Amarin Corporation plc (AMRN) Earnings Call Transcript & Summary

Welcome to Amarin Corporation's National Lipid Association Scientific Sessions 2020 Late-Breakers Discussion, where select scientific publications presented over the weekend will be discussed. This conference call is being recorded today, December 14, 2020. I will now turn the conference call over to Alina Kolomeyer, Director of Communications at Amarin.

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 National Lipid Association Scientific Sessions 2020. We are honored today to be able to bring to you for your consideration the opinions of an esteemed group of clinicians and scientists. Opinions expressed by the clinicians and scientists on this webcast are theirs alone. They have neither been scripted nor previewed by Amarin. While Amarin values their perspective, we may not necessarily agree with their statements and, therefore, necessarily disclaim responsibility for such opinion. This audio webcast is intended to provide summaries of recently presented scientific data for consideration by Amarin's investors with use of voices independent of Amarin because we at Amarin believe strongly as an institution that a robust marketplace of ideas will lead to the best understanding of the significance of clinical data. 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 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, December 14, 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 and the risk factors section of our most recent Form 10-K filed with the U.S. Securities and Exchange Commission, SEC. This call is intended for investors in Amarin and is not intended to promote the use of Amarin's VASCEPA outside its approved indication. I will now turn the call over to Dr. Craig Granowitz, the Chief Medical Officer of Amarin.

Thank you, Alina, and I wanted to thank and introduce our esteemed panel today of investigators, all of whom presented data at the most recent National Lipid Association Meeting, which concluded on Saturday evening. I'll introduce the panelists now. The first is Dr. Preston Mason, who is a member of the Cardiovascular Division at Brigham and Women's Hospital, a teaching affiliate of Harvard Medical School. Dr. Mason is also President and Co-Founder of Elucida Research. The second panelist is Dr. Michael Miller, who is at the University of Maryland Medical System in Baltimore, Maryland. And the third panelist is 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 the primary investigator for the REDUCE-IT trial. So with our panelists here, I thought I would provide some context of why this session is important. And I think at Amarin, we've always tried to follow the science. And I think in this regard, like most of the time, the science is an excellent guide. And I think it's interesting that of the late breakers that were presented at the National Lipid Association, 2 of the 3 of them were related to icosapent ethyl in what on the surface might seem as very different uses. Dr. Miller will be talking about results from the REDUCE-IT study, which is a reminder, and Dr. Miller will tell us is a cardiovascular risk-reduction study of icosapent ethyl with statins in certain high-risk patients. And Dr. Bhatt will be presenting results from COVID-infected patients. And the question is, what is the relationship between cardiovascular risk-reduction and symptomatic but ambulatory COVID patients? And that's why I hope the basic science of Dr. Preston Mason and some of the work that he presented here and has presented recently will be this common link that ties it all together and provides a scientific foundation for understanding the context of these seemingly very different clinical benefits of icosapent ethyl, VASCEPA, that were presented as late-breakers at the National Lipid Association Meeting. So with that, Preston, I thought it might be worthwhile for you to share with our group some of the key data that you presented at the NLA Meeting and really sort of bucket it a bit, if possible, into sort of some of the cardiovascular risk-reduction findings and perhaps then some of the findings that might be more relevant in an antiviral or anti-inflammatory setting. So Dr. Mason, I'll turn it over to you to give a brief overview of your findings.

Thank you, Craig, and I'm delighted to be part of this discussion this morning with such steamed faculty members. I had at National Lipid Association about 6 presentations looking at different aspects of how EPA affects vascular function as well as other organs, particularly the human lungs. And that has helped inform us about some of these amazing new findings presented by Dr. Bhatt. And so the link, I believe, between Dr. Miller's presentation and Dr. Bhatt is that a key finding for REDUCE-IT was that, that most powerful predictor of benefit was the circulating levels of EPA in the body, indicating that EPA is directly affecting aspects of the disease process to cause its reduction in cardiovascular events. So our objective in our research is to look at how does EPA directly influence these mechanisms of disease that are common not only cardiovascular disease but even in infectious diseases like COVID-19. And the common denominator we're seeing with EPA is its ability to protect the cells that line our blood vessels as well as that are integral to the lungs against the damaging effect of cytokines associated with inflammation. So in our studies, we looked at both blood vessels as well as human pulmonary cells or lung cells and evaluated the ability of EPA to mitigate or to prevent the damaging effect associated with the so-called cytokine storm that has been implicated in the disease process of COVID-19. And in both cases, we found very interesting results. In the lungs, we found that EPA was able to significantly reduce a number of proteins that are linked to inflammation. And also, very importantly, it reduced the levels of ACE, or angiotensin-converting enzyme. You may have heard of that in the context of how the virus enters a cell through the A2 pathway. So this novel effect we're seeing on ACE is -- has broad implications, of course, for patients with COVID-19, but we saw a number of other inflammatory cells that were -- or excuse me, inflammatory proteins that were mitigated by the treatment. And I won't go into all the details, but they got everything, from how macrophages are activated, to aspects of how the cell protects itself. And then the final thing I'd like to say is that in these blood vessels and these endothelial cells that align our vessels, there's some very important protective molecules produced, called nitric oxide. And this has various cardioprotective as well as protects the lungs. And specifically, it interferes with the ability of the virus to enter the cell and to replicate. And in our findings, we found that EPA compared to other omega-3 fatty acids was able to enhance the ability of these cells to produce nitric oxide. So an intriguing observation that may be relevant to both the benefits Mike -- or Professor Miller talked about in REDUCE-IT as well as Dr. Bhatt's observations in patients with COVID 19.

