Amarin Corporation plc (AMRN) Earnings Call Transcript & Summary

Welcome to Amarin Corporation's American College of Cardiology's 70th Annual Scientific session discussion where select scientific publications presented over the weekend will be discussed. This conference call is being recorded today, May 17, 2021. I would 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 American College of Cardiology's 70th Annual Scientific session. 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 opinions. 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 for clinical use in reimbursement and regulatory settings and for commercial prospects for VASCEPA. These statements are based on information available to us today, May 17, 2021. We may not absolutely 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 indication. I will now turn the call over to Dr. Craig Granowitz, the Chief Medical Officer of Amarin.

Thank you, all. Before getting into the content of the meeting, I'd like to introduce our 3 esteemed panelists today, 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 the President and Co-Founder of Elucida Research. The second panelist is Dr. Matthew Budoff, Director of Cardiovascular CT at The Lundquist Institute and Professor of Medicine at the David Geffen School of Medicine at UCLA. Our 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 primary investigator for the REDUCE-IT study.

So Preston, starting with you, if you could just give a top line summary really of your takeaways from all of the experiments you've done looking at the various agents in the various model systems that you studied and shared with this group, what some of the key takeaway points are?

Yes. We reviewed the fact that omega-3 fatty acids behave very differently under conditions of inflammation and under conditions of atherosclerosis where we see excess cholesterol [indiscernible] membranes. What we're presenting at ACC includes 2 of such studies where we looked in a remarkable way at the full gene and protein expression in endothelial cells and human endothelial cells following conditions caused by cytokine IL-6 or inflammation. And we saw very different patterns in protein expression between EPA and DHA as well as some studies with the eicosapentaenoic acid. And it's quite clear that they behave very differently in response to inflammation. We see EPA in a sense down regulating or tampering down on the increase in pro-inflammatory cytokines and proteins. Whereas DHA has a much weaker effect in eicosapentaenoic acid as we had a totally different almost pro-inflammatory effect. So we're seeing clear differences among these omega-3 fatty acids at the cellular level, which is helping to inform the clinical work that's been presented at this meeting as well.

So Preston, thank you. What is really new about this? Because, again, I think you've shown before and others have shown some of the biological parameters, but this data seems to be far more detailed and far more clear and specific. What's different about these studies than the past?

Well, here we're allowing -- we're looking globally at full protein expression within the cell. So we're looking not only at EPA, but it's various metabolites, the specialized pro-resolving mediators, we're seeing the full complement of EPA and its metabolites on cell function under stress or inflammatory conditions. So instead of looking at perhaps 1 or 2 proteins, we're literally following thousands of proteins, and in particular, several hundred that are highly significant with respect to changes in expression.

So Preston, again, I think that's pretty profound. Did you expect to see that level of change in that many genes from these simple -- seemingly simple omega-3s?

That's a great question. We didn't know what to expect. No one has ever really tried to accomplish this. But yes, we were impressed by the full array of proteins that were changed with respect to expression. And remember that some proteins are up regulated and some are down regulated. And it's a symphony, if you will, of changes and movements that create an overall synthesis by which the cells are being modulated by these particular fatty acids. But the profound differences among them was impressive, when we contrasted the changes with EPA, for example, with DHA.

So really, it is the end result of the up and down regulation of hundreds of genes that lead to what I would call the preservation of endothelial homeostasis in the face of a number of different noxious stimuli, which generally tend to down-regulate the homeostatic protective function of the endothelial cells.

Exactly. For example, we saw under conditions of inflammation and up regulation of a number of detox enzymes. So you can imagine there's a rush of reactive oxygen species being triggered by this inflammatory stimuli. And then the presence of EPA, we see all of that gets down regulated, cooled down or reduce the stress caused by that inflammatory assault. And only to a lesser extent do we see with DHA. So yes, we're seeing a give and take between the pro-inflammatory assault and the ability of EPA to restore endothelial homeostasis.

And that, Preston, again, I know some of your data that you showed, this is a number of different progenitor endothelial cell lines. It's not just vascular. Is that right?

Right. We've extended this to pulmonary endothelial cells, which is very important in terms of modulating cardiovascular homeostasis. For example, the release of ACE is significant in the pulmonary. We saw a significant reduction in ACE with EPA. And we're also looking at brain and other tissues as well. And we've even extended it into other cell types like, macrophages, where, again, we see this impressive effect of EPA on restoring normal homeostasis for the cell.

Terrific. Now Matt, in your work, and I know that you've presented a broader range of studies beyond EVAPORATE. When you hear what Preston is saying, first, if you could just summarize some of the results that you shared. And then how some of the things that Preston just covered might be relevant to the findings that you see in EVAPORATE and CHERRY and [indiscernible] and other broad translational imaging studies.

