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

Good morning, everyone. Welcome to Esperion's Research and Development Day. We're very happy to be here. Thank you for checking in from wherever you came. And for those of you online, again, thank you. So a really exciting day. We're really happy to be here today, really looking forward to sharing some very interesting science with all of you, and we'll go through the agenda in just a moment. So our forward-looking statements and disclosures. As you know all of these, I won't be reading them, but please take a look. This is our leadership team in attendance today. Again, folks will be available during break and also we have some time after the meeting. Please take the time to introduce yourselves to our team members. They are here in the front. It's -- some of the folks you don't get to see every day as well. So I think it will be a really good opportunity for all of you to meet each other. These are our esteemed guests that will be here today, and I'm going to take a bit of time to just go through their CVs, if you will. So first is Dr. Christos Mantzoros, who is the Professor of Medicine at Harvard Medical School, Chief of Endocrinology, Diabetes and Metabolism; and a global leader in obesity, insulin resistance and MASLD. [Audio Gap] metabolic hormones in liver disease has led to major scientific breakthroughs and over 1,100 publications. Dr. Mantzoros is also the Editor in Chief of the Journal of Metabolism, the premier journal in this field. Also is Dr. David Cohen, who is the Chief of the Division of Gastroenterology, Hepatology and Endoscopy at the Brigham and Women's Hospital; and a Professor of Medicine at Harvard Medical School. He's a leading hepatologist whose research in liver metabolism and MAFLD has shaped the field and informed innovative therapies. And Mary Pressley Vyas, a dedicated patient advocate, advancing research and patient support for PSC; Co-Founder of PSC Partners Canada and currently Vice President of Strategic Initiatives at PSC Partners Seeking a Cure. So I really want to thank our guests for also coming in from different places, one from Europe, Boston, et cetera. So happy to have them here and can't wait to hear their talks. Here is our agenda for today. As you can see, it's a very deep dive into the field that we'll be speaking about today as it relates to PSC. You'll not only be hearing about the science, but you'll also be hearing, as I mentioned, patient advocacy and support, and you'll be hearing from patient themselves. We thought it's very important. A lot of times when we talk about drug development, we just talk about the drug, et cetera. It's not often we get to bring forward what does it look like from a patient's perspective. And I think that's something that all of us sometimes maybe lose, I don't know. We've all been patients. And again, it's always nice to hear the perspective of a patient. So looking forward to hearing from the patient as well. So just a quick reminder, we have a 3-pillar strategy for success here at Esperion. The first one, expand bempedoic acid franchise globally. We continue to show growth in our franchise and still believe in the blockbuster, over $1 billion worth of sales in bempedoic acid. This is something that's not only done by us at Esperion here in the United States, but we have global partners with Daiichi Sankyo in Europe and in Japan with Otsuka Pharmaceuticals, who will be launching NEXLETOL and NEXLIZET in the third or fourth quarter of this year. And last, but not least, we are in the process of developing a triple combination. We're very excited about this. We mentioned this at our last earnings. This will not be a focus of today's discussion, just as an FYI. It's something we will speak about at our next earnings, and that will be as we announced on May 6th in a few weeks. We want to reach sustainable operating profitability. Our key focus is on revenue growth, also expense management and paving the way to profitability. And that is -- again, none of these are in any particular order, but they're all very and extremely important. And last, but not least, and for the very reason why we are here today, it's about expanding our pipeline and showing the advancement that we've made in our pipeline and also the fact that, for later dates, and we'll discuss how do we also add other products into our bag in the meantime. But for today, we'll be focusing on the advancement of our pipeline. It will be a very exciting day. Again, thank you for being here. And with that, I'm going to turn it over to Dr. Stephen Pinkosky.

Well, thank you very much for the introduction, Sheldon. And good morning, everyone. It's an absolute pleasure to be speaking with you today. As Sheldon mentioned, my name is Steve Pinkosky. I head up Drug Discovery and Preclinical Development here at Esperion. And we're really excited to introduce our next-generation ATP citrate lyase inhibitor program. Before I talk about where we're going, let me just take a minute and talk about where we're coming from. So as a reminder, and as you heard from Sheldon, Esperion has built a strong portfolio really rooted in innovation around the enzyme target, ATP citrate lyase. As a reminder, Esperion is the first to discover, develop and commercialize the first-in-class ATP citrate lyase inhibitor bempedoic acid, known as NEXLIZET. We built on this success with the fixed-dose combination, NEXLETOL, and we're continuing to build on this success with triple therapy of bempedoic acid, ezetimibe with -- combined with either atorvastatin or rosuvastatin. So just as a reminder, we've been working on this portfolio for essentially decades. We've invested significant resources in developing the biology and understanding around ACLY. And what's important is that these bempedoic acid-related products not only provide new options for patients with cardiovascular disease, but they really provide validation for the mechanism of ACLY, its pharmacologic inhibition being disease-modifying, in this case for cardiovascular disease. But during our discovery and development process, we began to learn very early on that ACLY and its inhibition with bempedoic acid was really just scratching the surface for what this target could deliver. And this is the genesis for what you're going to hear about today. That's our liver-targeted program, focusing on liver disease, our primary -- initial focus on primary sclerosing cholangitis. We also have another program focusing on renal disease. We're not going to say much more about that today. You'll hear an update later on from us. So before we could make the investment in the next-generation ATP citrate lyase therapy, we really wanted to make sure we could differentiate from first-generation inhibitors. We had really good understanding of biology that extends beyond the role of ACLY in cholesterol and lipid metabolism. But what we didn't have yet was a full-length crystal structure of ATP citrate lyase. And that's what you can see on the right-hand side, so homotetramer. And it was with this, in combination with what we have been learning over decades of research, that really allows us to bring to bear all of the modern-day approaches to drug discovery, to really deliver a fully optimized, differentiated, next-generation inhibitor, really focusing [Audio Gap] improve potency and specificity in case -- orders of magnitude beyond what first-generation inhibitors can deliver. And importantly, target cell types other than what are targeted by bempedoic acid. Cell types that we know are critical in the initiation and progression of other diseases, such as liver disease. Also, we want to take advantage of some technologies that weren't available in the initial discovery of bempedoic acid, such as big data bioinformatics. And we want to use these approaches to do a deep dive and to better understand these pathways related to ACLY in these patients and begin matching these new pathways with the patient population we think would benefit the most. So to do this, we actually rebuilt the Esperion R&D program. This is just a visual representation of that. We have 2 primary research arms. At the top, you can see the liver program. We also have the kidney program that I talked about. We also have an exploratory effort on oncology, but this is exploratory, as I mentioned, and really just in support of the liver research and kidney research that we have going on. Again, I just want to highlight the fact that we're going to be focusing on the left-hand side of your screen, the liver targeted program for today. And you'll see a theme, as we walk through the day, we're starting rooted in human genetics. You'll hear from Dr. Mantzoros, really giving us that evidence that ACLY is linked to other diseases other than cardiovascular disease. And then I'll come back and we'll talk a little bit about a multi-omics approach, which really helps us dig into those mechanisms that are mediating those effects. And then we use this information ultimately to set the design criteria for next-generation inhibitors and make sure they're optimized to engage these pathways, ultimately to generate compounds that we can validate in preclinical disease models, and we'll show you some of that data today. And then ultimately, all of this works together to inform a biomarker strategy, and that's where we'll end with the presentation today. So with that, I'm going to hand it off to Dr. Mantzoros. He's going to walk through and sort of redefine the mechanism for ACLY and talk a little bit more about that genetic evidence. Dr. Mantzoros, please. Thank you.