Thank you, Dr. Mason. Could you comment, before Mike can provide some clinical correlate of the EPA levels out of REDUCE-IT, a bit on the different effects that different omega-3s might have on some of these parameters? Because they're not all the same, right?

Correct. So 2 points I'd like to make. One is consistent with Dr. Miller's presentation, the benefits of EPA are clearly dose dependent. So you need to achieve these higher pharmacologic levels like in REDUCE-IT to get these type of benefits. So that's my first point. My second point is we're very careful in our experiments to always compare EPA to other common omega-3 fatty acids. You may have heard of DHA. That's often used in combination in some of the trials that have failed to show benefit. And indeed, we do not replicate the benefits of EPA with these other omega-3 fatty acids or mixtures of omega-3 fatty acids. So that was a common thread in almost all of our presentations that you can't replicate the benefits of EPA with other omega-3 formulations.

Thank you, Dr. Mason. I think there's another point that at least you've stressed to me on many occasions is that the quality of these omega-3s are also very sensitive to a number of commonly encountered environmental factors such as oxygen, temperature and others. Are those important factors as well to the activity? It's not only the EPA versus other omega-3s, but it's also the quality and the stability of the particular EPA. Is that not right?

That's absolutely correct. In fact, in one of my presentations at NLA, we specifically looked at mix of omega-3 fatty acid that's very commonly used by consumers and sometimes even patients, and that is from dietary supplement. And we found that in addition to being damaged by oxidation due to inadequate manufacturing controls, it also contained other fatty acids that are considered harmful for patients with cardiovascular disease, such as saturated fat. So it depends completely on the formulation, the preparation and the rigorous FDA oversight that a prescription medication would require. So yes, we continue on that theme that you should not substitute a proven FDA-approved therapy with dietary supplements or other formulations of omega-3 fatty acids for the reasons you just discussed, both from the basic science, what we know about them template, as well as the lack of manufacturing approaches that can actually damage and even render them, if not neutral, maybe even harmful to the patient.

Thank you, Dr. Mason. Just to be crystal clear on that point, you're referring to those other preparations, both in terms of other non-EPA constituents. But my question was particularly focused on the EPA molecule itself, that, that molecule can also be oxidized or easily mishandled, and that could affect its activity. Is that...

Yes, completely it does.

Could you tell us a little bit more about the EPA itself, not the other omega-3s or other constituents, that might be a component of the prescription medication?

Correct. So I believe that in 2017, we published a study where we compared EPA in the pure form that has not been damaged to one where we simply let the EPA get exposed to oxygen even for a small amount of time. And then we tested them. And we found that when the EPA was damaged or oxidized, it no longer replicated the favorable biological activity we saw with the undamaged or the pure EPA that was not damaged but done under prescription-type conditions.

That's very helpful context because I know that you've certainly educated me, and I think that Drs. Miller and Bhatt feel the same way that it is the combination of the omega-3s, and it seems like it's related to the EPA level, and I'm going to turn it over to Dr. Miller in a moment to share his EPA results. But it's also the individual EPA preparation itself. And especially for something like CVD risk-reduction or COVID, there are no potential easy biomarkers that may or may not correlate with the clinical effect that's seen, especially in a complex, long-term disease like cardiovascular risk-reduction for major cardiovascular events. So I think maybe Dr. Mason, unless Dr. Miller or Dr. Bhatt, you have any further questions or clarifications on what Dr. Mason covered.

