Amarin Corporation plc (AMRN) Earnings Call Transcript & Summary

Thank you all for joining what we believe will be a stimulating and useful discussion about key cardiovascular therapeutic data presented at this year's American Heart Association 2022 Scientific Sessions and their impact on patient care in both the United States and Europe. We know you are very busy, and we are grateful for your perspectives and input on data presented at the AHA Scientific Sessions. I'm Dr. Steven Ketchum, Executive Vice President, President of R&D and Chief Scientific Officer at Amarin.

And I'm Nabil Abadir, I'm the Senior Vice President and Chief Medical Officer at Amarin. Turning to our panel. Can I ask each of our participant to please briefly introduce yourself, starting with Dr. Cory?

Good morning, everyone. I'm Dr. Payal Kohli. I'm a noninvasive cardiologist and a preventive cardiologist at University of Colorado in Denver. I trained at Harvard Medical School, Brigham and Women's Hospital, and University of California, San Francisco. And I've been involved in the field of preventive cardiology and research in preventive cardiology for over a decade. It's a pleasure to be here with you all today.

Thank you, Dr. Kohli. Dr. Libby?

Yes. I'm Peter Libby from Boston's Brigham and Women's Hospital and the Harvard Medical School, and I'm a general and preventive cardiologist with a research interest in atherosclerosis.

Thank you. Dr. Boden?

Yes. Good morning, everyone. I'm Bill Boden. I'm Professor of Medicine at Boston University School of Medicine, and I'm at VA Boston Healthcare System. I have been involved in clinical trials, mostly in ischemic heart disease, but in preventive cardiology, and previously was a study co-chair of the AIM-HIGH trial, comparing niacin with placebo.

Thank you for that. Dr. Catapano?

Hello, everyone. My name is Dr. Alberico Catapano. I'm Professor of Pharmacology, University of Milan. I'm interested in lipid and lipoproteins as they relate to atherosclerosis since a long time and also, obviously, on the effect of nutrients and active drugs.

Great. Thank you all. So before we begin, I just want to remind everyone that today's conversation will be recorded and may be shared with external audiences, including potentially media and investors. I'd also like to remind everyone that the opinion of all participants are solely their own. Amarin has not in any manner influenced and may not necessarily support and/or endorse any of the opinions or statements that may be made by participants during this event or otherwise. That said, I really would sincerely like to thank all of the participants for their honest and unbiased answers as we discuss, and for their overall participation in today's event. It really is appreciated for you all to be with us today. So with that, let's begin and then turn it to Steve.

Great. Thanks, Nabil. And first, we're going to touch on the prominent trial results and the impact on patient treatment. This weekend, we saw a presentation with the full results of the prominent study, the latest in a series of cardiovascular outcomes trials including ACCORD-Lipid and FIELD in which fenofibrates and the broader class of fibrate drugs have failed to demonstrate a CV benefit for statin-treated patients with the high risk of CV disease. Despite overwhelming evidence that they have not demonstrated any benefit in reducing cardiovascular risk, fibrates continue to be extensively prescribed for approximately 2 million Americans annually, most often along with statins.

Let's start with you, Dr. Boden. What are your thoughts on what these results mean for the fenofibrate class and their use by clinicians in statin-treated patients with the high risk of CV disease?

