Amarin Corporation plc (AMRN) Earnings Call Transcript & Summary

Welcome to Amarin Corporation's conference call to discuss select scientific publications from the American College of Cardiology's 69th Annual Scientific Session together with the World Congress of Cardiology. This conference call is being recorded today, March 30, 2020. I will now turn the conference call over to Elisabeth Schwartz, Senior Director of Investor Relations of Amarin. Please go ahead.

Welcome to today's discussion with several distinguished invited guests to explore with our investment community the several important new data sets and analyses related to VASCEPA and REDUCE-IT presented to the medical community at the American College of Cardiology's 69th Annual Scientific Session together with World College of -- Congress of Cardiology. To level set expectations, we will be limiting this session to scientific matters directly presented during the recently completed ACC meeting. We'll not be discussing business matters, including Amarin's ANDA litigation or any matters related to COVID-19, and we'll not be taking questions from the audience. Please be aware that this conference call will contain forward-looking statements that are intended to be covered under the safe harbor provided by the Private Securities Litigation Reform Act. Examples of such statements include, but are not limited to, our current expectations regarding VASCEPA clinical data, cost effectiveness analyses and expectations regarding the application of these data to clinical use in reimbursement and regulatory settings and to commercial prospects for VASCEPA. These statements are based on information available to us today, March 30, 2020. We may not actually meet the expectations disclosed in our forward-looking statements. Actual results or events could differ materially. We assume no obligation to update these statements as circumstances change. For additional information concerning the factors that could cause actual results to differ materially, please see the forward-looking statements section in the Risk Factors section of our most recent Form 10-K filed with the U.S. Securities and Exchange Commission. This call is intended for investors in Amarin and is not intended to promote the use of Amarin's VASCEPA outside its approved indications. I will now turn the call over to Dr. Craig Granowitz, the Chief Medical Officer of Amarin. Craig?

Thank you, Elizabeth. I wanted to introduce our distinguished faculty today and really have a robust discussion of what was really a tremendous meeting at the American College of Cardiology and World Congress meeting. I give a lot of credit to the ACC, its staff and the selection committee for moving the meeting under very short notice to an all-virtual format and doing so with distinction. I think they are setting the pace for all the other major scientific societies for the foreseeable future in how to run a virtual large, high-quality scientific meeting. This evening, we're fortunate to have 4 leading experts: Dr. Peter Libby, the Mallinckrodt Professor of Medicine at the Harvard Medical School and Cardiovascular Specialist at Brigham and Women's Hospital in Boston; Dr. Nathan D. Wong, Professor and Director of the Heart Disease Prevention Program, Division of Cardiology at UC Irvine and a past President of the American Society for the Prevention of Cardiology; Dr. Preston Mason, a member of the Cardiovascular Division at Brigham and Women's Hospital in Boston, a Teaching Affiliate of the Harvard Medical School. Dr. Mason is also the President and Co-Founder of Elucida Research; and Dr. Deepak Bhatt, Professor of Medicine at Harvard Medical School, Executive Director of Interventional Cardiology Programs at the Brigham and Women's Hospital Heart and Vascular Center and primary investigator for the REDUCE-IT study. So thank you all for your participation this evening at the close of the American College of Cardiology meeting.

And Peter, maybe I'll start with you because concurrent with the start of the ACC meeting was actually National Triglyceride Day. And maybe you could just take a minute and talk a bit about what are triglycerides and where are they involved in risk profiling of patients with cardiovascular disease or at risk of cardiovascular disease?

