Background

AMP kinase (AMPK) is an energy sensor implicated in regulation of lipid metabolism, inflammation, and insulin sensitivity. We aimed to assess efficacy and safety of PXL770, a novel direct AMPK activator, in patients with non-alcoholic fatty liver disease (NAFLD).

Methods

STAMP-NAFLD, a randomised, double-blind, placebo-controlled phase 2a study, was done across 15 US clinical sites. Patients aged 18–75 years with liver fat content of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned (1:1:1:1), via an interactive web response system, to receive oral PXL770 250 mg once daily, 250 mg twice daily, or 500 mg once daily, or matched placebo. Patients were stratified according to type 2 diabetes status and study site. The primary endpoint was relative change in liver fat content from baseline compared with placebo at week 12, assessed by MRI-PDFF. The primary endpoint was analysed in an ANCOVA model with treatment and stratification criteria as factors and baseline liver fat content as a covariate in the modified intention-to-treat population, defined as all as-randomised patients who received at least one dose of study treatment. Safety was analysed in the safety population, defined as all as-treated patients receiving at least one dose of the study treatment. The trial has been completed and the final results are reported. The trial is registered with ClinicalTrials.gov, NCT03763877.

Findings

Between March 29, 2019, and March 13, 2020, 387 patients were screened, of whom 120 were included in the modified intention-to-treat and safety analyses (30 in the 250 mg once daily group, 30 in the 250 mg twice daily group, 29 in the 500 mg once daily group, and 31 in the placebo group). The mean relative change from baseline in liver fat content at week 12 was −1·1% in the placebo group, −1·0% in the 250 mg once daily group (mean difference versus placebo 0·1% [95% CI −15·4 to 15·7], p=0·99), −14·3% in the 250 mg twice daily group (−13·1% [–28·1 to 1·8], p=0·084), and −14·7% in the 500 mg once daily group (−13·5% [–28·5 to 1·4], p=0·076). At least one treatment-emergent adverse event occurred in 23 (77%) of 30 patients in the 250 mg once daily group, 20 (67%) of 30 patients in the 250 mg twice daily group, 21 (72%) of 29 patients in the 500 mg once daily group, and 21 (68%) of 31 patients in the placebo group. The most common treatment-emergent adverse event was diarrhoea (five [17%] of patients in the 250 mg once daily group, seven [23%] in the 250 mg twice daily group, six [21%] in the 500 mg once daily group, and none in the placebo group). No life-threatening events or treatment-related deaths occurred.

Interpretation

PXL770 treatment did not meet the primary outcome of liver fat improvement compared with placebo. Treatment was well tolerated. Given indications that metabolic features improved with PXL770 treatment, AMPK activation might be a promising pharmacological target for patients with type 2 diabetes and NAFLD, and could also be considered for further assessment in patients with non-alcoholic steatohepatitis.

Funding

Poxel.

中文翻译：

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PXL770，一种直接 AMP 激酶激活剂，用于治疗非酒精性脂肪肝病 (STAMP-NAFLD) 的疗效和安全性：一项随机、双盲、安慰剂对照的 2a 期研究

背景

AMP 激酶 (AMPK) 是一种能量传感器，参与调节脂质代谢、炎症和胰岛素敏感性。我们旨在评估 PXL770（一种新型直接 AMPK 激活剂）在非酒精性脂肪肝（ NAFLD ）患者中的疗效和安全性。

方法

STAMP-NAFLD 是一项随机、双盲、安慰剂对照的 2a 期研究，在美国 15 个临床中心进行。通过 MRI-质子密度脂肪分数 (MRI-PDFF) 评估，基线时肝脏脂肪含量至少 10% 的 18-75 岁患者符合条件。患者被随机分配（1:1:1:1），通过交互式网络响应系统，接受口服 PXL770 250 mg 每日一次、250 mg 每日两次或 500 mg 每日一次或匹配安慰剂。根据 2 型糖尿病状态和研究地点对患者进行分层。主要终点是通过 MRI-PDFF 评估的第 12 周时肝脏脂肪含量相对于基线与安慰剂相比的相对变化。主要终点在 ANCOVA 模型中进行分析，其中治疗和分层标准作为因素，基线肝脂肪含量作为改良意向治疗人群的协变量，定义为接受至少一剂研究治疗的所有随机患者. 在安全人群中分析安全性，定义为接受至少一剂研究治疗的所有接受治疗的患者。试验已经完成，并报告了最终结果。该试验已在 ClinicalTrials.gov 注册，NCT03763877。

发现

在 2019 年 3 月 29 日至 2020 年 3 月 13 日期间，筛查了 387 名患者，其中 120 名纳入改良的意向治疗和安全性分析（250 mg 每日一次组 30 名，250 mg 每日两次组 30 名）组，500 mg 每日一次组 29 人，安慰剂组 31 人）。第 12 周时肝脏脂肪含量与基线的平均相对变化在安慰剂组中为 -1·1%，在 250 mg 每日一次组中为 -1·0%（与安慰剂的平均差异为 0·1% [95% CI - 15·4 至 15·7], p=0·99), -14·3% 在 250 mg 每日两次组中 (-13·1% [–28·1 至 1·8], p=0·084 )，在 500 mg 每日一次组中为 -14·7%（-13·5% [–28·5 至 1·4]，p=0·076）。250 mg 每日一次组 30 名患者中的 23 名（77%）、250 mg 每日两次组 30 名患者中的 20 名（67%）发生了至少 1 次治疗中出现的不良事件，500 mg 每日一次组 29 名患者中有 21 名（72%），安慰剂组 31 名患者中有 21 名（68%）。最常见的治疗出现的不良事件是腹泻（250 mg 每天一次组中有 5 名 [17%] 患者，250 mg 每天两次组中有 7 名 [23%] 患者，500 mg 每天一次组中有 6 名 [21%]组，安慰剂组没有）。没有发生危及生命的事件或与治疗相关的死亡。

解释

与安慰剂相比，PXL770 治疗未达到肝脏脂肪改善的主要结果。治疗耐受性良好。鉴于 PXL770 治疗可改善代谢特征的迹象，AMPK 活化可能是 2 型糖尿病和 NAFLD 患者的一个有希望的药理学靶点，也可以考虑对非酒精性脂肪性肝炎患者进行进一步评估。

资金

像素。