Yes. Thanks very much, Steve. Well, by way of background, I think we've known for decades from epidemiologic studies that elevated triglycerides are an independent risk factor for CV disease and were based on more recent Mendelian randomization studies that triglycerides are in the causal pathway for developing incident cardiovascular events. So clearly, there's been a compelling rationale for targeting triglyceride reduction pharmacologically. I should note that between 1987 and 2005 in the pre-statin era, there were 5 placebo-controlled trials of fibrates in over 20,000 patients, which showed evidence of benefit with gemfibrozil, both in the Helsinki Heart Study and [ BA Hit ], but interestingly, not with bezafibrate or fenofibrate. But again, these were all in the pre-statin era. More recently, in the statin era, studies with both fenofibrate, notably the ACCORD trial and with niacin, the AIM-HIGH and HPS2 THRIVE trial, all showed significant reductions in elevated triglycerides as well as HDL raising, but with no reduction in incident cardiovascular events. Though post-hoc analysis in these trials showed potential benefit in a subset of patients with the lowest tercile of HDL and the highest tercile of triglycerides regarded as having the highest CV risk profile and the likely target population with the greatest potential benefit for TG lowering. So over these decades, our attention has shifted from exploring whether these agents are primary dyslipidemic interventions as opposed to being adjunctive therapies with statins which could then reduce dyslipidemic residual risk. And I think we all recognize that everything in dyslipidemic risk is not LDL alone. So prominent targeted specifically, this population of patients with type 2 diabetes, elevated triglycerides in the range of 200 to 500 milligrams per deciliter as well as an HDL of less than 40 milligrams, 69% of whom had established coronary heart disease. And altogether, almost 10,500 patients were randomized with pemafibrate, 0.2 milligrams BID or placebo during a median 3.4-year follow-up with the trial primary endpoint of nonfatal MI, stroke or neurovascularization or CV death. And it's interesting to also stress that 96% were receiving a statin, of which 2/3 were receiving a high-intensity statin. So despite a significant 26% triglyceride reduction and a 5.1% increase in HDL as well as significant reductions in VLDL [ run-rate ] cholesterol, APOC3 by 20% to 30%, pemafibrate did not reduce cardiovascular event rates in patients with type 2 diabetes also characterized by a mild to moderate hypertriglyceridemia, low HDL and well-controlled LDL, nor was there any reduction in the components of the primary or secondary endpoints. So this was a stunningly negative trial for CV event reduction in a population precisely preselected to presumably benefit from this agent. And I should also add that there was no heterogeneity across any of the prespecified subgroups, notably women, primary versus secondary prevention by statin intensity or with baseline lipid values above or below the population means. Also of note from a safety perspective, there was a twofold increased risk of venous thromboembolism and a significant renal adverse effect, noted both in terms of development of CKD as well as acute kidney injury. And there was a possible beneficial effect on NAFLD and NASH. So what factors explain the fact that this trial turned out to be neutral? Well, again, in the editorial that accompanied the paper by Dr. Pradhan in the New England Journal, the editorialist, Salim Virani, attributed the lack of efficacy to the lack of overall decrease in ApoB levels during significant triglyceride lowering. And overall, despite the documented decreases in remnant cholesterol with pemafibrate, non-HDL levels did not change significantly compared to placebo where the percentage change in ApoB level was 4.8%, while LDL levels increased by 12% in the pemafibrate group. These findings also support prior observations by Brian Ference, et al, that in order for lipid-lowering therapies to show a beneficial effect, there needs to be a net reduction in ApoB containing lipoprotein levels, and that this is vital and the -- that the ApoB lowering effect of fibrates may thus be negated or offset by the co-administration of moderate to high-intensity statins. And then lastly, by stimulating the activity of lipoprotein lipase, pemafibrate may have led to an increased efficiency in the conversion of remnant lipoproteins to LDL that as remnant cholesterol levels were decreased at the expense of increasing LDL and ApoB with no overall net change in non-HDL cholesterol. So in order for therapies to lower triglycerides and to be effective in the statin era, especially using high-potency statins they probably have to increase clearance of triglyceride-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL. So where does this bring us now that this very important trial has just been published? I guess we'd have to say that the fibrate ship has sailed. It's hard to find any compelling justification to be using this agent or any of the other fibrates for reducing triglycerides and residual cardiovascular risk, or particularly, residual dyslipidemic risk. So it is my perspective that we only have one proven therapy to date. And that, of course, is the use of the purified EPA agent icosapent ethyl that was shown, I think convincingly, in the REDUCE-IT trial to stand alone or apart from all these other therapeutic interventions in terms of reducing incident cardiovascular events. Thank you.

Great. Thank you so much, Dr. Boden, for that thoughtful summary across the efficacy, safety and some of the lipid lipoprotein findings in PROMINENT. Turning to you, Dr. Libby, how do you think this should change patient treatment? And what would you say to a general practitioner or primary care physician that asked you about these results in the overall fibrate class?