Yes. I think one of the most important things that we were able to see is over a very broad number of different studies, quantitative coronary angiography, intravascular ultrasound, OCT and even CT angio, we see a consistent effect of EPA on plaque progression, slowing progression or inducing regression. Conversely, in the [indiscernible] trial where they use DHA and EPA, we saw absolutely no benefit, no plaque progression across any of the different end points. And that trial is 30 months, so 2.5 years. So it was much longer than EVAPORATE. It was much larger than EVAPORATE. And really, I think proved that these differences between EPA and DHA translate into lack of atherosclerotic end points.

Well, thank you, Matt. And again, when you listen and see some of Preston data, I mean just tell us a little bit about the cellular interplay in plaque development and how some of the results from the cell type that Preston is studying might be relevant to underpinning the biology that you just shared of the differences between DHA containing omega-3 preparations and Icosapent ethyl EPA containing preparation.

Yes. So I mean, if you think about the impact on the vessel endothelium, the lipid monolayer and how DHA is incorporating differently, I think that shows us that it has a direct effect on the [indiscernible]. Even when you delve deeper into some of the stuff that we're demonstrating at the American College of Cardiology looking at fibrous cap thickness, looking at lipid length and lipid plaque wall development, we see changes with EPA that are very favorable. And again, in trials like [indiscernible] we don't -- we can't emulate that because of the DHA clearly having different exertional effects on the endothelium and on the atherosclerotic plaque [indiscernible].

Right. And Preston, if you could comment a bit first on some of the cellular interactions between, let's say, the macrophage and the endothelial cell or the platelet and the endothelial cells or the neutrophil in the endothelial cell. And then perhaps, Matt, you can comment on how that might affect plaque either progression or regression, I think that would potentially be very helpful context. So Preston, again, you've now extended your experiments in not only in individual cells, but interaction between various cell types of the endothelium and the innate immune system.

So yes, the endothelium plays an early and persistent role in the development of atherosclerosis, as we know. And the early stages include endothelial dysfunction where adhesion molecules are expressed, which then recruit circulating white blood cells, monocytes into the blood vessel. So among the various things we're seeing with EPA is a down regulation of these adhesion molecules under these [indiscernible] conditions. So there's less attachment of the monocytes as well as neutrophils. And we'd also see less interaction with platelets. The other signal related to platelet is that endothelial cells produce nitric oxide. And in the presence of EPA, we enhancement in nitric oxide release. And that has direct anti platelet effects, this nitric oxide, along with other signaling molecules. And then as we go further along, we see the neutrophils if they're allowed to incorporate, they begin to degranulate. And in a remarkable finding we see EPA downregulates thousands of proteins that regulate that process of neutrophil degranulation in contrast to [indiscernible] or even DHA to a lesser extent. So we're seeing that EPA through the endothelium is modulating a number of events associated with the progression of atherosclerosis, whether it's adhesion of the monocytes, whether it's neutrophil degranulation, and whether it's the activation of the macrophages.

So thank you, Preston. So Matt, when you hear what Preston is doing and it's remarkable because these are happening simultaneously but independently, When you see -- and a lot of Preston's data is literally brand-new and being presented this year what he just covered. And then when you see the results from EVAPORATE or CHERRY or some of the other imaging studies that have been done previously by other groups in other countries, I mean, do you find that reassuring? Surprising? How would you sort of put it in context?

Yes. No. I mean I think it's very, very reassuring. I think Preston is now able to demonstrate the mechanistic benefit of EPA on the mechanistic study of EVAPORATE. In other words, how we're seeing these plaque progressions occurring. And you can imagine the neutrophils and the macrophages are so important. In atherosclerotic development macrophages become foam cells and that is really the pathway by which we end up with these atherosclerotic plaque. So if you're inhibiting neutrophils and macrophages, you're clearly stopping the path of -- with EPA. And obviously, that's not occurring with other products.

Thank you. So Deepak, now that you've given a couple of presentations. As you think about this, what is sort of the unifying pathophysiologic themes that you're hearing here that you think are relevant to some of the results that you shared in terms of clinical benefit and risk benefit?

