Safety and efficacy of a novel ANGPTL4 inhibitory antibody for lipid lowering: results from phase 1 and phase 1b/2a clinical studies

Abstract

Background: 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.

Methods: 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/m². Participants in part 1B weighed at least 70 kg and had a BMI of 30-40 kg/m². Participants in part 1C weighed at least 59 kg and had fasting triglycerides in the range of 200-500 mg/dL. The primary objectives were to assess the safety and tolerability of a single subcutaneous injection of MAR001 up to and including 141 days post-dose and to assess the pharmacokinetics of single-dose subcutaneous administration in healthy participants. MAR001 was subsequently assessed in a randomised, double-blind, placebo-controlled phase 1b/2a study in participants with metabolic dysfunction. The study was done at two sites in Australia. Eligible participants were adults with hypertriglyceridaemia (in the screening range of ≥1·7 mmol/L and ≤5·6 mmol/L; ≥151 mg/dL and ≤496 mg/dL) and a history of type 2 diabetes, or a screening homeostatic model assessment for insulin resistance (HOMA-IR) value greater than 2·2 and abdominal obesity (defined as waist circumference >88 cm for women and >102 cm for men; > 80 cm for Asian women and >90 cm for Asian men). The primary objective was to characterise the safety and tolerability of multiple doses of MAR001 in participants with metabolic dysfunction. The phase 1b/2a study is registered with ClinicalTrials.gov, NCT05896254.

Findings: 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).

Interpretation: 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.

Funding: Marea Therapeutics.