Right. So thanks to Bill for the wonderful exposition of the study which preoccupied us for 7 years. So I was very involved with the initiation of PROMINENT and helped with its conduct. It was led superbly by doctors Pradhan and Ridker and really met wonderful performance metrics despite the pandemic, which really was a challenge to clinical trials all over. And I think that Bill highlighted that we designed this trial to answer the question that was raised by all the secondary analyses of the prior fibrate trials. There were numerous meta analyses performed by experts that suggested that if we enrolled people with the high triglycerides and the low HDL, then we would have a winner. And certainly, we, at the outset of this trial, were convinced that we had a winner. The drug pemafibrate from the Phase II trials looked like it was very effective and very potent. It is not the same as fenofibrate. It's a selective PPARalpha modifier and had some properties that gave us some assurance that we weren't just doing a me too because we were quite convinced that fenofibrate, particularly in combination with statins, had some drug-drug interactions. As a matter of fact, the U.S. FDA withdrew the approval of the combination of extended release niacin and of the fenofibrate preparations in conjunction with statins. So we were really surprised and disappointed by the results, particularly because in my basic science laboratory, we'd done work with PPARalpha which really indicated we were on the right track. So this is another example of how we really need to be careful about extrapolating from preclinical data which can look beautiful and assume a result. You've got to do the randomized clinical trial. We did that, and the results were exactly as Bill suggested. We really were surprised that the DSMB suggested that we halt this study prematurely for null, a null result, for futility. So for me, when I have to talk to my colleagues and general practitioners, really I think that the ensemble of clinical trials with the fibrate class suggests that they will not reduce benefits in the era of statins and effective control of ApoB. And certainly, we're getting better day by day at the control of ApoB. So what's the role of fibric acid derivatives? Well, I might reach for it in patients who have extremely high levels of triglycerides or triglyceride-rich lipoproteins who might be at danger for pancreatitis. I would, of course, first, and I teach this to my fellows every session I do with them, first, there's lifestyle. We have to control the carbohydrate intake, exercise, weight loss, decrease alcohol, always check the thyroid function and look at the drug list to make sure we aren't giving them something that can raise triglycerides. And if I did all of that and we still had super high triglycerides, let's say, greater than 500, then I might reach for the fibrates for prevention of pancreatitis. I think for cardiovascular risk reduction, we have absolutely no way forward. I like what Bill said about the fibrate ship has sailed. Now I think in PROMINENT, we did see a signal for benefit for fatty liver. And this is something that really warrants follow-up, careful follow-up. And also, there's the possibility, as we saw in some of the post-hoc analyses of some of the other fibrate trials, for microvascular benefit. And certainly, our diabetic population is very much at risk for microvascular disease. So I think really, generally, for use in cardiovascular risk reduction, I think we need to look beyond the fibrates at this point. Let me just add parenthetically that we in the U.S. have to engage in conversations with the pharmacy benefit managers and obtain prior authorizations, and in particular, for the use of icosapent ethyl and the alternative, which they fax to us when they're denying us ability to get the drug for the patients often suggests that we use fenofibrate. And I think that this will be another arrow in my quiver when I try to spend the enormous amounts of time and effort to get access for drugs which are proven in clinical trials for my patients. So where do we go with triglycerides? It's a horrible gap. We will talk about the evidence that the benefit of icosapent ethyl doesn't seem to depend on triglyceride lowering or baseline triglyceride levels. So where do we go with those triglyceride high patients? I think that there are a number of trials that are underway. We were sorry to see vupanorsen not undergo further development, but maybe the drugs that target APOC3 or the [ and PTLs ] will give us a tool to use in these patients once we've exhausted our lifestyle and run the drug list measures to try to control the triglycerides.

Thank you, Dr. Libby. Dr. Catapano, did you want to share maybe your European perspectives on the PROMINENT results and how they impact patient care?

Well, first of all, let me say that I completely concur that ApoB should be the factor to look at because it will be -- captures the number of atherogenic particles that are circulating. And it's not by chance that at least in the European guidelines, it will be -- it's a secondary role for therapy in people with high triglycerides because [ traditional dense cell ] do not tell you the whole story. So that's the bottom line. You should decrease the number of particles, not just the triglyceride. And there are very complicated issues you can discuss there about physiopathology, but that's the bottom line. The other important point, though, is, as Peter said, we have to be careful in thinking of using fibrates because up to now, the evidence is there for cardiovascular benefit. We are in a corner. There is no evidence whatsoever for a cardiovascular benefit. Slight benefit might be in patients with diabetes for microcirculation effect that has been shown with fenofibrate. As a matter of fact, this has been also approved in Australia for that kind of approach. But beyond that, there is not much until to now. Finally, I would like to reiterate the possible news when triglycerides are elevated, especially in people with polygenic severe hypercholesterolemia, at that point, fibrate to avoid pancreatitis may be helpful when we have exhausted all the other approaches made.

Great. Thank you, Dr. Catapano. Dr. Kohli, did you have anything briefly to add before we turn to our next topic?

