Esperion Therapeutics, Inc. (ESPR) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Esperion event. [Operator Instructions] As a reminder, today's meeting is being recorded, and a replay will be made available on the Esperion website following the conclusion of the event. I would now like to turn the call over to your host, Sheldon Koenig, President and Chief Executive Officer of Esperion. Please go ahead, sir.

Thank you so much, and good morning, everyone. It's a great pleasure for us today on behalf of the organization to have an R&D Day. We're really excited of the agenda that we have before us today. First, forward-looking statements and disclosure for your benefit, we'll not cover that, but let me run through the agenda. We'll start with some opening remarks followed by following the science Esperion research and development. Our next item will be the importance of lowering LDL cholesterol and the royal bempedoic acid plays, which will be followed by the fire within inflammation is a common path in major chronic diseases and we'll follow or conclude the day with the Esperion pipeline, and we'll have the ability to have Q&A after all of the speakers. And with that today, just to go over who we have speaking with us today, Dr. JoAnne Foody, who I'll turn the presentation over to soon. But we're honored to have both Dr. Michael Gibson and Dr. Peter Libby. Both professors of medicine to speak to you today about Dr. Gibson, the importance of LDL cholesterol. Dr. Libby will talk about inflammation and the role that it plays. And then Stephen Pinkosky will go over the head -- who's our Head of Discovery, will go over the pipeline that we have here at Esperion. So where are we today? Esperion is really focused on reaching goals. We're very well positioned for today, tomorrow and the future. And that's a theme that you're going to hear from today through the next couple of months and years, et cetera. Today, our focus really is on NEXLIZET and NEXLETOL. Many of you have been following us, you tuned into our quarter -- our third quarter results last week. And it's all about today driving consistent growth, but really also preparing for a flawless launch of the CLEAR outcomes data. Again, today, we'll also be talking about the pipeline. But our focus for today is really NEXLIZET and NEXLETOL and CLEAR outcomes. And with that said, tomorrow is essentially also based on the CLEAR Outcomes study. And what we mean by that is we've talked about the fact that in January, we'll have our top line for CLEAR outcome followed by the full data release at the American College of Cardiology, which will take place in March of 2023. It's a very exciting time for us as it relates to CLEAR outcomes, and we're all very anxious for the data and are looking forward to it. The future is really about continuing to maximize NEXLIZET and NEXLETOL but also advancing our pipeline, which you'll hear more about later today. So with that said, I'm going to turn it over to Dr. JoAnne Foody, our Chief Medical Officer.

Thank you so much, Sheldon. We're absolutely thrilled to share the progress across our entire clinical development and discovery programs as we follow the science. First, as Sheldon mentioned, we're making really great progress on CLEAR as we continue to approach database lock and look forward to presenting our data in 2023. As Sheldon mentioned, CLEAR has the potential to be a landmark trial for patients and providers in the field as the field moves to early aggressive combination therapy. What's important, though, is while we've been diligently executing the trial to leverage the CLEAR data for patients and to commercialize the opportunity, we're also taking a very thoughtful approach to bringing new therapies in our pipeline assets forward. So let me share how we're thinking about that. As we've mentioned, we are following the science in areas of high unmet need with a strong early pipeline. And clearly, we already have our commercial assets of NEXLETOL and NEXLIZET. We're using novel approaches that fundamentally improve health outcomes at scale with a focus on oral small molecule therapies for metabolically driven diseases. We're looking at specialty indications with high unmet need with limited or no targeted therapies to date. And finally, we're looking how we can best leverage our world-class scientific expertise, our first-in-class ACLY inhibitor, bempedoic acid and move beyond that targeting important cardiometabolic pathways. How are we doing this? As many of you have heard, we've set up a world-class scientific advisory board that is guiding us in each and every step of the way as we move forward. We have strong intellectual property across all our existing compounds as well as our future platforms. We are taking a highly specific prioritization for indication and indication selection using big data as we leverage that. And finally, as you'll hear more from Dr. Steve Pinkosky, our Head of Discovery, we're leveraging technology partnerships as we approach scientific development across not only more traditional technology partners, but also novel partnerships using big data, data science and AI. So today, we'll highlight the assets of NEXLETOL and NEXLIZET based on our backbone of bempedoic acid, we'll discuss our oral PCSK9 allosteric inhibitor as well as introduce you to our ATP citrate lyase or ACLY inhibition platform. So let's step back a moment and remind you that despite where we are today, there are over 18 million U.S. patients alone in need of further cardiovascular risk reduction, specifically through LDL cholesterol goal. Despite the therapies we have, nearly 80% of very high-risk patients do not meet a guideline-recommended LDL-cholesterol goal. Currently, 8.7 million patients in the U.S. don't reach their LDL-cholesterol goals despite taking a statin and patients continue to struggle with their medications. It's estimated that up to 20% of individuals who could be treated with a statin experience a problem with their statins. 1/3 of patients discontinue statin treatment within a year and nearly 10 million patients in the U.S. with high LDL-cholesterol are not on statin often due to tolerability concerns. It is in this landscape that Esperion takes a look at how to develop therapies today with NEXLETOL and NEXLIZET and tomorrow to address the significant unmet need. This is not just an issue in the U.S. despite the availability of effective therapies, the global burden of cardiovascular disease on the health system continues to rise. As we are well aware, cardiovascular disease accounts for more deaths than any other disease. And even with COVID, cardiovascular death are still the #1 killer globally. There are more than 135 million ASCVD patients worldwide, and it's estimated that only 20% reach their LDL-cholesterol goals in real world despite existing therapies. We expect unfortunately that global cardiovascular costs will surpass $1 trillion by 2025 and that 18 million lives will be lost globally to cardiovascular disease in this year alone. Finally, after years of decline, the number of lives lost to cardiovascular disease is on the rise again. And if we think about the overall economics, it's not just for current heart attacks, but strokes and death that continue to drive health care costs estimated to be nearly 55% and continue to result in lost productivity. So clearly, we have an epidemic on our hands that needs continued therapeutic option. So again, as Sheldon mentioned, we are looking at following the science. We're addressing the unmet need today with our therapies, including NEXLETOL and NEXLIZET now approved in 30-plus countries worldwide. We are looking tomorrow to the successful execution of our CLEAR outcome study with top line results Q1 of 2023 with the potential to expand our label to cardiovascular risk reduction and to a broad population in need. Recall that this could put NEXLETOL and NEXLIZET as the only oral LDL agent since statins to have a cardiovascular risk reduction in their label. And finally, today, we'll focus more on the future, what our early pipeline platform is to address multiple risks across multiple disease states, focusing on our oral PCSK9 and our ACLY inhibitor platform to optimize metabolically diseases like liver, kidney, even cancer, neurology and beyond. So just to remind you where we sit today, understand that our clinical development program has reached over 60,000 patients in over 30 countries, and we have a large integrated scientifically rigorous program that establishes bempedoic acid as a new standard of care, whether it be in lipid lowering, whether it be an anticipated outcomes with our CLEAR outcome study or whether it be in real-world evidenced with health care system partnerships in the U.S. or real-world evidence, again, ensuring the value of these therapies to patients. And again, our unprecedented CLEAR outcome study as much as we're focusing on our pipeline in the future, we recognize the importance of CLEAR outcomes today and in the near-term future as the first of its kind unprecedented cardiovascular outcome study in patients who cannot maximize or tolerate a statin. As you're well aware, this is one of the largest cardiovascular outcome studies to date, is fully enrolled, achieved 100% MACE-4 and last patient last visit was achieved last month. Again, we believe that this is a highly differentiated trial with the highest baseline LDL cholesterol of any recent non-statin cardiovascular outcome study, and again, because cardiovascular risk reduction is based on absolute LDL reduction positioned for success. It's long duration as well as the differentiated anti-inflammatory and glucose effects of bempedoic acid could provide even greater risk reduction. We continue to anticipate top line press release in January of 2023 and targeting full data presentation at a scientific meeting Q1 of 2023. Now with that, I'd like to hand over to an esteemed global trialist, world-renowned cardiologist, Dr. Michael Gibson, who is Professor of Medicine, CEO at BAIM and Perfused Research Institute at Harvard Medical School. Mike?