Well, it's Deepak Bhatt. I won't say that I have any clarifications, but I just have to express my admiration to Dr. Mason. I think the science he's doing is just incredibly revolutionary. And it's just -- I think when one looks back with the lens of history and time, people, scientists, physicians will say that, that was really incredible work that's just opened up a whole new paradigms of thinking. So I just wanted to contextualize the sort of work that Dr. Mason is doing.

I would second that.

Okay. Well, very good. And thank you, Dr. Mason, for taking some very, very complex science over years and making it approachable for all of us to understand and bring into our own use and domains of expertise. Dr. Miller, it would be wonderful if you could give a summary more into the context of what those results might actually mean. So could you give a brief overview of what you presented at the NLA Meeting?

Sure. So at the National Lipid Association Late-Breakers Session last evening, I presented data from the REDUCE-IT trial that evaluated levels of icosapent ethyl EPA in the blood. And the idea was to see what might explain the considerable benefit we saw in REDUCE-IT. You saw a 25% reduction in primary end point. And we couldn't explain that by virtue of the triglyceride reduction. So what other possibilities could explain the benefit? And so this study looked at the levels of EPA. And what we found was compared to the baseline measure at -- with each successive year, we saw a pretty significant and consistent rise in EPA levels that default from baseline. And what that was directly associated with was a benefit with respect to the primary and secondary end points in the study. And that included heart attacks, stroke, cardiovascular death, total mortality and so forth. So that the higher the on-treatment EPA level in our patients in the REDUCE-IT trial, the greater the benefit observed on these end points. So it was very consistent. We saw this with the primary end point, the secondary end point, again, total mortality, any -- heart attack or stroke or the need for bypass surgery or coming in with unstable angina. So again, illustrating the notion that serum EPA -- on-treatment serum EPA was very important correlator of benefit observed in the study. I will also state that the levels here, we would look at the EPA levels in the REDUCE-IT trial. Another study that had come out that had been presented a couple of months ago was the STRENGTH study that used the combination of EPA and DHA. EPA levels were not quite as high compared to what we identified in the REDUCE-IT trial. And that may have in part been a basis for why the STRENGTH study was negative. Now why would EPA and DHA defer, and Dr. Mason eloquently discussed that a little while ago to some extent, but he's also done nice work to show that there are differences at -- in cell membranes. There's also differences in how DHA behaves compared to EPA. EPA reduces oxidation, as anti-inflammatory effects, improves endothelial function. DHA may, in effect, oppose some of these effects, such as impairment and oxidation. So for these reasons, having a high level of EPA on treatment in the REDUCE-IT study appears to be the main driver for the benefit observed, and perhaps some of the studies that have been negative in recent years have been generally using the combination of EPA, DHA. And perhaps DHA may oppose some of those effects.

Thank you, Dr. Miller. Great summary. I just want to peel back a bit more on some of the way that the body manages and handles icosapent ethyl and then its metabolites. Now I know that there are some specialists who wonder -- who know this, but I think for many of us, it's always worth a reminder that what's called the volume of distribution or where is the molecule ultimately residing in the body. Dr. Miller, could you comment, or maybe Dr. Bhatt or Dr. Mason, on is most of the EPA floating around in the bloodstream and is that where it's acting? Or is it really not acting at the blood level and it really -- while the correlation might hold for one preparation of EPA that we could feel confident based on having a large outcome study, could we make those assumptions generally around other EPAs per se? Maybe Dr. Miller, you could comment first.

Yes. Yes, that's a great question. I think I would like to believe that if you have a fair amount of EPA in the bloodstream, then that would also suggest that there would also be EPA in tissues. Now to what extent some of these tissues might have more EPA working at the level of the membrane, I don't know if we know that specifically, but I believe there is that correlation.

Dr. Bhatt, your thoughts?