Yes. A couple of quick comments. So I love Bill's analogy of the ship sailing, but I would say it's a nail in the coffin for fibrates. And I do want to emphasize that the clinical inertia around fibrates should really make this a game-changing trial even though it is an old trial because it's one of the most commonly written prescriptions out there. And I think we really need to embrace the fact that we're just treating the number. We're not treating the risk when we write a prescription for fibrates. And that's a paradigm shift, I believe, in internal medicine and cardiology and primary care because for the longest time, based on the excellent summary Bill just gave us, there's been a lot of momentum around this class of medication. So I hope that people really take this trial as kind of one of the final trials that does put to rest that question. And I hope we start to change the way we think about fibrates like we think about LDL as an oversimplified lower is better type of strategy, and we shift instead to treating cardiovascular risk for patients with moderate hypertriglyceridemia.

Great. Thank you, Dr. Kohli, and thanks to all the panelists for sharing their perspectives on the PROMINENT trial. Nabil?

Thanks, Steve. So I think that's actually an excellent segue to our next topic. So now let's turn our attention to the exciting data from RESPECT-EPA study that was presented at the late-breaking session on Sunday at AHA here. So just a quick reminder, RESPECT-EPA was an open-label study. It was funded by the independent Japanese heart foundation, it's not a pharma company sponsor, to determine the effect of 1.8 gram per day dose of a highly purified EPA on the risk reduction for cardiovascular events in Japanese patients with a low EPA ratio treated with statin. So these are all statin-treated patient. We expect EPA investigators concluded that 1.8 grams of EPA provided a borderline statistically significant risk reduction in its composite binary endpoint, and a clear statistically significant risk reduction in the prespecified secondary endpoint. Additionally, in a post-hoc analysis to control of the attained EPA levels, the investigators reported a statistically significant reduction in the primary endpoint. So exciting data for treating patients with EPA. So turning first to you, Dr. Kohli. What are your thoughts on the trial design and the results of the study? And what is the takeaway for you from this data?

I would say that overall, I found that RESPECT-EPA was very consistent with the prior trials that we have seen. And at this point, we have kind of 3 major cardiovascular outcomes trials with EPA. One is the JELIS trial from 2005. One is REDUCE-IT, of course, from 2018 and most recently RESPECT-EPA. But I want to be sure here that we're comparing apples-to-apples because we don't want to make an apples-to-oranges comparison. So I want to dive a little bit deeper into each of those trials just to understand what the differences were. So JELIS had mostly actually a primary prevention population 80%, only a 20% secondary prevention population. And there was not a lot of good background statin use that was pravastatin 10 or simvastatin 5 with a median LDL of 178. Now we did see benefit in that secondary prevention population in JELIS, and that was with 1.8 grams of EPA, also open label. And that's what really prompted the development of the RESPECT-EPA trial in Japan, which was just a secondary prevention trial. So 100% of patients in this trial had preexisting coronary disease. We don't know exactly what the doses of statins were used. But from contemporary Japanese studies, we think probably low or moderate-intensity statin. But the LDLs in this trial were well controlled. So that was the big difference between JELIS and RESPECT. We had an LDL of 80 milligrams per deciliter. So that seems more like a contemporary cohort to REDUCE-IT where that LDL was about 76 milligrams per deciliter. But one of the major differences I find between RESPECT-EPA and REDUCE-IT was the median triglycerides. So as we've talked about before, triglycerides being a marker of risk or perhaps causally involved in the risk, the population in RESPECT-EPA had median triglycerides of 120. So it's a very different population from REDUCE-IT, where those median triglycerides were 219 or so. So based on these studies, we see a kind of an overall lower risk population. Now as you pointed out, Nabil, the authors did try to enrich for patients that had low EPA levels at baseline. But if you actually compare the EPA levels coming into the trial in RESPECT versus in REDUCE-IT, you'll see that REDUCE-IT, the baseline EPA levels were about half what they were in RESPECT. So the patient population coming into REDUCE-IT, lower EPA levels to start with, higher triglycerides, around the same LDL, around the same number of diabetics, but a different phenotype than what we saw in RESPECT. But very clearly, you see the curves diverging at 4 years even though the primary endpoint had borderline statistical significance. We do see that. One of the challenges of an open-label design, which in Japan, it's not considered ethical to use placebo, so it's often an open-label design, is that you can have a high rate of dropout. And we did see that in this trial. We saw about a 30% rate of dropout occurring in the RESPECT trial and what is being reported as an intention-to-treat analysis. So we're kind of losing a little bit of power with all that dropout. So we have a smaller patient population, only about 1,200 patients per arm. We have a patient population that's lower risk based on their triglycerides and based on the observed event rates. We have a high rate of crossover or patients stopping the EPA early. We have a lower dose of EPA at 1.8 grams rather than 4 grams in REDUCE-IT. And despite all that, we saw the curve starting to diverge and some statistical significance of the secondary endpoint. So to me, this is just adding to the body of literature that we already have on EPA suggesting that EPA does have beneficial biological effects, and I'm actually not all that surprised by these results.