Great. Well, thanks, Joanne. Very excited to be here with all of you today. I'm going to talk about the importance of LDL lowering. You wouldn't think we'd have to talk about that. But I got to tell you, I have an elevated LDL. I went into my primary care doctor. I had to spend at least 5 or 6 e-mail exchanges with a Harvard-trained, Former Harvard Chief Resident convincing them that lower is better. And we're going to talk about how that really is important in the upcoming slides. So we're doing well. I mean, we've loaned a lot of battles over the past 30 or 40 years. But the war continues. As you heard from JoAnne, Sheldon, cardiovascular disease remains the #1 killer. But look at this, back in about 2010, we started to kind of turn the corner, forge worse outcomes. We're not quite sure why this is. We think some of it may be because we're not investing as much in preventive care. I think something happened in 2013 that set us back a bit, and that was when the guideline committees reversed their stance on setting targets or goals. And that was some epidemiologists saying, "Well, yes, lower is better, but we're not so sure that achieving lower levels improves outcomes. A lot of disagreement with that. We bind that the data is very compelling not just from epidemia logic data that lower is better, but from trial data that setting a target and lowering LDL is better. But sadly, my primary care doctor shows that there's still a lack of knowledge that lower is better. What we also know is that we're spending a lot of money on disease care and treating something once the events happen rather than health care, preventing events. Here you see we're spending trillions of dollars by 2051, it's estimated that we will be spending $25 trillion a year on atherosclerotic care. Again, the balance being mostly on treating disease that has occurred rather than on prevention. Now if we pivoted to spending more on prevention and less on managing the disease that's already occurred, we can actually save costs. But this is a large international discussion that we need to have. All of you probably on the call know this, the higher the LDL, the higher the risk of adverse outcomes. Here you see an eightfold difference in the risk of mortality as your LDL goes up. So yes, epidemiologic data, observational data suggests that lower is better. The big question is, can we do anything about it? And yes, in trials by lowering LDL, we lower event rates. And what you see here is the classic curve put together by all the trialists and it's been done over about 40 or 50 years now, that any drug that increases the LDL receptors lowers risk in a consistent fashion. Now this is true both of statins. They're nonstatin therapies like Zetia. There are PCSK9 inhibitors that have a different pathway, but it doesn't really matter how you get there. Lowering LDL really does improve outcomes. Now there are 2 curves here. One is a under 4-year duration curve that's in red. And the other curve is if you've been treated for 4 or more years, notice that the event reduction is higher with the longer duration trials. And that's an important point. We're now learning that not only is lower better, but earlier is better. And here's some mathematical modeling that I'm going to send to my boys who are in the 30s. By the way, both of -- both of them PhDs, both of them gone to their internists to review the lower is better data with their internist, both of them on statins and the reason is shown here. If you begin to lower your LDL by 50%, and in your 30s, you can cut down your risk of later events by 80% -- by 50%. Notice that the longer you wait to become aggressive, say, a 60-year-old if you start then and cut your LDL by 50%. You had about 27% lowering of events. So earlier is better. And look over on the right-hand side, if you begin at age 40, and that's the kind of greenish curve and lower your LDL by, say, 33%, you get better outcomes than if you wait, so you're 55 and lower more aggressively by 50%. So earlier is better. This new concept is called cholesterol years. You multiply the years of exposure by your LDL and you get kind of an integrated writ lifetime exposure and risk to that LDL. We're going to return to that on the very last slide. This is the good news. This is the good news about earlier is better. The bad news is with certain drugs, say, statins, if you initiate them, you might have a higher risk of diabetes. So we are looking for drugs that are safe as well as effective. And that's why bempedoic acid is going to be so important because not only does it lower LDL, but it also, as you're going to see, has some favorable effects on glycemic control. We have seen good reductions in events. Those are the bars here going down. Yes, we've seen some pretty good relative risk reductions. But look at the height of the arrows relative to the height of the bars, the height of the arrows, that's how much risk remains. That's how much residual risk remains after we have lowered LDL. So we have more residual risk than the risk we eliminated. So we're doing well, but we have a ways to go. We ran this registry from my Institute, the BAIM institute, called the GOULD registry. These are people who have atherosclerosis disease, and we looked at how they were being cared for, this information just makes my head want to explode. I mean only 32% of people achieved an LDL lower than 70. And only 15% got it down to part where they should be below 55%. This is a real failure of implementation science. Another staggering number. intensification of lipid lowering only occurred in 17% of people who really needed it, again, mind blowing. And finally, went 21% had only 1 lipid panel in 2 years and 11% didn't have a liquid panel at all. So we have a challenge out there in education and understanding. We have to do a better job in implementation. Let's talk a little bit about a drug that's the first drug in its class, bempedoic acid. It's a first-in-class ATP Citrate Lyase or ACLY inhibitor. Very quickly, this step or where this blockade occurs, occurs above some of the HMG-CoA reductase step. So it works above or before the step where statin works. Now very important, it increases the LDL receptors. And finally, here's a real differentiating feature from statins. It does not work in the muscle, whereas you do see statins are active over in the muscle. That's why it may be much more tolerable. Now it's also at the intersection of a lot of energetic pathways. And we're going to talk a little bit about how it may improve glycemic indices and glucose tolerance in some of the upcoming slides. We don't have time to go do all the back science that led to the approval of the drug. There are a couple of studies. The CLEAR Harmony study and CLEAR Wisdom study. In these studies, bempedoic acid reduced LDL in those people who are statin intolerant, who had known coronary artery disease or who were at high risk based on their risk factors for coronary artery disease. The next study looked at a combination CLEAR combo where the drug was combined with Zetia and achieved, again, significant reductions. Finally, in the lower right-hand side is retrospective data, showing that you improved patients lysemic indexes and potentially reduce their risk of moving on from prediabetes to diabetes. So we faced a diabesity epidemic in this country One of the reasons I'm excited about bempedoic acid, it's a twofer. It is not only reducing LDL, but as you're going to see, I hoping the CLEAR outcome study it also improves the progression to type 2 diabetes. We've got to take a whack out of both those if we're going to improve outcomes. There is a design paper out there describing this pivotal CLEAR outcome study. Again, we know bempedoic acid reduces LDL. This study is going to look at whether it improves outcomes. And this is being done in about 14,000 patients. Here's the design here. Who's in the study. These are people who are unable to tolerate statin therapy, who have coronary artery disease or who are at high risk for coronary artery disease, and you have to have a fasting LDL of greater than 100 or equal to 100. It's a pivotal study. It's a Phase III study. It's double-blinded, people aren't going to know if they got the bempedoic acid or not, placebo-controlled, it's a cardiovascular outcome study. 14,000 patients with 90% power to detect a 15% relative risk reduction in the primary endpoint. We're going to compare that to other studies in a moment. It's pretty similar to what they powered for. And the primary endpoint is going to be 4-point MACE, and we'll talk about that in a minute. People are getting randomized 1:1 to either standard of care, there's a run-in period to make sure they tolerate the drug that they're meeting the entry criteria and then they get randomized. This is an event-driven trial. It will go until there are at least 1,620 of those 4 component MACE events. It will go also until there's at least 810 cardiovascular deaths, MIs or strokes. And it's anticipated that this is going to take, obviously, over 2 years of treatment. Why am I excited about this? This is the first cardiovascular outcomes trial, not just the lipid trial but an outcomes trial to look at this new ACLY pathway. It's the first outcomes trial for bempedoic acid. 78% of these folks are on no statin, no statin. About 22% are on low doses of statins, both of which -- because they couldn't tolerate it. It will be about 14,000 or more patients who are at high risk. There's equal representation of women, which is very important. We do understand that they may get it a little later, but they also have bad cardiovascular outcomes. I would say 70% of the folks are secondary prevention patients, about 30% are primary prevention patients. And here's, I think, one of the most important things. This is the first cardiovascular outcomes trial to have predefined efficacy endpoints for new onset diabetes and glycemic control, again, a big differentiator from statins, which may increase the correction to diabetes or worsen glycemic controls. So we'll be looking at hemoglobin A1c and progression. As it turns out, the threshold was 100, but it turns out these folks have an LDL in general about 140. What's the primary endpoint? The primary endpoint is one that's been used very traditionally. It's a 4 component endpoint, cardiovascular death, nonfatal MI, nonfatal stroke or coronary revascularization, all very important outcomes to patients. Some of the secondary endpoints will be cardiovascular death and MI stroke. That's the traditional 3-component MACE. The other one will be all cause mortality, death MI, and revasc. And finally, we'll be looking at each one of the individual endpoints. Some of the biomarkers we'll be looking at are obviously LDL, but also inflammation, CRP. And importantly, again, I can't emphasize this enough, the absolute change in hemoglobin with A1c and progression to or new diagnosis of diabetes. If you remember one slide today, I think this would be the most important slide to remember. And it puts this CLEAR Outcome study into context with some of the previous studies in different agents. So over on the far left, you see ezetimibe in the middle you see evolocumab and alirocumab, 2 PCSK9 inhibitors. And in the far right column, you see CLEAR outcomes. So different class of drug here, first-in-class drug. The baseline LDL is higher than it was in the other studies. The median duration -- the median duration here is going to be longer than in the PCSK9 trials. I think that's unbelievably important. One of the funniest things I watched was watching some of the FOURIER folks trying to get their trial done quickly. Let's beat the other competitor. Let's get the trial done quickly. Let's enroll a lot of people and get done very quickly. It takes time for these drugs to work. Some of the effects don't begin to kick in between 6 months to a year. And if you rush it, you may have a good relative risk reduction, but you will not see the same absolute risk reduction. So by going longer, you will accrue more events. You'll see a larger absolute risk reduction, which is very important because it's the absolute risk reduction that drives the number needed to treat. So I'm very excited. We're going longer here. The hazard ratio is in keeping with other trials, about a 15% relative risk reduction. But again, the longer we go, the bigger the absolute risk reduction. No effect on CRP, from PCSK9 inhibitors or Zetia. But here, we do know that this drug lowers CRP 18% to, say, 33% in other Phase III studies. So I'm hoping we get a little extra kick from the CRP reduction on top of the LDL reduction. A little added benefit is a little additional weight loss seen in previous studies. And again, the other additional kick, I think we're going to see here is that effect on glucose control. Again, this drug is acting at that nexus of energy metabolism, no effect on hemoglobin A1c for Zetia and the PCSK9 inhibitors. On the right-hand side, you do see the reductions we see in hemoglobin A1c with this drug and then a 20% reduction in the progression to diabetes. That's at a year, that's at 1 year. Here, we're going to go 3.8 years. I think we may see even bigger absolute numbers of patients where we prevent that progression to diabetes. It's very exciting. What we've learned in heart failure, we have 5 drugs we often use. We learned in hypertension. We got 3 drugs at least. We learned that biology has a lot of escape mechanisms. And we got to take a lot of different shots on goal and different pathways to be effective. I think we're seeing that also in the lipid-lowering side. We have a long ways to go in reducing events. I'm very excited by all the new shots on goal that we see, and that's why I'm very excited about bempedoic acid. So I do think it will require a multidrug combination. Personally, I do expect that bempedoic acid will play a major role in that team like strategy of multiple drugs. And I would really like to congratulate the company on investing so aggressively in the preventive medicine space. It's where we got to be. Finally, -- let me end with a slide from my mentor. I've worked with him for 37 years now. He wrote out an article how to live 100. If anyone knows how to do it. It's Dr. Braunwald, he's 95, who's been pretty successful. He and I like to compare our LDL levels. He's beating me, by the way. And he's done a nice job of promoting this concept of cholesterol years. You can never be too rich, too thin, have too low of an LDL or have it for too long. And you multiply that LDL by the years. And once you start to get up at around 4,000 to 5,000, that's when you start to get clinically manifest disease. So you want to live to be 100 start, LDL lowering when you're 30 is my answer. Thanks for having me today. I hope you learned something from our symposium.

