美国Marea治疗公司Ethan J Weiss团队研究了新型ANGPTL4抑制性抗体降脂的安全性和有效性：1期和1b/2a期临床研究的结果。相关论文发表在2025年5月15日出版的《柳叶刀》杂志上。

遗传学研究已经确定血管生成素相关蛋白4 （ANGPTL4）是甘油三酯代谢的关键调节因子，也是降低动脉粥样硬化性心血管疾病（ASCVD）风险的一个有希望的靶点。人类ANGPTL4功能丧失无不良后果，与甘油三酯和残余胆固醇降低以及2型糖尿病和ASCVD风险降低有关。然而，由于不良反应，ANGPTL4抑制剂的开发一直被推迟

MAR001在一项首次人体、随机、安慰剂对照、单次递增剂量的1期研究中进行了评估，其中参与者接受单次皮下注射MAR001或安慰剂。该研究由诺华生物医学研究中心（Cambridge， MA， USA）开发和实施。1A部分的合格参与者是年龄在18至65岁之间的健康男性和女性，体重至少为50公斤，BMI为18~30 kg/m²。1B部分的参与者体重至少为70公斤，BMI为30-40 kg/m²。1C部分的参与者体重至少为59 kg，空腹甘油三酯在200-500 mg/dL范围内。主要目的是评估单次皮下注射MAR001在给药后141天的安全性和耐受性，并评估健康参与者单次皮下给药的药代动力学。MAR001随后在一项随机、双盲、安慰剂对照的1b/2a期代谢功能障碍研究中进行了评估。这项研究是在澳大利亚的两个地点进行的。符合条件的参与者是患有高甘油三酯血症的成年人（筛查范围≥1.7 mmol/L和≤5.6 mmol/L；≥151 mg/dL和≤496 mg/dL），2型糖尿病病史，或胰岛素抵抗（HOMA-IR）值大于2.2的筛查稳态模型评估和腹部肥胖（定义为女性腰围88 cm，男性腰围102 cm）；同时（亚洲女性80厘米，亚洲男性90厘米）。主要目的是表征多剂量MAR001对代谢功能障碍患者的安全性和耐受性。

在高饱和脂肪饮食中，ANGPTL4基因敲除小鼠，包括肠系膜淋巴结脂质积累、全身炎症、不良临床症状和生存率降低。研究团队之前报道了MAR001（一种ANGPTL4抑制抗体）的开发和临床前特征。研究组报告了ANGPTL4抑制的综合安全性评估，包括对人类肠系膜淋巴结结构中ANGPTL4基因缺失的新分析和两项早期临床试验。

研究组没有发现人类种系ANGPTL4功能丧失的临床不利证据，这为启动人类研究提供了临床前支持。在2017年11月20日至2019年9月10日期间，在第一项随机、安慰剂对照、单次递增剂量的人体1期研究中，1A部分招募了32名健康参与者：其中6人分别接受了15 mg、50 mg、150 mg或450 mg的MAR001治疗，8人接受了安慰剂治疗。1B部分招募了12名参与者：9人接受450 mg MAR001治疗，3人接受安慰剂治疗。1C部分招募了12名参与者：8名接受450 mg MAR001治疗，4名接受安慰剂治疗。在2013年11月24日至2024年7月1日期间，在多剂量1b/2a期随机、双盲、安慰剂对照研究中，55名参与者被随机分配接受皮下注射安慰剂（19名参与者）或150mg（10名参与者）、300 mg（9名参与者）或450 mg（17名参与者）的MAR001，随后是12周的安全随访期。MAR001是安全的，总体耐受性良好，研究组组没有观察到治疗相关的全身炎症生物标志物升高或肠系膜淋巴结大小或MRI评估炎症的变化。MAR001 （450 mg）经安慰剂调整后，第12周甘油三酯平均降低52.7%（90% CI为77.7 - 28.3），残余胆固醇平均降低52.5%（95%，76.1 ~ 28.9）。这些试验支持进一步研究和开发MAR001作为一种有前景的潜在降脂疗法，以降低ASCVD的风险。

研究结果表明，MAR001抑制ANGPTL4可以安全有效地降低循环甘油三酯和残余胆固醇。

附：英文原文

Title: Safety and efficacy of a novel ANGPTL4 inhibitory antibody for lipid lowering: results from phase 1 and phase 1b/2a clinical studies

Author: Beryl B Cummings, Mark P Joing, Page R Bouchard, Mark N Milton, Peter F Moesta, Vyas Ramanan, Andrew Lane, Joe Hirman, John W Trauger, Eleftheria Maratos-Flier, Andrei Voznesensky, Igor Splawski, Amitabh V Nimonkar, Meghan M Flaherty, B Alexander Yi, Daniel Meyers, Francois Huet, Sukhdeep K Sahambi, Denise P Yates, Douglas Hom, Markus Hinder, Craig T Basson, Chris ODonnell, Evan S Siegelman, Chris E Garrett, Joshua Lehrer-Graiwer, Rebecca A Juliano, Ethan J Weiss