Well, I think in total, it's a nice conversion of basic science data, [indiscernible] data from Dr. Budoff and then clinical trial data from REDUCE-IT. I think it really makes for a beautiful scientific story where all bases recover. So it seems like one really corroborates with the other shows. So we've got a clear elucidation I think, of some of the basic signs in regards to EPA and mechanisms of action, though it's an evolving science, so there's a lot more that I think we'll learn in coming years. But along with that, the imaging has been very consistent showing effects on plaque progression being reduced. Some might even say in some circumstances regression of plaque. And then clinical trial events that are also influenced. And some of these effects seem to be pretty early. It's interesting that in EVAPORATE even at 9 months, many different parameters of plaque composition and volume were significantly influenced. It's also true in Cherry were on intravascular ultrasound that study looked I would have said much earlier than an [ IDA ] study where we should look at to 8 months or so and found significant effects on plaque progression rates of EPA. But that matches very nicely what we've seen in the now published REDUCE-IT revasc analysis that just came out in circulation relatively recently where the other benefit kicks in pretty early where there's a lower rate of revascularization pretty much right out of the gate with [indiscernible] versus placebo and consistently statistically significant by about 11 months. So later on the time that effects were documented in CHERRY and in EVAPORATE, we're seeing a clinical effect in a large randomized blinded trial. So to me, it's a beautiful conversion of multiple lines of evidence supporting the value of EPA.

Well, thank you. And I guess the pilot study that was done in Toronto on COVID infection, again, talking about rapid onset of action, perhaps you can just summarize how quickly the time line was for onset of biological effect in [indiscernible] because that was even a shorter period of time.

Yes. It's a really good point you raised there in that 2-week study within the icosapent ethyl [indiscernible], there was a significant reduction in CRP, which wasn't seen in the control [indiscernible]. Now limitation of that study other than its modest sample size was that there was no placebo there, but nonetheless, it did show an effect of CRP within the icosapent ethyl group. And that was in the context of outpatients -- relatively healthy outpatients with COVID or who were COVID positive. But it does further fluctuates the fact that there are anti-inflammatory effects of EPA are [indiscernible], I guess you could say in a variety of experiments models, the sort of thing Dr. Mason and other scientists are doing. It's interesting as you report from another group that corroborated the initial observations [indiscernible] in terms of EPA and DHA and different effects that they can have. But again, from the Toronto pilot, more data supporting an anti-inflammatory effect of icosapent ethyl. So there's basic science data, there's data from cardiovascular patients and how we've been [indiscernible] COVID positive patients in effect on CRP. So it's -- As I mentioned before, multiple different lines of evidence supporting a true a [indiscernible] effect of icosapent ethyl, surely, it reduces triglycerides, but we know from other trials reduction in that biomarker per se doesn't always lead to reduction in cardiovascular events. But I think the reduction in triglyceride-rich lipoproteins, the effects on various anti-inflammatory pathways, the antithrombotic effects, albeit modest, all those different effects and likely more that we had yet to fully understand or even describe contribute to the large degree of clinical benefit that we're seeing in REDUCE-IT. And I think you make a good point too about the early is something to really think about clinically, I mean, that is REDUCE-IT with a stable outpatient population, they were high-risk patients by virtue of having high normal or modestly elevated triglycerides in a fasting state in that case, despite dietary counseling and despite adherence to statin therapy. So the triglyceride elevation ended up being a potent marker of risk in the trial. But the fact that it was a stable outpatient population, I think in some respects may deflect attention from this early benefit that we've seen that I think could be quite relevant to inpatients. So for example, we've done some subgroup analysis from REDUCE-IT that have been presented REDUCE-IT PCI, REDUCE-IT CABG, looking at those patients with a history of PCI CABG in the past, showing large relative and large absolute risk reductions But again, these are people that have PCI CABG in the past, you can imagine that the degree of benefit might be even larger if the therapy were initiated more proximal to the event as opposed to just months or years later.

I think those are great points. And again, just to put in context, the studies that Dr. Mason talked about are on the order of hours of exposure or at most days, what Dr. Budoff is presenting is really over a period of months. And what Dr. Bhatt is mentioning is really the gamut in some of the acute studies, like the COVID trials, it's a matter of days. The early separation of the curves in those that are post-acute event is on, I would call, 10 months or 12 months and then the ultimate impact on MACE is over years. And I guess the end of it [ PPARs ] will be on heart failure, which is sort of really years to decades of repeated MACE events that generally lead to heart failures, repeated insults, repeated infarcts that ultimately lead to catastrophic loss of cardiac contractility.