Thank you, Dr. Gibson, and thank you for your insights and that stage is right. I'd now like to turn over the conversation to Dr. Peter Libby, another world-renowned cardiovascular researcher and clinical expert. He's currently the Mallinckrodt Professor of Medicine at Harvard Medical School and a cardiovascular specialist at Brigham and Women's Hospital. Dr. Libby?

Yes. It's great to be here and share with you some of my ideas about how inflammation is a common path in major chronic diseases. We commonly held inflammation as responsible for a number of acute conditions. So we have fever, things like pneumonia and other acute illnesses, that's it. Everyone agrees that inflammation is important. But what we've come to appreciate in the last couple of decades, as indicated in this cover of Time Magazine, many of the chronic diseases that we formally attributed to wear and tear, to aging to just the cost of business in life, actually involve inflammation, heart attacks, cancer, Alzheimer's and what can we do to fight inflammation. In particular, chronic disease that is [ drafted ] by me for many peers. And Mike, I've got you beat that Dr. Braunwald might go back more than 50 years together. Is atherosclerosis. And the atherosclerosis takes root when we go from the normal vessel shown in the upper left-hand corner here to the beginning atherosclerotic region, where we get these unwelcomed visitors the inflammatory cells, the white blood cells, leukocytes that enters the innermost layer of the artery. There's been a long phase that is clinically silent or stable that is the progression of the disease sort of under the hood of the plaque, not causing clinical symptoms. And then there are the thrombotic complications of this disease shown on the upper right and the lower right as well. These are blood clots obstruct blood flow can do so suddenly and are a major cause of heart attacks and many stroke. And what we've learned is that inflammation is critical in all of these steps from the beginning to the end of atherosclerosis. So what can we do about it? And we studied inflammation in the blood vessel cells and in the white blood cells for many years in the laboratory. But how do we take that and move it towards the clinics that we can actually help our patients. And this is a proposition that has adopted by me for the last 15 to 20 years and targeted anti-inflammatory therapy, improved cardiovascular outcomes, not in the petri plate, not in experimental animals but in human beings. I was fortunate to be able to instigate and co-lead the first of a large trial with a specific anti-inflammatory agent aimed at improving outcomes in those who survived a heart attack or a mild cardio infection. The study is known as the canakinumab anti-inflammatory thrombosis outcome study or CANTOS for short. And what we used was a very selective monoclonal antibody that could neutralize a pro-inflammatory cytokine that I had studied in my laboratory since the early 1980s, inflammatory points data. As you can tell from it being #1 is the primordial pro-inflammatory mediator, a member of the cytokine family. And we enrolled over 10,000 people in a study that lasted almost 4 years. We reported the top line results in 2017 in the New England Journal, and the study met its primary prespecified endpoint which then allows us to look at another analysis that was prespecified in the statistical analysis plan. And that was to look at the people who actually responded to the drug back by lowering the marker inflammation and call high sensitivity CRP, hsCRP, a greater than 2 milligram per liter. And as you can see by comparing the green bars to the placebo in red and the people who did not respond well to the antibody is gold. There was over a 30% decrease in cardiovascular mortality and in all-cause mortality, the Holy Grail of all clinical trials. Now it turns out that the population that we enrolled in this study and accentuated risk for certain kinds of cancers that are involved with inflammation. In particular, lung cancer because of course smoking is a risk factor for having that first heart attack. And also, we selected people who had a marker of inflammation being above average. That is they have an elevated high-sensitive CRP, which we know from the oncology literature is actually an independent risk factor for cancer. And we had actually convened a group to look at cancer endpoints from the getgo in this study because there was a good deal of preclinical evidence that the tumor microenvironment also involved inflammatory signaling with [ essential ] endpoint. And indeed, in this exploratory analysis, this was not part of our statistical analysis at all, but we had our ears and eyes perked up for this, we saw a dramatic effect on incident lung cancer. Here is the data that shows at the highest dose that we used in this trial and over 77% reduction in fatal lung cancer, and this was a dose-dependent effect, and it was really quite remarkable. As a matter of fact, one of the reasons that we don't have canakinumab in our momentarium for cardiovascular disease because the sponsor of this trial got very excited about the cancer results and has launched a number of studies to check this hypothesis as priority. So the point here is that inflammation is a common contributor to many chronic diseases, cancer, aging and cardiovascular disease. And with one of my oncology colleagues and friends, Sebastian Kobold, we are trying to expand the concept of cardio-oncology. Now I'm not going to take you through this complicated chart, but I want to convey to you that although on the upper side, we think the cancer on the left is due mostly to somatic acquired mutations in our DNA. And atherosclerosis on the right is due to the classical risk factors that you can all take off. But once you get the ball rolling, although I would say that we're limiting more of the cancer is involved with some of the same risk factors for atherosclerosis and the atherosclerosis can also involve somatic mutations. But once you get that ball rolling, the biological processes that are depicted here in the extreme columns are very, very similar. The same biological processes, although we call them different things. And mediators that cause these changes in the tissue are quite similar. This is the alphabet soup of inflammatory mediators in which many of us win. So let me simplify that to this generic chronic inflammatory disease, where we have the T cells, the T cell committee is like the Joint Chief of Staff, and they send signals to the soldiers, the mononuclear phagocytes monocytes macrophages, if you will. And they then impinge on an epithelial cell that's aligning cell of the tubular structures or other structures in our body and [ endothelial ]cell. And they cause a stereotype set of follow-ons, proliferation of cells, fibrosis, recruitment of white blood cells and growth of new blood vessels, angiogenesis. And what we call the epithelial cell or the mesangial cell depends on our union card. It depends on what our clinical specialty is. But the bottom line is that a whole variety of different chronic diseases as well as the acute diseases depend on the same pathway. So I call this slide my, we all study the same disease slide. So take home point, many diseases share cellular and molecular mechanisms and inflammation is one set of processes, pathways that transduce all of these various stimuli, which can provoke the disease and amplify it and cause changes in the tissues that lead to the disease. So I'd like to thank some of the people who helped with the work in my laboratory through the decade and the funders who made this work possible. Thank you very much.

Thank you, Dr. Libby. Thank you for those insights and your expertise. I think the more we learn about the science that we have, for example, in our ACLY inhibition, the more we believe in its potential as a targetable pathway beyond atherosclerosis. I'd like to now hand over to Dr. Steve Pinkosky, our Head of Discovery, who will talk a bit about our oral PCSK9 program as well as our ACLY platform as we move to the future. Steve?

