Antibody targeting ANGPTL4 cut triglycerides up to 45.5% in phase 2b trial

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A monoclonal antibody that blocks a protein called ANGPTL4 lowered fasting triglycerides by roughly two-fifths to almost half against placebo within twelve weeks, according to results from a Phase 2b trial presented at the American Heart Association's meeting and published in the New England Journal of Medicine on the same day.

The trial, TYDAL-TIMI 78, enrolled 235 adults with elevated triglycerides and remnant cholesterol across 48 centres in the United States, Canada, Australia and New Zealand. Participants were assigned at random to one of three doses of MAR001, 300, 450 or 900 mg injected under the skin every four weeks, or to placebo, for 24 weeks. At week 12, the placebo-adjusted reductions in fasting triglycerides were 39.1%, 40.9% and 45.5% across the three doses, each statistically significant, and the effect was still there at week 24.

The higher people started, the further they fell. Among those with baseline triglycerides of at least 300 mg/dL, placebo-adjusted reductions reached 52.8%, 53.7% and 57.2%; among those at or above 500 mg/dL, reductions from baseline reached 72.2%. At the top dose, just over half the participants, 51.7%, reached normal triglyceride levels below 150 mg/dL, against 3.4% on placebo. Remnant cholesterol, a carrier of cardiovascular risk, fell by a placebo-adjusted 37.3% to 40.8% across the doses.

The figures line up across the sources that carry them. The company behind the drug, Marea Therapeutics, reports the same 39.1% to 45.5% range as the New England Journal of Medicine paper, and a report drawing on the Mass General Brigham team that led the trial gives the same range and the same 235 participants. The safety numbers, adverse events no more frequent than with placebo, no cases of pancreatitis, no deaths, come from the company's release of the trial data.

That safety detail carries weight because the people who most need triglyceride lowering often carry diabetes too: the company notes that up to 70% of people with severe hypertriglyceridemia also have type 2 diabetes, and a treatment that cuts fats while worsening blood sugar would be a poor trade. Through 24 weeks there was no worsening of HbA1c or other markers of glucose control, and serious adverse events were less common on the drug than on placebo, 2.8% against 6.9%. Lead author Michelle O'Donoghue, a cardiologist at Mass General Brigham, said the findings were particularly encouraging given how few options exist for severe hypertriglyceridemia, where many remain at risk of acute pancreatitis despite current therapies.

The next step is already under way. Enrolment has begun in Part B of the same trial, aimed at about 100 people with severe hypertriglyceridemia, and Marea is developing a longer-lasting version of the antibody, MAR005, as its planned Phase 3 candidate. Whether the triglyceride drops translate into fewer cases of pancreatitis and cardiovascular events is the question the longer studies will have to answer.