Thank you very much, Dr. Kohli. Any of the other participants would like to add any comments on -- Dr. Catapano, I can see you [ would like ] to add something to the design of the study and the results. Please go ahead.

I think it is important to bear in mind that of all the trials that came out recently, if you look at the plasma levels that were achieved with EPA, you have a clear signal that in the trial where you got an increase that was persistent, you see a benefit above [ put up the ] threshold. Even in this trial, you can see that if you take away below 30 and above 30, respectively, in the treatment and placebo arm, you can see even a better separation there, indicating that if you achieve a higher level of EPA, you get a better result. But if you go back to REDUCE-IT it's a key message there that the extent of the benefit looks like is related to the plasma levels you have achieved. The higher you go with the plasma level you achieved and the data you have from the starting point, the better you're off. So I think this is a substantial point in terms of pharmacology to make you understand that there is something that is somehow dose related, if you will. And this is, from my view as a clinical pharmacologist, this is a very important point to bear in mind.

Absolutely. Thank you, Catapano. On the study of the design, Dr. Libby, Dr. Boden, anything that you would like to add on to that point?

I actually have a question for Alberico, who's the pharmacologist here. So if I'm not mistaken, both JELIS and RESPECT-EPA were done with the free assets rather than the ethyl ester. And does it make a difference, Alberico, whether we have the ethyl ester as was used in REDUCE-IT in icosapent ethyl or free assets?

I think the key difference is the bioavailability that is prompter and higher, so you have higher peaks per dose at the same dose with ethyl ester as compared to the natural form, if you will. But in the end, it's cleaved and then it's the natural form of handing out. So it's not that the active product is, if you will, like a per drug, which is not the case, but the ethyl ester is cleaved very easily. So it's just a matter of making it more available, biologically available. And of course, that is a drag because of that.

Thank you. Dr. Boden, anything from your end regarding the design of the study or the results of this specific study?

I think these have been covered already. I mean clearly, I think that RESPECT-EPA adds to the body of scientific evidence that the purified EPA intervention is associated with better outcomes. Obviously, there are limitations to the design of RESPECT-EPA. We all recognize that. So I think it has to be interpreted in that context. There -- and certainly, we know that the strength investigators have disliked the REDUCE-IT trial and keep looking for other reasons to explain why the study was positive rather than negative like that study was. But I have a question maybe for both Drs. Libby and Kohli. When we look at placebo-controlled statin trials, we see that the Kaplan-Meier curves for cardiac events really separate promptly within a matter of months, weeks to months. And yet with both the icosapent ethyl and even some of the earlier fibrate trials that showed benefit in the pre-statin area -- era, we see that there's a delay in the separation of the KM curves. And what do you think explains this delayed benefit that we see rather than a more immediate benefit?

Do you want to start?

I was going to make a comment that there may be benefits to things like sudden cardiac that could sometimes take time to manifest themselves. I also think, and I'd love to hear the rest of the panel's input on this in terms of what we're discussing about bioavailability and plasma EPA levels, how long does that take to translate into changes in inflammatory parameters, changes in metabolism and some of the downstream changes that could cause some of those physiologic effects because to your point, Bill, what we saw very clearly in RESPECT was superimposable curves until about 4 years when they started to separate. And that's taking into account the fact that as time goes on, there's attrition in terms of how many people are staying on treatment, how many people are continuing to stay compliant with their randomization arm. So I think part of it is that biophysiologic mechanisms may take some time to manifest. And part of it is that some of the end points that we're seeing clear reductions in do take a few years to manifest themselves. But I'll make the point that when it comes to MI, for example, in REDUCE-IT, we do start to see a benefit very early, perhaps even before 1 year. So I think there are differences in the types of endpoints that we're looking at. Now of course, in the RESPECT trial was a composite of many different end points. And we see that the secondary endpoint, which had more sudden cardiac death and CAD endpoints, was positive. So I think all of those are possible explanations for why some of this could be. What are your thoughts, Peter?