Well, thanks so much, Joanne, and hi, everyone, a pleasure to be speaking with you today. Yes, I'm going to be providing an update on the pipeline of Esperion, the early pipeline, focusing primarily on 2 assets, our oral PCSK9 inhibitor program and our next-generation ATP citrate lyase inhibitor program or ACLY. Both essentially build on the success ultimately of bempedoic acid, as you know, bempedoic acid discovered, developed and commercialized here at Esperion as a first-in-class LDL-cholesterol lowering therapy. We plan to build on that success by developing a first-in-class small molecule PCSK9 inhibitor therapy. Now moving to the next-generation ATP citrate Lyase program, also building on the success of bempedoic acid. But here we're building on the science. The scientific development that occurred as we moved bempedoic acid forward, and we appreciate now is nicely highlighted by both Dr. Gibson and Libby of the broader role of ACLY at the nexus of metabo -- that offers additional therapeutic opportunities not only in liver but extrahepatic tissues as well. First, I'm going to spend a few minutes talking about our oral PCSK9 inhibitor program. I think most of you are familiar with the mechanism for those interested on the right-hand side is a kind of a detailed illustration. But simply put, on PCSK9, we know it binds LDL receptor targeted for lysosomal degradation, Therefore, inhibition of PCSK9 increases LDL receptor activity, thus increasing catabolism with LDL particles from the blood in reducing LDL cholesterol. PCSK9 is a very well validated target. We know based on multiple cardiovascular outcome studies from the monoclonal antibody program that reductions in LDL cholesterol resulting from PCSK9 inhibition are associated with cardiovascular risk reduction as well as significant human genetic data, including mendelian randomization studies. Currently available therapies, monoclonal antibodies and siRNA injectables, monoclonal antibodies are, of course, associated with a higher cost. And I think an unanswered question for the siRNA is long-term safety that we will be finding out eventually. But the point here is that the LDL cholesterol lowering space has traditionally for decades been a once-daily oral small molecule therapeutic approach, and there are currently no small molecule oral therapies available for PCSK9 inhibition. The reason for this is, and we have to talk a little bit about structure and function of PCSK9. On the left-hand side, you can see this is PCSK9 and then the interface where PCSK9 binds with the LDL receptor is highlighted in yellow here. And many drug developers initiated their discovery programs initially with small molecule approach, but the problem here is that interface is broad and featureless and not amenable to disruption with small molecules. This case is kind of to the far right-hand side, where drug developers then took a strategy for monoclonal antibodies, highly specific, much larger, bulkier and are capable of binding this interface. And as you can see in green, much larger and can disrupt this interaction. In an attempt to achieve some middle ground, you can see in the center, some recent success with peptides and looking to take the advantages of large biologics in terms of specificity and reducing the size to disrupt the LDL receptor binding interface. But here, often encounter pharmacokinetic challenges, and we can also be expensive. So what Esperion aims to do is bring this very well-validated target PCSK9 back to an oral once-daily small molecule approach. And we believe we have a strategy that can circumvent some of the barriers that prevented others from being successful in the past. If I could direct your attention to the right -- on the left-hand side, again, just restating the traditional approach, which is direct binding of inhibitors at the binding site between 2 proteins. This approach has not been successful to date and what we're aiming to do is illustrated on the right-hand side, which is take an allosteric approach, which utilizes binding sites outside of that interface that are more amenable to small molecules, which then upon binding promote structural changes, which propagates through PCSK9 ultimately on changing the structure of that interface and diminishing LDL receptor binding. So just to highlight that we are making progress with this program, and we are aiming to file IND late 2024 or early '25. Now I want to switch attention to our next-generation ATP citrate lyase inhibitor program. And here is the opportunity for Esperion to begin thinking beyond LDL cholesterol lowering as we think about the metabolic pathways and where ATP Citrate lyase will suffice. And I think both again, Dr. Gibson and Libby talked about the potential beyond LDL cholesterol lowering and the opportunity for multiple therapeutic opportunities. So just as we were the first to develop a first-in-class ACL inhibitor with bempedoic acid, we want to continue to lead in this space. by continuing to invest in developing the science, putting together through a variety of discovery partnerships, a world-class scientific advisory board and generating our own internal data to really uncover new insights and new therapeutic opportunities. But all along the way, given the scope and magnitude of the potential opportunities in front of us, we really want to find a clear process to get focused as quickly as possible, and we'll talk a little bit more about that process in a minute. Before we talk about the specifics of our program, I do want to talk more specifically about ATP citrate lyase and really tie in some concepts that were nicely presented by Professor Libby. And this is the idea of common underlying mechanisms of disease. And the reason this is so relevant for ATP citrate lyase because it does sit at the nexus of multiple metabolic pathways. And what it does is senses nutrient availability, energy status of the cell, and it coordinates metabolic adaptations to make sure that metabolic states are balanced with the energetics of the cell and nutrient availability. So this is important because in the context of metabolic disease and of course, also taking account environmental and various genetic factors in case of, for example, Western Lifestyle, where we know that energy positive energy balance resulting from the consumption of [ tellers ] and excess energy expenditure can result in disruption of ATP citrate lyase specifically, ultimately promoting metabolic arrangements in multiple different cell types, which can manifest as multiple risk factors we've highlighted here, including inflammation, Dr. Libby talked about dyslipidemia insulin resistance. And we know many of these risk factors can ultimately -- and many of them are actually causal in more life-threatening diseases such as cardiovascular disease and cancers and NASH. So therefore, by targeting ATP citrate lyase, we think we can work further upstream in the causal process of many of these pathological conditions and restore energy balance. And so really just want to highlight the fact that there's been an emergence in the last couple of years of ACLY in the literature making very clear connections to formalizing the enzyme and pathways connecting it to a cellular identity, direct roles and inflammation through regulating macrophage function, implications for nonalcoholic fatty liver disease has been published as well as even autoimmune diseases as well as chronic kidney disease and fibrosis. So multiple opportunities for us to think about. And we've even been continuing to develop other science internally through research collaborations. This is just an example of one of those collaborations looking at, and we've looked at many models of metabolic disease. We just want to highlight that using our first-generation inhibitors to generate proof of principle data in terms of the hepatic broad effect of ACLY inhibition in the liver. And for those interested in the data themselves on the right-hand side showing the effects of ACLY inhibition in green. We see broad effects on liver fat, hepatocyte injury, inflammation and fibrosis. And I think important for these types of inhibitors are effects on a -- favorable effect on atherogenic lipids. So