All right. Thank you very much. It's a pleasure to be here today and talk about ACLY as a regulator of energy nexus. We'll go from physiology to pathophysiology, then to therapeutics. Before I start my presentation, as a doctor, what I see today in our society, the epidemics we see in our society, are due to dysregulation of energy intake and energy expenditure: hyperlipidemia, fatty liver disease, you name it, rare and common diseases. And if we go from the total organism down to the cellular level, you see here on the left that the mitochondria is the energy factory of the body. So glucose, amino acids, fatty acids are getting into the cell and they find their way to the mitochondria where ATP, the energy coin for our life, is generated. And this is when everything works fine, right? If we go to the left -- to the right, when this system is dysregulated, there is a disruption of normal energy production. And the utilization is primarily linked to TCA cycle function and dysfunction. Listed here quite a few diseases, but this is only a small part of what is affected by the system in life. So cardiovascular diseases, kidney diseases, and we'll talk more today about liver and gastrointestinal diseases. So getting deeper into the system, on the left, there is the canonical TCA cycle, the Krebs cycle, led to a Nobel prize quite a few decades ago. And this is a primarily catabolic pathway that consumes lipids and carbohydrates to generate ATP, energy production, as I told you earlier. And this occurs only in mitochondria. On the right, we have the noncanonical TCA cycle. And this is a primarily anabolic pathway. Where do we see this? In cells that there is demand for more energy, either cells proliferate, cancers, you name it. So it occurs not only in mitochondria, but also in the cytoplasm and nucleus. So you see there in red, ACLY leading to acetyl CoA, in addition to the ATP. So most of us know about the role of this system in cholesterol and bile acid synthesis, and I will talk briefly about it. But there is other very important processes, like de novo lipogenesis, insulin resistance, protein regulation, that remain, to a large extent, not fully elucidated, but we start working on this. All right, cholesterol/bile acid synthesis. This has been leveraged by Esperion, which is the first -- has developed bempedoic acid, which is the first and only approved ACLY inhibitor. So it's FDA approved to lower LDL cholesterol and reduce the risk of myocardial infarction and coronary revascularization in adults. How does this work? So you see the molecule in the blue, bempedoic acid to the right, blocking ACLY and limiting, decreasing the levels of acetyl CoA and LDL cholesterol. And this is established. All right, how does this work? The activity is restricted to hepatocytes, liver cells. You see this on the right, ACLY has an active site, where coenzyme A should go bind and activate it. What the molecule does is giving us a prodrug, bempedoic acid, is converted in liver cells to an active drug, bempedoyl CoA. And this goes in the same pocket, the active site and prevents coenzyme A from working. It's very simple, but very beautiful. So it inhibits ACLY by directly competing for the active site with coenzyme A. This is established. We know this. So what happens with epigenetic regulation, protein regulation, de novo lipogenesis, right? We can see the importance of these molecules in several disease states, rare, but also very common. And I'm using a metabolic dysfunction-associated steatotic liver disease as an example to show you how this works in humans. This is a common disease, 30% of the population are affected. Until recently, we did not even know what this disease was. We would call it cryptogenic. I hate to reveal my greek background, but cryptogenic means we did not know what it is, crypto and genic. Then we called it nonalcoholic, because we realized it was not associated with alcohol. But now we know what it is, right? It is caused by dysregulation of energetics, right? So what happens, very quickly going from the left to the right, 30% of the population are affected, unmet clinical need. We did not have diagnostics or therapeutics. Now we are working on this. So from left to right, from a healthy liver, which means less than 5% fat. But if we are bombarding the liver with fatty acids, an unhealthy lifestyle, especially those who are genetically predisposed to develop disease, right, dysregulated energetics lead to deposition of fat in the liver. When this exceeds 5%, the body knows that it should not be there, it's foreign, and sends macrophages to remove it to phagocytose it. Very important function. Physiology, beautiful. But if this is prolonged over months and years, this becomes pathophysiology. Macrophages inflammation should not be there. And then this leads over time to scarring, fibrosis, liver failure or hepatocellular carcinoma or liver transplant. So we are doing more liver transplants these days because of dysregulation of energetics than because of alcohol or hepatitis, very important. So keep in mind this as we speak about ACLY inhibition, about fat, macrophages and fibrosis stellate cells. If you do studies in mice with obesity and fatty liver, you will see that ACLY expression is upregulated in the livers of mice, albeit the mouse is an obese, super obese mouse with fatty liver and type 2 diabetes. MRNA levels, 1.5 -- 1.4-fold higher in macrophages from patients, now we are moving to humans. And ACLY protein levels in livers of patients with MASH/MASLD versus controls are increased. So the question is, is it true, true and unrelated or is it causal? And if it is causal, can we intervene? So we are fortunate at this stage and age in science to not have to wait for years and years of clinical trials because we can get hints. We can get pretty good information from large data sets. So UK Biobank, 500,000 people. In Europe , FinnGen, similar. MVP, 1 million Veterans [Audio Gap]. And in addition to clinical data, we have genetic data. So all of us are randomized by nature in terms of genes that predispose us to have higher or lower levels of a certain molecule. And the same is true for ACLY. So some of us have normal ACLY levels and others have lower because of our genetics. So if we have the means to study the genetics, get the information in the middle from the electronic health records, right, and try to associate genetics, control for confounding factors and link them to disease, we can get pretty good information. We can predict what will happen in the future. So -- and that's what we did. I will show here some data that refer to liver, but we have other data we are not going to present today. So liver disorders, liver cancer first, as a screening, right? Are these related, these ACLY levels related? So we went first to the UK Biobank. We got about 400,000 adults, 40 to 69 years old, who were recruited about 20 years ago. So 46% male, 54% female, middle aged. Only 1/3 were physically active. So we have all the anthropometric biochemical clinical data. And we have questionnaires, physical measures, electronic health records from their doctors, diseases and cancer registries, you name it. We have all the data we need, right? So -- and we looked whether ACLY inhibition by nature, right, throughout our lives may have protective effects on reducing the risk of liver cancer or other disorders. So here on the top, we have liver cancer data. It's a statistically significant decrease in liver cancer. And liver disorders, in general, also statistically significantly lower. So the plot thickens. Nature tells us that if you have lower ACLY, you will fare better, everything else being equal. We went deeper and we used a composite hepatic event score or component, which is used in clinical trials today. The FDA uses this, right, in the clinical trials. So it's a composite, hepatic encephalopathy, hepatic decompensation, you can read it, acute-on-chronic liver failure, hepatocellular carcinoma, this is established. Again, highly statistically significant, lower. So we have other data. To summarize what we found, is that phenotypic study of these subjects, PheWAS data, supports a causal role of ACLY dysregulation in many liver disorders, including MASLD, hidden epidemic unmet clinical need today; chronic hepatitis; liver transplant; et cetera. So coming back, right, to the model disease I decided to show you, right? The same process is happening not only in MASLD fatty liver disease. I present this as an unmet clinical need. The same process happens in other common diseases, like cardiovascular disease, fat in the vasculature leads to inflammation and inflammation leads to fibrous cap and rupture of the cap leads to myocardial infarction and cardiovascular events. But happens also in more rare diseases, like the disease we are going to discuss later, right? It makes sense, right? So it's a multifactorial disease. Some people have genetic predisposition, especially people in Latin America, they have certain gene mutations that make lipid metabolism in the liver more dysfunctional and they are at higher risk. Of course, the elephant in the room, pun intended, is obesity and inactivity in our society. If you bombard your liver with free fatty acids, right, of course, they will be fat deposited in the liver. But obesity comes not only with unhealthy diet, but also with insulin resistance and insulin resistance leads to lipolysis and de novo lipogenesis. So lipolysis from fat and de novo lipogenesis in the liver, so the liver creates more fat. And this leads, as I told you earlier, and you can see this here, in macrophages going there and then stellate cells causing fibrosis. So we need to do something about it, right? And we need to address it at probably more than one level. And this is where ACLY could work. It works at the level of the mitochondria, the energy factory of the body, of the cell. It works for de novo lipogenesis, limits de novo lipogenesis and insulin resistance. And we have evidence that it also works at the level of macrophages and hepatic stellate cells, so for inflammation and fibrosis; one after the other, the stages of this disease. All right, so what I tried to tell you today, right, with my presentation is that ACLY inhibition has broad applicability to reduce liver disease. They tells us lower the ACLY activity, the better the outcome for several liver diseases. I used one, a very common disease, steatotic liver disease as an example, but there is other diseases like less frequent that follow the same mechanism and could benefit from this medication. So the MASLD provides a broad population to investigate novel connections of, say, ACLY to liver disease and genetically predicted associations of decreased risk of liver disorders through ACLY inhibition justifies deeper investigation through research, including multi-omic analysis, and prompts us to think about leveraging these pathways by creating the next generation of ACLY inhibitors that would be addressing these conditions in the future. And having said that, I'll give the podium back to Dr. Pinkosky to go deeper into research. Thank you.

Well, thank you very much, Dr. Mantzoros. Really a pleasure to watch you go through all that, and we appreciate the collaboration. So Dr. Mantzoros, I think, has now reframed the ACLY mechanism, I think extending it beyond the way we have traditionally thought about it in the context of bempedoic acid, extending the biology beyond cholesterol metabolism and now cardiovascular disease, showing strong human genetic evidence for the impact of ACLY expression on liver disorders and liver diseases. So now what I'm going to talk about is how we get deeper insight into what pathways are actually responsible for these effects so that we can then think through our design criteria for our next-generation inhibitors. So liver disorder, liver diseases can manifest from a variety of etiologies, involving multiple cell types, multiple systemic factors and really, therefore, no one data set, even a multi-omic data set, can capture the complex pathophysiology of liver disease, let alone help us explore the multiple opportunities that ACLY modulation could offer. Therefore, we took an integration-first approach where we actually took multiple multi-omic data sets, data sets that are from biopsy samples from healthy subjects, from subjects with MAFLD/MASH. And we built a multi-omic network, essentially that can represent the disease holistically. And then we could begin, through these multilayers, inferring new connections of ACLY to disease, and then moving all the way to the far right of the screen through a series of complex analysis steps, do a deeper contextualization of these pathways and begin looking beyond, as Dr. Mantzoros' MAFLD/MASH, to see which of these novel ACLY pathways are involved in other disease states and what patients might benefit most from its modulation. So here's -- it's a busy slide, but here's just a graph representing a pathway enrichment analysis of this multi-omic network. And I think really looking at the lollipop plot on the left-hand side, the thing to take from this that's important is -- important validating evidence is that we see a lot of pathways associated with ACLY in this multi-omic network that we know. We know that this pathway is involved in cholesterol and lipoprotein and metabolism and lipid metabolism. But what's important, what we can begin to see, and this is a fairly deep dive into these pathways is other mechanisms that are very consistent what Dr. Mantzoros talked about, pathways linked to mitochondrial metabolism and function TCA, oxidative phosphorylation. Looking just to the right in the bar graph, these are color-coded bar graphs that color code to the actual data sets at the bottom. So you can see to build this multi-omic network, where we took bulk RNA-seq data, microarray data, single-cell RNA-seq, single nuclear RNA-seq and serum proteomics, and we can see the relative contribution of each of these different data sets to the new pathways we have identified. The black represents pathways that are represented across the entire network, across the data sets. What we can see is that many of them are represented from all the data sets. But we can already begin to see, and I think best highlighted in the red, kind of maroon color, is that some of these pathways are highly enriched for specific data sets. And I think most notable is the cholangiocyte data set here suggesting the potential for new biology in a new cell type, the cholangiocyte. And we know the cholangiocyte is a key cell type that is important in bile duct integrity and function. Another thing we could do is begin to further contextualize this information. We can begin looking for how these different pathways cluster and how they relate to processes that we know are associated with disease initiation and progression. We put this in the context of the ACLY mechanism. Again, we know the connection, the cholesterol metabolism, bile acid metabolism, lipid metabolism that's highlighted on the top and bottom on the right-hand side. But what we can see is a cluster of new pathways associated with disease initiation and progression that are linked to ACLY that we think are linked now to these novel pathways that Dr. Mantzoros has highlighted, that are linked to this TCA function. So we see familiar pathways, cellular stress response and obvious connection to multiple diseases, drug metabolism, transcriptional regulation. And most notable, I'll just draw your attention to the red ECM regulation. ECM is extracellular matrix. This is a process that's critical in controlling fibrosis. And so already from this multi-omic approach, we're identifying novel pathways linked directly to fibrosis, among many other that are linked to the ACLY mechanism. To understand the importance of these gene signatures we've identified, we can do a few things. So as I mentioned, we have bulk RNA-seq data. And what's really compelling about this data set is that we actually have samples from control subjects versus just metabolic disease subjects. And we also have samples, biopsy samples that extend through the progression of fibrosis. And as a control, we take that cholesterol signature that we all know so well from bempedoic acid, and we can look at how this signal applies to these patient populations as they progress through disease. And as expected, when we look at this cholesterol signature associated with ACLY, we see it's upregulated when we look at MAFLD patients versus control. And then as these patients progress to fibrosis, we can see that this pathway doesn't essentially change, it doesn't capture the progression of more advanced disease. By contrast, when we look at this novel ECM pathway, this fibrosis pathway we identified on the right-hand side, here, you can see something different emerge. You can see, yes, an increase in this ACLY fibrosis pathway when comparing MAFLD patients versus control. But what's interesting is as these patients progress through more advanced stages of fibrosis, you can see this ACLY gene signature associated with ECM regulation increase. And this provides us really important evidence that this pathway is relevant in the progression of advanced disease and gives us even further confidence that this is a pathway we want to understand better. As I mentioned, we had several others, this is just an example of one we're showing. What's important about this particular signal and why we focus on this, though, is it actually represents a culmination of disease that's injury, that's inflammation, immune cell recruitment, ultimately manifesting in effects and dysregulation of fibrotic processes. Other things we can do is we can look at these novel pathways that we've identified, their connection to disease and begin looking at how they essentially rank to other disease states beyond MAFLD. That's what you can see on the left-hand side. This is the association ranking of these associations through ACLY to different diseases. And as you would expect, based on what you've seen already, we can see a tight association between ACLY and metabolic disease. We can see associations to other diseases that have overlapping pathophysiology, such as alcoholic hepatitis or chronic hepatitis and viral infections or alcoholic liver disease, that's not necessarily surprising. And we see some other diseases emerging, such as cholangitis. On the right-hand side, this allows us to understand which cell types themselves are actually contributing to these signals. And I think what's really key about this ACLY mechanism, as you can see, there are multiple cell types, including inflammatory cells, immune cells, fibrosis cells, epithelial cells such as hepatocytes. And again, the cholangiocyte emerges at the top. And this became very interesting to us because the cholangiocyte in the context of ACLY is new and sort of unexpected for us. The links of the pathways to various forms of cholangitis were intriguing to us. And when we look deeper into the terms of what's really behind these associations, we see mechanisms closely linked to chronic, immune and bile acid-related mechanisms. And this really set us up to put together a mechanistic hypothesis for the role of ACLY in the progression of a disease, such as primary sclerosing cholangitis. So I think Dr. Mantzoros painted a really nice description of the ACLY mechanism, talking about its multifaceted component. Here, we put it in the context of how we understand PSC. Starting on the left-hand side, you can see these are the pathways we know better. These are pathways that would be related to injury. This is the cholesterol, the bile acid component of the mechanism. It's also the fatty acid component of the mechanism, kind of the substrate-driven injury component. We also have signs, based on what Dr. Mantzoros showed, about noncanonical versus the canonical TCA cycle that there might be positive impacts on oxidative stress, which we know is an important injury in this disease state. And then we have, on the right-hand side, a whole variety of activities that are associated with this acetyl CoA pool that Dr. Mantzoros talked about. That in different cell types can really feed multiple processes. And pro-inflammatory cells, it can propagate inflammatory cytokine production. And in hepatic stellate cells, which you'll hear a little bit more about from Dr. Cohen in a minute, can promote fibrotic processes. So what you can see from this mechanism is a multifaceted component affecting injury, the response to injury, inflammation, immune cell recruitment, and those -- that sort of feed forward cycle ultimately driving fibrosis with a potential impact directly on that process as well. So with that, I think I'm just going to capture where we're at right now. So I think you heard from Dr. Mantzoros that ACLY plays a much broader role in metabolism, it had nexus of energy metabolism, that in different cell types plays very specific effector cell functional roles. He provided evidence now that ACLY, through this nature's randomization process, is actually linked to disease states other than cardiovascular disease, disease such as liver disorder and liver diseases. And then we dove a little bit deeper into the mechanisms using multi-omic approach initially from patients with MASLD/MASH to match against what Dr. Mantzoros showed, but then extended that understanding to get deeper insight into patients we think could benefit from pharmacological modulation of a disease, such as PSC. We identified those cell types that are going to be important to target. As I stated before, and I think as Dr. Mantzoros highlighted, the bempedoic acid mechanism is locked into the hepatocytes. And what we're seeing from this analysis is that we need to engage this target in multiple cell types that we know are critical for the progression of these other liver-related diseases. And then finally, we showed you our mechanistic working hypothesis for the role of ACLY, a multifaceted contribution to injury, inflammation, immune response and then, finally, fibrosis. And we're going to talk a little bit more about the steps we take to validate this information in a few minutes here. But first, I want to hand it over to Dr. Cohen, who's going to give us an update on the disease state for PSC and talk a little bit about some of his research on ACLY as well. So Dr. Cohen, please.

