A discussion on CV risk reduction beyond statin therapy: Exploring the role of Icosapent ethyl

Thank you very much for these excellent presentations and maybe we can start with the mechanism. Chris, you alluded to different mechanisms. So what is your view on the triglyceride lowering? Is this important for the event reduction or is it a bystander effect?

Thank you, Ulrich. This is a key question, obviously, given the nature of the patients we recruited to REDUCE-IT. I have a mixed mind on this because we don't yet know the answer. What we shouldn't do is discard what is known about the effects of EPA and DHA on triglycerides with a clear reduction in the largest triglyceride-rich particles that are potentially highly atherogenic as we have seen in the MARINE and ANCHOR study. A 42% reduction in those particles might be a significant indicator of where the benefit comes from. The other thing that is important is again, as was mentioned, the triglyceride to HDL ratio might be picking out individuals who had the highest levels of remnants and atherogenic lipoproteins. And there, we did see a significant interaction with the outcome in the REDUCE-IT trial. So my suggestion is that we need to do a lot more work. Number one. But number two, we actually need to not discard the idea that triglyceride-rich lipoproteins are important in the risk reduction. However, it's not simply the number of VLDLs that is reduced or the kind of microns, for that happens, as I mentioned, for EPA and DHA. The question I have that we don't have the answer to is: What is the nature of those particles? If EPA stabilizes the surface of the remnant particle in a way that DHA does not, or the different fatty acids that are there provoke different inflammatory reactions.

So in terms of triglyceride lowering, that is the focus at the moment in terms of pathogenesis. And we don't know enough about triglycerides and triglyceride-rich lipoproteins remnants in atherosclerosis as yet. By decades of work we will be able to say: Yes, that is correct, or no, we can eliminate that from the benefit equation.

Now with regards to potential anti-inflammatory effects that you alluded to. I believe there was no heterogeneity

with regards to high sensitive CRP. Which of course, is not the only measure of inflammation, but it is something that gives an overall temperature of inflammation, in terms of the vasculature.

My thoughts on that were that, in the CANTOS trial and other trials, where CRP was lowered, you got benefits in people with initially high CRP levels, but whether this is enough, as in some of the other trials, low dose methotrexate,

you actually got no benefits at all from anti-inflammatory reactions. So I'm just looking for a signal which reproduces, that would say there is a contribution here for an anti-inflammatory effect on a large scale. But we didn't see that. We can't eliminate the idea that it might be the anti-inflammatory effects within the atherosclerotic plaque that we just cannot detect. But that's an argument from absence, rather than an argument from positive people.

Wouter, what an elegant talk. You showed us this actually impressive 25% risk reduction in a well treated population. Now, what is the other side of the coin? You alluded to a few disbalanced events with regard to bleeding and also atrial fibrillation. Would you like to comment on tolerability and potential side effects?

I think if you showed us something works extraordinary well, and I think this is a trial with an impressive 25% risk reduction. You should always look at a potential downsides and potential safety issues. Well, I actually do think that there are very little serious side effects and very little potential serious things that we should take care of. The only interesting thing, and it's very interesting that it was actually a problem, was that you saw a slightly higher incident of AFib in the active group and no one has a clear

idea how that should work, it is unprecedented. And you saw that connected with a slightly higher bleeding issue, that could be connected or could not be connected to the fact, of course, of patients on AFib will be anticoagulated. It is very difficult to dissect that. So, it is an interesting observation. We have no formal way of explaining it, I don't have it either. It has never been observed before. Also not in the other trials. The whole team should look at it.

There was a signal in the STRENGTH study as well and also in the OMEMI study.

But they are again tiny.

Yes. We are talking about very few cases and there was a subanalysis showing that efficacy was the same and there was no difference in patients without hospitalization for AFib previously. So it's extremely well tolerated apparently.

So, you have experienced it as well. Do you have a clue what it could be? Because it's difficult to envisage.

I do not know. I am reading with interest these data on membranes that Chris showed to us. But this is really only a hypothesis,

that it could be some change of membrane potential. But we shouldn't even talk about it.

And Wouter, from your clinical perspective. We have heard that 10 to 20% of patients in secondary prevention would fulfil the criteria of trigger sites above 150. Last patient population, so the question is: What is the first patient we should treat? What are criteria for patient selection for this compound?

