👤 Eleftheria Maratos-Flier

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. 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/m 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). 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. Marea Therapeutics. Show less

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

Increased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fructose consumption in humans and rodents and may play a functional role in this nutritional context. Here, we sought to define the mechanism by which fructose ingestion regulates FGF21 and determine whether FGF21 contributes to an adaptive metabolic response to fructose consumption. We tested the role of the transcription factor carbohydrate responsive-element binding protein (ChREBP) in fructose-mediated regulation of FGF21 using ChREBP knockout mice. Using FGF21 knockout mice, we investigated whether FGF21 has a metabolic function in the context of fructose consumption. Additionally, we tested whether a ChREBP-FGF21 interaction is likely conserved in human subjects. Hepatic expression of In summary, ChREBP and FGF21 constitute a signaling axis likely conserved in humans that mediates an essential adaptive response to fructose ingestion that may participate in the pathogenesis of NAFLD and liver fibrosis. Show less