Yes. No, I was just going to opine on this. It's an interesting conversation high. I think there are, of course, hardcore scientists like Dr. Mason that are working on this. And then their trial is -- of course, we're doing trials and we're measuring biomarkers, and we're sort of dabbling in the science. But especially when it comes to omega-3 fatty acids, the sciences is really very, very complex. And I think you've raised a good point here. The plasma or serum levels are relatively easy to measure, though there's some tricks to the trade there, too. But what would probably really matters from a patient health perspective is the tissue levels, what gets into the tissue. And the reality is we don't have an easy way of measuring that. So people that are doing research in this area and trials were often just measuring plasma or serum and hoping that, that really is correlating with something going on at the tissue level. And at least in the case of REDUCE-IT, it does appear to because there's a very strong and statistically significant correlation between achieved on-treatment levels of EPA and reductions in a variety of different ischemic end points. And including in end points that we didn't see significant reductions in the overall trial, such as heart failure, were at the highest achieved levels of EPA, there are significant correlations with lower rates of heart failure. So I think there are several things going on. The dose matters. The formulation matters. It probably matters that a threshold level be reached of EPA concentrations in the tissue. And I think it also matters what other stuff is in the product. So if there are other omega-3 fatty acids, other fatty acids in general, saturated fats, all subject to oxidation, perhaps prepared in a way, as Dr. Mason was alluding to, that doesn't prevent that type of oxidation. Studies that are then performed can be very misleading. The omega-3 fatty acid literature is fascinating, but it's full of all sorts of rather simplistic errors in some cases. Maybe not that simplistic, but for people that maybe aren't immersed in the field, I think they're just common sorts of errors that occur, and Dr. Mason mentioned one of them, where if the product is oxidized and then you're doing studies of it, you can get all sorts of associations that end up being misleading. So I think what we have with icosapent ethyl, what we know at this point is that it's a pure EPA. It's prepared, processed, packaged, delivered in a way that prevents oxidation, and that at the doses that have been studied in REDUCE-IT, we're able to achieve a level of EPA in the body that results in large therapeutic cardiovascular effects. And everything beyond that, I think, is a point of discussion and ongoing research. But that part, we can be sure of. There, the linkage between the basic science and the clinical trial outcomes is quite solid.

Thank you, Dr. Bhatt. And I appreciate you and Dr. Miller and Dr. Mason bringing that context forward is the vast majority, which is well more than 90% of EPA, ends up in the tissues, not in the bloodstream. And at least for the case of icosapent ethyl, VASCEPA, that particular formulation, a 7-year outcome study that Dr. Miller just highlighted demonstrated that, that correlation of plasma level does correlate to clinical outcome. But I think the ability to generalize that to other preparations, even of EPA, remains very much an open question, especially when there's no surrogate biomarkers to measure. And I think one of the key points from the STRENGTH trial, and I know we don't have time to go into it, is even though there was a significant reduction in triglycerides, there was absolutely no clinical effect demonstrated in major cardiovascular events, but there were certain side effects that were seen in the active group. So it's clear that the drug was doing something, but something quite distinct from what was achieved with icosapent ethyl, VASCEPA, in either the REDUCE-IT study or the JELIS trial. Are there any other comments or questions for Dr. Miller? Or Dr. Miller, are there any other points that you want to bring up? Because otherwise, I think we'll transition to Dr. Bhatt going forward. So Mike, are there any comments that you'd like to add that we missed?

No. I mean I would just again emphasize what you said. It's like -- and what was said by Drs. Mason and Bhatt, that is pure EPA formulation does make a difference. And we now have 2 studies that show that, of course, REDUCE-IT, and prior to REDUCE-IT, that led to REDUCE-IT was the JELIS trial. So we have evidence of purified EPA. And then when you have a combination of EPA, DHA, several studies have not demonstrated to be beneficial. So again, we need to kind of hone in and see whatever differences might exist between both. But we know triglyceride lowering occurred similarly in both studies, and yet REDUCE-IT was positive and STRENGTH was negative.

Before we leave the subject of bioavailability because I think that's very important, I wanted to share with everyone the results of another experiment we presented here at NLA. And Dr. Bhatt was a co-author on this study along with Sam Sam Sherratt, who works alongside me. In this experiment, we delivered EPA and other omega-3 fatty acids to cells, and we then measured the amount that was taken up by the cells. And the key finding from this was that when EPA was delivered to the cells, it was rapidly taken up and metabolized into a variety of anti-inflammatory mediators. By contrast, when we administered like DHA, we found that it didn't get metabolized very quickly. And also, it increased levels of other fatty acids like arachidonic acid, which are pro-inflammatory. So that was the first time someone has observed the differences between even these 2 omega-3 fatty acids with the way the cell rapidly takes it up, metabolizes or doesn't do that. So I can assure you that EPA is very rapidly taken up when coming from the bloodstream in the form of lipoproteins and delivered to cells. And those cells rapidly put that EPA to work in the form of metabolism in ways that will protect the cell from inflammation and enhance this important signaling molecule I spoke about before, called nitric oxide. So I just wanted to add that. Thank you.

