Cummings Beryl B, Bouchard Page R, Milton Mark N, Moesta Peter F, Ramanan Vyas, Trauger John W, Maratos-Flier Eleftheria, Voznesensky Andrei, Splawski Igor, Nimonkar Amitabh V, DiPetrillo Keith, LaSala Daniel, Pan Meihui, Flaherty Meghan M, Huet Francois, Sahambi Sukhdeep K, Dong Jijun, Knee Deborah, Cebe Regis, Huber Thomas, Lehrer-Graiwer Joshua, Juliano Rebecca A, Weiss Ethan J
Marea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USA.
Marea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USA; Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA.
EBioMedicine. 2025 May 12;117:105748. doi: 10.1016/j.ebiom.2025.105748.
Angiopoietin-like protein 4 (ANGPTL4) inhibition is a promising approach to manage atherogenic dyslipidaemia and residual atherosclerotic cardiovascular disease (ASCVD) risk. Human ANGPTL4 loss-of-function (LoF) is associated with reduced plasma triglyceride (TG), remnant cholesterol (RC), and apolipoprotein B (ApoB) levels, and lower risk of type 2 diabetes and ASCVD, without observable safety concerns. However, development of ANGPTL4 inhibitors has been stalled by adverse findings in Angptl4 knockout mice fed a high-saturated-fat diet (HSFD), which show lipid accumulation in mesenteric lymph nodes (MLNs), systemic inflammation, severe adverse clinical signs, and reduced survival.
Here, we present the development and preclinical characterisation of MAR001, a humanised monoclonal ANGPTL4 inhibitor antibody. We assessed single-dose MAR001 efficacy in hypertriglyceridemic (HTG) non-human primates (NHPs, n = 4), and safety in two NHP toxicology studies: a 15-week subchronic study with a standard or HSFD (n = 36), and a 9-month chronic study exclusively on an HSFD (n = 24).
In HTG monkeys, single-dose MAR001 treatment reduced plasma TG by up to 58%, non-high-density lipoprotein cholesterol by 38%, ApoB by 30%, and RC by 59%. In safety studies, MAR001 was well tolerated without clinically adverse findings with either diet. Animals fed an HSFD exhibited minimal to moderate foamy macrophage formation in MLNs, but importantly, these histological findings did not progress to degeneration, necrosis, inflammation, fibrosis, or other reactive changes, and with no evidence of systemic effects, including no evidence of systemic inflammation or clinical adverse signs.
MAR001 improved plasma lipid profiles in NHPs without clinical adversity, even during prolonged HSFD feeding. The favourable NHP safety profile aligns with human ANGPTL4 LoF findings, and contrasts with the severe pathology in mouse knockout models on an HSFD. These findings supported MAR001 clinical studies reported in our concurrent publication, which demonstrated robust lipid improvements without lymphatic pathology. Overall, these findings support continued development of MAR001 as a promising new therapy for ASCVD risk reduction.
Marea Therapeutics.
血管生成素样蛋白4（ANGPTL4）抑制是一种有前景的治疗致动脉粥样硬化性血脂异常和残余动脉粥样硬化性心血管疾病（ASCVD）风险的方法。人类ANGPTL4功能丧失（LoF）与血浆甘油三酯（TG）、残余胆固醇（RC）和载脂蛋白B（ApoB）水平降低相关，且2型糖尿病和ASCVD风险较低，未观察到安全性问题。然而，在喂食高饱和脂肪饮食（HSFD）的Angptl4基因敲除小鼠中出现的不良发现阻碍了ANGPTL4抑制剂的开发，这些小鼠在肠系膜淋巴结（MLN）中出现脂质蓄积、全身炎症、严重的不良临床体征并缩短生存期。
在此，我们展示了人源化单克隆ANGPTL4抑制剂抗体MAR001的研发及临床前特征。我们评估了单剂量MAR001在高甘油三酯血症（HTG）非人灵长类动物（NHP，n = 4）中的疗效，以及在两项NHP毒理学研究中的安全性：一项为期15周的标准或HSFD亚慢性研究（n = 36），以及一项仅针对HSFD的为期9个月的慢性研究（n = 24）。
在HTG猴子中，单剂量MAR001治疗可使血浆TG降低高达58%，非高密度脂蛋白胆固醇降低38%，ApoB降低30%，RC降低59%。在安全性研究中，MAR001耐受性良好，无论采用何种饮食均未出现临床不良发现。喂食HSFD的动物在MLN中表现出最小至中度的泡沫巨噬细胞形成，但重要的是，这些组织学发现并未进展为变性、坏死、炎症、纤维化或其他反应性变化，且没有全身效应的证据，包括没有全身炎症或临床不良体征的证据。
MAR001可改善NHP的血浆脂质谱且无临床不良反应，即使在长期喂食HSFD期间也是如此。有利的NHP安全性特征与人类ANGPTL4 LoF的发现一致，与HSFD喂养的小鼠基因敲除模型中的严重病理学形成对比。这些发现支持了我们同期发表的关于MAR001的临床研究报告中的结果，该报告显示脂质有显著改善且无淋巴病理学改变。总体而言，这些发现支持继续开发MAR001作为一种有前景的降低ASCVD风险的新疗法。
Marea Therapeutics公司。