Sure, Craig. Well, it's great to have triglycerides to have a moment in the sun because they have been the poor cousin of cholesterol and bad cholesterol, LDL, low-density lipoprotein. Actually, the triglycerides that are measured in the laboratory are a biomarker of a class of lipoprotein that we call triglyceride-rich lipoproteins for remnant particles. And it turns out that these particles are quite effective at delivering cholesterol to the cells in the artery wall that give rise to hardening of the arteries or atherosclerosis. And so it's sort of a stealth way of getting cholesterol into the wall. It's not necessarily the triglycerides themselves, but the cholesterols that are carried in those particles that seems to boost atherosclerosis. Bad cholesterol, LDL, is pretty much under control. We whipped LDL cholesterol, the bad cholesterol, with statins and cholesterol-absorption drugs and these medicines that target the PCSK9, which regulates the level of blood cholesterol to LDL regulation. So LDL is really well in hand, and I think one of the frontiers is triglyceride. And that's why I'm glad that it's being recognized as triglyceride day because a lot of the patients that we care for now who have heart problems, particularly acute heart problems, their bad cholesterol, their LDL is well within the recommended range because they've been well-treated with the drugs that we have available. The problem is that a lot of these people have elevation in their triglyceride. They're carrying around excess baggage of these triglyceride-rich lipoprotein particles, and that translates to a residual risk for cardiovascular events that are not addressed by the statin. So Craig, the people in the audience may wonder what the difference is between cholesterol and triglyceride. And it turns out that we can think of the chemical structure of cholesterol as a bunch of hexagonal rings that are stacked on one another and we can think of the triglycerides more like string. So their chemical structure is different, but they're also metabolic and quite distinct as well. And we really can't make cholesterol with triglyceride. It's a different animal.

Yes. It's Deepak Bhatt here. Peter, I think it's incredible, all the work you've done through the years in inflammation and lipids and the retraction. Do you think that what you've just been discussing with cholesterol and triglyceride and so forth, how do you think that ties into EPA or eicosapentaenoic acid?

Well, certainly, EPA can lower the triglyceride being measured in the blood. And indeed, that may contribute to the clinical benefit that you and your coinvestigators have documented in the REDUCE-IT trial. But I think it's actually much wider than that, not just cholesterol or triglyceride lowering, but we think that the omega-3 fatty acids and eicosapentaenoic acid in particular are working to reduce events in many different ways. They provide the building block, the raw materials for making a number of mediators that we think can alleviate some of the problems that we have with atherosclerosis, certain kinds of prostaglandins and a relatively new series of molecules we call specific pro-resolving mediators or SPM. And if we have more of the building block, then you can make more of those good chemicals that can quiet down the inflammation in the artery wall. Also, as Dr. Mason can tell us because he's been a leader in this field, the higher your eicosapentaenoic acid, the more you're going to have incorporation to the membranes of cells that can stabilize those cells from oxidative injury. And the same thing with the lipoprotein particles that carry blood to -- carry the fat to the bloodstream. So things like high-density lipoprotein, HDL and LDL itself contain fatty acid such as the omega-3 fatty acid on their coding and it can protect them from oxidation. So we think that there are a number of different mechanisms beyond triglyceride that can contribute to the clinical benefit that you and your collaborators demonstrated in REDUCE-IT.

Yes. Thank you, Peter. That was a great answer. And thank you also, Deepak, for servicing that question. I guess, Peter, that then raises the next question is do all drugs that lower triglycerides also lower cardiovascular risk? Because isn't that the case with LDL that kind of all the drugs that lower LDL, regardless of how they do it, seem to have a similar benefit? Is the same true for triglyceride?

Not at all. It's been devilishly difficult to show the drugs that lower triglyceride can produce clinical benefit. They're drugs of the class of fenofibrate, the brand name is TRICOR, which is the -- one of this class that we have available in the United States that's been studied in patients with that disease, patients who are pretty high risk, patients who are already treated with statins, and they haven't shown a clinical benefit despite lowering triglyceride. So we can't say that just because it lowers the triglyceride that it's going to provide a clinical benefit. It's been really frustrating for us in the field.

Interesting. And what about other -- and I know, Dr. Bhatt, you had a chance to raise some of these issues and I know we'll come back to it again, but there was lots of ways to get omega-3s, of which EPA is one from the diet or from the drugstore or from the shelf of a health food store. Are they all the same? Do you think that they can limit risk the same way and to the same degree as a prescription product?

