Weekly Journal Scan: Angiopoietin-related protein 4 inhibition as a novel approach to atherogenic lipid targeting

This comment refers to ‘Safety and efficacy of a novel ANGPTL4 inhibitory antibody for lipid lowering: results from phase 1 and phase 1b/2a clinical studies’, published in The Lancet, http://doi.org/10.1016/S0140-6736(25)00825-6. This first-in-human, company-funded study evaluated MAR001—a first-in-class human monoclonal antibody targeting angiopoietin-like protein 4 (ANGPTL4)—for its lipid-lowering potential, tolerability, and preliminary safety profile in both healthy individuals and patients with metabolic dysfunction. The study included both single-ascending-dose and multiple-dose, randomised, placebo-controlled trials. The phase-1 study (parts 1A–1C) assessed tolerability and pharmacokinetics in healthy volunteers, including obese subjects (part 1B) and those with elevated fasting triglycerides (part 1C), while the phase 1b/2a trial evaluated repeated dosing in patients with dyslipidaemia and metabolic dysfunction.1 A total of 111 participants were enrolled across all cohorts. In the single-ascending-dose part 1A (n = 32; doses of 15, 50, 150, and 450 mg of MAR001 vs. placebo), participants were healthy adults aged 18–65 years with a body mass index (BMI) of 18–30 kg/m2. In part 1B (n = 12; 450 mg of MAR001 vs. placebo), participants had a BMI of 30–40 kg/m². Part 1C (n = 12; 450 mg of MAR001 vs. placebo) included individuals with fasting triglyceride levels of 200–500 mg/dL. In the randomized, bicentric, double-blind, placebo-controlled 1b/2a phase, 55 patients with metabolic dysfunction were randomized to receive MAR001 at doses of 150 mg (n = 10), 300 mg (n = 9), 450 mg (n = 17), or placebo (n = 19). Participants were adults with hypertriglyceridaemia (range 151–496 mg/dL) and had to meet either diabetic criteria or exhibit insulin resistance, with a homeostatic model assessment for insulin resistance (HOMA-IR) > 2.2, along with abdominal obesity (sex-specific waist circumference thresholds ≥102 cm for men, ≥88 cm for women). Exclusion criteria included peripheral lymphadenopathy, peritonitis within 5 years of the study start, hypersensitivity to any monoclonal antibody, clinically significant illness, or current use of bodyweight- or lipid-lowering therapies (for Parts 1B and 1C). In the single-dose study of 56 healthy individuals (mean age 47 years, 79% males, 57% Whites, mean BMI 29 kg/m2, mean fasting triglycerides 144 mg/dL), the participants receiving MAR001 showed dose-dependent reductions in fasting triglycerides by up to 47%, and placebo-adjusted reductions in triglycerides and remnant cholesterol of −69% and −66%, respectively, by day 15. Post-prandial triglyceride excursions were also reduced by 43% (placebo-adjusted −72%). HDL cholesterol increased by 13% without major changes in LDL or total cholesterol. Drug exposure was maintained for over 40 days, as reflected by persistent triglyceride and remnant cholesterol lowering, and returned to baseline concentrations by day 57. In the multidose 12-week phase 1b/2a study (median age of participants 46 years, 47% males, 69% White, mean BMI 34 kg/m2, mean fasting triglyceride 190 mg/dL), MAR001 led to dose-dependent, placebo-adjusted, triglyceride reductions at week 12 by −41% (150 mg), −50% (300 mg), and −53% (450 mg), and similar reductions in remnant cholesterol (−37%, −49%, and −52, respectively). Triglycerides and remnant cholesterol reached maximal reductions around week 6 for the higher-dose. HDL increased by 19% at the highest dose, while non-HDL cholesterol decreased by 7%. MAR001 was well tolerated across doses with no serious adverse events or persistent inflammatory biomarker elevations. 15 (27%) of 55 participants had an adverse event of special interest (5 in the placebo group, 2 in the 150 mg group, 2 in the 300 mg group, and 6 in the 450 mg group). MRI and laboratory measures showed no detectable lymphatic abnormalities, liver fat changes/ascites, mesenteric inflammation and no change in insulin resistance. Furthermore, the analysis of electronic medical records from the UK biobank found no evidence of increased risk of abdominal or other lymphatic diseases in carriers of heterozygous and homozygous ANGPTL4 frameshift loss-of-function mutation. LDL-cholesterol lowering has long been and still represents the primary objective of lipid-lowering therapy. Alongside, triglyceride-rich lipoproteins (TRLs), including very-low-density lipoproteins (VLDL) and their remnants, have emerged as causal contributors to atherosclerotic cardiovascular disease (ASCVD), supported by robust evidence from both genetic studies and large-scale epidemiological analyses.2,3 