I just -- I've got to interject one last point about the EPA analysis that Dr. Miller presented. He focused on the drug and its effects quite appropriately. The point I'm going to make is perhaps a little bit of a silly one, I think, to really have to engage in, but I'm going to anyway just given some recent remarks that have been made. The analysis from REDUCE-IT of EPA clearly shows that there is a tight correlation between achieved on-treatment EPA levels and cardiovascular outcomes benefits. This is true even when the analysis is adjusted for adherence, adherence to the study drug, adherence to statins and a bunch of other things that were thrown in the multivariable model. So it's a very tight correlation. But there's another important part of it, a bit of a more subtle point that one won't usually think of because there's no reason to ever think about this sort of thing. But if there were any sort of effect from a placebo in the trial, you wouldn't expect a dose response then with the drug. That is the fact that there is essentially a dose response curve that we've generated in REDUCE-IT EPA is strong evidence that it is a drug effect, that it's not some sort of weird interaction or effect of a placebo here. If this were a case, let's say, theoretically of a placebo causing harm and not a drug causing benefit, well then, why would there be a correlation between the achieved on-treatment EPA levels from the drug and outcome? One did explain 98% of the benefit in various sophisticated statistical analysis, the triglyceride reduction explaining the remainder. Why would that actually be? It is actually ironclad evidence that it is the drug that is producing all the effects in this trial and not some sort of odd, unusual placebo effect that is occurring in a randomized, double-blind trial. And of course, as Dr. Miller alluded to, the results of the JELIS trial that was positive that had no placebo in a randomized, open-label design. So just to really put all aspects of that EPA analysis in the limelight. It certainly proves that the predominant mechanism of action of icosapent ethyl is the level of EPA that is attained likely in the tissue, but we measured in the blood. And that it really shows that it's a drug effect, not some other byproduct of trial design or placebo or anything else.

Great point, Deepak.

Thank you, Dr. Bhatt. Extremely important point to make and reinforce. So I thank both of you, Dr. Bhatt as the principal investigator and Dr. Miller as the presenter at the NLA Meeting for this important contribution to the literature. Dr. Bhatt, I wanted to now transition to the CardioLink study. But I think before we go into the details of the CardioLink study, I know that you have been working with Amarin for many, many months now on a far more comprehensive program, letting the biology guide us to the fact that icosapent ethyl, VASCEPA, may have activities at multiple steps in the COVID infection process, both before, during and after acute infection. Would you take a moment, please, and share with us your thoughts and perspectives on the breadth based on the biology of the program that we are currently conducting or thinking about?

Yes, absolutely. So there's, of course, now from REDUCE-IT, great evidence that icosapent ethyl provides large risk reductions for appropriate patients. It's defined in, for example, the FDA label, the Health Canada label. No question about that. The major challenge, I think, is implementation science, making sure patients who could benefit get the therapy. Beyond cardiovascular, there's lots of research going on with icosapent ethyl. Some is sponsored by Amarin. Some is investigator-initiated. Some is here in the U.S. A lot of it's outside the U.S. And for people that are really interested, we won't have the time on this call to go through it all, but there's a review article that came out in a European Heart Journal supplement just last month where it talks about -- or what should I say, we talk about potential future uses of icosapent ethyl beyond cardiovascular prevention. So for anyone that's interested in the broad picture of what's going on out there with icosapent ethyl or at least what's going on that we know about, there's probably other research, too, in the neurological domains, in terms of cancer, in terms of infectious disease, that's a good review. As far as COVID goes, there's a large program going on sponsored by Amarin with respect to icosapent ethyl. And one study that I'll point out is MITIGATE. That's being done by the Kaiser Health Care System. Drs. Go and Ambrosy are ones heading that study, and that is a pragmatic trial. So it's a fascinating design, an open-label trial of high cardiovascular risk adults, folks over the age of 50, no prior history of COVID that have established atherosclerosis, where they're being randomized icosapent ethyl or the usual care. And the study is examining end points such as moderate or severe confirmed viral upper respiratory infections, worsening clinical status due to a confirmed upper respiratory infection. So it is a fascinating study that is looking, not just at the potential COVID-related morbidity but other sorts of associated infectious morbidity that tends to occur this time of year, like with influenza, for example, or other sorts of coronaviruses or rhinoviruses that are floating around this part of the globe and season. So really fascinating study. And it will be interesting to see what it shows. It's really charting new territory. Another study that I'll mention is PREPARE-IT 1. This is being done by colleagues in Argentina. The academic medical center known as ECLA is running that study, Dr. Rafael Díaz and colleagues. And what we're doing in that study is randomizing 2,000 essential health care workers, so doctors, nurses, cleaning staff, personnel that are involved in aerosol-generating procedures relative of COVID-19 patients and laboratory staff, the nice folks that are running these COVID-19 tests, and just the general population at risk. So 2,000 folks randomized f icosapent ethyl versus placebo, and their goals are to look at the percentage of conversion to SARS-CoV-2 positivity, looking at the World Health Organization descriptive score of COVID-19. So lots of different things that are being looked at with respect to COVID-related morbidity. But equally important, I think, regardless of that COVID hypothesis in the trial is that we're studying 4 grams twice a day for 3 days as a loading dose in that trial. So we'll get to a study that was just presented at the National Lipid Association as a late-breaker in a moment. But this is a 2,000-patient study where essentially 1,000 patients are getting that loading dose. So we're going to have a ton of data about the safety and tolerability of that loading dose, which, yes, I hope it works out in this situation of COVID and the pandemic. But regardless of that aspect of things, I'm hoping can serve as a prelude to any number of studies, maybe funded by Amarin, maybe investigator initiated, who knows, looking at initiation of that type of loading dose in folks that are hospitalized with a heart attack or a stroke right at the time they come in or patients that are undergoing stenting procedures or bypass surgery procedures. So opens up a whole world of possibilities. And I'm happy to report that as of today, we've got over 1,400 patients randomized in PREPARE-IT 1. And PREPARE-IT 2, which actually looks at people that are COVID positive at baseline, we just launched this past week. So very exciting work that's going on with icosapent ethyl that will teach us a lot about the drug. These trials, of course, don't have triglyceride entry criteria, much broader people, in some cases, not even patients, but people that are getting icosapent ethyl and this loading dose aspect, I think, will be really informative.