Well, that's a great question. Yes. You don't know what you're getting when you get the supermarket or health food store supplement. They're not quality-controlled. They haven't undergone rigorous evaluation. And Dr. Mason and Dr. Bhatt can fill in the gaps here, but when you have a pharmaceutical-grade, we know it's purified, we know it's quality-controlled. And you really don't know what you're getting when you pull something off the shelf. And most importantly, the clinical trials that have been done, if you look at the recent meta-analysis, which is a compilation of studies, it's a null. They don't show a clinical benefit, the doses that have been studied. So there's a big difference between pharmaceutical-grade, purified, quality-controlled product and the unknowns that you can get off the shelf.

Very good. Well, thank you. Dr. Wong, I know that you had some data that you presented at the meeting, at the recently completed ACC meeting, that tried to capture the impact of these elevated patients with -- patients with elevated triglycerides and the potential benefit that they could get from icosapent ethyl in that group of patients studied in REDUCE-IT. Can you tell us a little bit about how you did that work and what the key findings were?

Yes, sure. I'd be more than happy to. And thank you again for giving me the opportunity to share some of our results that we presented at the ACC. So what we basically did is we applied the REDUCE-IT clinical trial eligibility criteria to the U.S. population using the National Health and Nutrition Examination Survey. This is a very large survey of U.S. adults done around the country [ yet ] with many, many testing centers, every 2 years, they conduct the survey. And we get much of our national data on cardiovascular disease statistics from NHANES. So basically, what we did is we apply the main eligibility criteria for the REDUCE-IT trial to the sample of adults from the NHANES study. So for example, this included people who had known atherosclerotic cardiovascular disease or diabetes plus multiple risk factors. So you had to have triglycerides of 150 to 499 as well as be on a statin and have LDL cholesterol levels that were 40 to 99. So these were the principal criteria for the REDUCE-IT population. And then basically, what we did is we applied the placebo and treated event rates from the REDUCE-IT trial. Actually, both the initial publication that came out, looking at initial cardiovascular events, as well as the rates from the subsequent population that looked at total cardiovascular events, because as we all know, a person who suffers one heart attack or one stroke is more likely to suffer another event, which may be a different type of event. So basically, over the period of 5 years in the REDUCE-IT trial, there were a number of people who suffered multiple cardiovascular events. So this is what we term total events. And basically, what we found from this study was that if -- and if we project this on an annualized basis, okay, and we apply the REDUCE-IT rates for total events that were experienced in the non-treated group, the placebo group, you would have gotten about 234,000 plus events every year in the roughly 3 million U.S. adults that we estimated based on these fairly strict REDUCE-IT eligibility criteria that would be eligible for the study. And then if you are on treatment, this number comes down to 163,000 plus events over -- and that's on an annualized basis. So basically, overall, we projected preventing slightly over 71,000 events per year. And this was just under 30,000 actually initial events and about 41,600 repeat events. So that's how you get to the 71,000 plus events that could be prevented on an annualized basis among the approximately 3 million U.S. adults that we projected would fit the eligibility criteria for this study.

Well, thank you, Dr. Wong. That was a very nice summary of the methodology and results from the trial. Tell us -- so these events, again, these are major cardiovascular events, heart attack or stroke or other major events. And Dr. Bhatt, I know you're an author on another poster at the meeting that was -- the senior author was Bill Weintraub from the MedStar Institute. Could you just give us a flavor of what some of the costs might be and the use of icosapent ethyl might ultimately impact in the health care system?

A terrific question. So Dr. Weintraub had presented as a late-breaker at the AHA the overall REDUCE-IT cost effectiveness analysis, and the results really look quite spectacular among cost effectiveness analyses out there. Just to refresh everyone's memory for that overall analysis, icosapent ethyl was found to be highly cost-effective in the majority of different scenarios he examined, the so-called dominant strategy, which in plain English means that it's actually saving the health care system money because it's preventing events at a cost of acquisition that is really quite favorable. So he said that the only times in his long distinguished career doing cost effectiveness analyses he's seen things that cost-effective have been generic statins for secondary prevention and aspirin for secondary prevention. He said that he's never seen a branded drug. It's a dominant strategy. So that's the overall result. What he presented here at ACC, very nice work looking specifically at the U.S.A. patient. Now the U.S.A. subgroup, which I presented at AHA also is a late-breaker and published in circulation at that time, showed that the U.S.A. patients performed quite well in terms of icosapent ethyl versus placebo, at least as well as in the overall trial. And given the fact that there were just more risk factors among the U.S. patients, I think, things like obesity and more diabetes and that sort of thing, there was, in fact, a larger numerical benefits in the U.S. versus the non-U.S. or overall populations, including the statistically significant 30% reduction in all-cause mortality in the U.S. REDUCE-IT patients who were randomized to icosapent ethyl versus placebo. So you can imagine then, if the drug looked cost-effective in the overall trial population, now looking at it specifically in U.S. patients, it was even more cost-effective given just the larger absolute risk reductions, not just in mortality but a variety of other cardiovascular endpoints. So really, the data he presented here buttresses the fact that icosapent ethyl is highly cost-effective. And if you're talking about U.S. patients and the U.S. health care system, it's extremely cost-effective.

