Olezarsen Doesn’t Lower Plaque Volume: Essence-TIMI 73b

NEW ORLEANS, LA—Olezarsen (Ionis Pharmaceuticals), an antisense oligonucleotide that targets APOC3 messenger RNA (mRNA), does not reduce noncalcified coronary plaque volume despite lowering triglycerides and remnant cholesterol among patients with moderate hypertriglyceridemia and elevated cardiovascular risk, according to data from the Essence-TIMI 73b trial.

Presentation ACC 2026

Essence-TIMI 73b CCTA Trial: Effect of APOC3 Inhibition with Olezarsen on Coronary Atherosclerosis

This coronary computed tomography angiography (CTA) subanalysis of the phase III trial, presented at the 2026 American College of Cardiology Scientific Session and simultaneously published in Circulation, showed there were 63.9%, 71.9%, and 16.0% reductions in triglycerides, remnant cholesterol, and apolipoprotein B, respectively, with olezarsen compared with placebo at 6 months, with no significant change in LDL cholesterol.

At 12 months, though, there was no difference in the percent change in noncalcified plaque volume between study and control groups (placebo-adjusted least-squares mean difference 2.98%; 95% CI -3.4 to 9.3; P = 0.36).

To TCTMD, lead author Nicholas Marston, MD, MPH (Brigham and Women’s Hospital, Boston, MA), said he wasn’t altogether surprised by the findings as the analysis was conducted mostly to learn more about the triglyceride hypothesis.

“Ultimately, what we saw was that these patients were pretty well treated,” he said. “Even though the triglycerides were high, their overall atherogenic protein particles weren’t that high. Additionally, even though the triglyceride levels were reduced significantly, the change in apoB was modest—a 16% reduction—and what we really care about is the absolute difference. . . . When you lower LDL by 11 points, I don’t expect to see that much of a difference.”

Additionally, the short study duration hampered the researchers ability to find an effect, Marston explained. “I actually think that there’s a real likelihood that if this was something that you were treating longer-term, for 4 or 5 years, that you would see some benefit.”

Nishant Shah, MD (Duke University School of Medicine, Durham, NC), who commented on the findings for the media, echoed the fact that the study patients were “really well treated, relatively speaking, compared to the real world [where] these patients even aren’t on basic therapies like statin.” He is eager to see how the cardiovascular outcomes with olezarsen, and perhaps any plaque progression differences, play out over time.

Still Much to Learn

The US Food and Drug Administration has already approved olezarsen to lower triglycerides in adults with familial chylomicronemia syndrome, but its effectiveness and safety in the broader population of patients with hypertriglyceridemia has been the subject of more recent studies.

For this analysis, researchers included 468 patients (median age 63 years; 31% women) from Essence-TIMI 73b who had triglycerides ≥ 150 mg/dL, with or at high risk for cardiovascular disease, and noncalcified plaque on baseline CCTA. In total, 349 were randomized to olezarsen and 119 to placebo between 2022 and 2024, and all underwent repeat coronary CTA at 12 months. Almost all (97%) received lipid-lowering therapy in addition to their study drug.

At baseline, median triglycerides were 249 mg/dL, remnant cholesterol was 53 mg/dL, and noncalcified plaque volume was 125.3 mm³.

On top of not impacting noncalcified plaque at 12 months, researchers found no differences between the study arms for changes in low-attenuation, calcified, or total plaque volumes as well.

“This is an important trial looking at a group that we see a lot in clinical practice,” said Alison Bailey, MD (West Virginia University, Morgantown), the discussant for the study. “We know historically that this group has increased residual risk when they’re optimized on lifestyle, which is [where] we first start with triglyceride lowering. We optimize their lipids, including statin therapy, and then some of the additional add-ons included in selective populations, icosapent ethyl, to lower cardiovascular risk. I think this was a novel trial looking at a new pathway.”

While olezarsen did “what it was supposed to,” she questioned how APOC3 targeting would play into future clinical trials.

“In this moderate group where we’re thinking about ASCVD risk, the question of ‘Does lowering triglycerides reduce cardiovascular risk?’ remains important,” Marston said. “We wanted to try to get a clue in that here and ultimately had a negative study. But I don’t think that means [that] a longer outcomes trial . . . would be negative.”

He likened olezarsen to ezetimibe in that the latter drug did have a negative imaging trial in ENHANCE but a positive outcomes trial with IMPROVE-IT. “That’s kind of how I’m thinking about this, and so I do think there’s potential for using this drug for having long-term cardiovascular benefit,” Marston added.

Panelist Ron Blankstein, MD (Brigham and Women’s Hospital, Boston, MA), called Essence-TIMI 73b unique in that “this is one of the largest trials done to date looking at serial coronary CTA as a measure of efficacy.” He echoed the opinion that 1 year might be too short to draw meaningful conclusions, though he said, “I think this is a potential future pathway for looking at efficacy of therapies before we move on to very large trials.”

“Ultimately, the cardiovascular outcomes trial needs to be done to know if we have benefit,” Marston concluded. “But I think if we were doing this study again, would we go a little longer, maybe try to start with higher apolipoprotein B levels so there was more ability to change the absolute reductions. Those may have helped us see an effect.”