Highlight
- MAR001, a novel ANGPTL4 inhibitory antibody, safely reduces triglycerides and remnant cholesterol by approximately 50% in early-phase clinical trials.
- Human genetic loss-of-function analyses show no adverse impact on mesenteric lymph node architecture or systemic inflammation, alleviating prior animal model safety concerns.
- Phase 1 and phase 1b/2a studies demonstrate good tolerability across healthy and metabolically impaired adults, supporting further therapeutic development.
Study Background and Disease Burden
Angiopoietin-like protein 4 (ANGPTL4) is a critical regulator of triglyceride metabolism and has emerged as a compelling therapeutic target for the reduction of atherosclerotic cardiovascular disease (ASCVD) risk beyond traditional lipid-lowering strategies. Elevated triglycerides and remnant cholesterol are established contributors to ASCVD, yet their management remains suboptimal, particularly in patients with metabolic dysfunction such as type 2 diabetes and abdominal obesity.
Loss-of-function variants in human ANGPTL4 correlate with lowered plasma triglycerides, reduced remnant cholesterol, and decreased risk for type 2 diabetes and ASCVD without apparent adverse effects. These genetic findings contrast with adverse phenotypes observed in ANGPTL4-knockout mice fed high saturated fat diets—lipid accumulation in mesenteric lymph nodes, systemic inflammation, and reduced survival—raising safety concerns that have delayed drug development.
MAR001 is a humanized monoclonal antibody designed to inhibit ANGPTL4. Preclinical characterization had suggested efficacy and acceptable safety profiles. The present research focuses on robust clinical safety and efficacy assessments, alongside novel evaluations of mesenteric lymph node architecture in humans harboring ANGPTL4 loss-of-function alleles, addressing key translational barriers.
Study Design
MAR001 was investigated in two early-phase clinical trials:
1. A first-in-human, randomized, placebo-controlled, single-ascending-dose Phase 1 study comprising three parts:
– Part 1A enrolled healthy adults aged 18-65 years, BMI 18-30 kg/m², body weight ≥50 kg.
– Part 1B included healthy adults with BMI 30-40 kg/m² and weight ≥70 kg.
– Part 1C enrolled individuals with elevated fasting triglycerides (200-500 mg/dL) and weight ≥59 kg.
Participants received a single subcutaneous injection of MAR001 at escalating doses (15 mg to 450 mg) or placebo, followed for safety, tolerability, and pharmacokinetics up to 141 days post-dose.
2. A Phase 1b/2a randomized, double-blind, placebo-controlled, multiple-dose trial in adults with metabolic dysfunction, conducted at two Australian sites.
– Eligibility criteria included hypertriglyceridaemia (≥151 mg/dL and ≤496 mg/dL), history of type 2 diabetes, or insulin resistance measured by HOMA-IR >2.2, with abdominal obesity defined by waist circumference thresholds.
– Participants received subcutaneous MAR001 at doses of 150, 300, or 450 mg or placebo, with safety and efficacy monitored over treatment and a 12-week safety follow-up.
Primary endpoints centered on the safety and tolerability of MAR001, alongside exploratory assessment of lipid parameter changes.
Key Findings
Genetic analyses of humans with germline ANGPTL4 loss-of-function variants revealed no evidence of adverse mesenteric lymph node changes or systemic inflammation, providing translational reassurance relative to prior murine data.
In the first-in-human single-dose trial, 56 participants were enrolled across three cohorts with varied dosing and BMI ranges. MAR001 was generally safe and well tolerated at all dose levels up to the highest 450 mg dose, with no treatment-related serious adverse events or systemic inflammatory biomarker elevations.
The phase 1b/2a multiple-dose trial included 55 participants randomized to placebo or MAR001 at 150 mg, 300 mg, or 450 mg. Safety profiles were consistent with single-dose findings, with no significant adverse events or MRI-detected changes in mesenteric lymph node size or inflammation.
Importantly, the 450 mg MAR001 dose produced substantial lipid-lowering effects by week 12, with placebo-adjusted mean reductions in triglycerides of 52.7% (90% CI: -77.0 to -28.3) and remnant cholesterol by 52.5% (90% CI: -76.1 to -28.9), demonstrating rapid and durable efficacy.
These lipid reductions exceed typical triglyceride-lowering responses from other pharmacologic agents and suggest a potent mechanism related to ANGPTL4 inhibition.
Expert Commentary
ANGPTL4 inhibition represents a promising avenue to address residual cardiovascular risk related to triglyceride-rich lipoproteins. This first clinical evidence supports MAR001 as a well-tolerated and effective agent, with robust lipid-lowering in populations at high metabolic risk.
The comprehensive safety evaluation, including analysis of mesenteric lymph node morphology via MRI and human genetic data, addresses prior preclinical concerns that had impeded ANGPTL4 inhibitor development. Moreover, the lack of systemic inflammation signals enhances confidence in translating these findings to broader clinical populations.
Limitations include relatively small sample sizes and short overall follow-up duration. Future trials should expand participant diversity and longer-term assessments to confirm sustained efficacy and rare adverse event detection.
Biologically, ANGPTL4 modulates lipoprotein lipase activity, regulating the hydrolysis of triglyceride-rich lipoproteins. MAR001’s selective blockade restores lipolytic function, thereby reducing circulating triglycerides and atherogenic remnants, consistent with observed clinical lipid changes.
Conclusion
The clinical development of MAR001, a novel ANGPTL4 inhibitory antibody, demonstrates a favorable safety and efficacy profile in early-phase trials. By markedly lowering triglycerides and remnant cholesterol without observed systemic inflammation or lymph node toxicity, MAR001 offers a potential transformative approach to mitigating ASCVD risk in patients with metabolic dysfunction.
These promising findings warrant advancement into larger, longer-term studies to validate cardiovascular outcomes and further establish MAR001’s role in lipid management beyond conventional therapies.
References
1. Cummings BB, et al. Safety and efficacy of a novel ANGPTL4 inhibitory antibody for lipid lowering: results from phase 1 and phase 1b/2a clinical studies. Lancet. 2025 May 31;405(10493):1923-1934.
2. Watts GF, et al. Managing residual cardiovascular risk in patients with triglycerides and remnant cholesterol elevation. J Clin Lipidol. 2021;15(3):350-361.
3. Dewey FE, et al. Gene-based tests of association for rare variants: application to hyperlipidemia. Circulation. 2020;141(15):1234-1243.
4. Gaudet D, et al. ANGPTL3 inhibition, diabetes, and lipid metabolism: relevance for ASCVD. J Am Coll Cardiol. 2020;75(16):1789-1794.
5. Ridker PM, et al. Lipid lowering and inflammation: the evolving landscape of cardiovascular risk management. Nat Rev Cardiol. 2022;19(6):345-359.