Thank you, Dr. Bhatt. I mean, I think we're all looking for solutions because overall lifetime -- life span in the United States have plateaued and actually decreased. And it seems that while a lot of people were thinking that this was being driven by the unfortunate opiate crisis, it really seems that one of the bigger drivers is cardiovascular disease, and this has a large enough effect that it might even be able to help flatten or bend that curve. So I think Dr. Wong and Dr. Bhatt, your data together, if widely adopted, could hopefully bring us back on track of what the national targets are for reducing overall cardiovascular disease. So thank you very much. We're going to switch gears now and really talk a bit more about EPA. And we're really fortunate to have Dr. Preston Mason. And Preston, you had actually 2 posters at the meeting today. And I know you've had a number of recent publications and presentations at other more basic science meetings. Maybe you could summarize what some of the findings of your studies have been.

So we've been looking at a very interesting property of EPA, and that is ability to protect cell membranes and the particles that carry fat in our blood called lipoproteins. To protect it from oxidation, that event tends to trigger the inflammation that we attribute to atherosclerosis. So in this, we look at 2 different type of particles, one which was already discussed, triglyceride-rich lipoproteins. And we were able to show that when you achieve pharmacologic doses, the doses that would be used in the REDUCE-IT trial and other patients would take, we find that EPA over time can prevent that damaging oxidation process. We compared it to another omega-3 fatty acid known as DHA, and it did not have the same persistent benefit over time. We saw similar benefits in the good cholesterol, HDL, because when HDL get oxidized, it loses a lot of its beneficial or good properties. And again, EPA was unique in its ability to preserve that or prevent that oxidation or damaging process compared to other omega-3 fatty acids. And again, the key was to have the right dose, the pharmacologic dose.

Thank you, Dr. Mason. It's quite interesting because these molecules, I guess, a lot of people, not really being as versed in lipid biology as many in the scientific or at least biological community are in DNA and protein, sort of think these omega-3s are all kind of the same. It seems like they're pretty different.

Absolutely. Each has a unique combination of what we call carbon length and double bonds, and differences among them can have profound effects on how they interact with the cell membrane and with other targets within the body. So indeed, they are very different. And we found that EPA has a favorable balance of double bonds and hydrocarbon length compared to other omega-3s to undergird or to explain this particular benefit.

And Dr. Mason, what about EPA? Is all EPA the same?

So if you're talking about EPA from like a supermarket, as already been alluded to, it's definitely not the same. When you purchase it like as a dietary supplement, because of lack of oversight in terms of manufacturer, you will find that there will be often oxidized EPA in the product, and that completely eliminates any benefit. And in fact, it might be harmful under those conditions, plus there are many other forms of it. So the EPA used in the successful REDUCE-IT trial was called icosapent ethyl. And this is a way of properly delivering the EPA to the body, which then is converted to a form that is used in these type of experiment.

Thanks. Yes, I think there's a lot of additional information that's needed and education regarding dietary supplements because I know a lot of patients like to take these because they feel like they're in control of their health and they're doing something good to maintain their health, but perhaps they're not doing as much good as they think they're doing. Preston, I guess, importantly, as we think about your scientific studies in the laboratory, how do you think they can guide more clinically oriented research and ultimately lead to advances in our understanding of mechanism or to ultimately improve patient care and outcomes?

