Amarin Corporation plc (AMRN) Earnings Call Transcript & Summary

That's a terrific tour de force, and thank you, Deepak, for that. Just to the point of reference, and again, all the comparisons aside, is that the levels achieved in the STRENGTH trial is according to the JAMA publication for a median of [ 90 ], which just to put it in context, is below the starting point of the Japanese patients in the JELIS study. So again, while preparation was delivered with Epanova in the STRENGTH trial, there was very -- not very much EPA, ultimately because the blood levels, and again, all the caveats aside with blood levels, but even the blood levels achieved were not very high. Matt, just speaking of Japanese, just to close out your comments. I know that the Japanese have published extensively on other imaging methodologies, both EPA preparations and mix omega-3 preparations. Can you comment on the overall takeaway from the effects seen in those, looking at the EPA versus the EPA/DHA mixtures?

Yes, certainly. So if we -- EVAPORATE was a serial CT angiography trial. There was a similar trial that was done -- serial CT angiography trial that was done using EPA plus DHA. It was a 30-month trial and almost 300 subjects, so larger and longer than the EVAPORATE trial. And that trial demonstrated no benefit on any plaque volume across the board by being on a mixture of EPA plus DHA, so I think very concordant with what we've seen with STRENGTH, with what we've seen with OMEMI, what we've seen with 5 prior DHA/EPA mixtures. We now have 7 trials in a row that show that if we have EPA plus DHA, we don't reduce events. We have similar parallel data with EPA alone has a positive effect. The Japanese also did a trial called CHERRY, which was intravascular ultrasound, and showed that when we add EPA to a statin, there is more significant reduction in plaque based on the more invasive intravascular ultrasound imaging. So I think we have great concordance that EPA monotherapy has a positive effect on atherosclerosis, IVIS and CT, and combination therapy with EPA/DHA does not have a benefit. And there's no difference between the groups when you use a mixed EPA/DHA, which I think, again, goes back to a lot of Preston's work demonstrating the potential adverse effects of DHA on coronary plaque?

Thank you, Matt. I'll just again ask one more detailed question. You may or may not have this information. But did any of those mixed EPA/DHA imaging studies mentioned anything about reduction in triglycerides or inflammatory markers?

Yes. So there almost always is, especially within these trials, there is triglyceride lowering. I don't remember the exact number in the 2 trials I quoted, but both of them had positive effects on C-reactive protein and triglycerides with EPA and with EPA/DHA. So I think that our -- the effects that we see are independent of triglyceride lowering. I think that's been well demonstrated in REDUCE-IT as well as in other studies. And certainly, in my EVAPORATE trial, the triglyceride reduction was nominal. So the benefits that we saw were not related to triglyceride reduction. But we do see a reduction in CRP as well. And I do believe that an anti-inflammatory process is beneficial, in general, especially with pure EPA, as we've seen.

Thank you, Matt. So we're going to pivot now to the clinical, but I just want to summarize a couple of the key points that were made by our first 2 presenters. I think Dr. Mason really gave a summary of some of the physical, biochemical and biological differences in experimental systems between EPA and EPA/DHA. Dr. Budoff mentioned that there are differences in the imaging with a pure EPA, the identical EPA preparation used in VASCEPA in the EVAPORATE trial, both at 9 months and then at 12 months. And then other data that has been done with other preparations in Japan and other places showed very similar results of correlating imaging with the JELIS trial in Japan or imaging with the REDUCE-IT study in the West. And again, to me, the STRENGTH result is no surprise based on that parallelism being extended to the impact on imaging at 30 months with a mixed DHA/EPA preparation and the fact that STRENGTH had no clinical outcome. If you don't see anything on plaque or plaque regression, you don't see the same kinds of effects in basic biological systems, why would anyone think that there would be a clinical outcome that would be seen in a large PVD outcome study. So again, I hope that, that provides people with some context as we now pivot in the second half of this program to some of the clinical data. With that, Dr. Verma, could you summarize the results that you found in your sub-analysis of REDUCE-IT?

