Marea Therapeutics has linked its lead candidate to a 53% placebo-adjusted mean reduction in remnant cholesterol, positioning the biotech to start a phase 2b trial imminently.
San Francisco-based Marea emerged last year with $190 million to advance a pipeline led by MAR001, an antibody that targets ANGPTL4. Marea believes inhibiting the protein can augment the activity of a lipid metabolism enzyme, and, in doing so, reduce remnant cholesterol. Research suggests non-HDL, non-LDL cholesterol, called remnant cholesterol, is associated with risk of death and cardiovascular events.
Marea tested the ability of MAR001 to lower remnant cholesterol by randomizing 55 people with high triglyceride levels to receive one of three doses of the antibody or placebo every two weeks. After 12 weeks, remnant cholesterol was down 37.4% to 52.5% in the MAR001 cohorts versus placebo. Marea also tracked placebo-adjusted reductions in triglycerides of up to 52.7%.
The biotech saw the biggest effects on remnant cholesterol and triglycerides in patients who received the highest doses. Drilling down into a subgroup of patients with significantly elevated triglyceride levels, Marea reported placebo-adjusted mean reductions in remnant cholesterol and triglycerides of up 66% and 64%, respectively.
Marea said MAR001 was “generally well tolerated, with no clinically significant findings, and no findings of elevated systemic inflammatory biomarkers or changes in mesenteric lymph node (MLN) size or local inflammation as assessed by MRI.” The focus on systemic inflammatory biomarkers and MLNs reflects the problems that killed off early attempts to target ANGPTL4.
Mice deficient in ANGPTL4 suffer significant injury to the intestines and lymph nodes when fed a high-fat diet. Regeneron saw similar effects, including accumulation of lipids in MLNs, when it gave its ANGPTL4 antibody to monkeys. Novartis also invested in the target before licensing MAR001 to Marea.
With Marea planning to move into phase 2b by mid-2025, the biotech is at the vanguard of work to drug ANGPTL4. Lipigon Pharmaceuticals is running a phase 2 trial of an antisense oligonucleotide designed to inhibit the production of ANGPTL4.