👤 Daniel LaSala

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. Show less

Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead molecule with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency. The effort led to the identification of an achiral, carboxylic acid-bearing compound 16 (TAP311) with excellent pharmacokinetics in rats and robust efficacy in hamsters. Compared to anacetrapib, the compound showed substantially reduced lipophilicity, had only modest distribution into adipose tissue, and retained potency in hypertriglyceridemic plasma in vitro and in vivo. Furthermore, in contrast to torcetrapib, the compound did not increase aldosterone secretion in human adrenocortical carcinoma cells nor in chronically cannulated rats. On the basis of its preclinical efficacy and safety profile, the compound was advanced into clinical trials. Show less