I think studies like this really provide a weight of evidence for the broad effects of this pathway and have imputation across multiple of different disease states. One of the other tissues that we've looked into with our first-generation inhibitors in the kidney. In this case, in particular, we're just giving you an example in a disease called autosomal dominant polycystic kidney disease, or ADPKD. This is a genetic disease caused by mutations in PKD-1 or 2. And what this results in is unchecked proliferation of specific cell in kidney and results in the any fluid build cyst, which can affect the structure and function of kidney. And so we've looked in in vitro models and have shown that ACLY inhibition affects cyst growth. And when we look in disease models, in vivo that we capitulate the disease in humans, we see very nice effects with ACLY inhibition on primary endpoints such as kidney weight and kidney function. And on the right-hand side, I just show you an example of some of the data the primary data reading out of these studies on the left is really the control in the open bar and showing you the standard of care to after that medium and high doses, reduce kidney weight and then you can see bempedoic acid, the fourth bar from the left, giving you results similar to or even improved over on tolvaptan. Importantly, I think a key feature of this mechanism is it's complementary to multiple different approaches. And you can see in combination of both ACLY inhibition and tolvaptan promote effects greater than -- and either alone. Some of the other things we've observed in these studies are broader effects that could extend more to kidney protective effects, which is biomarkers of kidney injuries, such as KIM-1 as well as anti-fibrotic effects. Again, pulling in this concept that ACLY, [ if there's ] these broad effects on multiple pathways at root cause. I want to just build on something that Dr. Libby talked about he established this very nice connection between inflammation and cancer. And we've established and have shown you a role directly for ACLY inhibition in inflammatory cells, but I also want to highlight the fact that there is this close association between metabolic disease and disruption of lipid metabolism that also can promote tumor genesis, colonization and metastatic capability of tumor cells. In fact, tumor cells exploit mutations that ultimately result in advantageous effects on lipid metabolism to support rapid proliferation, resistance to therapy and can even promote relapse. And I just want to make the point that ACLY has been shown to directly be involved in many cancers for metabolic reprogramming that occurs and contribute significantly to the rewiring of metabolism that meets the Warburg metabolism and we know it's an important adaptation that can sustain its unchecked cooperation. Again, there are many examples in the literature of the role of ACLY in cancers, just highlighting a couple of them here, some recent publications demonstrating a critical role for this pathway in glioblastoma. Certainly in hepatocellular carcinoma again study showing in combination with standard of care as beneficial effects as well as beneficial effects in renal cancer and beyond. So this now brings us to our next-generation ACLY inhibitor program. And I think we've established a pretty clear rationale, I think, importantly, is bempedoic acid providing really solid clinical validation for engaging the target. And despite its excellent profile, it's important to note that bempedoic acid was not designed prospectively with ACLY inhibitor was actually discovered in a phenotypic screen, and therefore, we think there's tremendous opportunity to optimize therapy. And we, therefore, think bempedoic acid is really only scratching the surface of what this target can yield. I think another catalyst for initiating this program is now just recently the published full-length crystal structure of ATP citrate lyase, which now allows us to bring all the contemporary capabilities of modern drug discovery and also the identification of allosteric regulatory binding site on ACLY, which is very attractive from a pharmacological inhibition and binding mode perspective. So I think taken with all of this, the opportunity here in front of us is to discover and develop multiple next-generation ATC citrate lyase for 1 or more different disease states. As we kick off this process and we've actually been working toward this now for quite a while, we want to take a comprehensive approach at the strategy -- towards our strategy. I think a critical part of this, given the rapid expansion of the role of ACLY in various disease states is to bring experts in and help advise us on where we might want to focus. I think JoAnne touched on the scientific advisory board already. But again, then also bringing in new technology partnerships so that we can take advantage of all the new capabilities and accelerate our decision-making and expand our insight into the target. Of course, a solid IP strategy critical to lock value in for Esperion and continue to develop the science, continue exploring opportunities for pharmacological intervention in this pathway. The biggest challenge here is I think the opportunities, the scope in front of us, many opportunities. And so we have worked hard to define a process that gets us to a focused strategy as quickly as we can while taking advantage of all the recent opportunities. I have one diagram here just to give you a bit of insight into how we are doing that. If you just look at the top sort of triangle. What this represents is the various partnerships we brought in that allow us to bring in big data analytics to understand and uncover potential new insights that are not necessarily obvious and also continue to develop and generate our own data to feed into these analyses as well as our own internal expertise and ATP citrate lyase and all along through the guidance of our Scientific Advisory Board, rank order, identify, and new indications to focus on. Once we've done that, then we've taken multiple development and commercial and clinical opportunities and establish a short list, and this is essentially where we're at. Now I just want to highlight that given the number of opportunities in front of us, we decided to do this in 2 stages. On the left-hand side, we call this program 1. This is a liver-targeted approach, and this is supported by, I think, our expertise in ACLY liver biology. Certainly, the connections that have been made in multiple liver disease states supported by the capabilities of our discovery program, and I think we're well aligned with the Scientific Advisory Board in terms of focusing here first. This program aims to identify -- is in lead optimization phase and we aim to identify our indication in 2023 and target time is 2024. We have a second effort, we'll call it, Program 2, which is looking at tissues beyond the liver. And here, we have a distinct set of scaffolds that are under evaluation. These opportunities also rank very high in our indication identification and rating process, and we're working through all these opportunities now what we're trying to think of. This aspect of the program is in lead identification phase and we aim to for indication selection by 2023 and target IND by 2025. And then finally, the last slide is, I think, a way to capture all the concepts that we've talked about here today, again, common mechanisms of disease and ACLY at the nexus of multiple pathways, integrating environmental factors, genetics, diet and exercise and playing a critical role in the spectrum of processes ranging from autoimmunity, lipotoxicity, cell injury, inflammation, fibrosis, proliferation and tumor genesis. These are all common pathways that are associated with various liver diseases. I think maybe the most obvious that might be front of mind is NAFLD/NASH, we acknowledge the development challenges associated with focusing on this, and we're keen to better understand the role of ACLY and other disease states such as hepatocellular carcinoma and cholestatic diseases, rare diseases such as PSC and PBC and lipid storage diseases. And with that, I will conclude the talk, and I'll hand it over to Sheldon.