Sure. So first, let me start by just expressing my gratitude to Professor Deepak Bhatt and the REDUCE-IT Executive Committee and Steering Committee for this real privilege to be involved in a very important analysis from the REDUCE-IT trial called REDUCE-IT CABG. And as you've kindly already introduced me, I'm a cardiac surgeon at the University of Toronto in Toronto, Canada and also a professor at the University of Toronto, both in surgery and pharmacology. And it has been really a wonderful experience learning more about icosapent ethyl, both from a clinical standpoint and from a translational standpoint, as we just heard some wonderful new data. This compound is a -- it's are formidable antiatherosclerotic agent. It's like nothing we've seen before. Whether we understand the biological underpinnings or not is completely irrelevant, in my opinion, because at the end of the day, for the doctor or the surgeon or the cardiologist in the trenches who's trying to reduce risk for patients in front of them, they have to apply the clinical data, and they have to apply it in the most evidence-based and rigorous fashion to reduce events for those patients. And I think the meticulously done REDUCE-IT trial with the highly statistically significant P values, the change in Health Canada guidance that we've had, at least in our country, has really represented a sea change for our patients at high risk. And I personally think it has been a -- it is a privilege to have these kinds of strategies in our hands to reduce the risk of vulnerable patients at high-risk for cardiovascular events. So having said that, let me tell you a bit about the story of coronary artery bypass graft surgery and why we are so excited here in Canada in that regard. First and foremost, leading up to REDUCE-IT CABG, there were an assigned REDUCE-IT REVASC, which is another analysis that was presented by Dr. Ben Peterson and Professor Deepak Bhatt just recently at the SCAI meeting and then at TCT, that demonstrated that this strategy really prevented the need for new revascularization. So patients who had an MI or patients who had cardiovascular risk factors oftentimes require open heart surgery or require to get angioplasty or stent. And that is really the translational end point to what Dr. Budoff has been presenting in the EVAPORATE study, that if the therapy can slow or halt or regress the process of rust developing in the pipes or atherosclerosis, then the translational endpoint of that should be a reduction in the need for these highly invasive and costly procedures like angioplasty and surgery. And it turned out that, in fact, there was close to a 30% to 40% reduction in the need for angioplasty or the need for bypass surgery. In fact, at least in my career, I haven't seen any strategy that can mitigate the need for patients to undergo bypass surgery on top of statins by 40%. So we took one step further in the REDUCE-IT CABG analysis that was presented at the American Heart Association meeting a few days ago and asked the question, not about prevention of the need for bypass surgery, but what do we do for people who have had bypass surgery. And I think everyone would agree on this line, and I hope our listeners would agree as well, that having bypass surgery really represents a patient who is at significant atherosclerotic risk. They have to have a certain amount of risk to first require bypass surgery. And then once they have bypass surgery, their ongoing risk persists. They have risk of having a second heart attack, requiring revascularization and dying. And we are always looking for strategies to reduce that risk with lipid lowering. We're choosing the right drugs for diabetes, for weight reduction, sending people to cardiac rehab. We really pull out everything that we have in our toolbox to be able to prevent these individuals at high-risk from having a recurrent event. It's also a big investment from a health care system when we've invested in someone to need bypass surgery, want them to have fewer recurrent events. So under Professor Bhatt's guidance, we looked at the REDUCE-IT database in the about 1,800 patients in REDUCE-IT who had prior bypass surgery. And we looked at the patients who received either placebo or icosapent ethyl or VASCEPA. And what we found was that for the hard MACE outcome, which was the secondary outcome in the trial, which is the 3-point composite of either dying from a cardiovascular cause or having a heart attack or having a stroke, there was a 31% relative risk reduction. For the overall primary outcome of the trial, there was a 24% relative risk reduction. Now I want to just put that in context to everything else that we've seen in REDUCE-IT thus far. The relative risk reductions seem very consistent no matter how you slice and dice the data. But what is incredibly impressive in this analysis is that this population yields the highest absolute risk reduction of any of the analyses that have been presented thus far. The absolute risk reductions are in the order of 6%. And just to put that in context, that is greater than any novel antihyperglycemic therapy to treat diabetes. It's novel. It's just greater than things that we're seeing in low-dose rivaroxaban in the COMPASS trial, for example, it is higher, of course, than what we see with other lipid-lowering strategies, including PCSK9 inhibitors. So this represents really a game-changer, in my opinion, that you take people post bypass surgery, who are well treated, 90% of them are on lipid therapy. Their blood pressures are reasonably well treated. And now you can further reduce their absolute risk by 6%, with a number needed to treat of only 16 or 17. So I'm sure you can sense the excitement in my voice here because we don't have many tools in our toolbox to be able to really change the natural course and natural history of a patient following open heart surgery.

Thank you for that great summary. I guess, Matt, you raised an important comment during your thoughts that there was actual -- if you compare the patient to their baseline, there was regression in some -- at least some of the parameters of plaque. Do you think that's consistent then or a part of why Dr. Verma just commented on why the event rate reduction, whether relative or absolute, was so large is that the plaque was stabilized, but in some cases, actually lessened during the course of treatment?

