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. For those of you online, again, thank you. It's 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. We'll go through the agenda in just a moment. Let me get the slides to advance. I'm pressing the big green button, but it's not advancing. Great. Our forward-looking statements and disclosures, you know all of these. I won't be reading them, but please take a look. This is our leadership team in attendance today. Folks will be available during break. Also, we have some time after the meeting. Please take the time to introduce yourselves to our team members. They're here on the front.
It's some of the folks you don't get to see every day as well. I think it'd be a really good opportunity for all of you to meet each other. These are our esteemed guests that will be here today. I want to take a bit of time to just go through their CVs, if you will. 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. Metabolic hormones and 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 NAFLD has shaped the field and informed innovative therapies. Dr. I'm sorry, 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. I really want to thank our guests for also coming in from different places, one from Europe, Boston, et cetera. 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. You'll be hearing from a 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. I think that's something that all of us sometimes maybe lose. I don't know. We've all been patients. Again, it's always nice to hear the perspective of a patient. Looking forward to hearing from the patient as well. Just a quick reminder, we have a three-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. 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. That will be as we announced on May the 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. That is, again, none of these are in any particular order, but they're all very and extremely important. 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, we'll discuss how do we also add other products into our bag in the meantime. For today, we'll be focusing on the advancement of our pipeline. This will be a very exciting day. Again, thank you for being here. With that, I'm going to turn it over to Dr. Stephen Pinkosky.
Thank you very much for the introduction, Sheldon. Good morning, everyone. It's an absolute pleasure to be speaking with you today. Sheldon mentioned, my name's Stephen Pinkosky. I head up Drug Discovery Preclinical Development here at Esperion. 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. 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 a fixed-dose combination, NEXLETOL.
We're continuing to build on this success with triple therapy, bempedoic acid, ezetimibe combined with either atorvastatin or rosuvastatin. 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. What's important is that these bempedoic acid-related products not only provide new options for patients with cardiovascular disease, they really provide validation for the mechanism of ACLY, its pharmacologic inhibition being disease-modifying, in this case for cardiovascular disease. 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. 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. 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. What we didn't have yet was a full-length crystal structure of ATP citrate lyase. That's what you can see on the right-hand side, so a homotetramer.
It was with this in combination with what we had been learning over decades of research that it 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 on improved potency and specificity in case orders of magnitude beyond what first-generation inhibitors can deliver. 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 were not available in the initial discovery of bempedoic acid, such as big data bioinformatics.
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. To do this, we actually rebuilt the Esperion R&D program. This is just a visual representation of that. We have two 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. 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.
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. 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. 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. We'll show you some of that data today. Ultimately, all of this works together to inform a biomarker strategy. That's where we'll end with the presentation today. 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. If we go from the total organism down to the cellular level, you see here on the left that the mitochondrium is the energy factory of the body. Glucose, amino acids, fatty acids are getting into the cell. They find their way to the mitochondria where ATP, the energy coin for our life, is generated. This is when everything works fine.
If we go to the right, when this system is dysregulated, there is disruption of normal energy production. The utilization is primarily linked to TCA cycle function and dysfunction. Listed here are quite a few diseases, but this is only a small part of what is affected by the system in life. Cardiovascular diseases, kidney diseases. We will talk more today about liver and gastrointestinal diseases. 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. This is a primarily catabolic pathway that consumes lipids and carbohydrates to generate ATP, energy production, as I told you earlier. This occurs only in mitochondria. On the right, we have the non-canonical TCA cycle. 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. It occurs not only in mitochondria, but also in the cytoplasm and nucleus. You see there in red, ACLY leading to acetyl CoA in addition to the ATP. Most of us know about the role of this system in cholesterol and bile acid synthesis. I'll talk briefly about it. There are other very important processes like de novo lipogenesis, insulin resistance, protein regulation that remain, to a large extent, not fully elucidated. 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. It is FDA approved to lower LDL cholesterol and reduce the risk of myocardial infarction and coronary revascularization in adults.
How does this work? 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. 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 give us a prodrug, bempedoic acid, is converted in liver cells to an active drug, bempedoyl CoA. This goes in the same pocket, the active site, and prevents coenzyme A from working. It's very simple, but very beautiful. It inhibits ACLY by directly competing for the active site with coenzyme A. This is established. We know this. What happens with epigenetic regulation, protein regulation, de novo lipogenesis?
We can see the importance of these molecules in several disease states, rare, but also very common. I am using the 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. We called it non-alcoholic because we realized it was not associated with alcohol. Now we know what it is. It is caused by dysregulation of energetics. What happens very, 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.
