-Hi. I'm Matthew Budoff. I'm a professor of medicine at the UCLA School of Medicine in Los Angeles, California, and today I'm going to be talking about icosapent ethyl and some of the mechanistic clues to understanding the benefits of omega-3s. These are my disclosures.

We've had remarkable data from multiple clinical trials from Japan, including the JELIS trial and a trial by Nosaka, looking at event reductions with icosapent ethyl or EPA. However, this data comes to us from a US-based trial called REDUCE-IT. REDUCE-IT has had multiple publications, and really Deepak Bhatt has championed this great prospective, double-blind, placebo-controlled trial demonstrating that if you put patients on icosapent ethyl, which is a precursor to EPA or one of the omega-3s, then you end up with a remarkable event reduction. This is some of the latest data that we've published. This was published in the Journal of American College of Cardiology in 2022, and you can see those patients who've had a prior MI experienced a 35% reduction in MI, stroke and cardiovascular death by being on icosapent ethyl. The differentiator here for this product as compared to other products on the market is this is purified EPA, so there's no DHA, the other omega-3, that is commonly found in supplements.

I wanted to show you some of the interventional data, some of the plaque regression data to understand why we see event reduction with icosapent ethyl. This is a study called CHERRY. This was an EPA plus statin versus statin monotherapy trial. They used 1.8 grams of EPA, where in the REDUCE-IT trial in the US-based trials we used 4 grams po q day. Here you can see that there was plaque regression. 81% of the patients experienced some plaque regression significantly more than the statin monotherapy arm.

This is another study using intravascular ultrasound, or IVUS, looking at EPA plus pitavastatin, and again, the combination on the right resulted in 50% of patients experiencing regression in this trial as compared to only 24% of those experiencing regression with pitavastatin monotherapy.

Here you can see another trial looking at fibrous plaque volume. As you know, calcified plaque and fibrous plaque is thought to be more stabilizing, and the low attenuation plaque or the lipid-laden plaque is thought to be more concerning. Here you see that icosapent ethyl or EPA, 1.8 grams a day, added to statin therapy reduced the lipid volumes and increase the fibrous volumes in coronary plaque, thought to be very stabilizing for future cardiovascular events.

Here you can see a trial using OCT, another interventional technique, that demonstrated that those patients taking rosuvastatin plus 1.8 grams of EPA had thicker fibrous cap. Fibrous caps got thicker on the combination of therapy as compared to statin monotherapy. We also looked at changes in the lipid arc, and there was more regression of plaque similar to the previous trials looking at EPA plus statin versus statin monotherapy, and we saw the lipid length go down significantly more.

The final interventional trial I want to show you is called the LINK-IT trial. This is a trial looking at neoatherosclerosis, new blood vessel formation. You can see the lipid index got better, regression in blue with combination of EPA plus 10 milligrams of rosuvastatin as compared to rosuvastatin monotherapy. You can see macrophages improved, and target lesion revascularization as an endpoint of the trial was significantly improved. All of these effects demonstrate that the combination of adding EPA to rosuvastatin therapy really reduces cardiovascular plaque.

What about looking at this with CT angiography? We can do a baseline scan, a follow-up scan much less invasive than the previous studies.

This is a trial out of Japan from Nagahana, basically showing that if you used pure EPA, you had the least amount of plaque progression on the left. If you had combination EPA plus DHA, you had more progression and the control group, of course, had the most. We know that it's this purified EPA that has the largest benefit, both clinically from outcome studies, as well as looking at plaque progression trials.

This is a study that I was the principal investigator of, the EVAPORATE trial. Again, 4 grams of EPA, and in blue, regression of atherosclerosis. You can see all the components of atherosclerosis regress with EPA plus statin as compared to statin monotherapy in red, highly significant and very correlative to the REDUCE-IT outcome study.

We then looked at plaque characteristics, what we call advanced plaque metrics. This is using therapies, looking at the same study but now looking at lipid-rich necrotic core, fibrous cap thickness and intraplaque hemorrhage. What you saw is improvements along all of these metrics documented by CT, not by intravascular ultrasound, but we can see improvements in the lipid-rich necrotic core, in intraplaque hemorrhage and an increased fibrous cap thickness. We had a migration of atherosclerotic plaque to a more stable phenotype.

We did use a mineral oil-based placebo. Some people said that might have been toxic, so we compared the rates of progression of a mineral oil-based placebo versus a cellulose-based placebo. You can see those two lines are perfectly superimposed. We do not believe that mineral oil contributed to the plaque progression, and it was really the regression of EPA, and that's also validated by all of those trials I showed you from Japan where they did not use mineral oil. I really don't think mineral oil is a major player.

The last study I want to show you is called the HEARTS study. This is a large trial, 285 subjects randomized to statin plus omega-3 or statin monotherapy. This used a high-dose EPA plus DHA, or no omega-3 for 30 months, and did not show any significant benefits. No plaque metrics changed, suggesting that when we add DHA, we lose some of the protective effects of the EPA that we've seen in so many previous trials.

When we think about this as we conclude, we have now strong data to support the elegant marriage of clinical trials and outcomes studies like JELIS, REDUCE-IT, and the NOSAKA trial, and imaging trials that I showed you, like EVAPORATE and CHERRY, demonstrating consistent benefits of EPA on both outcomes and plaque reduction. Compared with placebo, icosapent ethyl significantly reduced multiple plaque components including vulnerable plaque, lipid-rich necrotic core, intraplaque hemorrhage, and an improved fibrous cap thickness all stabilizing. Conversely, when we use combination EPA and DHA, we have no positive effects on outcomes. The large STRENGTH trial recently reported showed no benefit. The OMEMI trial showed no benefit, and we have no benefit on atherosclerosis. Either two negative trials, HEARTS and AQUAMARINE, show when you combine EPA and DHA, you don't improve atherosclerotic plaque.

As we really put this together, here you can see a list of the potential benefits of purified EPA on plaque. It has multiple components that are positive, including endothelial dysfunction, improvements in oxidative stress. It also has positive effects on inflammation and plaque and, of course, has that plaque stabilizing effect, which I described, which improves fibrous cap thickness, while decreasing some of the plaque components of vulnerability.

All put together, we have positive outcome studies, now three positive outcome studies, multiple positive plaque studies demonstrating all of the benefits of purified EPA on the coronary vasculature. With that, I'd like to thank you very much for your attention, and have a great day.

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