Well, not all of the statin trials, particularly the earlier ones with the less effective statins, had immediate or early separation of the curve. But we got lucky with the statins because we had 2 mechanisms operating. We had the well-known and well-accepted LDL lowering effect, but also there are the so-called pleiotropic effects of statins, in particular, an anti-inflammatory effect that is independent of LDL lowering. Probably depends on the prenylation of small G proteins because the pathway that leads to the synthesis of cholesterol beyond the enzyme, the HMB-CoA reductase, which is a target of statins, there are polyisoprenoids with modified proteins. And there's also the induction of transcription factors such as [ group LF Factor II ] that can orchestrate a series of anti-inflammatory, anti-thrombotic and profibrinolytic mechanisms on cells. So we got lucky with statins. We have a two-fer. We have the LDL effect, which might take a little bit longer in many patients to provide benefit, and then an effect which we can see on inflammation within the first 30 days.

My question for Dr. Catapano and others is also you mentioned the on-treatment achieved EPA levels. And it's interesting because if you actually look at the data, the on-treatment EPA levels in respect at 145 micrograms per milliliter was very similar to what we saw in REDUCE-IT, which was 144 micrograms per milliliter. But the delta EPA was very different. There was also a difference between the EPA to arachidonic acid ratio that we achieved on treatment in REDUCE-IT versus RESPECT. So to me, it raises the question of whether we need to personalize which phenotypes of which patients are most likely to benefit from some of these EPA interventions, particularly if they're coming in with a higher EPA level. But I'm curious to hear your comments because we did achieve for on-treatment levels with both RESPECT and REDUCE-IT, but of course, we saw very different effect sizes because they started in different places, and it was a different population, a Japanese population that tends to have higher EPA levels at baseline.

Yes. This is the bottom line. It is a fact that nutrition impinges on the level you have as well, and that's what matters there. So I do not have an answer to your question. My educated guess will be the patients who start with lower levels of EPA are the ones who are likely to benefit the most from that treatment. Having said that, there is no proof. But there is just my educated guess. But many people will be support -- many biologists will be supporting this with stating if you are low, you are likely to benefit more because you restore the levels for many activities there, many biological products that are derived from the activity of EPAs and so on. So I think it makes sense. But no, not always everything that makes sense is right. So we need further proof for that.

Thank you all for this very exciting conversation regarding the clinical data of the trial. Now let's move to the practice. So looking at these results in the larger context, we now have 3 cardiovascular outcomes trial. Yes, very different in design but consistently showed the benefit of EPA in reducing cardiovascular risk in statin-treated patients. So I would like to ask the participant here, each of you of their view on the use of EPA in patients management, now that with the broader and consistent data set. So since, Dr. Catapano, you started the end of this conversation, so I'm going to start back with you. What would you say about that? How would you manage those patients?

I mean as always, this is the challenge you are facing when you have to decide something in modern medicine. And indeed, it's even more so in this field because you have a different type of trial by different design and even different compounds, if you will, that have been used there and doses as well. So to summarize all the message that personally I perceive from these trials is, yes, people will help, would be a benefit to the patient introducing cardiovascular events, provided that, one, they have an increased EPO B and they have high triglycerides. That's the area where I can see something I would be confident to use this product. Then we can expand further. But let's first to go there and make sure that we have something to target. If you have low EPO B, very low levels of EPO B and very low levels of non-HDL cholesterol, I don't think you will get a huge benefit there. But if you were in a condition where you were with an increased remnant, which is a wrong way to mentioned those things, but just to make it clear to you, it's the LDL cholesterol and it will be in the LDL, I think those are the patients you should target. And those are the ones that mainly do not reduce their burden when you treat them with statin because we're usually starting to not decrease largely through this, right, in the normal elevated range, not the very high range.

Thank you, Dr. Catapano. So again, patient management. Dr. Libby, how do you see that?