Yes. No, absolutely. And I think that when you look at the time course, I know Deepak showed with REDUCE-IT REVASC, in general, the time-to-benefit was 11 months, and we showed positive plaque changes as early as 9 months, that, that's very concordant with less plaque, more stable plaque. And the combination should lead to less events over time, less bypass grafting and less revascularization and, of course, less ischemic events as you stabilize the plaque.

Terrific. I want to now move really to Professor Catapano. I think on this call, you had the privilege and opportunity to be a discussant of 2 important omega-3 studies that were presented at this meeting. The third was really looking at atrial fibrillation from the VITAL study, which was a primary prevention, really sort of population-based survey study, which I don't think we'll have the chance to talk much about today. But Professor Catapano, could you give your sort of takeaway observations that you made during the AHA meeting as a discussant of the OMEMI and of the STRENGTH trials?

Yes. I think in general, the take-on message from the discussion we had is -- I had is the following. There are several possibilities that might explain the discrepancies between REDUCE-IT and STRENGTH [ then ] OMEMI. By the way, STRENGTH and OMEMI, they go to the same end point -- result, although the population is quite different. Certainly, the OMEMI clarifies the concept that, that is not the population, in my view, that has been selected. Because in the OMEMI, all the patients had, had a recent myocardial infarction. Although they are quite old, but that was the point. So I don't think the different kind of population may explain the differences between REDUCE-IT and STRENGTH. What I think is one -- the difference, the biological difference, the biological effects of the different fatty acid, that in my view is the first plausible explanation for the differences between the trials. However, there are some other possible differences determinated to the dose. It might well be that also the dose and the levels achieved of EPA makes the difference. it was a highlighted just a few minutes ago, the levels in the STRENGTH were up to [ 90 ] in the -- as a median. In the REDUCE-IT were well above [ 140 ]. So it may well be that biologically, there is a threshold effect for the incorporation of these fatty acids into membranes that will elicit different results. Again, the window is open for the fact that DHA may not have major effects and may even counteract the positive effects of EPA, so this is another point. But in my view, the less possible effect is the one -- to explain the difference is the placebo effect. That was mentioned over and over. And I [ tend ] to believe this is not the case. With [ JELIS ] trial, the only limitation of that trial is not at the mineral or placebo, and then the results are exactly consistent with what has been seen in other studies with VASCEPA, so I think -- with EPA. So I think this is quite important point to bear in mind. Different drugs, different results.

Thank you, Professor Catapano. Deepak, I'm going to put you on the spot again a bit and ask you -- I know there was a study that you pointed out to me recently that was done in Japan. With different formulations of identical or purportedly identical EPA molecules, since there are generic EPA molecules in Japan as well as the innovator, I believe that was -- the principal -- or first author was [ SUA ]. Could you describe those results as well?

Okay. What I'm saying is the way fatty acid -- especially this long-chain of [ wholly ] saturated fatty acid that's prepared, you have to go very careful to it because obstruction from other resources has some key points that needs to be well conducted. And if you make it -- that with procedures, that will not allow you to get, really, of the carryovers that you have, especially when you get something from marine sources, fish. You make the -- well carryover contaminants that may not give you a good result, [ thinking, yes, from ] the clinical point of view.

Thank you very much. And...

Yes, I agree with everything Dr. Catapano has said. And this particular study you were citing, that specific formulation just didn't achieve what it was supposed to in terms of EPA levels. And I think this really points to the fact that if you studied one preparation, you've studied one preparation, you really can't extrapolate across different ones. The STRENGTH trial that you're discussing, I think, is a really well done, important study. And I congratulate those investigators. And what it has shown us is definitive evidence that, that particular product doesn't work, despite lowering triglycerides. So to me, that's actually an enormous scientific contribution. Despite being able to lower triglycerides significantly, the drug is still completely unable to influence ischemic events in aggregate, isolated end point, secondary end points despite causing atrial fibrillation. So the science there is fascinating. And it really tells us, I think, if you've got a particular compound, and that was a mixture of different omega-3 fatty acids in Epanova. But even if you got a compound that is ostensibly just in EPA, the proportion of EPA might vary at the levels of EPA that may achieve, and blood or tissue may vary. The degree of oxidation may vary. Dr. Mason's work has shown this before, that depending on the preparation, various omega-3 fatty acids can be -- and other fatty acids that might be in preparations are subject to oxidation. And this can undo any benefit that might otherwise have been expected to accrue. In fact, it might even help negate some benefit of other compounds within the preparation that might have otherwise been beneficial. So I think in medicine, we often like to oversimplify things and just put things in a class, right? Statins are a class. SGLT2 inhibitors are a class. Sometimes that's right, and sometimes that's wrong. But in the case of omega-3 fatty acids, even if we're speaking specifically about EPA preparations, it's much more intricate and complicated than that.

