A glycine-based compound developed at the University of Michigan has demonstrated promising results in reducing atherosclerosis and vascular calcification in nonhuman primates, according to a new study published in Signal Transduction and Targeted Therapy.
The drug candidate, known as DT-109, was originally developed to treat severe fatty liver disease but has now shown significant efficacy in limiting the formation of atherosclerotic plaques in both the aorta and coronary arteries of primates fed a high-cholesterol diet.
Dual-Action Mechanism Targets Both Liver and Cardiovascular Disease
DT-109 was first developed in 2019 after researchers discovered that impaired glycine metabolism could trigger non-alcoholic fatty liver disease. In a 2023 study published in Cell Metabolism, the compound successfully reversed fat buildup and prevented scarring in the livers of mice and nonhuman primates with nonalcoholic steatohepatitis (now renamed metabolic dysfunction-associated steatotic liver disease or MASH).
"The emergence of DT-109 as a dual-action drug capable of treating both MASH and the vascular complications associated with atherosclerosis marks a significant advancement in the treatment landscape," said Jifeng Zhang, Ph.D., research professor of cardiovascular medicine at University of Michigan Medical School and co-author of the study.
This dual efficacy is particularly important given that MASH, which affects nearly 7% of the global population, is strongly associated with an elevated risk of atherosclerosis—a primary driver of heart attacks and strokes worldwide.
Beyond Cholesterol: Addressing Inflammation and Calcification
What sets DT-109 apart from current standard treatments is its ability to address multiple pathological processes simultaneously. During the study, researchers found that DT-109 not only suppressed plaque formation but also halted critical processes leading to vascular calcification, which contributes to arterial stiffening and plaque instability.
"These results are of particular importance because they suggest that DT-109 could not only reduce atherosclerotic lesions but also prevent the vascular calcification that exacerbates arterial stiffness and plaque vulnerability in advanced atherosclerosis," explained Eugene Chen, M.D., Ph.D., co-senior author of the study and Frederick G. L. Huetwell Professor of Cardiovascular Medicine at University of Michigan Medical School.
The compound achieves this in part by reducing signaling from the NLRP3 "inflammasome" protein complex, which plays a necessary role in vascular calcification and chronic inflammation associated with atherosclerosis.
Advantages Over Current Treatments
Current standard-of-care for atherosclerosis primarily involves lipid-lowering medications such as statins and PCSK9 inhibitors. While these treatments manage cholesterol levels, they fail to prevent vascular calcification and the progression of atherosclerosis, leaving patients at continued risk for cardiovascular events.
"DT-109 presents an opportunity to address the root of the issue, rather than managing complications as they come up," Chen noted. This upstream approach could potentially transform treatment paradigms for both conditions.
Promising Path to Clinical Translation
The research team's use of nonhuman primate models presents a distinct advantage that could accelerate the clinical evaluation of DT-109. Unlike genetically modified mice, primates exhibit a more accurate representation of human atherosclerosis and metabolic dysfunction.
"There is significant demand yet limited options for effective drug therapies to treat MASH, which leaves a critical gap in medical treatments that can effectively address both liver dysfunction and its cardiovascular effects," Zhang emphasized.
In the study, researchers fed nonhuman primates a cholesterol-rich diet for 10 months before treating them with oral DT-109. The positive results in these models strengthen the potential for successful clinical translation.
"Given its ability to reduce liver damage, modulate lipid metabolism and inhibit the inflammatory pathways driving atherosclerosis, DT-109 is positioned as a groundbreaking candidate for clinical trials," Chen concluded, "with the potential to significantly improve patient outcomes and reduce the risks associated with cardiovascular events in those with MASH."