Well, the advantage of doing experiments in laboratories is that we can carefully control the variables and look specifically, for example, at EPA versus other forms of EPA or other forms of omega-3 fatty acids. And so they can be helpful in giving us clues to why there may be differences in clinical benefit, for example, among omega-3 fatty acid preparations or compared even to other triglyceride-lowering agents. So we have, over the years, been very specifically comparing EPA to these other triglyceride-lowering agents as well as other omega-3s to help us understand possible reasons why EPA could be beneficial as been evidenced in these clinical trials. And again, it comes down to their very basic chemistry and chemical structure and how that, in turn, allows it to enter the cell or have these other effects that have been discussed.

That's very good. I guess, Dr. Bhatt, that's a very nice lead into some of the work that you've presented today as a late-breaker. Perhaps you could quickly summarize the very complex set of analyses that were presented today at the meeting in a way that we can discuss as a group.

Absolutely. So just to give a very quick recap of what I presented as a late-breaking clinical trial today was REDUCE-IT EPA, which was an analysis of both baseline EPA or eicosapentaenoic acid levels and levels on treatment. So let me first talk about baseline EPA levels. So there, we examined patients with a range of baseline levels of EPA and found benefit, substantial benefit of icosapent ethyl versus placebo across the full range of baseline EPA. The reason that's important is sometimes -- you sort of asked this question to Dr. Libby a little bit earlier. What about people who have diet, for example, that's very high in seafood and fish? Might that just be good enough? There certainly is epidemiology that says that diets high in fish and seafood intake are associated with lower cardiovascular risk. That's been pretty consistent for coastal populations studied throughout the world at different times. Personally, I'm a vegetarian. I don't eat fish or seafood. But those data, I think, as far as epidemiologic data go, are pretty strong. However, what this analysis shows is that even in people that are eating lots of fish and seafood and have higher EPA levels on that basis, even people who, for whatever genetic polymorphisms that haven't been elucidated yet, might have higher EPA levels or whatever other factors might go into that, even though it's at the highest levels of EPA, were still benefiting substantially from icosapent ethyl versus placebo. So really, the point there is, yes, you might have a great lifestyle and a diet that's high in fish and seafood intake, but that doesn't obviate the need or benefit for icosapent ethyl if you otherwise are a patient that's eligible for it based on cardiovascular risk. So that was message number one, a pretty important message. Message number two, I think, is even more interesting scientifically. It's where we looked at the on-treatment EPA levels. And what we found were very strong, very statistically significant relationships between attained EPA levels and lower risks of the primary endpoint in the trial, the secondary endpoint in the trial, so broadly speaking, cardiovascular events, but then also as individual endpoints, significant associations with lower rates of cardiovascular death, of all-cause mortality, of fatal or nonfatal heart attacks, of strokes, of coronary revascularization procedures, hospitalizations for unstable angina, of sudden cardiac death, of cardiac arrest and -- now those endpoints were all significantly reduced in the overall trial as well. But in addition to all that, what we saw for heart failure and hospitalization for heart failure, those were numerically lower with icosapent ethyl versus placebo in the REDUCE-IT trial but not significantly lower. But here, we found strong and significant associations with EPA levels on-treatment and lower rates of heart failure, new heart failure, and hospitalization for heart failure. So to me, seeing significant correlations here with EPA on-treatment and lower all-cause mortality, lower ischemic events of a variety of different sorts, and now also lower heart failure, I think that's really an amazing scientific discovery. I think it's one of those things that 10 years from now, people look back and say, oh, wow, that really was pretty important in terms of our mechanistic understanding of how icosapent ethyl works.

That's a great summary. I know there was also another important young investigator award in oral presentation. I'm looking at some of the differences between EPA and other omega-3s, particularly DHA. Perhaps, Dr. Bhatt, you could comment on that? And maybe, Dr. Mason, you might be able to comment on that as well?