Sure. So there's lots of provocative data out there about icosapent ethyl and EPA more broadly in a variety of disease states and for things like COVID or heart failure, I think we need more research, larger randomized trials to be completed before really using the drug specifically in those circumstances. But what's clear is that in cardiovascular population that is patients with established cardiovascular disease or at high risk of it that the benefits of icosapent ethyl kick in pretty early, much earlier than I think most doctors or even investigators involved with the trials necessarily had appreciated. And I think as a practical point, then it means that one can certainly delay the decision to start icosapent ethyl. It's not like [indiscernible] when you've got a window of opportunity that might be missed. So yes, you could start the icosapent ethyl whenever you might want. But there is sort of a cost to doing that where there are potential ischemic events that could have otherwise been averted by earlier initiation of therapy. So one thing that's been discussed is whether patients were at risk be identified, not just in the outpatient setting as hopefully people are already doing post REDUCE-IT in accordance with the [ labeling, ] but also identify potentially in patients who might be candidate folks that are already on maximally tolerated statin doses but still have residual cardiovascular risk, still have a triglyceride that's elevated with that sort of patient benefit from inpatient initiation, at a minimum, perhaps sort of buttressing in that patient's mind, the importance of that therapy and perhaps enhancing adherence over the long term. Obviously, there are formulary and cost and other issues that come into play, but as a general principle, that seems to be like a good way to reduce residual cardiovascular risk instead of waiting for a follow-up appointment, say, in a month or 6 months or a year where some ischemic event might occur in that intervening period.

Thank you, Deepak. I guess before we close, sort of integrating it all Deepak with hearing Dr. Mason's description of the data, the consistency but the differences between DHA containing compounds that are mixtures with EPA and a pure icosapent ethyl or EPA and then hearing Matt's summary of the data, I mean, are you surprised then that the results that we're seeing with the STRENGTH trial is, again, I think this is an important question that is being raised because I think there's a lot to be learned by comparing and contrasting, even taking into [ account the limitation of ] doing so. But when you see the results from the STRENGTH study and you see the results from the REDUCE-IT study, I mean, what is -- it's either affirming or surprising from what you've heard from the other presenters today?

I think it's all very affirming that it's a very consistent story if one looks at the totality of data, basic science data imaging data and also clinical trial data. The various mixtures of omega-3 fatty acids, whether dietary supplements or whether prescription medications have all led to trials that have been neutral, that is not meeting their primary end point in the overall trial study. It's been a very, very consistent story. And all the trials to date of pure EPA whether done in the Western world or in Japan, have all been positive. So the drug matters. You can't just -- to say that all these drugs were omega-3 fatty acids, that would be lumping things together in a way that's inappropriate. And physicians do tend to be lumpers rather than splitters, and that's generally speaking, okay, the SGLT2 inhibitors, the class, [ tremendous ] class, most of them seem more or less similar, maybe some have stronger data than others. But if you look at the GLP-1 agonist on the other hand, well, there you couldn't just say it's a class effect to use any of them for the purpose of reduction of cardiovascular events. There are certain drugs and certain trials worked clearly robustly and other ones were entirely neutral, showing no benefit on cardiovascular events. So It's not always appropriate, fair or scientifically accurate to say, "Oh, it's a class of drugs, everything from 1 trial of 5 for a drug -- a different drug study in another trial. The omega-3 fatty acid of biologies, I'd say, even far more complex than the GLP-1 agonist. And if you studied an omega-3 fatty acid preparation, you studied the omega-3 fatty acid preparation. You really can't generalize. And at least the story for EPA, icosapent ethyl, every trial to date has been positive whether we're talking about imaging studies such as CHERRY and EVAPORATE, and there are also other Japanese studies that we didn't refer to, and also if one is talking about JELIS or REDUCE-IT, so -- and there's also another small randomized Japanese trial, all of these trials have been positive with respect to their primary end points. So I would actually say it's unusual in medicine to have such a story of consistency where there are multiple randomized trials, some placebo controlled, some not with EPA, but all positive and just great basic science buttressing the clinical trial science. So I think it's as good as it gets scientifically in terms of a compelling logical story.

Well, thank you. I think that's a great capstone, Deepak, summarizing the remarkable body of work over many, many years of the faculty that are on this particular call. When you think about Dr. Nathan, Preston, you have working on this area for 5 or 10 years, really peeling this back from the basic science of integration of these and membrane flexibility and fluidity, Matt, you really did evaporate over a period of 5 years. And Deepak, you've been involved in this really now for more than 10 years to generate this data. So when I think about the amount of effort of your teams and the patient commitment and sacrifices to our level of understanding to be able to bring it to this point is very humbling and the importance, both of the scientific method but of individual patient faith and commitment into helping us understand better how to develop new medications that might not help that individual patient but are really good for humanity. So I wanted to thank you all for this time in this discussion today and really for the commitment of you and your teams and your patience to summarize in 30 minutes, which is net decades worth of work of you, your teams and the patients that have participated. I thank you all for your time and participation at Amarin's American College of Cardiology's 70th Annual Scientific Session discussions, and thank you to everyone who tuned in.

Thank you, ladies and gentlemen. This does conclude today's conference call. You may disconnect your phone lines at this time, and have a wonderful day. Thank you for your participation.