From left to right, from a healthy liver, which means less than 5% fat. If we are bombarding the liver with fatty acids, unhealthy lifestyle, especially those who are genetically predisposed to develop disease, 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. Sends macrophages to remove it, to phagocytose it. Very important function. Physiology, beautiful. If this is prolonged over months and years, this becomes pathophysiology. Macrophages, inflammation should not be there. This leads over time to scarring, fibrosis, liver failure, or hepatocellular carcinoma, or liver transplant. We are doing more liver transplants these days because of dysregulation of energetics than because of alcohol or hepatitis. Very important. 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 or obese mice and obese, obese, super obese mouse with fatty liver and type 2 diabetes. mRNA levels 1.4-fold higher in macrophages from patients. Now we're moving to humans. ACLY protein levels in livers of patients with MASLD versus controls are increased. The question is, is it true, true, and unrelated, or is it causal? If it is causal, can we intervene? We are fortunate at this stage in 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. U.K. Biobank, 500,000 people in Europe, FinGen, similar MVP, 1 million veterans. In addition to clinical data, we have genetic data.
All of us are randomized by nature in terms of genes that predispose us to have higher or lower levels of a certain molecule. The same is true for ACLY. Some of us have normal ACLY levels and others have lower because of our genetics. If we have the means to study the genetics, get the information in the middle from the electronic health records and try to associate genetics, control for confounding factors, and link them to disease, we can get pretty good information. We can predict what would happen in the future. That is what we did. I will show you here some data that refer to liver, but we have other data we are not going to present today. Liver disorders, liver cancer first as a screening. Are these related? Is ACLY levels related? We went first to the U.K. Biobank.
We got about 400,000 adults, 40- 69 years old, who were recruited about 20 years ago. 46% male, 54% female, middle-aged, only 1/3 were physically active. We have all the anthropometric, biochemical, clinical data. We have questionnaires, physical measures, electronic health records from their doctors, diseases in cancer registries, you name it. We have all the data we need. We looked whether ACLY inhibition by nature throughout our lives may have protective effects on reducing the risk of liver cancer or other disorders. Here on the top, we have liver cancer data. It is statistically significant decrease in liver cancer and liver disorders in general, also statistically significantly lower. The plot thickens. Nature tells us that if you have lower ACLY, you will fare better, everything else being equal. We went deeper.
We used a composite hepatic event score or component, which is used in clinical trials today. The FDA uses this in the clinical trials. It is 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. We have other data. To summarize what we found is that phenotypic study of these subjects, figures 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. Coming back to the model disease I decided to show you, 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. It makes sense. It is 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, of course, there will be fat deposited in the liver. Obesity comes not only with unhealthy diet, but also with insulin resistance. Insulin resistance leads to lipolysis and de novo lipogenesis. Lipolysis from fat and de novo lipogenesis in the liver.
The liver creates more fat. This leads, as I told you earlier, and you can see this here, in macrophages going there and then stellate cells causing fibrosis. We need to do something about it. We need to address it at probably more than one level. 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. We have evidence that it also works at the level of macrophages and hepatic stellate cells. For inflammation and fibrosis, one after the other, the stages of this disease. All right. What I tried to tell you today with my presentation is that ACLY inhibition has broad applicability to reduce liver disease.
Nature 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. There are other diseases like less frequent that follow the same mechanism and could benefit from this medication. The muscle 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. Having said that, I'll give the podium back to Dr. Pinkosky to go deeper into research. Thank you.
Thank you very much, Dr. Mantzoros.
Really a pleasure to watch you go through all that, and we appreciate the collaboration. 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. 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.
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 MASLD, MASH. We built a multi-omic network, essentially, that can represent the disease holistically. Then we could begin through these multi-layers, 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.
MASH, to see which of these novel ACLY pathways are involved in other disease states and what patients might benefit most from its modulation. It's a busy slide, but here's just a graph representing a pathway enrichment analysis of this multi-omic network. 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. 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 with 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. You can see to build this multi-omic network, we took bulk RNA-seq data, microarray data, single-cell RNA-seq, single-nuclear RNA-seq, and serum proteomics. 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. We can already begin to see, and I think best highlighted in the red kind of maroon color, that some of these pathways are highly enriched for specific data sets.
I think most notable is the cholangiocyte data set here, suggesting the potential for new biology in a new cell type, a cholangiocyte. We know the cholangiocyte is a key cell type that is important in bile duct integrity and function. Another thing we can 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 to cholesterol metabolism, bile acid metabolism, lipid metabolism that's highlighted on the top and bottom on the right-hand side. 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 highlighted that are linked to this TCA function.