Thank you, Dr. Bhatt. So just to put that in context before you go to the actual data. There are 3 other much larger studies that are running, really, what I would call in the earlier phases of what is probably going to be a lifetime of COVID disease and symptoms for many patients with long COVID is to prevent or minimize the severity of infection. That's what we're calling MITIGATE, as well as the treatment of the early stage of COVID infection, which will be the study that you're going to discuss in a few moments, and the second of the 2 trials in Argentina that you mentioned. But all told, we're really on the order of 3,500 or more COVID-treated patients with a very large number of controls, either matched controls in the case of the Kaiser study or placebo-controlled drug controls in the case of the 2 studies in Argentina. But to me, the most important element from the CardioLink study, as you've already mentioned, was the safety. And I know that we all felt very strongly that we needed to establish safety first because this drug has never been studied in this patient group before, before even contemplating studying larger groups of either the general public or patients in any setting. And I know that you felt equally strongly to me as the rest of the steering committee members who are listed on the abstract that we always wanted to put safety as our primary focus. And when we felt comfortable with the safety, we felt more comfortable moving forward, particularly with a study in COVID-infected patients in much larger numbers of people. So I just wanted to reiterate that point and my thanks to you as the co-PI in all of these studies and our other collaborators of putting patient safety always first.

Yes, absolutely. That's always first and foremost in these trials that we're doing. So perhaps I can now explain the COVID-19 CardioLink-9 study. So this was presented as a late-breaking clinical trial at the National Lipid Association, so really recent data. And I've got to congratulate and thank my co-investigators in Toronto, who just did a spectacular job in the middle of a pandemic doing a trial and doing it really quickly and going from the trial closing to presentation within just a couple of weeks. So just an amazing effort to show how despite this tragedy of a pandemic, health care workers or -- and scientists are mobilizing, trying to do what we can. So what the COVID-19 CardioLink-9 study consists of is 100 patients who are ambulatory outpatients with a confirmed COVID positive test. So they've got to have a positive SARS-CoV-2 test within the prior 72 hours and be symptomatic, which many of these folks, as you know, are. That is having more than -- or at least one or more than the following: a fever, cough, a sore throat, shortness of breath, myalgia or muscle pain. And then we enrolled 100 of these sorts of COVID positive patients, outpatients, again, and randomized them to either icosapent ethyl or usual standard of care control. So it's an open-label trial. There was no placebo in this particular trial, and the icosapent ethyl dosing was this larger loading dose. This is the first human experience with at 4 grams twice a day for 3 days, and then that was followed by the usual dosing of 2 grams twice a day or a total of 4 grams per day for the next 11 days for a 14-day or 2-week treatment period. The biomarker end point was change in hsCRP within the icosapent ethyl arm over that 2-week period, and the clinical end point was the change in the FLU-PRO score that I'll describe in a moment from randomization to day 14, again, in the icosapent ethyl arm. What we found, first of all, with respect to tolerability is the loading dose was tolerated really, really well. And there were no discontinuations specifically due to problems with the loading dose. So within the context of a modest sample size, but in people that were feeling kind of crumby, the dose was tolerated quite well. So we were really encouraged by the loading doses. You alluded to it, it is being studied in a much larger trial, PREPARE-IT 1, but this first signal -- this first human use of a loading dose was really very encouraging. So that's the loading dose part of things, which I think is actually going to be a major contribution to the study, not necessarily for COVID but for all the other disease states where I do think a loading dose could make an even bigger impact than we've already seen in REDUCE-IT. If you recall, in REDUCE-IT, there was a large reduction in revascularization and large benefits in the subgroups of patients with prior stenting and prior bypass surgery. That was despite the fact that in REDUCE-IT, we excluded the patients who are sort of at highest risk of those complications. We weren't enrolling patients right there in the hospital at the