Yes. So when confronted with the patient with the pattern of high triglycerides and maybe with diabetes in secondary prevention or primary prevention, the first thing is lifestyle. It's lifestyle, lifestyle, lifestyle. And we have new tools for weight reduction which may help our patients achieve better control of body weight. Then I ran the list early, and of course, I didn't say the obvious thing, which is control of diabetes. And again, we have great new tools for treating glycemia that also confer cardiovascular benefit, so diabetes control. And then patients who meet the entry criteria for REDUCE-IT, I would certainly have a discussion with them about starting icosapent ethyl. I have patients who are on icosapent ethyl, and I have the wounds of the battles with the pharmacy benefit managers to show for it. And I do have a discussion with some about atrial fibrillation. I would not necessarily go into someone who is at high risk for atrial fibrillation, who had bouts with atrial fibrillation in the past without -- certainly without a discussion, certainly without very clear evidence. But I think that the results that we've learned at this meeting suggests that fibrates are not going to be on my list and that the evidence for EPA in cardiovascular risk reduction in patients who meet the entry criteria of REDUCE-IT seemed like a reasonable option for use in clinical practice.

Thank you very much, Dr. Libby. Dr. Kohli, again, patients management.

I think this has reinforced what I was already doing after REDUCE-IT, and it's really emphasized to me that not all fish oils are created equal. And that's, I think, an important take home message as well for clinical care, that combination of fish oils or different EPA preparations may have different bioavailability, may have different actions. So it's also reminded me that those triglycerides, as we've discussed, are a very important marker. So we can't just put every chronic CAD patient with persistent risk. But we have to try to identify the ones with elevated triglycerides that may benefit from EPA preparations and pick the right patient population. Moving forward, I'm hoping some research will emerge where we can start doing on-treatment EPA levels, checking our patient EPA levels as we're deciding whether to put them on IPE. I feel like that will be a very compelling way to personalize the risk reduction that we offer our patients because at this point, we're really using a shotgun approach. And I see the future of this field as using more IPE, but using it in a targeted and personalized fashion for those patients that are most likely to benefit.

Makes sense. Thank you, Dr. Kohli. Dr. Boden?

I think if we look over the last 20 years, I think we'd have to agree that the patient profile that we now deal with in 2022 is different than we dealt with in the late 1990s or 2000 where everything was centered on LDL reduction with statins, and appropriately so. The trials and the evidence supported that. But the phenotype that we see today with the twin epidemics of diabetes and obesity are exactly the substrate of patients who we see all the time in clinic. I see them every week. They're on a high-potency statin. Their LDLs are most often below 70. They have persistently elevated triglycerides and/or a low HDL, and we need to focus on residual risk reduction. Now again, residual risk reductions, there are at least 4 different strategies here. There is thrombotic risk reduction. There's inflammatory risk reduction. There's glycemic risk reduction, and of course, there's lipidemic risk reduction. So I think we have to recognize that this is 1 of 4 or more strategies in terms of trying to optimize the outcomes of our patients where we need to have a more pluralistic view of pharmacotherapy supported by the evidence. And again, I think the evidence is very concordant in terms of JELIS, RESPECT-EPA, and in particular, REDUCE-IT.

Absolutely. Thank you again, Dr. Boden. So Dr. Catapano, I don't mean to keep on putting you on the first spot here, but I would like to ask you a question, and I'm going to address it to the rest of the panel in a minute. But -- and we know this is going to happen. But what would you say to those who believe this result should be discounted given the limitation of the study design that we just discussed? What would be your response to that?

Well, obviously, each study has its own limitation, and the studies coming from Japan, we do know have this kind of limitation. However, there is a point in favor. You don't have any mineral oil around there and still you see a trend for a benefit, which I think we didn't discuss, but it's important to take on board. The message is there. I think has to be acknowledged that this is an important piece of information that adds to our approach to the patients. So as we said, the trial has limitation. But you have to look at things in the complexity and the whole data which we have available, not just one trial. If you were to look only for one trial, then you can be misjudging things. And things are going in the same direction. Everything is consistent, appears to bring the benefit. The extent of the benefits still we may discuss, but certainly is there and is highly significant. So in my view, those specific trial-by-trial point are to be overcome, but a general view that is consistently benefited the peers to build up [indiscernible] EPA. And in my view, it's mainly EPA that is the driver for this benefit. And using a mixture between 2 type of long chain fatty acid and saturated [indiscernible] may not be the good solution.

Thank you, Dr. Catapano. Dr. Libby?