Well, thanks for the opportunity to be here. And with that really nice introduction, I wanted to move forward. So [Audio Gap] that Dr. Mantzoros has discussed. And the point here is that it's really relevant to other disease states and particularly one we're going to talk about, we've alluded to, and I'll go into more deeply, called PSC. The cell -- Dr. Pinkosky talked about several different cell types. The liver is composed of a number of different cell types, mostly it's hepatocytes, that's the liver cell that we think of. But there are other resident cells, the bile duct cells, the cholangiocytes, the macrophages, we call Kupffer cells. And then there's the stellate cell, which is the fibroblast of the liver. The liver responds to injury just like any other tissue, just like your skin. If you scratch your skin, you can cause a scar. If you injure the liver, you cause a 3-dimensional scar and we call that fibrosis. And the cell behind that is the stellate cell. So even if we don't know what causes the liver disease, the damage and consequences that we deal with in the clinic relate to the fibroblast or the stellate cell. What happens in the liver, like other tissues, is when there's injury that occurs, the stellate cell goes from a quiescent state to an activated state, and that requires energy, and ACLY is involved just as we saw from Dr. Mantzoros. And so we study those cells in the lab. And what I wanted to just show is some evidence that is recent in our lab, how ACLY might be involved. And so on the left side of this slide here, we can see if we take a human stellate cell line, which we use in the lab, we stimulate it to go on to its program to cause scar, we use TGF beta, that's a stimulus. And you can see that upregulates the level of ACLY in the cell. So we've got more ACLY doing its thing. And on the middle side, the middle panel of the slide, the mitochondrial respiration, that shows that we can actually measure that the cell is using increased energy. It's burning carbohydrates, it's burning fats. That's why it consumes oxygen. And it's mitochondria, we put it through a number of paces. All of that's very consistent. And on the right side of the slide, you can see that glycolysis, which is the consumption of carbohydrates, increases as well. So all that then suggests that ACLY might be involved. It's associative. Here, we can provide a little more evidence that, that's actually what's going on. So again, the left side of the slide, we're familiar with. The right side of the slide, we're measuring in tissue culture, using oxygen consumption, the respiratory capacity of the cell. And so on the left slide, you see when you add that TGF beta, you ramp up the activity of that kind of cell. And then on the right panel on the right side, the gray bar is the control, it's the quiescent stellate cell. When you add TGF beta, then you increase the respiration. And then what we can do is we can use antisense oligonucleotides to knock down ACLY. And you can see that if we use a control siRNA, that's the blue bar where you have increased respiration, but as soon as you reduce the ACLY level, you reduce the oxygen consumption. So overall, the activation state can be addressed by simply attacking ALCY. And so that's really sort of an Achilles heel, potentially, in the stellate cell that can be leveraged in the interest of treating a fibrotic disease. So an important fibrotic disease that we'd like to think about today, and I'm going to talk about it from sort of the clinical science standpoint and you'll hear -- and I'd like to make some comments about this from the provider standpoint. And then you'll hear later, I think, some compelling information from the patient side. So what is this? Primary sclerosing cholangitis. Whenever we use primary in clinical medicine, that's code for we don't know. And so it's a sclerosing cholangitis that we don't know what its cause is. It is complex disease with great unmet need. It's characterized by progressive inflammatory and fibrotic diseases that injures bile ducts. And you heard Dr. Pinkosky talk about ACLY in the cholangiocyte, that's the cell that characterizes bile ducts. Unclear etiology, that's the primary, but probably multiple mechanism. No approved therapies or cure to halt PSC, and death or liver transplantation expected with 1 to 2 decades after diagnosis. So here's a little provider story. So if -- 35 years ago, when I was a less gray version of me; starting out my clinical fellowship in hepatology and gastroenterology, I could go to my Thursday afternoon clinic, which I still have today, and see patients A and B. Patient A, I could say, you have a disease that meets all these criteria. I don't know what it causes -- it's caused by. It can destroy your liver and you can end up with liver transplantation. Patient B, I would say exactly the same thing. In my career, patient A had non-A, non-B hepatitis. Through the last 35 years of my practice, I could tell that patient in a few years, you'll have hepatitis C. I could tell that patient, now we have early therapy, so I can cure 5% of you with a very toxic drug. But the bottom proposition, clinical proposition is there, so it's worth the risk. And in the ensuing 30 years up to about 2015, I could say to a patient, now I'm going to give you a pill, you can take it for 8 weeks, there's a 100% chance that it's going to cure you. And 10 years after that, in my clinic, I almost never see hepatitis C patients because they're cured by internist and they're not referred. Patient B, 35 years ago, had primary sclerosing cholangitis. And 35 years later, I see exactly the same thing. We have had no progress in the care of these patients over my entire career. And with the kind of science we just saw, I think we're at an inflection point, I hope, where maybe in my lifetime, I can go back and say those things I said to the patients with hepatitis C. So what is PSC? So PSC is a progressive disease. We've seen stages of fibrosis. And like most chronic liver disease, PSC progresses through the stage 0, 1, 2, 3 and 4; 4 is the stage of fibrosis we call cirrhosis, which leads to liver transplantation or death. 0 to 15 years is usually the time line when you diagnose a patient with primary sclerosing cholangitis. First thing they do is go online, even though I tell them please don't go online or just go to the American Liver Foundation website, PSC Partners, just read that, but they don't. They go online and they see I'm out of here in 10 years. And -- but there's reason for concern. Not everybody goes down exactly the same pathway, and we hold out hope for cures in the future. PSC is called a rare disease. It's rare, but it's not that rare because those of us who are hepatologists, all hepatologists take care of at least some PSC patients. But to give you numbers here, there's about 46,000 patients diagnosed with PSC across the country, 30,000 in Europe, 6 to 16 per 100,000. So in a city of 1 million people, there's a number of them running around, and this is probably underdiagnosed. This is mostly a disease of males, at least as it's enriched and diagnosed now. And it's a disease that hits in the prime really of life. And 25 to 40 years of age is where we characterize the peak. But as you'll hear, this extends well into youth. And so it is not uncommon to find pediatric patients with PSC. And when they do, and as you'll hear compelling personal story later, these are really a lifetime of disease without really good treatment options. So you can see there on the left, children with PSC experience complications within 10 years of diagnosis. I have these patients in my practice. There's 1.5 cases per 100,000 in the pediatric population. And children with PSC, 30% of them will require a transplant within 10 years of diagnosis. And if they get to transplant, the concern there is that there's like a 30% recurrence rate of the disease. So you can be talking about more than one transplant if one proceeds and everything goes well. So living with PSC is really balancing the patient's life and disease. I've taken care of a lovely young school teacher now with rather advanced PSC, and it's just watching somebody essentially be heroic every day. These -- the most prominent symptoms that we deal with are fatigue, often associated with depression. The other really difficult symptom of the many here is pruritus. Pruritus is just a fancy word for itching. And this is related to the cholestasis, the inability to secrete bile. So substances circulate within the circulation and cause people to itch. And you know how annoying itching when your foot itches and you're driving hell, right? You can imagine this is 24/7. And so these patients have difficulty sleeping, they have difficulty functioning, they don't even know they're itching themselves and the itching can be so severe that excoriations and injury and cellulitis can occur from -- just from the itching. As the disease progresses, then you have symptoms of jaundice, encephalopathy, that's confusion related to liver disease, fevers, chills, pain and ultimately, things like ascites and splenomegaly. So -- and all we can do is respond to the symptoms because we really can't -- there's really no therapy now that addresses any of the multiple factors that lead to these symptoms. The other thing that we really worry about in patients with PSC is that this is a premalignant condition. So if we confine our focus to the liver, what we worry about most is down there on the right, which is called cholangiocarcinoma, of which there's up to a 20% incidence in the lifetime of a PSC patient, so 1 in 5. And compared to the general population, you can see that's an enormous enrichment of 400 to 1,500x risk. Hepatocellular carcinoma, which is just what we think of as regular liver cancer, is elevated, as is gallbladder carcinoma. And the problem here is that we really don't know how to watch patients for the development of particular cholangiocarcinoma. There's no good guidelines. We do the best we can. And the risk here is if we discover this cancer like even a minute too late, then the patient is no longer a liver transplant candidate. And so the treatments are poor, and this is an important source of mortality in this condition. The other problem is that PSC is associated -- has a tight association with inflammatory bowel disease. So they're closely linked conditions. Most patients with PSC have either ulcerative colitis or a colonic form of Crohn's disease. And so that's most often. And so even if we can't find it, we assume the patients have it. And that's important because another -- number one, they just have this whole other disease entity that needs to be treated. And the frustrating thing is that we have great treatments for inflammatory bowel disease that completely don't work for PSC. So they're on any number of therapies, but their PSC goes unattended. And there's an increased risk of colorectal carcinomas in patients with inflammatory bowel disease. That's well described. There's lots of screening for those that occurs, but this is just one more thing these individuals have to deal with. So PSC places just this ongoing, never-ending physical and psychological burden on patients. So that's why of the patients in my practice, these are among the rarer, but I know them the best. So every 6 months, they're getting blood tests. Every 3 to 6 months, they're getting ultrasounds. Every 6 to 12 months, to screen them for liver cancer, colonoscopies related to their IBD. And these are patients too that are in their 20s, colonoscopy every year. And they need MRIs because these cholangiocarcinomas are difficult to find. And then for their itching, itching is a very difficult symptom to manage medically. The medications that we have don't work very well. And so all we can do when the itching gets bad enough is to subject patients to what are called invasive procedures called ERCPs, where you go in and you look for the most scarred down areas of the bile ducts and try to open them up. You clean debris out of the bile ducts. And I wouldn't want to have one ERCP and I wouldn't want to have one ERCP. And my school teacher patient, who I mentioned to you, has probably three a year. And in fact, a couple of weeks ago, she called up and she said, I think I'm starting to itch. I'm a bridesmaid in a wedding in the Dominican Republic, can we just do it? And so she had an ERCP and then a couple of days later, went off to her wedding and felt modestly better. So there is an ongoing need, needless to say, to develop disease-modifying therapies and -- for these patients. And what excites me and what has me in the game here is that doing something like this, even though we don't know intrinsically what is the exact cause of PSC, we know that all these processes contributes. And if we can address them, even without addressing the root cause of, again, this primary disease that we don't know the cause of, we really think we can make some progress. So I think this is a very exciting opportunity. We love -- I'm also interested in lipid metabolism and have been following the ACLY program over many years. And it's really nice to have a mechanism that's already tested, and we haven't seen a lot of downsides that can possibly be redirected towards this terrible disease. So I think we're at break time now. And the next thing after the break, I think you'll hear more about the personal side of this. So thank you for your attention. [Break]

Okay, welcome back. Thanks, again. Okay, so I'm going to introduce Mary from PSC Partners, and she's going to, as David mentioned, give us an overview of the personal side of PSC. So Mary, please.