time of their heart attack, where the drug, I think, would have had an even larger effect than we saw in REDUCE-IT. So at any rate, that's an important part, I believe, the loading dose, and we'll get further safety and tolerability data from Argentina. The other part of this study was to examine the impact on biomarkers and symptoms. And as far as those 2 things go, the hsCRP data, I thought, was really very encouraging. It showed that within the icosapent ethyl arm, there was about a 25% reduction in hsCRP levels, and this was statistically significant. So this is, of course, in keeping with what has been already demonstrated with icosapent ethyl and other studies like REDUCE-IT and MARINE and ANCHOR. But those are all studies where there's some degree of triglyceride elevation, either sort of folks with high normal or modestly elevated triglycerides in REDUCE-IT or ones that are substantially higher in ANCHOR or very high in MARINE. But nevertheless, these were patients who weren't put into a trial because of high triglycerides. Over half had totally normal triglycerides at baseline. It's interesting how many didn't have elevated triglycerides, if you use 150 as a cutoff in this ambulatory population, but that's a topic for another day. But nevertheless, in a population that wasn't enriched for triglyceride elevation, we're still seeing this anti-inflammatory effect. So scientifically, that's interesting. Having said that, I'm personally someone that likes biomarkers and thinks that they're fun to study and talk about and publish about, but ultimately, I care about how patients feel, what clinical outcomes are affected. So these were ambulatory outpatients. So we didn't have anyone that was dying or ending up on a ventilator or like that in the context of the type of patients enrolled. But these were a highly symptomatic bunch that is coming into the trial. They had lots of symptoms, lots of different muscle pains, for example, myalgias. Over 90% in each arm of the trial had myalgias. About 2/3 had a cough. About half or so were febrile, that is having a fever. So lots of different symptoms. About 10%, 20% short of breath as well. So that was a highly symptomatic group that we enrolled but people that weren't at death store. These were ambulatory outpatients. And that's the context in which we saw the hsCRP changes, and we also examined this FLU-PRO score. So probably people that aren't immersed in influenza research have not heard about the FLU-PRO score, but it's a patient-reported outcome. So it's patients describing their symptoms, in this case, at baseline, and study end, and it's a validated instrument for influenza research. So if you look at different influenza trials and drugs of influenza trials and so forth, you'll see the FLU-PRO score in there. And it's really patients describing across a variety of domains how they're feeling, what is not feeling good, what is aching and so forth. So that is something that we examined. And what we found in this validated patient-reported outcome measure was a significant difference within the icosapent ethyl arm, that is from a baseline of 14-day significant improvement in the FLU-PRO score that was true of the total FLU-PRO score and true of different domains, things like body, systemic symptoms, and interestingly, chest respiratory symptoms as well. There was a slight increase in minor GI side effects with icosapent ethyl versus the control arm. But again, as I mentioned before, other than that, really well tolerated. So significant changes, improvements in the FLU-PRO score for how patients felt overall, that was our primary clinical assessment, but also in specific domains, the body, systemic domain, the chest respiratory domain. So -- and the differences, even if one compares between groups, were significant, the caveat being this was an unblinded trial, so patients were aware of what treatment they were receiving. The one other thing I'll mention before opening up for discussion here is that we also looked to see if there was a correlation between the improvement in FLU-PRO scores with icosapent ethyl and the decrease in hsCRP with icosapent ethyl. And interestingly, there were highly significant correlations between the 2. So the change in CRP seemed to correlate with the improvement in the FLU-PRO scores in the icosapent ethyl arm. Again, interestingly, not in the usual care arm. So it did look like it was true, true and related, again, within the context of a modest-sized trial that was unblinded.

Thank you, Dr. Bhatt. Great summary. I'm going to ask you just one more definitional question because I know I've received a number of questions on this topic as well and was one that you discussed at some length during the presentation is, what is a D-dimer? And what does that mean?