Issue&Volume: 2025-05-15

Abstract:

Background

Genetic studies have established angiopoietin-related protein 4 (ANGPTL4) as a key regulator of triglyceride metabolism and a promising target to reduce atherosclerotic cardiovascular disease (ASCVD) risk beyond traditional risk factors. Human ANGPTL4 loss-of-function shows no adverse consequences and is associated with reduced triglycerides and remnant cholesterol, and a reduced risk of type 2 diabetes and ASCVD. Nonetheless, development of ANGPTL4 inhibitors has been delayed due to adverse findings in ANGPTL4-knockout mice fed a high saturated fat diet, including lipid accumulation in mesenteric lymph nodes, systemic inflammation, adverse clinical signs, and reduced survival. We previously reported the development and preclinical characterisation of MAR001, an ANGPTL4 inhibitory antibody. Here, we report a comprehensive safety assessment of ANGPTL4 inhibition, including novel analysis of genetic ANGPTL4 loss on mesenteric lymph node architecture in humans and two early-phase clinical trials.

Methods

MAR001 was evaluated in a first-in-human, randomised, placebo-controlled, single-ascending-dose phase 1 study with three parts in which participants received a single subcutaneous injection of MAR001 or placebo. The study was developed and conducted by Novartis Biomedical Research (Cambridge, MA, USA). Eligible participants enrolled in part 1A were healthy men and women aged between 18 years and 65 years with a bodyweight of at least 50 kg and a BMI of 18–30 kg/m2. Participants in part 1B weighed at least 70 kg and had a BMI of 30–40 kg/m2. Participants in part 1C weighed at least 59 kg and had fasting triglycerides in the range of 200–500 mg/dL. The primary objectives were to assess the safety and tolerability of a single subcutaneous injection of MAR001 up to and including 141 days post-dose and to assess the pharmacokinetics of single-dose subcutaneous administration in healthy participants. MAR001 was subsequently assessed in a randomised, double-blind, placebo-controlled phase 1b/2a study in participants with metabolic dysfunction. The study was done at two sites in Australia. Eligible participants were adults with hypertriglyceridaemia (in the screening range of ≥1·7 mmol/L and ≤5·6 mmol/L; ≥151 mg/dL and ≤496 mg/dL) and a history of type 2 diabetes, or a screening homeostatic model assessment for insulin resistance (HOMA-IR) value greater than 2·2 and abdominal obesity (defined as waist circumference >88 cm for women and >102 cm for men; > 80 cm for Asian women and >90 cm for Asian men). The primary objective was to characterise the safety and tolerability of multiple doses of MAR001 in participants with metabolic dysfunction. The phase 1b/2a study is registered with ClinicalTrials.gov, NCT05896254.

Findings

We found no evidence of clinical adversity in human germline ANGPTL4 loss-of-function, adding to preclinical support for initiating human studies. Between Nov 20, 2017, and Sept 10, 2019, in the first-in-human, randomised, placebo-controlled, single-ascending-dose phase 1 study, part 1A enrolled 32 healthy participants: six each received 15 mg, 50 mg, 150 mg, or 450 mg of MAR001, and eight received placebo. Part 1B enrolled 12 participants: nine received 450 mg of MAR001 and three received placebo. Part 1C enrolled 12 participants: eight received 450 mg of MAR001 and four received placebo. Between Nov 24, 2013, and July 1, 2024, in the multidose phase 1b/2a randomised, double-blind, placebo-controlled study, 55 participants were randomly assigned to receive subcutaneous injections of placebo (19 participants) or MAR001 at doses of 150 mg (ten participants), 300 mg (nine participants), or 450 mg (17 participants), followed by a 12-week safety follow-up period. MAR001 was safe and generally well tolerated, and we observed no treatment-related systemic inflammatory biomarker elevations or changes in mesenteric lymph node size or inflammation assessed by MRI. MAR001 (450 mg) yielded placebo-adjusted week 12 mean reductions in triglycerides of 52·7% (90% CI 77·0 to 28·3) and in remnant cholesterol of 52·5% (76·1 to 28·9).

Interpretation

ANGPTL4 inhibition with MAR001 can safely and effectively reduce circulating triglycerides and remnant cholesterol. The findings of these trials support further research and development of MAR001 as a promising potential lipid-lowering therapy to reduce risk of ASCVD.

DOI: 10.1016/S0140-6736(25)00825-6

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00825-6/abstract