Thank you so much. Well, Dr. Cohen set the stage beautifully describing the unmet need of those living with PSC. I live immersed in this topic daily, but it's always sobering to have the situation summarized so clearly. I, too, would like to start my talk with a less gray version of myself. So I'm going to go back 10 years ago. I am a proud and hopeful mom to a teenager, my first born, a 16-year-old super motivated swimmer and an excellent student, a generally nice person. I get dragged out of bed at 5:00 a.m. daily by this energetic kid to get the ride to the pool for a few hours of intense swimming before school. I try really hard not to be that annoyingly proud mom. All of us in the family are so excited about this kid's future, the first grandchild on both sides of the family. Soon, it will be off to university and the exciting process of launching into adulthood will start. There are so many moments in our PSC journey that I can share. Here's one that I think most parents can relate to, the sound of a kid vomiting. It's the end of a long day of the pool, regional championships. The swimmer has hit a personal best on breaststroke. So the dream of swimming for a college team is looking really good. We are all exhausted and happy. We've all gone to bed when I hear somebody rise, and I recognize that distinct sound, most parents know from childhood illness, a kid is vomiting. This is getting to be way more than childhood illness or food poisoning. This vomiting has been happening way too often. This kid who is shining with peak fitness and youth, something is very weirdly not right. The pediatrician is not too worried. But after a year of tests, nothing has been found. And I'm simply fed up, enough with the pediatrician, off we go to the ER in the middle of the night. Looking back, I think the contrast of the events of the day, a personal best and yet being so sick at the same time, it finally kicked in that something is seriously wrong. At the ER, they tested liver enzymes, which were sky high. And within weeks, there was a diagnosis and lots of new vocabulary. So what's involved in a diagnosis, the PSC tests, lots of tests, blood tests and ultrasound; magnetic -- MRCP, imaging of the bile ducts, liver biopsy in this case; scopes, all kinds of scopes up and down; ERCP, which was described; bile duct brushings; and bone density tests. And after all of that, we get this diagnosis of PSC, autoimmune hepatitis, ulcerative colitis and fibrosis Stage III. And then we get the news of what this means, the risks that come with that diagnosis: cholangiocarcinoma, hepatocellular cancer, colectomy, cirrhosis and end-stage liver disease. This disease is chronic and progressive. There is no cure and no proven treatments. There aren't even really very good prognostic models. It could be 10 years, it could be 20 years, could be 30 years. As was mentioned earlier, there's an organ allocation system that deprioritizes PSC patients. So it's hard to get an organ for liver transplant. And there's a chance of PSC returning post liver transplant, up to about 30%. And then there's the daily symptoms. They're highly variable across the PSC population. In our case, weight loss, brain fog, debilitating fatigue. Fortunately, for this patient, the offal pruritus, the itching, the entire body itching, is not a problem. So what do you do? Well, I can tell you what I do. Everybody responds differently to a situation like this. But I can tell you what I do. I put my head down and I get to work. I put away my plans to return to my profession as an institutional asset manager, a quant. And I learned everything I could about the liver and about PSC, and I continue to do so daily. I started volunteering for PSC Partners, co-founded a Canadian affiliate and I'm now on staff. The purpose of my being here today is to share some patient perspectives, but also to share what we, the patients and our community, are doing to support patients, but importantly, from the perspective of an investor, how PSC Partners supports research and drug development in PSC. So PSC Partners Seeking a Cure, our mission is to drive research to identify treatments and a cure for PSC while providing education and support for those impacted by this rare disease. PSC Partners is an established and impactful patient advocacy organization dedicated to working with an engaged and actively participating PSC patient community, industry and global organization to find treatment solutions. We prioritize and support drug development by providing impactful ways to derisk and support clinical trials through various initiatives, including novel regulatory-grade real-world data collection. The organization was founded in 2005 by Ricky Safer, who founded this organization after being diagnosed with PSC herself and not finding resources available to her. And the organization is located in Denver, Colorado, with the Canadian affiliate in Toronto. So here are some of our initiatives to support the PSC community, support and education. We have a very deep website with a lot of medically accurate information, pscpartners.org. We host an annual conference for patients and caregivers. We have webinars and online support. We have a mentorship program, and that's just some of our programs. We are active advocates for PSC. We participate in the PSC Forum at the Center for Collaborative Research. We are on the steering committee at the Pediatric Cholestatic Liver Disease Forum. We hosted with the FDA an externally led patient-focused drug development meeting in 2020. We have rich engagement with many rare disease patient advocacy networks. We share resources and support each other. And we engage with the regulators. We had a critical path innovation meeting with the FDA around our real-world data collection. And we have invested in our own research program. We have a scientific staff. We have a Chief Scientific Officer on staff. And some of the projects here -- are summarized here. One is the WIND Prospective Synthetic Cohort, which I'll talk about more in a moment. We have a research grants program that's been going on for 20 years, and we've given out over 111 seed research grants to researchers. We have a patient registry, an IRB-approved patient registry that has over 2,600 patients providing patient-reported data on their experience. We've established an international collaborative research network to support collaborative projects sponsored by and informed by the patient perspectives. And then just here are a couple of projects that are ongoing. We are developing regulatory-grade tools to assess PSC symptoms, particularly fatigue, brain fog and pain over the liver. We just launched a cholangiocarcinoma patient survey to try to understand how patients are being informed and educated and followed for the cholangiocarcinoma risk. And we just completed an acute cholangitis patient survey to understand the experience of patients living with this. So let me talk about WIND-PSC for a moment. WIND-PSC is this real-world data collection project that we have launched. This is a study design that improves on a typical natural history cohort. This is a global prospective multicenter observational cohort with patients being followed for up to 5 years. We are looking to enroll up to 2,000 patients across North America and Europe by 2027. And the data collection is compliant with FDA standards on submission. We are collecting pretty much everything that happens to these patients during this time, but in particular, liver-related endpoints that are consistent with current FDA guidance, medical records, laboratory tests, procedures and medications. This project has been uniquely designed specifically for the intention of regulatory purposes. This provides regulatory-grade adjudicated longitudinal data to support accelerated clinical trial study design. This will enable -- the data will be available for use as a synthetic placebo arm for Phase IV or open-label extension trials following initial accelerated approval. And it will create a large clinical and biomarker data set to establish individual and/or composite surrogate endpoints for eventual use and accelerated approval pathway. So I'd like to go back to my story. It's not really my story. I'm a caregiver. I'm not a patient. So I'd like to introduce [ Fred Fabermick ]. He is a patient living with PSC, and he, as Dr. Cohen said, is somebody who is heroic every day. But before we meet [ Fred ], I just want to return to my story as a caregiver. It's now been 10 years. My team is now a young adult, and their story is now about their health. It's their story. It's not mine to tell. What I can tell you is that a year ago, I became a living donor and donated 2/3 of my liver. The recipient was not my young adult. I don't know who it was. But knowing too many people now that I love who live with chronic liver disease, I was personally moved to help somebody in need before my liver was too old to be no longer of use. So the patient experience is, of course, much more important than the caregiver experience, and I'd like to introduce [ Fred ] now. Hi, Fred. Thank you so much for joining us today. Why don't we start with an introduction? Tell us about yourself, you, [ Fred ], not your PSC.

Hi, Mary. So I live just outside of Atlanta, Georgia. I've been here close to 25 years now. I'm originally from Upstate New York and never grew out of the hockey love there. And I like to run and I love to make small furniture pieces.

Cool. Can you tell us how and when did you receive a PSC diagnosis?

Yes. I was diagnosed in 2004, but the process to get there was almost 9 months with lots of different tests. The only reason that I was going through the process was abnormal liver functions on a regular physical. So that started the process going, and I went through a number of different disciplines to finally get to the PSC diagnosis. And when I finally got it, I just basically felt like, oh, okay, I've got it, so it's got a name, I'll see you. Yes. I wasn't concerned as I had no symptoms.

So then what was it like for you living with PSC before transplant?

At first, it was nothing because I had no symptoms. But unfortunately, PSC is a progressive disease. And as the years went by, I did start to develop symptoms. First, I developed pruritus. And pruritus is itching, for people who don't know. But this is not the itching that you get from a mosquito bite. This is the kind of itching that you feel all over your body. At different points, I itched from the roof of my mouth to the tips of my toes with no relief really in sight. And that was really the worst symptom. And while it could be partially controlled with medication, the medications that I was taking were quite uncomfortable to take. And on top of that, they had some side effects of their own. Apart from pruritus, some other symptoms I experienced were fatigue, and this can be almost mind-numbing. In my case, it was probably less of a concern than others, but I know some PSC patients who simply can't get out of bed due to PSC fatigue. And another, I really experienced some strange mental side effects towards the -- when the disease really came to a head and I had a first transplant.

How has it been for you since transplant?

Transplant, and I've had two now. Transplant is a balancing act. Once you've had transplant and you develop PSC again since, so now I'm balancing transplant with PSC. The two treatments are kind of opposing each other. So one of the things that's happened post-transplant is that I developed lymphoma as a result of the immune suppression, allowing my internal Epstein-Barr virus to flourish, and I developed something called PTLD, which is a form of lymphoma, and that presented as internal bleeding in my colon. And in one instance, it was so bad that I almost couldn't step off -- take two steps without falling to the ground. So I just had really severe anemia from that. Other things that have affected me post transplant, I've been on steroids for I don't know how long. That's lowered my bone density. It's also caused me to have cataract surgery at the age of most people wouldn't even think of having it done. I had to have cataract surgery on both eyes because my cataracts got so bad from the steroids. And just other aspects in my case, I developed PSC again. And so PSC, then went again towards transplant again on the second try. And the effects that I felt there were just constant infections. I was hospitalized before my second transplant, probably 5 of the 8 months that preceded it with just maybe a dozen, two dozen infections, something like that, just a ridiculous number of infections that I had to go to the hospital to be treated. One of the things about living with PSC is that you see everything through the lens of PSC. And it's something you can't help. PSC affects your mindset to the degree that anything that may be happening to you in your personal life or in your health, you think might be related to PSC.

Well, I can't thank you enough for sharing your experience with us. Can you share what gives you hope for the future?

Yes. PSC Partners and in conjunction with different pharmas and scientists have all come together and were all pointing towards finding real treatments and potentially a cure, something that really wasn't available when I was diagnosed. But when people are diagnosed today, I'd like to tell them that this is the best time ever to be diagnosed with PSC.

I love that, thank you.