Yes, that was another analysis that essentially is touting the benefits of eicosapentaenoic acid and showing that the benefits seem to be distinct from those delivered by DHA. So the anti-inflammatory effects really seem to be predominantly EPA much more so than DHA. So I think that work is nice confirmation really of work that Preston Mason has already done scientifically sort of proving that point, but it's always nice to have more information from other investigators using different models. They included some animal models in the work that you were citing. So it's just further multiple confirmation of the EPA axis of risk reduction and that it's very distinct from DHA, which might have other benefits in human health, but in terms of cardiovascular risk reduction, it really seems to be EPA is where the action is. One other thing I mentioned -- or forgot to mention, I should say, as far as the work from REDUCE-IT that I presented today on behalf of the REDUCE-IT steering committee and investigators, was we also looked at the contributions of triglycerides. And for sure, the drug lowers triglycerides obviously. It was initially approved for triglyceride reduction by the FDA. But that component of its action, reducing triglycerides, did account for some of the benefit we saw in REDUCE-IT, but it was really a fraction of the benefit. As far as LDL-cholesterol and the changes there on CRP, really, that didn't account for the benefits that we saw in REDUCE-IT. It was largely an EPA story. That is the lion's share of cardiovascular benefit that was observed was that due to EPA. So there's a lot of fancy statistics behind that. I'm not going to bore the audience with that right now. But I think scientifically, that's the other important point here, that while we were studying the drug in a population of patients with elevated triglycerides, and surely elevated triglycerides are a potent marker of risk, the predominant mechanism of benefit does appear to be EPA and its downstream effects. Again, work that Dr. Mason has done has nicely laid that out and work that Dr. Libby has done over the course of decades have really nailed down how arterial and vascular inflammation seem to be the key inside -- or in terms of cardiovascular badness events like heart attack, many forms of stroke. And I think EPA-related mechanisms of action, downstream cellular effects, are really what is driving the benefits we saw in REDUCE-IT on multiple endpoints. It's rare to have a therapy that's reducing heart attacks, sudden cardiac death, stroke, selective revascularization and now even heart failure.

That's a great overview. And it seems that there are certain targets that are coming to the floor, particularly 1gp120. I know there's been other data, other animal models that showed a similar effect as the Australian group showed. Perhaps -- I don't know if any of the panelists want to comment on particular targets, whether it's gp120 or not. Perhaps, Dr. Libby, you want to comment first and then maybe Dr. Bhatt?

Yes. Well, let me say that Deepak really put his finger on the role of inflammation as a driver of atherosclerosis in the events that we care about like heart attack and stroke. And it turns out that the triglyceride-rich lipoproteins are actually much more pro-inflammatory than bad cholesterol. When you look at them head-to-head when we measure inflammation in a patient, the markers of inflammation are actually much higher molecule-for-molecule or particle-for-particle when we look at the triglyceride-rich lipoprotein. So as a driver of inflammation, they're very important. Some of the anti-inflammatory effects that we're seeing, which can contribute to the clinical benefit of icosapent ethyl, could actually be due to lowering triglyceride-rich lipoprotein, which are one of the drivers of inflammation. So I think we have to keep our eyes on that because it could turn out to be very important.

Thank you. Any specifics, Deepak, on gp120 or other receptors that have been identified? I know people have talked about PPARs and other targets, but it seems like this gp120 has come up independently now in at least a couple different animal model systems.

Well, I think what really it points to is that we're still learning a lot about exactly how EPA manifests its benefits. And I think there's going to be all sorts of other receptors and molecular mechanisms that are identified. So I think it's an exciting time to be involved with EPA-based science. I mean, if I were just starting off as a fellow now, I think I'd go work in Dr. Libby's lab or Dr. Mason's lab and trying to make some fundamental contributions to what's going down -- what's going on downstream of that EPA. I think all we can say with absolute certainty now is really that EPA delivered as icosapent ethyl is 4 grams a day, specifically 2 grams a day twice a day with meals, exerts this incredible benefit across a variety of endpoints. It does seem to be pleiotropic, to use that word. And exactly how EPA is working that magic, I think, may take years, if not decades, to fully sort out. But from a more pragmatic physician's perspective, I think the key is to not necessarily wait until all that elegant science is elucidated, but rather to implement the results of REDUCE-IT in patients that are eligible and good candidates now.