I forgot to mention that part of our finding. So I mentioned CRP, which was really the biomarker of interest. But we did look at other biomarkers, and one of them was D-dimer. And here, within the icosapent ethyl arm, again, we saw a significant reduction in D-dimer levels, baseline versus 2 weeks. And what D-dimer is, is a marker of thrombosis or clotting. So CRP is a marker of inflammation, D-dimer is a marker of thrombosis. And with COVID-19, also a variety of other disease states, but with COVID-19, we know that both things are out of whack, that is both inflammation is turned up inappropriately. So of course, you want some degree of inflammation to fight infections. But as sometimes occurs in any number of disease states, including COVID-19, the body's response to the enemy is worse than the enemy. That is there's inflammation that goes out of control sometimes in some disease states that's referred to as a cytokine storm. There's still a discussion about exactly what role that does or doesn't play in COVID-19, but inflammation that is excessive is a problem in a variety of disease states. There's also a problem in cardiovascular disease in terms of arterial inflammation, but that's a bit off-topic, though perhaps how icosapent ethyl could be providing benefit across different disease states that are, from a distance, seemingly unrelated. D-dimer, unlike CRP, is focused more on the blood clotting side of things, which where we know in COVID-19, I've seen this a number of times on the wards in the intensive care units, there's a lot of inappropriate blood clotting occurring, and that can result in things like blood clots in the legs, so-called pulmonary embolism where the clot goes to the lungs, that can be a fatal condition, strokes, heart attacks. A lot of bad cardiovascular events have blood clots behind them. So the effects here we're seeing on hsCRP and D-dimer certainly encouraging in the context of COVID-19 since inflammation and thrombosis are both bad players in COVID-19. But having said that, again, I find biomarkers interesting. What I found more interesting here was the clinical improvement in symptoms.

Terrific, Dr. Bhatt. One other question, if you could answer briefly because I know we're -- we've been on for quite a time, and I know this is an engaging topic for all of us, is there have been a lot of questions about the differences between a vaccine and a therapeutic. Could you just, again, from your perspective, to sort of summarize those differences and where these types of agents would be used?

Sure. Great question. And these are all complementary approaches. So certainly, in this trial, in this development program, we're not trying to unseek vaccines or in any way impugn vaccines. I'm really encouraged by the early data from the vaccines and look forward to seeing longer-term data and safety data in the general population. It does appear, for example, people that have allergies, we have to be cautious in terms of vaccinations there. But it's going to be rolled out soon, and health care workers will be among the first that will be getting the vaccine. But the reality is that's going to take a long time. The reality is not everyone is going to consent to getting vaccinated. And I think there's going to be a need for all sorts of additional approaches for people that are getting hospitalized, people that get COVID despite vaccination. We still need therapeutics for that inpatient phase of care. And likewise, for folks that still get infections either because they got vaccinated but still managed to catch COVID-19 or they just had refused vaccination, we need something for them, even the ones that are outpatients. There's a lot of morbidity from COVID-19 in symptomatic outpatients. And this is an area that has had relatively few in the way of effective therapeutics, at least for the sick inpatient. The data for dexamethasone, for example, and people on oxygen or on ventilation looks quite good. But for the symptomatic outpatient who just feels awful, and I must say, I personally know several physicians and nurses in that category, there's not really something right now that is approved and available. So I think the vaccination is something we should all be happy that it's now on the near-term horizon. But I still think there's going to be a need for additional therapeutics in this pandemic era. Furthermore, I'll say, at least as it pertains to the research we're doing with icosapent ethyl, we're happening to study it in a COVID-19 pandemic, but I'm not sure that what we're finding or that the work that Dr. Mason has been doing is necessarily just specific to COVID-19. It could have applications to just influenza or other sorts of related types of infections that carry lots of morbidity. By related, I mean, they're tall in terms of morbidity and mortality and high degree of prevalence. So I think this program that we're engaged in, in terms of evaluating icosapent ethyl is going to teach us a lot about the drug, its safety and tolerability in other populations, and hopefully provide some insights into whether it really does have a role in COVID-19 and other types of infection.

Terrific. And just as a reminder, neither the current therapeutics against the virus or against the inflammatory response to the virus or vaccines are going to have any likely impact on those with post-COVID, long COVID symptoms defined by patients that are PCR negative [indiscernible] positive. So that remains an entirely open area of research. I think, increasingly, the world is going to start thinking about as a number of recovered people starts running into the tens, if not hundreds of millions around the world. With that, are there any other questions or comments from anyone? I thought this was a great session with just a terrific panel. And I thank you all for your time as well as the listeners for their time and attention. I wanted to also thank the National Lipid Association for hosting what was a terrific meeting this year and for their holding the late-breaker session at the NLA Meeting. With that, I think we will draw the program to a close. Thank you very much.