Well, thank you very much, Mary. We can't thank you enough at Esperion for you, for [ Fred ] for sharing your personal story. Thank you to PSC Partners for everything you're doing for patients, also what you're doing for drug development. Obviously, it's stories like this that really give us, on the drug discovery development side, a sense of urgency. So thank you, again. Okay. So obviously, PSC is a devastating disease, not only for the patient, for the family. The question is, what is Esperion aiming to do about it? As a reminder, there is no approved therapy to slow, cure or halt the PSC. And I think we've painted a mechanistic rationale for why we think a next-generation ATP citrate lyase inhibitor could be beneficial in this disease state. We talked about a multicomponent mechanism, tackling the injury component of disease, the inflammatory immune response and the bile duct of this disease and how this self-perpetuating cycle can lead to fibrosis. Dr. Cohen presented this mechanism in the context of a multifaceted component of the different biochemical outcomes of ACLY activity. And here, we propose a rationale for its inhibition, again, touching multiple pathways that have been demonstrated and validated across a spectrum of different cell types. And I just want to highlight one more time that the next-generation therapy really is about tackling these new pathways, these different cell types, which cannot currently be addressed with bempedoic acid, which activity is limited to the cholesterol biosynthesis pathway. So the question is where do we even start? We understand the problem. We have a sense of the pathophysiology. Etiology is a bit unknown, but we have a really good understanding of the pathways for ACLY that are relevant to the pathophysiology of PSC and related liver diseases. And now we go back years where we actually started this effort. Really starting with the discovery program is all about what the starting material is. And we took a very, very comprehensive broad approach when we wanted to make sure we could deliver these fully optimized novel inhibitors. And to this aim, we initiated a virtual screening protocol. We took another approach, a knowledge-based approach, taking advantage of everything that's known around ACLY, it's binding sites, the potential ligands that we could build off of. And then we inject novelty and diversity into the screen using high-throughput screening with a custom novel rapid-fire mass spec high-throughput screening method. Altogether, we're 8 million-plus compounds is where we start. And as we work through the process, we end up today where we're at with just a few leads. As you can imagine, with such a diverse starting point, you can imagine we would have compounds that would bind multiple locations of ACLY. Here, you're looking at just a component of ACLY. The color coding are different known binding sites. We chose to focus on the allosteric binding site. These were prioritized early on in the program. Allosteric mechanism is favorable for a variety of reasons. Typically, there's small hydrophobic binding pockets where amenable binding by small ligands with drug-like properties. And this can provide us with a whole series of advantages listed kind of on the left. This allows us to really dial in the potency, the specificity, which just improves the profile of the potential drug overall. As I mentioned, we wanted to take this best-in-class world-class approach. We want to build on the success of first-generation inhibitors. But again, we want to -- now with the crystal structure available to us with this new pathway analysis information available to us, design nanomolar potency inhibitors and biochemical potency, cellular potency. We want to use multiple orthogonal readouts to ensure we have a very clear understanding of the mechanism. In this case, we're able to use ligand-bound cryo-EM structures to guide the design phase, an advantage certainly over the first-generation inhibitors. Demonstrating direct binding, develop multi-log structure activity relationship, make sure we have a very clear understanding of the binding mechanism, the binding mode so that we can pull forward only those most optimized compounds. Again, all of these attributes allow us to differentiate from bempedoic acid, as I've discussed. And then the next thing we need is a custom high-quality screening cascade to begin optimizing these compounds. So we took this multifaceted multi-tiered approach. I won't go too much into the details. But even early on in the program, we were focusing on not only an activity and the types of activities that we've talked about with these novel pathways, but also talked about the properties that make for a good drug-like start point. These are ADME properties. These are off-target liabilities properties so that we could begin designing those out, designing in the things we want. Ultimately, the highest quality compounds go into in vitro, in vivo screens, PK/PD studies in rodents and then finally, disease models, you'll see a little bit of those data today. And then this gets us to just a handful of lead compounds. That's where we're at, essentially selecting compounds based on the criteria on the left-hand side. We have multiple high-quality leads that we've prioritized. We've also got backups just in case we have to pull one of those forward. And this is just an example of kind of the profile that we aim for early on in the discovery process. I talked about the multiparameter optimization process. This is one of the leads themselves. We optimize on molecular properties. We optimize on potency, pharmacokinetics, off-target liability. And just an example, when we start with compounds, we see lots of red and yellow. And actually after years, now we're at a profile here where we've got greens. And this is a profile that's desirable and really gives us confidence with really no signs of liabilities. So what I'm going to do now is just talk through the lead candidate, ESP-1336. I'm going to walk through a little bit about some of the disease modeling, a little bit of the in vivo studies and just give you a sense of the quality and the state of this compound. So one of the first things we do is we just do simple studies just using regular healthy hepatocytes, once we develop the chemistry, we're satisfied with all those properties we talk about. We want to treat a cell type that we understand that's relevant for the disease, and we dose high and then we look using transcriptomics, in this case, what are the pathways is engaging. On the left-hand side, you can see the pathways we expect based on the mechanism as we understand it. On the right-hand side, you can see really just the enrichment of the pathways that we're engaged with our molecule ESP-1336. And you can see there's a correspondence between expected results and what we achieved. This gives us confidence that we have a highly selective and specific compound. The next step would then be to move into in vivo system, in this case, just normal healthy rodents treated at a very high dose or much higher than the effective pharmacological dose. Again, looking at liver transcriptomics on the left-hand side, you can see the enriched reactome pathway analysis, top 10 analysis on the left-hand side. And these are all the things we would expect to see in just normal healthy animals. We see impacts on sterile metabolism, cholesterol metabolism, lipoprotein metabolism, lipid metabolism. And on the right-hand side is just the clustering of these pathways so that we get a sense. In healthy tissue, we see the expected outcome on cholesterol and fatty acid metabolism. The question then is what about in the context of a disease setting? One of the first studies we did and this, I think, connects very well with what Dr. Mantzoros painted in terms of the mechanism, and that is this new link between ACLY and fibrosis in the context of metabolic disease. Now these are primary human liver micro tissues. These are essentially just assembled using primary hepatocytes, epithelial cells, Kupffer cells, stellate cells, and they form small little spheroids, liver spheroids. And we can stimulate a MASH-like phenotype in these spheroids by just essentially adding fat, sugar and some inflammatory stimuli. And we can induce fibrosis. And so it's a very relevant model system, very reproducible and considered to be highly translatable. And in the graph you can see on the right of the schema describing the model is that we can induce, as you look at the open circles versus the black circles, the MASH phenotype as marked by collagen composition score. And then when we look at the addition of increasing concentrations of ESP-1336, we can see a reduction in that collagen composite score. In this case, we use a reference agent ACC inhibitor, acetyl CoA carboxylase. This is an enzyme, I think Dr. Mantzoros touched on in the de novo lipogenesis pathway. Sometimes people think about ACLY as being simply in the DNL pathway. This is really just to highlight the difference in the mechanisms that inhibiting at the point of acetyl CoA carboxylas and ACLY, and that's kind of depicted on the scheme on the right-hand side. Pharmacological inhibition of either of those targets ultimately result in reciprocal regulation of acetyl-CoA. And it's this component of the mechanism that links to the epigenetic mechanism we talked about and the impact on the pathways that we've elucidated as being novel to ACLY. And it's this pathway and is supported by the ACC versus ACLY inhibition that shows us differentiation. When we look further beyond this fibrotic phenotype and we look at the transcriptome of these liver spheroids treated with ESP-1336, now we can begin to look at that multipronged mechanism that we talked about. On the left-hand side is really just a gene enrichment analysis. Here, you can see there's lots of gene sets that have been modified via ESP-1336. But on the right-hand side, we've just bucketed them into the mechanisms that we've described already. Multiple pathways linked to fibrosis, wound healing, myofibroblast proliferation, multiple mechanisms that fall within the inflammatory immune component of the mechanism, NF-kappaB signaling, TNF-alpha, interleukin signaling, chemotaxis signaling for immune cell recruitment and then those markers of liver injury. So those mechanisms linked to TCA cycle, cholesterol biosynthesis pathways that show that on the substrate level and the mitochondrial level these pathways are engaged with ESP-1336. Then we want to look in, in vivo disease models. Now here with PSC, there's not really one disease model that kind of recapitulate the disease that occurs in humans. As Dr. Cohen had highlighted, I think the etiology is still a little unknown, but we can capture different pathophysiological aspects of the disease. One of the first in vivo models, we use -- this is a tried and true model that's been around for decades, highly reproducible and highly interpretable. It is simple, where you just administer carbon tetrachloride to mice, and this causes kind of a nonspecific hepatic inflammation, ultimately resulting in fibrosis. And what you can see on the panels, these are histology images staining for collagen content within the liver. When we look at the control versus those mice that have been treated with CCL4, you see upregulation of that collagen staining. And in the presence of ESP-1336, you can see that this is reduced. A quantitative assessment in the upper right, and then we can even start to get glimpses of what's happening in the inflammatory component of the mechanism by looking at macrophage content within these livers, and you can see essential reversal of the macrophage content in this model. As I mentioned, each model comes with its pluses and minuses. This is another model, which is really meant to recapitulate kind of a slower progressing model of biliary obstruction. This is by adding DDC to the food. This is metabolized by the liver. It forms the small introductory porphyrin plugs, which eventually lead to the accumulation of bile acids in the liver and then injury, inflammation and fibrosis. And in this model, you can see on the left-hand side, the control without the DDC additive. On the right middle there, you can see what type of fibrosis is produced in this model, a significant fibrosis, particularly around the bile duct with that sort of onion skin phenotype that you typically see. With the addition of ESP-1336, you can see this is reversed. Again, a quantitative assessment of the total fibrosis in the liver. This is just total fibrosis across the liver is reduced, and we can begin picking up markers of liver injury such as liver enzymes in this model. Another model that we've looked at is a model -- it's also another food additive, but this one isn't a model necessarily a primary obstruction, but more a model that induces inflammation in the bile ducts, ultimately leading to fibrosis. And you can see, again, the same comparison, the addition of ANIT, this additive that causes inflammation results in increased collagen content in the liver, and then the addition of ESP-1336 reverses this. And you can see the quantitative assessment for fibrosis and liver enzymes here, again, showing almost a complete reversal, really, I think, highlighting the important component of this ACLY mechanism and its links to inflammation. And then the final data set we'll show here is a model called BDL, bile duct ligation. So this is a surgical model in which the common bile duct is tied off, and this leads to a very rapid and severe cholestasis. And as you can see, a rapid onset of inflammation and fibrosis. Same format, looking at the amount of collagen increase in the liver with the surgery versus control and the addition of ESP-1336. Again, looking at the multicomponent aspects of the mechanism related to injury, inflammation, immune response and fibrosis, you can see that multiple components move with the treatment of ESP-1336, alpha-smooth muscle actin representative of the activated hepatic stellate cell that you heard about from Dr. Cohen, but essentially reversed by the treatment of ESP-1336 when you look at the blue versus the purple bars. Necrosis in the middle, representing injury to the liver and dead cells induced by this injury, reduced by ESP-1336 as well as T-cell infiltration by the reduction, as you can see, of the total amount of T cells in the liver. And again, even in the severe model, we can pick up changes in markers of fibrosis. So I just want to summarize where we're at now. So I think we talked even going to the beginning of the presentation today that we really wanted to bring all of the most contemporary components of drug discovery to this program using multi-omics approaches, using contemporary discovery and hit finding techniques so that we could come up and optimize a fully differentiated next-generation ATP citrate lyase inhibitor. And then design a screen that allows us to optimize around the properties that we know are important for PSC as well as some of the properties we know are relevant in other liver diseases. Where we're at now is we have, as I mentioned, multiple leads, multiple backups and they've been derisked. They're highly potent, nanomolar potency against ACLY, and we've demonstrated good pharmacokinetic properties that support daily oral dosing. And I think you've seen multiple different disease models, a consistent effect across these disease models showing improvement in several liver-related outcomes. At the beginning of the talk, you'll recall, as we walk through human genetics, multi-omics, discovery and then the biomarker effort, we said all this work would culminate in a biomarker strategy. We use all of this information as well as additional information that we're always adding to the program, PSC patient-specific multi-omic data sets to really come up with and define and validate these novel mechanisms of ACLY, particularly in PSC and begin picking out biomarkers for target engagement of ACLY as well as markers that would be expected to move related to fibrosis, inflammation, immunity and injury. Just to recap the mechanisms that we talked about, I think you've seen this a couple of times now. ACLY inhibition shows promise to affect multiple different pathways through this energy nexus that Dr. Mantzoros highlighted. I think we've shown you even in preclinical models that we can touch each of these multi-component mechanisms of injury, inflammation and fibrosis. So we're feeling very confident in the leads that we've selected to pull forward. And I just want to highlight, again, there's no approved therapy for PSC. No therapy proven to slow, reverse or cure PSC. This multicomponent mechanism of our next-generation program that was designed to modify these outputs is really, I think, what Esperion is excited about. Just to talk for a minute about market opportunity. I think when we look at diagnosed prevalence, starting in the U.S., it's estimated to be about 46,000 patients. When we look in the EU, with about 30,000 patients. So together, U.S., EU, we're looking at a total of 76,000 patients. This, we think, is somewhere north of $1 billion market opportunity. And I just want to highlight a few other aspects to PSC. Again, there's no approved therapy. I think you've heard from the personal level, and I think you've heard from Dr. Cohen, the burden on the patients, the burden on the health care process and what this sort of prognosis looks for these patients and how devastating that can be. One to two decades, death or liver transplantation, right? That's tough news. With this sort of rare disease, we have opportunities to achieve orphan drug designation, potential for fast-track approval. And I just want to mention, I think, with [Audio Gap] Sheldon started out with, this is Esperion discovered internally developed program and wholly owned globally. So with that, I think we're off to a really strong start, just to give you some guidance on the time lines. We're in a stage now where we're nominating the final candidate. We're on track to do that kind of midyear, and this is where we initiate our preclinical derisking studies and the IND-enabling studies. We're on track to have our first pre-IND interactions with the FDA by the end of the year. And then we're looking at starting Phase I studies sometime in 2026. Now we have to, of course, meet with the FDA. But if you sort of project out potential development programs, this puts us right around a 2030 approval date, which, as you know, will kind of coincide with the LOE for bempedoic acid. So with that, I think we'll move to the next session. We're just going to have a brief little KOL panel discussion before we open things up more broadly. So, I'll welcome up Dr. Mantzoros and Dr. Cohen. Thank you. Well, you both did such a wonderful job providing additional context that some of these questions, I feel like might be a little redundant. You've walked through some of your personal experiences with the patients. But I wanted to start with you, Dr. Mantzoros. I think these human genetic approaches they've been around for a while. I know that as a drug discovery development, I put a lot of weight on these types of data. But I was wondering if you could just talk maybe a little bit more broadly about how these data are used, put maybe a bit more context around the results you presented, how researchers interpret these data and how drug developers view them?

