 名患者中有 29 名（26%）的 MASH 缓解且 NAS 改善 2 分或以上且无纤维化恶化（常见风险差 13.0%，0.7-25.3；p=0.0173）。最常见的治疗期不良事件是 COVID-19（denifanstat 组 112 名患者中有 19 名[17%]，安慰剂组 56 名患者中有 6 名[11%]）、干眼症症状（denifanstat 组 112 名患者中有 10 名[9%]，安慰剂组 56 名患者中有 8 名[14%]）和脱发（denifanstat 组 112 名患者中有 21 名[19%]，安慰剂组 56 名患者中有 2 名[4%]）。所有被认为与研究药物相关的不良事件均为 1 级或 2 级。denifanstat 组 112 名患者中有 13 名（12%）的严重不良事件（安慰剂组 56 名患者中有 3 名[5%]）被认为与药物相关。