I certainly agree with the tenors here. I think that this has been a very interesting weekend that, as we said, the fibrate and fibrate-like drugs, the ship has sailed. I think that really, they are niche drugs for prevention of hepatitis, although I think that, as I mentioned, the microvascular effects and the liver protective effects need further exploration. And I think what we've learned is we have now a third study with eicosapentaenoic acid suggesting that there can be a benefit for a large segment of our population and a growing segment, as Bill pointed out. So I think we need further studies. We don't understand the mechanism of benefit of EPA. It's something that -- what's wonderful about our field is that we're always learning what we don't know. And we have to inform our practice based on evolving data, and we need to keep digging to understand how we can, as Payal said, segment our population in a way to get the right drug to the right person and maximize the benefit based on that particular patient's profile. And we have increasing tools, including genetic tools, that are going to allow us to individualize our therapy plan in a shared decision-making mode with the patient in front of us that particular moment, because that patient is our boss. And we have to focus on the individual, their risk pallet, and take all of the data that we're showered with and try and integrate it for the benefit of that individual.

Thank you very much, Dr. Libby. And Dr. Boden?

Yes. I don't really have a great deal to add here. I think that their -- I think the data speak for themselves. I think this is an important subset of patients with hypertriglyceridemia for whom there is the need for additional event reduction. And I clearly think that IPE has stood alone as the only agent that we have available based on clinical evidence and trials that show a benefit. I think still too many people, in my opinion, and including some of our trainees have an agnostic view about triglycerides still. And I think one of the things that we need to do as educators is to make sure that our trainees or physicians understand the importance of not just focusing solely on LDL, but also on those patients with residually elevated triglycerides and we need to be, I think, more forthright and proactive about administering IPE in that context. And honestly, I think the only other remaining use for fenofibrate, as Peter said earlier, is those patients who, let's say, on IPE plus statin still have triglycerides above 500. The only, I think, indication for fenofibrate at this point would be for pancreatitis prophylaxis. But other than that, not for event reduction, of course.

Thank you, Dr. Boden. And finally, Dr. Kohli.

I would just say I'm surprised that we're having this conversation after such compelling results from a trial like REDUCE-IT, randomized controlled trial which was blinded and was placebo-controlled, where we saw the magnitude of benefit being so great that even if there was concerns about possibly an active placebo, it couldn't explain that magnitude of risk reduction. So I think that what we've learned over the last few years during the COVID-19 pandemic is that the science is not perfect. There's limitations to our trials. And we're scientists, of course, but we're also artists. And it's our job to interpret the scientific literature with a bigger picture understanding, as we've all sort of discussed today, of how this fits into which patients may benefit, how they may benefit, what the limitations of each of these studies are. So I think it's great that we've learned so much this weekend about triglycerides and the field of preventive cardiology and how we perhaps may be able to move that needle forward. But to all the points that have been made earlier, we cannot forget about this group of patients because of some of the equipoise and uncertainty in the trial designs in RESPECT and JELIS that maybe showed a smaller magnitude of benefit, but still very much biological activity of EPA. So I'm really looking forward to the future, the next decade of preventive cardiology and how we can continue to work on chipping away at that risk. And we've all discussed -- we heard from Peter all the wonderful lifestyle measures, all the new drugs that are available changing our thinking away from fibrates and really towards more biologically active substances, and using all the tools in our toolbox to try to treat our patients as fast as we can.

Thank you very much, Dr. Kohli. I think our group here had summarized it in a wonderful way, and I like Dr. Libby's comment about, that's the exciting part about this field. You get data, you get new data, you get new products, at the end of data it's a patient behind all that, that needs all this data to come to help be managing that. This actually has been an excellent discussion. I want to thank the panel incredibly for the incredible input and support in having this conversation. So thank you for providing your thoughts and perspectives on this key data presented at the American Heart Association during the Scientific Sessions. In our remaining moment together, I will open the floor to hear any final thoughts that you would like to share on what we covered today. Any comments? I know we had a long discussion, a lot of input, but I just don't want to close it before making sure that everybody are able to bring whatever they want to bring into this discussion.

Well, thank you for bringing us together. I always learn from my colleagues.

That's a journey, Dr. Libby. That's a journey.

Likewise. Likewise, it was a pleasure.

Thank you. So this brings us to the end of our discussion. Again, I repeat, your input has been invaluable as we continue to work to win [indiscernible] clinicians and patients. And by closing on behalf of the team here, we wish you a safe travel home from Chicago or wherever you are now, and look forward to speaking again. I'm sure we're going to reconnect again and talk about new data and new positive advances we can bring to our patient today. Thank you all for joining us.

Thank you very much.