Sure. We can go as much depth as the audience needs, right? But we have been relying on genetic studies for a long time. But in the past, we used to rely on the tip of the iceberg. So say, the knockout mutations, right, of -- that would create a hugely [Audio Gap] prominent, right, phenotype. And I can give examples, right, for rare diseases or more common diseases. For example, in the obesity field since we started talking about obesity, the leptin -- the mutation that caused leptin deficiency, no leptin at all, right, created a phenotype of a hugely obese child that was 70 kilograms when he was 3 years old and then led to leptin discovery, leptin development, this child was 30 kilograms when he was 7 years old. PCSK9 inhibitors, we can give these examples. But these were rare mutations found in laboratories of prominent scientists. And this led over time to the development of a more systematic approach. And the systematic approach is the huge databases, right? The UK Biobank, I think, was the first, 500,000 people, which are fully genotyped. Now we have the 1 million veteran program, 1 million veterans in the USA Pharma and your analysts and the audience may know that, they have moved on to create their own databases. So Regeneron, for example, has -- I'm not advertising one company or another, they have created their own database in association with healthcare systems, other companies. I should not have mentioned the name, I'm sorry. But this is where the field is moving, right? So we leverage data and this -- we live in a big data era, right? We leverage the data from huge numbers of people. And as I said, all of us are randomized by nature to the extent that we can isolate exposures, and in this case, the exposure is high versus low levels, right, of a gene or the product. And we have a lot of outcomes to correlate it. This is causal. This is a causal -- it's not just an association, it's causal. So it gives us a lot of confidence that what we see there is true and to make sure that what we see is not the fluke, we confirm it with a second database, right? And now as an Editor in Chief, I don't accept papers that do not have two databases. And we have confirmed it in a second database. So if we zoom in now through this pathway, it gives us confidence that if we have effective inhibitors of ACLY, then we'll see the outcomes that we see in large population studies. It's a very useful tool. I made a detour, but it's a useful tool, that's the bottom line, in my mind.

That's great. And I think you provided excellent evidence for the causal association of ACLY with liver disorders and liver diseases. But I'm curious also, can you derive anything about the safety -- on target safety...

Yes. Right. So this is something we do not have time to present, right? And the paper is not out yet. But of course, we have data on potential side effects, and we went systematically over each and every side effect that we could think or could have been recorded in the electronic health records. And we did not see any red flags.

Okay. And then just to maybe talk about mechanism, you did a great job walking through the multifaceted component and central sort of nexus component of the ACLY role in disease. Of course, we've decided to focus on PSC, but given the data set and the outcome of your analysis, I mean, what can you say more broadly about the target and maybe about the state of MASLD/MASH current therapies and sort of how you...

I'll try to be brief. I could be talking for hours, for days, but -- because this is so exciting. I think we can see it in two or three dimensions, right? One dimension is you have -- we have, at our disposal, bempedoic acid, which is proven, right, that we discussed, right? It works primarily in liver cells, hepatocytes. So one dimension one could see ACLY drug discovery developing would be liver, but then going from the hepatocyte to macrophages to fibrosis. This is one dimension, which will be very productive. But then we talked about other organs in other diseases. So yet another dimension and probably another phase of your drug development would be to take it from the liver to the kidneys or cancers in the future. So I see this as a potentially unlimited drug development effort. So you have like -- it's like driving. You have something just in front of you, you need to pay attention to. And probably you need to see where you want to go in the future, right? You have several destinations -- potential destinations in the future.

Yes, that's fantastic. And then Dr. Cohen, so we'll keep it on mechanism. I think you walked through some details of the ACLY mechanism. I talked a little bit about some PSC-specific aspects, but just wondering, just based on other therapies in development, what you know around ACLY? Can you kind of help provide a little bit more context for how you see the next-generation therapy being differentiated from not only BA, but what else is in development in this space?

Yes. So well, in terms of ACLY inhibition per se, I mean, to your point that I think this needs to be driven home is that -- certainly PSC is a confluence of the activity of multiple cell types in the liver. And to the extent that BA is hepatocyte specific, that could be an important driver in MASLD because we know that therapy, in the lipid accumulation phase of the disease, is probably among the most effective mechanisms now. So that's encouraging there. But really to -- the cholangiocyte in the stellate cell and in the immune cells are certainly important drivers in PSC because that's the phenotype. It's really a cholestatic disease, it's inflammation of the bile ducts. And so to be able to target multiple activities with the newer generation molecules that can penetrate these cells, I think, is going to be -- it should be very impactful in that space. And so -- and then the other aspects, what's in development? There is not a lot. We -- there are emerging ideas about PSC being -- is -- there's certainly some gut-liver access communication. So there are -- and certainly, fibrotic mechanisms are important. So there are molecules called integrins that you can approach and modify how the -- how permeable the intestine is so that chemicals, potential pro-inflammatory molecules that are absorbed in the setting of intestinal inflammation that could be a potential mechanism. And so there are therapies in that space. And also, the other aspect that integrins have is that one of the common problems as the liver is injured is that the liver has -- the blood vessels in the liver, the capillaries are very porous and that allows the liver to communicate with the plasma. And as they become less porous in an injury setting, that's thought to be detrimental as well. So other mechanisms are potentially impactful in that bile acids, reducing bile acids, but none of them really has the opportunity to span multiple mechanisms. So I think that certainly, all that drug development should be prosecuted. And I think like many -- like IBD, like hypertension, like other complex diseases, I think in the end, we were probably looking at combination approaches for successful mechanisms. But again, a lot of these are speculative and really need to be borne out in human models.

No, that's great. Thank you. And so you see a variety of patients, and you even highlighted the fact that you also see several PSC patients, even though it is a rare disease. You highlighted a few specific patients, I think, that were impactful, but I just wanted to give the opportunity to talk a little bit more about your clinical personal experience with PSC and anything else you might want to add?

Yes. It's -- again, as we think we've seen, I mean the humans -- the human cost of this is very high per patient. There's a lot of costs to the families, the caregivers, the health system because one thing we didn't talk about that the ongoing complications is not just the tests, but as the patient talked about with the infections, these are infections that are typically due to bile duct stricturing, and they lead to a problem called cholangitis, where there's -- when the bile ducts become so narrow, the bile can flow, infection follows, and it's very hard to clear, and it's repetitive. And so the healthcare burden and the cost to the healthcare system really expands quite dramatically. And so it's a very intensive relationship with patients and patients with their families. And I think that they have different manifestations, but I think there's a clear opportunity, even in a disease where we don't know the specific mechanism to intercede and to measure that intervention because it's -- what was most striking to me that the patient interview said was -- the guy very casually said, "Well, when I had my first transplant," I mean, having a transplant of any organ, particularly your liver, should be a once-in-a-lifetime proposition for almost anybody, and hopefully nobody. But this guy is like, "Oh, yes, I had my first transplant, then when I had my second transplant," so that's the kind of disease trajectory. He was diagnosed in 2004. So that's 20 years, he's already had two transplants. So whatever we're going to be measuring in impacting, it should be clear, I think, in the course of structured trials that we're getting some place, I guess.

Yes, okay. Great. And we'll just end things here, I think, on a positive note. I'll open it up to both of you, maybe start with you, Dr. Mantzoros. What gives you hope for not only these patients with PSC, but liver disease, in general, where do you see the field going in the next 5 to 10 years?

Yes. I think I said it, and I spoke maybe 2 months earlier, but it's an unmet clinical need, not only PSC, but liver disease, in general, unmet clinical need. A huge number of people. There is -- it's like an iceberg, if I can -- or a pyramid if -- so there is a few people like PSC, right, that have a huge need for an effective medication and right solution. And there is more and more with liver disease like MASH, right, MASLD, just starting, right, which may need a milder approach. But for all of them, I think -- and I'll come back to this, and there was a question during the break, it's difficult to believe that this is going to be the only therapy. We need combination therapies, we need lifestyle modification, we need an approach, we need an association with the patients, and I would applaud you for what you have done. We have an amazing partner there at a personal level, but also at the level of the organization. They have done a lot of work for you at this point, if I can use this expression, right, make it easier for you to advance it. I'm very optimistic you have a medication, which is safe, right? We have genetics proven mechanisms. I think the only question in my mind is how fast can you go?

That's always the question and not just...

And then I can right -- and then you can ask this question to your CEO, you can ask this question to your Business Development Officer, you can ask this question to the patients, right? And they will give you different answers, but you can ask the doctors there who treat the patients, right? But what I can see here is that you have managed to put together a village, the patients, the doctors, right, wining molecules, the rationale, and this is what makes me optimistic at the end of the day.

I would add to that, that these multipronged mechanism that we're excited about because PSC is really a perfect storm of that. But these aren't specific mechanisms that would just help in PSC. I think this is an inroad to a mechanism that really -- I think if I would take away one thing from those two pictures of the quiescent state and active state or the low energy and high energy that those are -- that's a lot of the difference between health and disease. And you've got an enzyme that's at the nexus of that. And so here we've got an unmet need, I don't think that when anyone would contest. But if you think about other fibrotic diseases, even adjuncts in fibrosis and inflammation is an important part of -- and drivers and enablers of any number of cancers that -- I think that developing this will lead to insights that I think are applicable to other disease processes. And certainly, in liver fibrosis is -- if we could really meaningfully address fibrosis and inflammation that drives it, that's the final common pathway in end-stage liver disease in driving most liver cancers. So there's a -- I think there's an enormous opportunity that comes along with applying this to a disease that is unusual because how many -- I try to think in other spaces, how many diseases one can pull out and say, "We just don't know what causes this, we don't know what causes it because we don't know what causes it, and we have nothing that treats it." None of our anti-inflammatories have. Autoimmune can't address this problem. So it's a great place to start, but I think that's just the start.