We see familiar pathways, cellular stress response, an obvious connection to multiple diseases, drug metabolism, transcriptional regulation. Most notable, I'll just draw your attention to the red ECM regulation. The ECM is extracellular matrix. This is a process that's critical in controlling fibrosis. Already from this multi-omic approach, we're identifying novel pathways linked directly to fibrosis, among many others, that are linked to the ACLY mechanism. To understand the importance of these gene signatures we've identified, we can do a few things. As I mentioned, we have bulk RNA-seq data. What's really compelling about this data set is that we actually have samples from control subjects versus just metabolic disease subjects. We also have samples, biopsy samples that extend through the progression of fibrosis.
As a control, we take that cholesterol signature that we all know so well from bempedoic acid. We can look at how this signal applies to these patient populations as they progress through disease. As expected, when we look at this cholesterol signature associated with ACLY, we see it's upregulated when we look at MASLD patients versus control. As these patients progress through 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, excuse me, MASLD patients versus control.
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. 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 MASLD.
That's what you can see on the left-hand side. This is an association ranking of these associations through ACLY to different diseases. 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. 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. I think what's really key about this ACLY mechanism is you can see there are multiple cell types, including inflammatory cells, immune cells, fibrosis cells, epithelial cells, such as hepatocytes. Again, the cholangiocyte emerges at the top.
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. We would 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. 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. 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 non-canonical 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. 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. In pro-inflammatory cells, it can propagate inflammatory cytokine production. In hepatic stellate cells, which you'll hear a little bit more about from Dr. Cohen in a minute, it can promote fibrotic processes.
What you can see from this mechanism is a multifaceted component affecting injury, the response to injury, inflammation, immune cell recruitment, and that sort of feedforward cycle ultimately driving fibrosis with a potential impact directly on that process as well. With that, I think I'm just going to capture where we're at right now. I think you heard from Dr. Mantzoros that ACLY plays a much broader role in metabolism, that a 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. Then we dove a little bit deeper into the mechanisms using multi-omic approach, initially from patients with MASLD and 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, 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. 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. Finally, we showed you our mechanistic working hypothesis for the role of ACLY, a multifaceted contribution to injury, inflammation, immune response, and finally fibrosis. We're going to talk a little bit more about the steps we take to validate this information in a few minutes here. 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. Dr. Cohen, please.
Thanks for the opportunity to be here. With that really nice introduction, I wanted to move forward. 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. Pikosky 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. There are other resident cells, the bile duct cells, the cholangiocytes, the macrophages we call Kupffer cells.
There is 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 three-dimensional scar. We call that fibrosis. The cell behind that is the stellate cell. Even if we do not know what causes a 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 is injury that occurs, the stellate cell goes from a quiescent state to an activated state. That requires energy. ACLY is involved, just as we saw from Dr. Mantzoros. We study those cells in the lab.
What I wanted to just show with some evidence that is recent in our lab is how ACLY might be involved. 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-β. That is a stimulus. You can see that upregulates the level of ACLY in the cell. We have got more ACLY doing its thing. On the middle side, the middle panel of the slide, the mitochondrial respiration shows that we can actually measure that the cell is using increased energy. It is burning carbohydrates. It is burning fats. That is why it consumes oxygen in its mitochondria. We put it through a number of paces. All of that is very consistent.
On the right side of the slide, you can see that glycolysis, which is the consumption of carbohydrates, increases as well. 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. 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. On the left slide, you see when you add that TGF-β, you ramp up the activity of that kind of cell. On the right panel on the right side, the gray bar is the control. It's the quiescent stellate cell. When you add TGF-β, then you increase the respiration. What we can do is we can use antisense oligonucleotides to knock down ACLY.
You can see that if we use a control siRNA, that's the blue bar where you have increased respiration. As soon as you reduce the ACLY level, you reduce the oxygen consumption. Overall, the activation state can be addressed by simply attacking ACLY. That is really sort of an Achilles heel, potentially, in the stellate cell that can be leveraged in the interest of treating a fibrotic disease. 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. You'll hear, and I'd like to make some comments about this from the provider standpoint. You'll hear later, I think, some compelling information from the patient side. What is this? Primary sclerosing cholangitis. Whenever we use primary in clinical medicine, that's code for we don't know.
It is a sclerosing cholangitis that we don't know what it causes. It is a complex disease with great unmet need. It is characterized by progressive inflammatory and fibrotic diseases that injure bile ducts. You heard Dr. Pikosky talk about ACLY in the cholangiocytes. That is the cell that characterizes bile ducts. Unclear etiology. That is the primary, but probably multiple mechanisms. No approved therapies or cure to halt PSC and death or liver transplantation expected within one to two decades after diagnosis. Here is a little provider story. 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 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. The bottom proposition, clinical proposition, is there. It's worth the risk. 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 eight weeks. There's a 100% chance that it's going to cure you.