May I just add another comment, Craig? It's Dr. Verma here, if I could.

Please.

I'd like to really strongly echo what Professor Bhatt just said, and that is -- and draw some parallels, at least, for your viewers and listeners to think about. And there's lots of examples where so-called agents within the same class behave differently. And one that comes to mind recently is the GLP-1 RAs. They're very large class of agents that stimulate GLP-1 and are used in diabetes and have been studied in large cardiovascular outcome trials. And some of them have -- all of them actually have similar effects on glucose lowering. Similar to how Epanova and VASCEPA have similar effects on triglyceride lowering. All of them have similar effects on weight. But there are differences with respect to cardiovascular outcome trials. Lixisenatide in the ELIXA trial, in a very high-risk population of patients, showed no benefit on major adverse cardiovascular events despite the fact that it belongs to a GLP-1 RA class and has similar pharmacology with respect to reducing glucose and with respect to reducing weight. And that's in contrast to other products that have actually slightly different pharmacological properties that have actually been shown to have benefit. So I think this should come as absolutely no surprise to anyone that just because one trial is neutral and the other trial is positive, that, that in no way either negates or strengthens anyone's position in any way other than saying that pharmacology is at action here. And really, the differences in the pharmacological properties are the reasons why we have these differences. And I think for -- at the end of the day, for the doctor who's taking care of patients, right? Let's bring it back to them. This is such great news that STRENGTH is being neutral, tells us that one strategy doesn't work, and REDUCE-IT being positive that tells us that one strategy works, it provides the doctor with the clear direction that they need to be able to reduce the risk for their patients.

And I think there's oftentimes a reinventing of the wheel every few years. I think a lot of people have forgotten about the CAST trial in the early 1990s. And that was a trial that looked at extra heartbeats, PVCs, as they're called. And there's no question that after a heart attack, you're having more PVCs, you do worse. It's a good marker of risk. And it's logical to think reducing PVCs would therefore also be good. But that study examined a drug encainide, and as it turned out, there was an increase in mortality with the drug, though it was very effective in suppressing PVCs. And triglycerides are a nice marker of risk. That is true. But as a target for therapy, I think STRENGTH very nicely shows that even if you can reduce triglycerides, that per se doesn't translate into risk reduction. And you just can't rely on surrogate markers. Ultimately, if you really want to see if something works, you have to do a large long-term trial, randomized patients and see what happens.

I think we can agree that in all these trials with omega-3, the effect on triglycerides is probably -- is not the driving force for reducing events. This is something we can agree. And even if you look at the [ GLP ] reduction, this is minor. However, please look at several papers, including [ medical randomization ] study that has been published, that indicated to get to the similar effect to 1 million more reduction of LDL, that is about 22% reduction [ in cardiovascular event ], it will need to reduce roughly to at least 200 milligrams per deciliter. So I don't think we can [ discount it. These are -- it's a ] truly a risk factor, causal risk factor. However, under the circumstances of this trial with the reduction we see of triglycerides, certainly the triglyceride reduction is now the driving force.

Very well stated. I'm going to just summarize right now, because I know we are at the limits of our time, is I hope that this session with this wonderful faculty who have such complementary perspectives and data sets shows that there are differences in biochemistry, in biology at the cellular level. There are differences at the level of the plaque and plaque biology and morphology. And those all directly correlate in the case of icosapent ethyl in the VASCEPA formulation with clinical outcomes achieved in REDUCE-IT. I think also, we've been able to clearly show that different formulations, particularly mixed omega-3s, do not provide those same benefits in cardiovascular outcomes, and they are consistent in their negativity, as consistent in their negativity as icosapent ethyl. VASCEPA is in its positivity across basic biology, across translational research and across large outcome studies. So I think to me, the data is all entirely consistent that STRENGTH delivered exactly what one would expect based on the basic scientific hypothesis, that REDUCE-IT delivered exactly what we'd expect studying this form of icosapent ethyl. And I'll take one last leap forward, is that on the basis of even differences in formulations of icosapent ethyl, it's very likely that different results will be achieved based on different excipients, different levels of oxidation and different levels of other smaller amounts of inevitable constituents in those formulations as derived from a natural product. So with that, I'd like to close this wonderful session. I wanted to thank our tremendous panelists who are joining us literally from most of -- across the globe, from Milano, Italy, from Boston, in the East Coast, from Toronto and from California. I wanted to say thank you all very much. Have a wonderful day. Bye.