Great. I think that's a great start, and this is a great place to end. And I just want to thank you. I can't thank you both enough for your partnership, your collaboration, your healthcare today and everything you do in your clinics every day. And again, thank you to Mary for sharing your experience and everything that PSC Partners does. So with that, I think we'll close this panel discussion, and then we'll open it up to questions more broadly, Sheldon and I...

So we're going to -- this is an opportunity to take questions from the audience now. So for those of you that have questions, I guess just raise your hand and ask. Joe?

Looking forward to more data from this program. I am Joe Pantginis, H.C. Wainwright. So two questions. First is a two-parter. Right now, with your preclinical modeling, do you have any lipid profile data in these animal models? And how it might compare to bempedoic acid? And the second aspect of that question is very forward-looking for the company. Any potential for life-cycle management with bempedoic acid in the future as patents expire?

Okay. So I'll take the -- so yes, great question, Joe. Thank you. And I'll have to say your question is probably getting at lipoprotein metabolism, LDL metabolism and maybe any comparison that could be made from the efficacy of next-generation versus bempedoic acid. And what I'll say, and I know both of you could probably expand on this greatly is that, unfortunately, these mouse models are not models to study LDL-cholesterol, right? These aren't -- this isn't where our focus is. We've been really dialed in and trying to extract the lipid independent effects of this mechanism. So LDL metabolism, HDL metabolism, just lipoprotein metabolism in general in rodent species is just not -- at least without genetic modification or extreme dietary modification is going to be relevant. So we don't measure those specifically for that purpose, so I can't really necessarily comment on that. But if the question really is getting at relative potency. As I think I highlighted, when we look at our cell data, when we look at our biochemical data, again, multiple orders of magnitude increase in potency, activity, specificity beyond what the first-generation inhibitors can accomplish.

I'll take the second question, Joe. Yes, I think it's important to note that ESP-1336 is really being developed specifically for PSC. I think it's also a gateway of others, as you can see, modalities from a hepatic perspective. As it relates to bempedoic acid and ESP-1336, 1336 is a completely different scaffold of molecule than bempedoic acid. As it relates to life-cycle management for bempedoic acid, we've talked about, I mentioned it today, the triple-therapy combination, which we'll be discussing more, and I would put that in the life-cycle basket as we move forward.

My second question is, obviously, this is very early for us. We'd love to get the physician standpoint, and then maybe the company's, any early brushstrokes you'd like to take as to the design of a first study, stage, course of the disease that you'd hit first, kinds of endpoints because -- since it's such a multifactorial disease?

David?

Yes. So that's a very good question because there's -- as you can see, there's heterogeneity in the disease. And there's not a consensus that there's a good biomarker for PSC, which is -- what's so helpful in LDL trials and those that you can really correlate a single response. But there's pretty good evidence that certain alkaline phosphatase, which is very helpful in primary biliary cholangitis sort of related also a cholestatic disease, I wouldn't call it related because we don't know. There is some evidence that those who respond well with alk phos' to therapies and interventions seem to do better over the long run. Certain fibrosis scores the ELF, enhanced liver fibrosis sort of proprietary test that can be done, now elastography. These are parameters that would be expected to follow in the disease progression that I would think could be reasonably integrated into a trial over a reasonable period of time with enough power, either single or combined to give you a readout whether something meaningful was going on. And there are a lot of clinical events in this disease. So I think early trials would be difficult to think about using clinical events in early phases, but once advanced into having some proof-of-concept and to design a trial, I think you could pick a sweet spot of this disease and intervene. Where -- I would think, in the established, but not end-stage disease what would be the sweet spot for intervening because it's easier usually to slow or prevent than to reverse fibrosis. We know fibrosis will reverse when you put a halt to the insult, but that takes a lot of time. So in the MASH thinking, we think about intervening in sort of late F2, early F3 patients so that we can present -- prevent the progression. And in PSC, he talked about his presentation, "I just have liver enzymes at the time, so I've got PSC," That would probably be a good time because you see it didn't take him very long to turn into a patient with symptoms and progression, and that's not an uncommon scenario. Especially when you have the opportunity to look proactively in this disease because in any -- the estimated prevalence of PSC in patients with ulcerative colitis is probably 5%, 6%, 7% by some estimates. So if you look into the rather large population of ulcerative colitis patients in the population and specifically start looking for aminotransferases, which we should be doing anyway, but everything doesn't get done that it should, you will rightly start picking up more of this presymptomatic than otherwise.

I agree. I will say two or three sentences on it. I agree. I could not have said it better than -- you are the expert. I would also say the following that it's difficult to be the icebreaker. You need to carefully design your studies, but the lessons that we can learn by designing the study, right, and doing the study. In the biomarkers, I would call them NITs, noninvasive tests, I don't want to make the same mistake and mention names, or imaging techniques will be useful not only for the rare disease, but also for more frequent applications in more frequent, more prevalent diseases later on. So we are going to learn a lot and set the stage for the next stages of development, if it makes sense.

And the other thing I would add is the PSC very -- in a compelling way, this community has put itself together as a resource to be studied. And in other disease states, even in nephrosclerosis, I mean, certainly, patients are motivated, but the community around this entity, again, which is rare, but not exceedingly rare, has assembled itself and lined up and said, "We're looking for interventions here." And so you've got registries and patients, and you don't -- you're not going to have to go out and build that infrastructure, it's there, and the idea is to partner with it and intervene. So...

Can I just add that we have an experience from some of the investigators that work with us that come to PSC Partners and ask for our help in recruiting for their studies or their trials. There's -- one investigator, in particular, has said, "We know when a patient comes to us and wants to be considered. If they come from PSC Partners, they chase us instead of us having to go out and chase participants." So hopefully, that will help with any trial...

And compliance and everything that goes with...

And you have done the groundbreaking work with the FDA and -- I mean this is amazingly important, in my opinion.

This is Kristen Kluska at Cantor. I have two questions. First, just on if we have any sense at all about the underlying path or mechanisms that are driving the pruritus effects for PSC? If this is correlated to the disease severity as well? And based on all the work you've done, if you believe ESP-1336 might have any potential to address this?

So pruritus is still a mysterious entity in the setting it typically occurs in cholestasis. So it is a feature also of primary biliary cholangitis and other things that have struck bile flow. There is some evidence that bile acids have to do with pruritus, but they probably are not solely responsible. So therapies -- there are therapies that are being developed called ileal bile acid transport inhibitors, or IBAT inhibitors, that prevents reabsorption of bile acids in the intestine and lower the levels because they're -- invariably, the bile acid levels are high in pruritus and that is almost a biomarker for intensity of itching. And these inhibitors have been developed for even rarer diseases of childhood that are associated with intense itching, but they've been demonstrated in PSC patients to have positive effects on pruritus. So to the extent that ACLY inhibitors will modulate bile acid synthesis and imbalance, there's some hope that they could have some intrinsic activity on pruritus themselves. And that is -- there -- and in terms of evaluating pruritus, there are very well-validated tools for understanding intensity of itching, frequency of itching and things like that. So in the trials that have -- those IBAT inhibitor trials, there are very quantitative scales for measuring that. So that could be quite readily incorporated into a clinical trial and measured as an outcome.

Great. Okay. Second question. You've demonstrated that ACLY was upregulated in certain liver disorders and that also lower gene expression correlates with greater protection. But I was curious if you have any data to support that the levels of this expression or regulation can also correlate with how severe the disease is to further show its evidence of role of effect in this disease?

So yes, it's a good question. That's what we're working on in the lab. We're trying to make specific genetic modifications and different cell types in the liver where we can control the expression and then look at the models that are available to study PSC to see if that works in vivo.

This is Dennis Ding with Jefferies. Two questions for me. One for Sheldon, perhaps big picture. As you think ahead over the next 5 to 10 years, what role does PSC in the pipeline have on your overall vision of the story? Meaning, do you envision the company being a bempedoic acid story that's eventually funded by BD upside from the pipeline? Or do you view it the other way around where it's mainly a pipeline-driven story and use bempedoic acid to kind of offset the cost with the program? And then my second question is just around the ACLY target. What do you think is the best target relative to some of the others in development, like the PPARs and the IBATs and things like that? Do you have more confidence in the underlying target or your own internal drug discovery capabilities to get the most potent molecule?

Steve, I'll do the first one and then turn it over to you for the second one if it works. So I think the way we think about it, and similar to what I said earlier, Dennis, is that bempedoic acid or NEXLIZET and NEXLETOL is also very big focus for the organization. This is a $1 billion-plus opportunity in the United States alone, and we see it that way. And I look at our pipeline, which is this is really the first time we've actually been able to put our pipeline on display. By the way, not to answer part of Steve's question, but we have a lot of faith and confidence in our laboratories and what we've developed on our own. But I view it as something that eventually makes our company bigger, makes it a larger organization over the next 5 years. We still have patent protection going till June of 2031, that's our base case for a bempedoic acid. And then we talked about the timing for this molecule would come in sometime right around there when that -- when we potentially could lose patent exclusivity. So one, it's more related to -- keeps Esperion ongoing, but grows us to a bigger company. And we've also mentioned that we have the capacity to do business development now and between then of looking into potentially bringing in another asset that's currently in -- whether it's in Phase II development, soon to be approved, et cetera. We've been very active from a business development perspective. So this is all about how do we make this a larger organization. The last thing I would say, based upon the science that we've demonstrated, which -- I am not a scientist, but as you can see, it's very sophisticated, and we've said this before, this is also an opportunity for partnerships and development. I think a lot of organizations are very intrigued and interested in what we've been doing from a fibrosis perspective. I think today further cements that, that we're one of the leading experts in that area. And again, this is just initially scratching the surface. We talked about liver today. There's other areas such as kidney; oncology, maybe later. So to me, it's a very big opportunity overall for the organization for Esperion. Steve?

Great. Yes. And I think it's a great question about the mechanism. It's one I'm very passionate about. I can maybe offer a first response, but then I'd be very curious to hear what Dr. Mantzoros and Dr. Cohen have to say regarding comparison and relative confidence versus other therapies in development. So I think what is so interesting about this mechanism -- I would just restate originally, we always thought about it in a very traditional sense in a linear pathway in the cholesterol biosynthesis pathway, a statin-like mechanism resulting in very similar compensatory response that yields an LDL lowering effect. Through all of the efforts that we presented today, we've got very good confidence that this is at metabolic nexus. And I think that's what makes this target so unique. It's not a metabolic nexus that results in one or two downstream effects, it seems to be cell context dependent. So for an example, we understand very well what happens in hepatocyte. That's essentially what we can achieve with bempedoic acid, but extending beyond that to these other cell types, that metabolic nexus controls other effector cell specific functions. For example, if you suppress that pathway via ACL inhibition in immune cell, you down-regulate overactive immune -- several immune functions. So the same for as Dr. Cohen discussed in hepatic stellate cells, the fibrotic processes or pro-inflammatory processes and macrophages. And I think that's extremely unique to this mechanism. It's -- ACLY is at a nexus, it's expressed ubiquitously, but upregulated under dysfunctional conditions. And so I would really want to turn it over to you to...