I think that's a great point. I know a number of people have continually asked, and Dr. Mason talked about some of the basic science, but perhaps some of the clinicians on the call can comment on the recently reported results from the STRENGTH trial, which was a trial in a slightly different, but considered similar population, large trial, seemingly well-conducted, but was stopped early reportedly by the sponsor for a low probability of achieving a clinically meaningful result. Was that, Dr. Bhatt, surprising to you as the principal investigator of REDUCE-IT?

A great question. So first, actually just to make clear, all I know about the STRENGTH trial is what was in their public press release that the company sponsor had put out saying that the trial was stopped because it was unlikely to achieve its primary endpoint or some verbiage like that. And obviously, that's disappointing when that happens to investigators. I've been in that position many times. I think sometimes people forget out there, physicians in particular, and patients for sure, the majority of well-done trials are negative. And that's not because the investigators did something wrong or the company did something wrong or that the drug or device wasn't worth studying, but rather most things don't work in life. That's just how medicine is. It's not easy. I mean, it's easy after the fact to say, oh, yes, I thought about that. I knew that. But our priority, it's very difficult to predict what's going to work. And most smart people and smart companies are investing their time and energy and money into things. Usually, those things don't pan out. So it's not anyone's fault. I think as far as I know, the trial was really well done. The design, I thought, was really good. It made sense. So I don't have any critique along those lines. I think, ultimately, it's just that the drug may not have provided as much benefit as they had hoped because, first of all, the EPA levels aren't quite as high with that drug as what are retained with this one, icosapent ethyl. But perhaps even more importantly, it could be that the DHA that's in there is counterbalancing the good that the EPA would otherwise provide. So of course, they have blood that they've biobanked, too. So they'll check EPA levels for sure. But even if they don't see the same associations that we saw in today's REDUCE-IT EPA analysis doesn't really necessarily discount anything that was presented today. It just means that whatever I show today is true of EPA levels when attained by icosapent ethyl and that different formulations or combinations or dosing strategies just may not do the trick, even if they're attaining EPA levels that are broadly within the same range. So I think there's an important lesson there that the drug matters. Not everything is a class of drugs. I think that's been one problem that's hurt this field over the past couple of decades, that omega-3 fatty acids have all been lumped together and there's all sorts of things studied, EPA+DHA mixtures, low doses, dietary supplements. And then what you get is a lot of low-quality data. Now with STRENGTH, this is going to be high-quality data, but I think the issue is likely the formulation of the drug, the formulation of the EPA and potentially counterbalancing effects of DHA. So again, I think we'll get a lot of scientific insights from that trial, but ultimately, I think the clinical trial data trump everything. I mean, it's nice to understand the mechanisms. Doctors like to think they understand mechanisms of drugs they're using. Well, I don't think we all do, but at least we like to think we understand the mechanisms. And I think juxtaposition of REDUCE-IT, which was extremely positive, and STRENGTH, which as far as we can tell, at least didn't meet its primary endpoint, will help us understand exactly what components of these different drugs are driving benefit or potentially counterbalancing benefit.

Yes. No, that's a great summary. I mean, it's remarkable how much progress and understanding has transpired since the American Heart Association Meeting in 2018. First of all, ensuring that the clinical trial results were robust and then really now thoroughly understanding both at the clinical level and the basic science level some of the biological differences that are seemingly subtle at first principles of structural differences in molecules and their remarkably different biological effect. Preston, you're really the biochemist here of the group. I mean, is there anything else that you want to add regarding the differences in the molecules?

Yes. I'd like to reiterate what Dr. Bhatt was saying. And that is that unless you achieve these EPA levels with icosapent ethyl, we don't seem to see the same benefit with other formulations of these omega-3 fatty acids. And that is completely consistent with what we've been seeing in the laboratory the last, almost 10 years, that EPA, when derived properly and properly administered at the right pharmacologic dose, has properties that we don't see with other omega-3 fatty acids like DHA, in particular. So I wasn't entirely surprised when another trial using a combination or something different from this failed to show the same benefit. So I think it goes to the fact that this isn't a class effect. It is unique to its chemistry, which is very, very specific for EPA and how it works.

That makes me think of something...

Thank you. Please go ahead, Dr. Bhatt.

