November 09, 2026
3 min watch
Key takeaways:
- A monoclonal antibody targeting ANGPTL4 reduced triglycerides at 12 weeks in adults with elevated triglycerides.
- The drug was safe and well tolerated.
CHICAGO — A monoclonal antibody that inhibits angiopoietin-like protein 4 was linked to triglyceride reduction at 12 weeks in adults with high triglycerides, researchers reported at the American Heart Association Scientific Sessions.
For the TYDAL-TIMI 78 phase 2b trial, researchers evaluated MAR001 (Marea Therapeutics) in doses of 300 mg, 450 mg and 900 mg compared with placebo. The efficacy analysis included 235 participants (mean age, 60.4 years; 39% women) with triglycerides 175 mg/dL or higher (median at baseline, 249.5 mg/dL) and high remnant cholesterol who completed at least one dose of the study drug.
MAR001 is not yet approved for commercial use in the United States.
“MAR001 is a monoclonal antibody that is designed to inhibit ANGPTL4. The rationale is that by blocking ANGPTL4, we can enhance [lipoprotein lipase] activity and enhance the clearance of triglyceride-rich lipoproteins,” Michelle O’Donoghue, MD, MPH, cardiologist with the Mass General Brigham Heart and Vascular Institute and senior investigator in the Thrombolysis in Myocardial Infarction (TIMI) Study Group, said during a presentation.
At 12 weeks, the primary endpoint of placebo-adjusted change in fasting triglyceride level was –39.1 percentage points in the MAR001 300 mg group (95% CI, –46.8 to –31.5), –40.9 percentage points in the MAR001 450 mg group (95% CI, –48.7 to –33.1) and –45.5 percentage points in the MAR001 900 mg group (95% CI, –53.2 to –37.8; P for all < .001), O’Donoghue said during the presentation.
The findings were consistent among prespecified subgroups and the treatment effect was greater in an analysis restricted to patients with baseline triglycerides at least 300 mg/dL, she said.
The percentage of patients who reached triglycerides less than 150 mg/dL at 12 weeks was 3.4% in the placebo group, 31% in the MAR001 300 mg group, 35.1% in the MAR001 450 mg group and 51.7% in the MAR001 900 mg group, the researchers found.
When O’Donoghue and colleagues stratified the cohort by baseline triglyceride level, they found that MAR001 reduced triglycerides at 12 weeks between 30.5% and 36.9% in those with baseline triglycerides less than 300 mg/dL, between 38.3% and 44.8% in those with baseline triglycerides 300 mg/dL to less than 500 mg/dL and between 57.4% and 72.2% in those with baseline triglycerides 500 mg/dL or more.
In addition, “MAR001 increased HDL cholesterol, and as was expected based on its class’s effects toward hydrolyzing triglycerides on very LDL particles to transform them into denser LDL particles, we saw a small absolute rise in LDL cholesterol, but importantly, there was a net reduction in atherogenic particles, as reflected by a drop in non-HDL cholesterol and apolipoprotein B,” O’Donoghue said during the presentation.
The rate of adverse events was 69% in the pooled MAR001 group and 78% in the placebo group, according to the researchers.
Serious adverse events occurred in 2.8% of those assigned MAR001 and 6.9% of those assigned placebo, whereas adverse events leading to discontinuation of the study drug were observed in 4.5% of the MAR001 group and 3.4% of the placebo group, O’Donoghue said.
In the MAR001 group, there were no cases of pancreatitis or elevated liver enzymes, she said.
“Inhibition of ANGPTL4 with MAR001 significantly reduced fasting triglyceride concentration across doses and was generally well tolerated through 24 weeks,” O’Donoghue said during the presentation. “The magnitude of triglyceride lowering appeared to be more pronounced among those with higher baseline triglyceride levels. Together with preclinical and human genetic evidence, these findings support further investigation of ANGPTL4 inhibition as a treatment for hypertriglyceridemia. As such, a dedicated phase 2b study, TYDAL-TIMI 78 part B, is now underway in participants with severe hypertriglyceridemia.”
Perspective
This was a trial of an ANGPTL4 inhibitor in patients that had elevated triglycerides. There was a dose-dependent reduction, so it appeared to be effective for that and appeared to be pretty safe and well tolerated.
There has been a lot of interest in targets such as ANGPTL3, remnant cholesterol and triglycerides for their potential to improve CV outcomes. There are some good data that look at remnant cholesterol and outcomes for CVD, peripheral artery disease, etc, but that has become increasingly difficult as other lipid-lowering therapies are proven, particularly as people get to very low LDL levels. The one drug in this space approved for CV outcomes is icosapent ethyl, but I think its benefits are independent of triglyceride-lowering. Fibroids haven’t worked.
In the past, this may have been a great place to show CV benefit. I think that’s increasingly challenging, and perhaps an initial place where these drugs may be very useful, as data from olezarsen (Tryngolza, Ionis) have shown, is pancreatitis prevention for very high triglycerides. I think there is a lot of promise there. This is a problem we have in the clinic, but it’s going to take time and probably a lot of effort to show CV benefit, and it’s going to have to be additive to what we already have.
It’s a little soon to know what might set MAR001 apart from other triglyceride-lowering agents. The efficacy looks good. The safety looks good. ANGPTL4 is a different target, and so maybe it’s an adjunct. What could it do in combination with other therapies? I don’t think we know yet how it would differentiate, but so far it looks like a promising mechanism. Pancreatitis and elevated triglycerides are an area where we haven’t had a lot of great therapies. Fibrates, despite the lack of CV benefit, are still used, so I think it’s nice to have these options. I think these agents are probably not in the short term going to be an adjunct for CV risk reduction, but hopefully maybe in the future.
Marc P. Bonaca, MD, MPH, FACC, FAHA
University of Colorado Anschutz Medical Campus
CPC Clinical Research
Disclosures: Bonaca reports no relevant financial disclosures.
Sources/Disclosures
Source:
O’Donoghue M, et al. LBS.05. New frontiers in cardiometabolic risk reduction. Presented at: American Heart Association Scientific Sessions; Nov. 6-9, 2026; Chicago.
Reference:
Disclosures:
O’Donoghue reports receiving grant funding from Amgen, AstraZeneca, Marea Therapeutics, Novartis and Pfizer and receiving fees for consulting and/or serving on a data safety monitoring board for Agomab, Amgen, AstraZeneca, Eli Lilly, Johnson & Johnson, NewAmstrerdam Pharma, Novartis, Novo Nordisk and Verve. The study was funded by Marea Therapeutics.
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