So I would agree with that. I -- having lived enough life at the intersection between drug development and patient care, mechanisms such as this that are turned on under conditions of stress in whatever cell type and are responding and perhaps responding in a way that's sustained and becomes now adaptive makes sense to target because they're most active in the state that you're trying to control. To your point about transcription factors, activators, what you're doing is driving a transcriptional mechanism that -- one arm of that may be the therapeutic response you're looking for, but though that gets into a condition of like you don't know what you don't know is occurring. And we can sit here and list any number of other shoes that have dropped when PPARs and LXRs and FXRs have been driven. These drugs have -- it's great. You activate LXR in a mouse and you can degrade -- feedforward degrade cholesterol. It just -- many other things happen and you just don't even know what they are. Here, we know what's happening acetyl -- citrates being activated to acetyl-CoA, and there is where it is. And if you think, well, what other instance of that? Well, statins targeted a specific enzymatic step. And here we are 40 years later, and another shoe has never dropped in statins. And so I think this is targeting in as clean a way as you can the nexus between health and disease. So that's what's attractive about it from my standpoint.

Did you want to add anything to that?

No, I fully agree. That's what history teaches us about transcription factors.

Jess Fye, JPMorgan. I have three questions. First, I think you said you expect you could secure a 2030 approval for this next-gen ATP citrate lyase inhibitor in PSC, so I guess that would mean filing in '29 and registrational data maybe in '29. So if you're entering the clinic in 2026, can you talk about how you see the development path between '26 and kind of delivering [indiscernible] data in '29? Would that be envisioning an adaptive Phase II/III to hit that? Second question, maybe for the physicians. What do you think about the potential of PPARs in PSC? I think there's been some interesting Phase II data there. And then, third, have -- for Esperion, have you investigated this mechanism preclinically in PBC? And would you consider development there?

And do you want to start with the scientific...

Sure. Yes. Maybe we'll go -- I'll start with the last question first. So regarding PBC, and I'll also -- I'll hand that off to you to add also Dr. Cohen. But I'll say that the models that we've studied currently, I showed you, I think, four different models, and all of them capture different aspects of pathophysiology. In each of these instances, I think that the impacts would translate very well between PSC and PBC. I think when you think about the injury-related bile acid inflammation, fibrotic processes, these are all sitting at that nexus that we're talking about in different cell types. So I would certainly expect to also apply. And I think that kind of is in line with the way we think about this program moving forward is there's clearly multiple opportunities in the future. So I don't know if David, you would want to add?

Yes. So I -- with respect to PBC, I think that for all the reasons, this could be helpful in PSC, I think those would translate jumping into that space and from a clinical perspective, PBC in -- even in my own career has evolved from a disease that I used to see it in later stages, it would present later. There wasn't a lot of management and -- prior to Urso. And so we tended to deal with the late stages of the disease. In most PBC patients now, they're caught earlier. The biomarkers of the disease, which are alkaline phosphatase and the anti-mitochondrial M2 fraction are very sensitive and specific. You don't even need a liver biopsy anymore. We catch it at an early stage and when placed on Urso. In my clinical experience, most patients respond. And it's a very rare patient that I meet with PBC that ever goes on secondary therapy. So -- and that being said, there are second -- OCA with secondary therapy, but now there are two PPARs that are probably more potent secondary therapy. So what's left on the table in PBC thankfully, is not -- I don't think is a lot. So I think that there could be crossover for a new mechanism like this, but in terms of diving in, improving that, I think the landscape would be complex considering what's the current standard of care and how effective it really is. Now the other question about would PPARs be effective in PSC, I mean there's some evidence that they seem to be somewhat helpful. And I do know colleagues who just use them because they -- there's not a lot else to offer and you're probably not doing harm with the ones that are more established. But to my knowledge the efforts are -- it's -- the mechanism is more limited. Again, there's a lot of pleiotropy in agonizing nuclear hormone receptors. And so it's important -- I think it's an important opportunity to pursue. But I'm not -- we'd have to be sanguine about how much effect they're going to have in the natural history of the disease.

Maybe two or three sentences to expand upon this. We know about PPARs for more than 20 years, not only gamma, but alpha, delta...

Alpha for 50 years.

Yes, combinations there, right? PPAR gamma, a lot have been tried. A lot of combinations have been tried, only one found its way to our therapeutic armamentarium. We have a lot of experience as clinical doctors with diabetes, cardiovascular and NASH. In the clinic, we almost never -- although one out of many was approved, in the clinic, I almost never go up to the highest approved dose because of side effects. We use it very, very -- we love it, but we cannot maximize. And I recently -- now we are trying to get some conclusions from MASH, which is related, I think. We recently analyzed all the data from clinical trials on PPAR gammas for MASH. The maximum we can see is -- and we published it, you can find it, is 30% placebo subtracted is like 25% to 30%, if I remember well of the population improves over a couple of years. So side effects, yes, they are effective. There's a lot of side effects. We cannot push the dose as high as we would like to. And even if they work, they work for a small -- relatively small percentage of the population that leaves huge room for other compounds, either alone or in combination with a low dose, PPAR gamma. If I can -- I hope we do not make it too complicated.

And then to your regulatory question. So on the slide, we actually said early 2030s, we didn't say 2030 specifically. But the point there, and we kind of made a joke about it on the stage, I think Dr. Mantzoros is saying you're going to hear that like how can we move faster? How can we move faster. That's a question Steve gets all the time, how are we going to move faster. And obviously, there's such an unmet need here with this disease. We're looking on how we can move as quickly as possible. And as we keep moving, we'll update you on the regulatory process and the specific dates. We're out of time, but happy to take another question or two. Yes. Paul?

Paul Choi from Goldman Sachs. My first question is for the KOLs on the panel. And just -- as you think about the various approaches to PSC here, are there any particular populations or subpopulations that you think would potentially benefit most from an ACL approach versus, let's say, integrins or FXR agonist? Or would it potentially open up additional populations that may have comorbidities like IBD and so forth? And then two quick ones for the company. First, just in terms of the market. Can you maybe just inform us in how many patients are sort of managing academic versus community settings and just sort of what diagnosis rates are versus the estimated prevalence? And then a quick regulatory question as well, which is in terms of the agency's current thinking in terms of pivotal trials, is it your understanding that something like a 2-year or 96-week study will ultimately be required with an endpoint like a [ 1-point change ] in fibrosis? Currently, is that sort of where the agency's thinking is? And just maybe just your thoughts on where the regulatory framework is?

We'll start with the science first, and we will go to the regulatory...

Yes, I mean I would actually probably defer the -- I think, the KOLs, I think on the...

Yes, I just want to -- I just want -- could you just restate your question?

Sure. Are there any particular patient types or subgroups that you think would benefit from an ACL approach versus other targets and modalities or would it open up additional populations like -- who may have comorbidities like IBD or something like that?

Yes, I -- considering the multifaceted potential benefit, I don't -- and ends are -- in our -- we really don't have a lot to subcategorize the patients with PSC as opposed to -- there are certain -- and at a certain point in the history, we thought there were maybe large duct versus small duct PSC, but none of that really has panned out to be speaking different clinical courses or anything like that. So I don't know if I would try to target this at a specific population. Again, there is some evidence in the trial -- in FXR even UDC that there are some patients who -- those who respond more robustly with certain metrics with alkaline phosphatase, for example, will go on to potentially have a modifiable clinical course. So you could say, perhaps you can imagine a thought experiment where you tried to induce some alk phos response with something available like UDCA. You identify a population that responds and then put your eggs in that basket as a pre trial. But other than that, I mean, that's just an opinion based on clinical experience. I think, again, I would try to get patient -- try to enroll patients where the disease is established, and you know that it's progressing like in the patient that we saw, like I've got biochemical and abnormalities a year later I have symptoms. That would have been a nice place to start in terms of where in the spectrum that you're trying to step in and create an outcome where you can power a study to see a reasonable effect? Does that sort of -- that's your question?

Great. And then to your question regarding regulatory where we are as it relates to market dynamics for lack of better words. Currently, we showed today that there's approximately 76,000 patients worldwide. We know that there's a lot of patients that aren't diagnosed or misdiagnosed, and we're early in the process of identifying what those leverage points are to; one, how do you better diagnose, et cetera. That's something that we'll be working on in the future. This is more of a, as we said, orphan disease. It's specialty related to your question of does this occur in the community and go to, I believe, an institution. I think diagnosis could start in a community, but again, it's been mostly dealt with specialists as you hear today. From an FDA perspective and a regulatory process, we're very early in the game as it relates to the FDA. But as you saw earlier today in the presentation, we do believe just based on the unmet need that this is a drug that could get fast-track designation, and that's what we'll be focusing on and then focus on the study necessary to achieve that.

Jason Zemansky with BofA. Maybe a question for you, Sheldon. Given the company's broad goals, some of which you've covered here in depth as far as the early-stage pipeline, some of which you've mentioned in your introductory remarks as far as growing the BA franchise, advancing your two triple combinations getting to sustained profitability. What are your priorities in terms of resource allocation here?

Yes. So we actually -- and I showed in my second slide, our guidance. So our guidance is very similar to -- as Ben would say before he gave guidance going into 2025, no surprise. 2025 looks very similar to 2024. So we don't see any type of additional expenditures, et cetera, necessary. And even to the point that we've gotten to today, we haven't had to do that. Our priority as an organization is to continue to execute and grow NEXLIZET and NEXLETOL. Again, we think, as I've said previously, we have a blockbuster capability in those products. And as we continue growing those products, it's also going to help us fund these other programs that we are currently engaging in. So -- but right now, for this year, for 2025, our guidance remains unchanged.

Serge Belanger from Needham. Two questions for the ESPR team. The first one, another one on the development path. Sounds like it's too early to talk about the late-stage part of it. But in the early stage, I think you highlighted a Phase I study starting maybe 2026. Would that be in healthy volunteers or patients? Just trying to get an idea when we could see proof-of-concepts for 1336? And then secondly, Sheldon, you talked about the company being active on the BD front. Is the focus there to leverage your commercial infrastructure or add on to the pipeline?

Yes. So I'll go first, and then Steve, have you answer the second one. So it really is -- from a BD perspective is to leverage our infrastructure. There's a lot of organizations out there right now who have products that are late stage Phase III who are in the process of waiting for a PDUFA date, have recently filed an NDA, but they don't have the capability or capacity to actually launch the product. And I think that's really the beauty of the Esperion. We have 155 salespeople. We have five medical science liaisons. We have an account team. We have a compliance department. All the things you need is a real organization to effectively launch a product. And we had companies actually come to us and talk to us about this as well as we proactively reached out to several companies. The point being though is we don't want to bring anything that's in the clinic. We're not going to take that risk. And honestly, we just can't afford that -- so we can afford this, but we can't afford that. But it's really, again, just leveraging our infrastructure. And I'll have Steve answer the question regarding healthy volunteers and proof-of-concept.

Sure. Yes, we can make this one quick. I think LeAnne clinically would probably agree with me when I say, yes, we would start with healthy volunteers.

Okay. All right. I think that is it. First of all, I just want to first by start saying, thank you, Mary. Thank you, Steve. Thank you, Dr. Mantzoros, and thank you, Dr. Cohen. Really just an amazing session. Mary, every time, I see like patients and hear your story -- that's why we all are here. And I think it is forgotten sometimes -- us and company and even those of you on Wall Street. So -- but it's a good reminder to see really what we are working on what our goals are. Really, again, why will we succeed? We have a patient-focused strategy. We talked about what we're trying to do here as an organization with our current franchise. And then today, it was really focused on the future. We have a scientific edge. I mean what you heard today was deep science, and thank you, Steve, again for all the work that you've been doing with all the years that you've been here for Esperion. We have deep expertise in ACLY biology, which we just think is really just an amazing platform of science. You saw all the potential doors that could be opened besides the one that we talked about today. It's novel and differentiated. The fact that we can target these multiple mechanisms of PSC progression, which haven't been seen before, I think, it's just a phenomenal breakthrough. And again, it's an opportunity, I think, for strong partnerships and research collaborations, and we're always open to that, always. So again, just really want to thank everyone. Thank you for all of you that attended today and have a great day. I think we're going to have lunch out there also. We're a little bit early, but I don't think anybody minds that. So thank you again, and have a great day.