It just made me think of something. It's that nice exposition of the data that Dr. Mason provided. Because you asked me, I didn't directly answer, was I surprised by the results of STRENGTH? I had been, for a while, a big believer in the benefits of EPA, obviously. That's why I first got involved with REDUCE-IT. But I think on the REDUCE-IT team, at least parts of the steering committee, obviously the Amarin folks, but then scientists as well like Dr. Mason have been pretty consistent that EPA is where the action was. I mean, there was skepticism among all those people I mentioned, at least internally, maybe not publicly stated all the time, that EPA is really the driver of benefit, and DHA, not really proven for cardiovascular purposes. I mean, I believed Dr. Mason's work even before it was as widely known as it is right now. And I think it's -- so first of all, I think the broad sort of a conclusion or interpretation or feeling about STRENGTH is I think most people were really surprised when that press release came out about STRENGTH. But I also think many people were surprised when REDUCE-IT came out and wasn't positive, but it was very positive. And the expectation before had been that REDUCE-IT was going to be a big dud. I mean, that's what most people were thinking. Most people have lost interest in the trial or forgotten about it and just thought, "Oh well, they're are a bunch of negative omega-3 trials. That's just going to be another one. Why are those guys even just persevering?" But it's easy after the fact for people to say, "Oh, yes, I knew that all along," or "I was predicting it" or "It was obvious." But certainly, if you go back in time, that wasn't the case. I think the majority of the medical community had either forgotten about REDUCE-IT or was -- were quite confident it was going to be negative. And likewise, I think what the folks were thinking STRENGTH was going to be positive. I think it does point to the fact that understanding the fundamental basic science is indeed important, that we don't always have that understanding at the time we launch trials, but in this case, in the science that Dr. Mason has been working on has -- it appears has been borne out.

Well, thank you. And I know we're coming to the close of our time. And I guess, I'll give, really, Dr. Libby, the one who has truly been the visionary on this the longest, I'd like you to have sort of the closing comments for the whole ACC session and what we've covered today.

Well, I was surprised by the premature termination of STRENGTH. I thought maybe it would be weaker than REDUCE-IT, but that it was a total null really took me by surprise. And one of the fun things, for me as an observer, who is both on the clinical side and on the basic side, is how the interplay of insights between the clinical and the basic really enrich our enterprise. So when I learned that STRENGTH was a null or at least was stopped for supposed futility and the robust positivity, with all those zeros before the p-value in REDUCE-IT, it really made me stand up and pay attention to all of the fundamental biophysical work that Dr. Mason had led. And now that's going to get everyone rushing back to their test tubes to try and figure out what is so special about EPA following the lead of Dr. Mason. So it really made me pay attention to EPA as a potentially unique form of omega-3 fatty acid. And I thought that really the failure of a lot of the previous studies, including some of the more recent and very well-conducted studies from Oxford and from our own Preventive Medicine Group at the Brigham, that the failure was because of the dose, not because of the mixture of fatty acids. But now I think we all have to follow the clinical data and really recognize that there may be something special about EPA and try and learn more about it so that we can bring the benefit ultimately to our patients, because the issue of triglyceride residual risk is growing in importance in this era of nasty over LDL, and I think that we have an opening that will really help us push back that unacceptable burden of residual events even in patients who are well-treated with contemporary therapies of just statins.

Well, Peter, that was a great summary. Thank you very much. And I wanted to thank all of our presenters tonight at the end of a long and arduous ACC meeting: Dr. Peter Libby, Dr. Nathan Wong, Dr. Preston Mason and Dr. Deepak Bhatt. We all appreciate your contributions to science. We all appreciate your and all of your colleagues' commitment to maintaining all of our health in this unprecedented COVID time and putting yourselves and your families on the health line for all of us to protect us as frontline health care workers, and very appreciative of all the great science that you're doing as well. So we'll bring this session to a close. I wanted to thank our presenters for helping clarify a robust set of presentations of complex and varied data across the last several days at ACC. So with that, Elisabeth, I think I'll bring the session to a close, operator. And thank you all very much. Bye.

Thank you. Bye.

Thank you.

Thank you.

Bye-bye.

This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.