Great. Thank you, Steve. Really appreciate it. Again, I just want to thank our speakers as well today with Dr. Michael Gibson and also Dr. Peter Libby. And just a few closing remarks. Again, just a few takeaways from today's presentation. Again, cardiovascular disease is the #1 killer. We know a significant unmet need continues to remain. We have a very big, as you heard earlier, a landmark trial with a CLEAR outcomes trial that will read out very soon, has the potential to be practice changing. And as we've said before, it will be an inflection point for Esperion. You've also heard our pipeline that is robust and uniquely differentiated. And I would just close by saying before we go to Q&A that Esperion is well positioned for success today, tomorrow and in the future. Again, thank you for joining our R&D Day, and I'll turn it back over to our operator for Q&A.

[Operator Instructions] With that, we'll take our first question from Paul Choi of Goldman Sachs. Okay. Well, while we help Paul, with the audio, we'll move on to the next analyst. So we'll go with Joe Pantginis with H.C. Wainwright.

Thanks for doing today in all the details. So I think my question links Dr. Gibson's comments with Dr. Libby's comments on the inflammation front. So I guess, from their standpoint, when you look at the demographics of CLEAR, not to play devil's advocate, but things that they're looking at the most when you look at the age of the patients and one of the things that I heard the most to was time on statins and other ways that patients have been on control, really going to Dr. Gibson's comment on time. The longer you're on control, the better you are with regard to outcomes. So just looking at the overall demographics of the study, is there anything you're specifically most interested in from a demographic standpoint...

JoAnne, I don't know if you want to take that, you're familiar with the demographics of the population. I guess I was here to see a high LDL on entry, which usually means people are pretty inflamed. So that was encouraging to see.

Thank you, Mike. Dr. Libby, any comments with respect to your spot on CLEAR?

Yes. Well, Clear is enrolling people who are statin resistant thus have not had the advantage of being the area under the curve of your [ closure ] to LDL on the good side. And so I agree completely with Mike that this is a group that the risk is enhanced and the inflammatory component as well as the direct LDL component because of the entry criteria in this study. So I think you have to step on the gas to test the brakes. And I think that this is a gassed up population.

So the next question will come from Joseph Thome at Cowen.

Maybe just an overall market question to see how uptake could change after the CLEAR outcomes trial because, obviously, the data presented early indicate that a lot of patients are not treated. And so from the physician perspective, maybe how many of -- or what proportion of these untreated patients with high LDL are really looking for a new option for therapy versus maybe not going to their physician, not getting their LDL checked and not having those contact points. And maybe how could superior outcome with this new data set improve that? Is it based on treatment guidelines? Is it based on Esperion's marketing efforts, what's the best way to unlock those patients?

So maybe I can start, and I'll turn it over to Joanne. Joe, I think it's a combination of all of those. It's a combination of clear outcomes will give us a different label than what we have today. It will reduce the burden of physicians going through complicated prior authorizations to actually get the drug approved. On certain barriers within the label that we have today as it relates to patients being on the maximum tolerated dose of the statin will go away. The fact of identifying patients with ASCVD will most likely go away. Many physicians don't know what ASCVD needs and they get frustrated when they want to write the drug and they cannot detail this in their prior authorization. Obviously, as well, guidelines will play a big part once the data is out there. We've already seen the incorporation of bempedoic acid into several guidelines. There's just actually most recently at ACC and the consensus paper we are positioned in the algorithm there as well. So -- and the last thing I would say is we've done a lot of market research. And what we have found with the physicians that they're frustrated that they don't have another tool. There's been more of this kind of fire and forget algorithm of the monostatin I try to get them as low as I can get, but I just can't get any further. And I think that's really something that not only we can help with, but we'll also be able to show what the results are based upon the CLEAR outcome of what that means from a residual risk reduction as well. Joanne, if you have any additional comments.

Yes. So thank you, Joe, and thank you, Sheldon. Obviously, we're joined by 2 clinical experts in the cardiovascular space. I'll just briefly say before I ask them for their input that for cardiologists and in the field of cardiology, outcomes are the ticket to entry. And I think just by virtue of the potential of having positive outcomes with bempedoic acid really will be a paradigm shift in accelerating the uptake as well as the adoption into clinical guidelines. Dr. Libby, any insights from you?

Yes. Now my practice is obviously biased because we're a tertiary [ partner ] group. But I said in the inordinate amount of time with my patients trying to convince them, despite all of the disinformation in the lay press, including very recently, that they need to take their statins. And believe me, having options that are available that are evidence-based that are non-statin drug will be a real boom for management of the statin reluctant patients. Last night, I had a very [ sad ] query from a prominent business in here in New York, who's one of my patients. This is why should I take this medicine when it's going to promote my risk of getting diabetes. And so he's a perfect kind of person where I'll have a conversation, a shared decision-making conversation, I will say, well, I really want you to have statins in the base. But guess what, we have some emerging medications, which may actually lower the risk of diabetes that might keep [ blunt ] the risk of instrument diabetes, small but real with statin. So I think there's a tremendous need for nonstatin agents for those who are reluctant to take that to those who cannot tolerate that.

Thank you, Dr. Libby, Dr. Gibson, any additional insights?

Yes. I think as researchers, clinical trialists, we often use the concepts of number needed to treat, NNT, NNH, number needed to harm. But practicing docs use NNB, number needed to blame. They don't want to get blamed for the myositis, the muscle pains, and they're a little hesitant. Well, I don't want to push it too hard because they might develop some muscle pain. And so they're hesitant. And then as Peter said, we have these patients coming to you with a lot of disinformation or misinformation about the harms and hazard of statins. So I do think this is the right drug at the right time to give people another alternative that counters the concerns about diabetes, that allows you to get the LDL down a little more safely. So I have Peter -- patients like what Peter said, we were very concerned about the diabetes, and this would be a great alternative.

So we'll try to take Paul Choi from Goldman again.

Thanks to Sheldon and the team for hosting the event. My first question is for Dr. Gibson, just with regard to understanding and interpreting CLEAR outcomes, FOURIER and ODYSSEY were on -- patients were on generally on high-intensity statin therapy. So how do you think about the comparability of those 2 populations?

Yes. I mean, yes, I think here, we're talking about people on maximally tolerated statins. They're very -- they are somewhat different. Again, the entry LDL here is much higher than it was in the PCSK9 inhibitor trials. So I do think, as I said before, the good news here is that they're going 3.8 years. that's 1.6 years longer than, say, in FOURIER, where you will have accumulation of more events. So I think that's another differentiating feature.