This evidence has led to TLRs being considered as potential key players in residual CV risk, which may persist even after optimal LDL-cholesterol reduction with statins.4 Despite their capacity to penetrate the arterial intima, promote inflammation, and deliver cholesterol directly to atherosclerotic plaques,5 TRLs have often been overlooked in routine CV risk management. This is partly due to the lack of solid evidence for a reduction in CV outcomes associated with TRLs-lowering therapies currently in use (fibrates and omega-3 fatty acids). This represents the main driver for the development of targeted TRLs-lowering interventions to complement LDL reduction in high-risk patients.6 ANGPTL4, Apolipoprotein C-III (APOC3), and ANGPTL3 play a key role in regulating lipid metabolism and the clearance of TRLs, and represent potential drug targets for treating dyslipidaemia and reducing the risk of ASCVD. Indeed, by inhibiting lipoprotein lipase, they slow down the clearance of TRLs, leading to increased levels of triglycerides.7 ANGPTL4 inhibition differs mechanistically from APOC3 and ANGPTL3 inhibition with potential further benefits. Unlike ANGPTL3, which suppresses both lipoprotein lipase and endothelial lipase, thereby lowering triglycerides and modestly reducing HDL cholesterol, ANGPTL4 primarily regulates lipoprotein lipase activity without significantly impacting HDL cholesterol. In contrast, APOC3 loss-of-function variants are consistently associated with reduced triglycerides and remnant cholesterol, increased HDL cholesterol, and a lower risk of ASCVD, with minimal effect on LDL cholesterol.7 Genetic studies showed that lowering ANGPTL4 is associated with decreased plasma triglycerides, remnant cholesterol and ApoB, and reduced risk of ASCVD.8 In contrast, animal studies in ANGPTL4 knock-out mice showed severe adverse effects, such as mesenteric lymphadenopathy and systemic inflammation, with decreased survival.9 Only one study assessed the pharmacological effects of ANGPTL4 inhibition in non-human primates and found no adverse safety signals.10 This is the first study to show that selectively inhibiting ANGPTL4 in humans leads to large reductions in triglycerides and remnant cholesterol, establishing a novel potential target for dyslipidaemia. Progressively greater reductions in triglycerides and remnant cholesterol were observed with increasing doses of the antibody MAR001. This supports the biological plausibility of a potential therapeutic effect in a population with hypertriglyceridaemia and metabolic syndrome, who are at high CV risk. Within the limitations of indirect comparisons, the reduction in triglycerides and remnant cholesterol with MAR001 appears to be greater than that observed with fibrates (about 26% in the PROMINENT trial)11 or omega-3 fatty acids (20–30% in the REDUCE-IT trial).12 However, the patients enrolled in the fibrate and omega-3 studies were also under lipid-lowering therapy, while only 5%–12% of the subjects in the multidose study were receiving a statin. Pharmacokinetic data support a monthly subcutaneous administration, which could improve patient adherence. Furthermore, the careful assessment of lymphatic tissue size and inflammation through MRI and inflammatory biomarkers represents a major strength of this study, which reinforces the safety data. Major limitations of the present studies are represented by the small sample size and the short follow-up duration, which do not allow assessing persistence of biochemical efficacy and only provide preliminary evaluation of safety. Moreover, the multidose study population was predominantly White and mildly dysmetabolic, with few participants on background lipid-lowering therapy. It should also be emphasized that 27 out of 28 authors of the present report are affiliated with the two drug companies involved in the studies of MAR001 and that the funder company had a role in study design, data collection, data analysis, data interpretation, and writing of the report. Overall, this study provides proof-of-concept that ANGPTL4 inhibition may represent a well-tolerated therapeutic strategy producing clinically meaningful reductions in plasma triglycerides and remnant cholesterol. While waiting for larger phase 2b studies and a major outcome trial, MAR001 represents another promising candidate in the evolving landscape of lipid-lowering therapies for patients with persistent CV risk despite standard therapies. D.P. received speaker’s fees from Daiichi-Sankyo. C.P. received consultant fees from AbbVie, and grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK and European Commission; he chaired the Scientific Advisory Board of the International Aspirin Foundation.