Well, the best way to answer this is, of course, stick to the criteria that the trial had because in this population it clearly showed benefit. Then the interesting thing is that part of the entry criteria were triglycerides and we saw no clear interaction with triglyceride baseline and triglyceride lowering, so that's a difficult thing. But the fact that we do not understand it fully does not say that we should not treat because the evidence is there. So we stick to this criteria. So this is patients with enhanced cardiovascular risk and somewhat elevated triglyceride level. So we should go for this because that's the safest way to go and it makes sense. Although we do not fully understand everything.

A question to you and also to Chris. Once we have started treatment and we have no parameter to monitor treatment. We have also no parameter to monitor patient adherence. And there was some interesting data presented on a poster by Deepak Bhatt, on a dose-response relationship, where the authors showed subanalysis of REDUCE-IT that achieved serum EPA concentrations correlated with risk reduction. Which I thought was a very informative presentation because this would point, number one, towards a pharmacological effect of the drug. And number two, could potentially explain that there are certain thresholds of serum concentrations that need to be reached in order to have the effect, and also to explain the difference to previous studies. So Chris, do you think that a certain threshold of EPA serum concentration needs to be reached for efficacy?

That would be the evidence from the trials. The presentation by dr. Batt showing that EPA needs to be about 100 mg per ml to gain the maximum benefit is very interesting. And as you say speaks to a pharmacological effect. The other aspect is the JELIS trial that we referred to early on. Also, they reached a high level of EPA starting from a much higher level baseline than the Europeans. So, it all kind of points to a bulk effect. A need for a high dose of EPA to gain the full benefit that you see. And that suggests that there is something going on that requires a high dose rather than a low dose. Which would suggest something about remnant formation or about cholesterol metabolism as opposed to a metabolic effect in terms of mechanism. So I do think we could use EPA as a marker, not for patients, but within trials to indicate where we are going to get the benefit. The big question is, of course, the offset that DHA applied, if we believe that the STRENGTH study is as equally valid as the REDUCE-IT study, which it seems to be of course. So we actually have to look at EPA by itself.

Wouter, should we measure EPA serum concentrations to monitor treatment and to maybe select a subgroup that could benefit the most?

Well, that would be a nice idea because then you could first see if it's an effect of high dosing only or if there are patient characteristics that you automatically get a high dose, even if you do not swallow all the full doses. Nevertheless, I think that would be rather impractical. So I think just going with the regimen of the trial and take the full dose is the best way to go.

So Chris, you mentioned very fascinating and also ongoing studies and concepts. From your perspective, what mechanism would you like to explore further if you could donate research money?

I would go with two features. One, I want to look at the quality of the triglyceride rich particles, the largest triglyceride rich particles and their remnants in individuals on a regular diet, on individuals given a high EPA, IPE content and on individuals given EPA plus DHA. And also look at macrophage metabolism in model systems given different amounts of EPA/DHA. Those are my two favourite mechanisms at the moment. And it has something to do with the way in which cholesterol and EPA interact. Possibly in remnants, possibly in macrophages.

And a final question to you, Wouter. Now, looking at the data, a very impressive 25% reduction of everything that's bad in a well treated patient population. Now, if you have a patient, secondary prevention with elevated triglycerides, who should not receive this compound?

Well, in principle, if you stick to the entry criteria, a lot of patients is actually good. So the idea is, of course, that you're hitting a novel pathway here and that could explain while you're well treated, although you are already well treated that you will have an additional risk reduction, because you're probably hitting another pathway than you did with solely LDL cholesterol lowering. Of course, that's a very important pathway, no doubt about it, but it may be interesting to hit another pathway as well. So with these patients, for instance, if you have recurrent events or perhaps diabetes or those kind of things, then it could be especially attractive.

I think this was an excellent closing statement. I would like to thank our three speakers for three fantastic presentations. We have learned from dr. Zambon about the residual risk and the importance of triglyceride-rich lipoproteins for residual risk, which is easy to detect. Also emphasized by the REDUCE-IT study is that we have options on top of LDL lowering. Wouter, you presented the REDUCE-IT study with all the details and the clinical implications and tolerability. So clearly a new option in our treatment armamentarium, for patients with cardiovascular disease. And Chris, as always, extremely elegant explanation of the pathophysiology and the mechanisms that are explaining or potentially explaining the observed effects.

It was great fun. Thank you very much. Thank you very much to our audience. And with this, I would like to conclude our sessions. Have a good successful meeting. Thank you very much.

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