Okay. And as a follow-up for Dr. Libby, with regard to the canakinumab CANTOS study, as you pointed out, patients had a much higher baseline C-reactive protein. Can you maybe help this audience understand sort of what magnitude of CRP change would be needed, I guess, to perhaps see a meaningful effect with regard to risk reduction?

It looks like Dr. Libby is no longer connected to audio. So we're going to have to pull him to another room to get him reconnected. Joanne, maybe we can move on to the next question or...

We can still hear him. Can you hear us in the room? We can still hear you as do Dr. Libby.

Okay. We weren't hearing him. Maybe just ask him to come a bit closer to the polycom.

Okay, sure. I think my answer was it in the CANTOS trial, we had a reduction in C-reactive protein of 36%, and that was associated with a clinical benefit. And I would say -- remind people that C-reactive protein is not actually a mediator of inflammation. It is a marker inflammation. It's like the thermometer to take the overall temperature of inflammation in the body. And I would say regarding the previous question of the distinction between the population enrolled in FOURIER and ODYSSEY outcomes and the CLEAR trial is that they're really apples and oranges because we're looking at a patient population who will not take or cannot tolerate statins, which is a huge unmet clinical need, as I say, in our referral practice, it seems like if every other patient doesn't want to take their statins for one reason or another. So having this option for those statin-reluctant patients and having an add-on that might have metabolic benefit, I think, is an enormous new arrow in our preventative quiver.

Thank you, Dr. Libby and apologies for any audio and video technology.

The next question comes from Jason Butler of JMP.

I appreciate the presentations. Again, for Dr. Gibson or Libby. I guess some question, why don't you think the PCSK9s have been more broadly adopted even with positive outcomes data? Obviously, legacy issues around price and access. But I guess to what extent does injection reluctance come up? And how will that -- obviously, that will be different with bempedoic as an oral option. And then second question, I guess, post-statin-era outcome studies, it's been harder to hit the individual MACE component endpoints individually. And Dr. Libby, you talked about the absolute event rates and duration really mattering here. So how do you think about the potential for clear outcomes to hit statistical outcomes on the composites, especially CV death?

Yes. Well, maybe I can start out by talking about the barriers for uptake of the anti-PCSK9 therapies, the antibodies. I spend an inordinate amount of time on prior authorizations. The barriers are enormous with the pharmacy benefit managers to get authorization for PCSK9. And you have to go through all kinds of hoops to get access to these drugs that are quite expensive. And I would say also for access to the enormous population in developing countries and in the lower middle income countries, that it's just unachievable to get the antibody. So having alternatives to the antibodies, including what Steve is working on with the allosteric modulator of PCSK9 as a small molecule where the cost of goods will be much lower, and hopefully, the pricing will be proportionately lower. It would be an enormous aspect that would allow us to see greater reduction in LDL. And with respect to injectables, let me make a counterargument here. We seem to have a supply issue for the high-dose semaglutide right now, which is an injectable, the legacy brand, which is used for weight loss. So people don't mind at all, taking shots to lose weight. And if we can educate the public appropriately, they won't mind getting a shot once in a while to lower their LDL and increase their longevity and chances of avoiding heart attack or stroke.

Yes. I share all the comments that concerns -- that Peter had, as a patient who has an elevated Lp(a), I recently was trying to get on a PCSK9 and lived through the process. My current vascular provider could not get approval by inclisiran, but was able to get approval for one of the other PCSK9 inhibitors and it took an enormous amount of time and effort. So it's really, really a problem. So there's, of course, the pushback to price. I think one of the things that happened with inclisiran is they linked themselves to the idea that you're getting vaccinated against heart disease, some of the earlier marketing pre-pandemic. But now post-pandemic, the idea of getting vaccinated against anything may not sound that good to a lot of people. The reason I think we may see something different here with respect to some of the outcomes is as follows. When you look at the ODYSSEY trial, as I recall, I do think it was the people with the elevated LDLs, as we recall above 100 and ODYSSEY did have a lower mortality and certainly much better outcomes. Here, in CLEAR outcomes, we're going to be starting off with an LDL of around 139. So I do think that gives us a lot more room to move in terms of seeing improvements in hard outcomes like mortality compared to some of the other studies. The other thing is we're going longer. Again, it takes time for these kinds of outcomes to emerge. So 3.8 years rather than 2.2 to 2.8 years gives you a little more time to achieve that hard endpoint reduction. And again, I want to underscore the fact that we're not just lowering LDL. We are also lowering CRP by, say, 20% if the prior studies play out. And also giving you a slightly lower hemoglobin A1c and better glucose tolerance. So I think it's higher baseline LDL, longer duration, additional short-sight goal with CRP and the glycemic control, all those could drive you to a better outcome and also possibly an impact on mortality.

The next question will come from Judah Frommer at Credit Suisse.

Thanks for all the detail here and for hosting. A couple of questions for us. First, I would say that it seems that it's fairly clear in the KOL community. And I would say amongst European physicians as well that lower is better in terms of lowering LDL. It seems the message is not as pervasive for community docs in the U.S. So how does that message get out more broadly? Whose responsibility is that? And how long does it take? And then secondary to that, how does Esperion think about capital allocation in terms of basically a relaunch of bempedoic acid on a positive CVOT along with funding these exciting pipeline opportunities.

So Judah, I'll take the first and happy to have any input from Dr. Libby or Gibson, and then I'll have Sheldon speak a little bit more to your second point. So I think clearly, as you've mentioned, the European community, including the European guidelines, EFC are really at a much lower level, much more guidance with respect to it. And actually, as I think about it, Libby as President of the International Atherosclerosis Society can speak to the global and why that's evolved. In the U.S., as Dr. Gibson mentioned, I think there's been a move away from LDL as a target and the gold. So from our perspective at here at Esperion, working with the cardiovascular community, the experts within the U.S., we are looking at bringing back more clarity around LDL cholesterol as a goal, including the opportunity to include that in guidelines as well as CMS measures we anticipated in 2024. I think the study in and of itself, a positive outcome study with CLEAR would do a tremendous amount for bringing a refocused effort with respect to LDL and the opportunity for an oral agent to reduce outcome. And as much as we have inclisiran available, although they will not have outcomes in 2026, just having Novartis in the space has done a lot already for increasing LDL. Dr. Libby or Gibson, any other thoughts from your perspective with regard to the messaging in the U.S. is lower is better?

Yes. Well, clinical inertia is clearly a difficult problem. And I would say, certainly, in the cardiology community evidence talks. So if you have a positive outcomes trial, that gives us who are trying to spread the word, a new platform to reinvigorate the message that lower is better. I'm very proud of the European guidelines, which were first author was François Mach, who is my personal research fellow. And I'm glad to see that they went to 55 milligrams per deciliter as their goal for secondary prevention for LDL. So certainly, the KOLs in Europe have got it, and the guidelines have been shrined, lower is better, at least on that side of the pond. And as I say, if we have a positive outcome trial, we will continue to talk ourselves, of course, trying to educate the clinical community and our patients that lower is better and having as Mike said, we have 5 drugs for heart failure. Not that maybe we said this is only, we have another one. And we have 3 or 4 drugs for hypertension. We may have to have multiple agents for lowering LDL that would be sort of tailored for each patient's individual pallet of risks and concerns that will allow us to get that LDL down. And I'd like to put the interventional cardiologists, Mike, out of business by being more aggressive with prevention.

Dr. Gibson, are you looking for retirement anytime soon?

I'd rather paint than calf, so that's fine here. But I do think it's not only time for a launch of a drug, it's going to be time for a relaunch of the lower is better statement. It needs to be a statement. It's not a hypothesis it is a fact. And we have a lot of statin deniers out there. If we can establish dislinkage between statins and the lower is better hypothesis and establish a linkage to getting your LDL down with this new drug, lower is better and get rid of some of the baggage of statins like diabetes, et cetera. I think we've got to do that. So KOLs, guidelines committees got to come together and have a relaunch of the fact that lower is better.

Thank you both. Sheldon, would you like to address the second question?

Yes. Let me just -- before I address the second question, Judah, let me just also just kind of maybe follow on more from a perspective, the CEO of Esperion as it relates to launch and relaunch, I think we would agree that we never really have that fair opportunity to launch back in March of 2020 with COVID, et cetera. One of the biggest drags, for lack of better words, on these products was awareness. And I think we have routinely consistently said that outcomes data is really, for lack of better words, that entry criteria, and that's the perfect time to launch to not only get awareness, but all of the things that Dr. Libby and Dr. Gibson has said as well. So it's going to be a great opportunity. Now as it relates to capital and capital structure, we've discussed before that we believe and we know that we have enough capital to get us through the CLEAR outcome study and beyond. We're comfortable through 2023. And we think that with a positive outcome study once the CLEAR outcomes read out, we're going to have many options as it relates to essentially showing up our capital structure. And at that time, we'll definitely initiate the right thing to do in order to continue not only for the benefit of NEXLIZET and NEXLETOL, but also being mindful about some of the pipeline products that you heard earlier in today's presentation...

The next question comes from Jessica Fye at JPMorgan.

Dr. Gibson and Dr. Libby, what do you think of as a clinically meaningful risk reduction on MACE? And I have a follow-up.

Mike, do you want to start? I mean, when we sit around the table trying to design studies, we figure what will our community accept as a real addition to the armamentarium, and we usually converge on something like 15%. And Mike, you design more studies than I have.

Yes. Usually, the number is 15%. That's usually something that compels a change in practice. The other number that's kind of out there is a 1% absolute risk reduction. That's something that in the past has compelled a practice change. So those are the kinds of numbers we kind of toss around.

And when you think about...

And we hear a lot about -- I'm sorry, Jessica, I can just say that we hear a lot about the PBMs are saying, well, there's no mortality benefit. And usually, the lack of a mortality benefit is simply a matter of time. And as we heard, there was sort of a rush to finish some of the PCSK9 antibody studies. But Esperion is being more patient and I think that there chances of reaching a mortality endpoint are greater than it would be if they had a shorter time.

And a high-risk LDL on entry, Peter Yes.

Great. So then my follow-up question is, when you think about the CLEAR outcomes trial and all the design features that kind of set it up for success, be it duration, high baseline LDL, the CRP profile. I guess, recognizing that the line from the cholesterol clinical trialists, relationship between LDL reduction and MACE risk sort of captures the LDL piece, considering maybe the relative CRP benefit of bempedoic acid versus statins. Do you expect the clear results to land on the line or be above the line or below the line? And why or why not.

Peter, I don't know if you want to handle that one. I kind of expect it to be as good as, if not better, than the line. The reason I think that is because, again, when you look at the lines here, there's -- you got to literally look at the 4-year duration line, I think. So I think you will see a higher event reduction because you're going to be on that line. And again, I think 20% CRP reduction over almost 4 years will also give you added benefit on top of the LDL reduction as may a little bit of weight loss, as may a little bit of hemoglobin A1c improvement. So I think it will -- it's set up or teed up to overperform relative to the line.

Yes. Well, Jessica, I don't have a crystal ball, and that's why we do the trials. And the proof of the pudding is in the results of the trial. But it is interesting that drugs that work in different pathways seem to converge on that cholesterol treatment trial as collaboration line, whether it's the PCSK9 agents that don't have the pleiotropic anti-inflammatory effect of the statins or ezetimibe. So it seems like LDL and the ApoB containing life of proteins are really the driver. And if we can lower the LDL, we can expect a benefit and it seems to be pathway agnostic to a first approximation. But again, we got to wait for the results of the trial. That's why we do the trials. And we've been misled so many times by thinking about biological plausibility or experimental results. We just got to do the trial, do the right trial. And I think that CLEAR is really asking the question in a pinpointed way and wait for the results.

The next question comes from Michael Yee at Jefferies.

Follow-up question is how the doctors think about the importance of the absolute LDL reduction, which is related to the high baseline versus the actual just percent reduction in the implications for the CLEAR outcome study. Put another way, if the study hits and is very successful, is it partly a wise study design, which benefits the high-base and LDL in statin-intolerant patients, which this would seem to be a very relevant drug for? And how does that relate to your view of the use in lower LDL patients or nonstatin intolerant patients and will Esperion have information on people who have like an LDL of 100.

Dr. Lily, could you expand on that?

Yes. Well, the issue of percent reduction versus absolute reduction depends on your starting point, depends on individual responses and all agents that I know have a waterfall plot that is that in vitro will respond to the drug differently. And I think that the splitting the hair is about whether it's an absolute drop or a percentage drop is something for the guideline people and for the epi community to write papers about. I just want to see the LDL come down. I don't care whether it's a percent or an absolute reduction. When I'm looking at a particular patient in front of me, I want to see that LDL to be able to come down.

The other thing is just like most studies, this is powered on the relative risk reduction, I'm sure. So that's where you can most likely expect to see to hit. -- we often look retrospectively at trials as to whether some of the statin naive or had been on statins. And when you're talking about this population -- and by the way, by the way, you generally see better results in a lot of the statin naive patients. Here, you have a population where they're not naive, they're just in experience. They either couldn't tolerate it, so they never really got it or they're not on it at all. So that may cover the ability to reduce events as well.

So just to close the loop on this, do you expect essentially the same risk reduction for people at 100 to 120 as for people at 140 to 160...

Well, again, I think going longer with all the additional benefits and having a higher baseline LDL portends a better possibility of an absolute risk reduction of a greater magnitude...

I think we have time for one more question. So Serge Belanger from Needham.

So just a couple. I guess the first one for Dr. Libby and Dr. Gibson. You both mentioned [indiscernible] prior authorization for the injectable PCSK9s, just curious how it compares to the prior auth process for bempedoic acid. And I guess what would be an adequate authorization process to increase usage of both of these products...

Peter, you can go first.

Yes. Well, I think having an outcome trial, it shows clinical benefit will make it easier to negotiate with the PBMs and the PBMs, all are different and they have ingenious ways of streaming obstacles in the path of getting proven therapies to patients. So I can't really speak to the criteria that the PBMs will use, but I'm convinced that when I write that appeal for medical need that having the results of a positive clinical trial in my back pocket will help.

Yes. I think that's very important, Peter. Say when it came down to inclisiran or one of the other PCSK9 inhibitors. So I was personally going to this process, the fact that there was no outcomes data really at this point, for inclisiran caused the PBMs to say, no, you need to use one of the other two, only if the person -- only if he can't tolerate one of the other PCSK9 inhibitors will we allow him to get inclisiran. Well, who's not going to tolerate a PCSK9 inhibitor. So they do up that bad roadblock. But I haven't really heard people having similar roadblocks in my experience with bempedoic acid. So...

Thanks, Dr. Gibson. I think this concludes the Q&A session. I'd now like to hand it back to Sheldon for concluding remarks.

Great. Thanks again. And again, thank you, Dr. Libby, and thank you, Dr. Gibson. I want to thank everyone that also joined the call today. We had over 200 individuals to join our call today for the R&D Day. We're looking forward to continue to update all of you on what's happening at Esperion. Of course, the next highlight, again, will be the top line report of CLEAR outcomes, which I can't say the date enough early in January with full data readout to occur at ACC in March of 2023. Again, thank you all for joining. I hope you share the excitement that all of us share here at Esperion, and have a great rest of the week. Take care.