Ten years after that, in my clinic, I almost never see hepatitis C patients because they're cured by internists, and they're not referred. Patient B, 35 years ago, had primary sclerosing cholangitis. Thirty-five years later, I say exactly the same thing. We have had no progress in the care of these patients over my entire career. 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. What is PSC? PSC is a progressive disease. We've seen stages of fibrosis. Like most chronic liver disease, PSC progresses through these stage 0, 1, 2, 3, and 4. Four is the stage of fibrosis we call cirrhosis, which leads to liver transplantation or death.
0- 15 years is usually the timeline 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 for the Cure. Just read that, but they don't. They go online, and they see, I'm out of here in 10 years. There is reason for concern. Not everybody goes down exactly the same pathway. 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. To give you numbers here, there's about 46,000 patients diagnosed with PSC across the country, 30,000 in Europe, 6-16 per 100,000.
In a city of a million people, there's a number of them running around. This is probably underdiagnosed. This is mostly a disease of males, at least as it's enriched and diagnosed now. It's a disease that hits in the prime, really, of life, 25- 40 years of age is where we characterize the peak. As you'll hear, this extends well into youth. It is not uncommon to find pediatric patients with PSC. When they do, and as you'll hear a compelling personal story later, these are really a lifetime of disease without really good treatment options. 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.
Children with PSC, 30% of them will require a transplant within 10 years of diagnosis. If they get to transplant, the concern there is that there's like a 30% recurrence rate of the disease. You can be talking about more than one transplant if one proceeds and everything goes well. 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. It's just watching somebody essentially be heroic every day. 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. This is related to the cholestasis, the inability to secrete bile. Substances circulate within the circulation and cause people to itch.
You know how annoying itching when your foot itches and you're driving, how you can imagine this is 24/7. These patients have difficulty sleeping. They have difficulty functioning. They don't even know they're itching themselves. The itching can be so severe that excoriations and injury and cellulitis can occur just from the itching. As the disease progresses, we have symptoms of jaundice, encephalopathy—that's confusion related to liver disease—fevers, chills, pain, and ultimately, things like ascites and splenomegaly. All we can do is respond to the symptoms because 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.
If we confine our focus to the liver, what we worry about most is down there on the right. It was just called cholangiocarcinoma, of which there's up to a 20% incidence in a lifetime of a PSC patient. One in five. Compared to the general population, you can see that's an enormous enrichment of 400-1,500 times risk. Hepatocellular carcinoma, which is just what we think of as regular liver cancer, is elevated, as is gallbladder carcinoma. The problem here is that we really don't know how to watch patients for the development of particularly cholangiocarcinoma. There's no good guidelines. We do the best we can. The risk here is if we discover this cancer even a minute too late, then the patient is no longer a liver transplant candidate. The treatments are poor.
This is an important source of mortality in this condition. The other problem is that PSC has a tight association with inflammatory bowel disease. They are closely linked conditions. Most patients with PSC have either ulcerative colitis or a colonic form of Crohn's disease. That is most often. Even if we can't find it, we assume the patients have it. That is important because, number one, they just have this whole other disease entity that needs to be treated. The frustrating thing is that we have great treatments for inflammatory bowel disease that completely don't work for PSC. They are on any number of therapies, but their PSC goes unattended. There is an increased risk of colorectal carcinomas in patients with inflammatory bowel disease. That is well described. There is lots of screening for those that occurs.
This is just one more thing these individuals have to deal with. PSC places just this ongoing, never-ending physical and psychological burden on patients. That is why of the patients in my practice, these are among the rarer, but I know them the best. Every six months, they're getting blood tests. Every three to six months, they're getting ultrasounds. Every 6-12 months, to screen them for liver cancer, colonoscopies related to their IBD. These are patients, too, that are in their 20s. Colonoscopy every year. They need MRIs because these cholangiocarcinomas are difficult to find. For their itching, itching is a very difficult symptom to manage medically. The medications that we have do not work very well.
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. I would not want to have one ERCP. My school teacher patient, who I mentioned to you, has probably three a year. 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?" She had an ERCP. A couple of days later, she went off to her wedding and felt modestly better.
There is an ongoing need, needless to say, to develop disease-modifying therapies for these patients. What excites me and what has me in the game here is that doing something like this, even though we do not know intrinsically what is the exact cause of PSC, we know that all these processes contribute. If we can address them, even without addressing the root cause of, again, this primary disease that we do not know the cause of, we really think we can make some progress. I think this is a very exciting opportunity. I am also interested in lipid metabolism and have been following the ACLY program over many years. It is really nice to have a mechanism that is already tested. We have not seen a lot of downsides that can possibly be redirected towards this terrible disease. I think we are at break time now.
The next thing after the break, I think you'll hear more about the personal side of this. Thank you for your attention.
OK, welcome back. Thanks again. OK, I'm going to introduce Mary from PSC Partners. She's going to, as David mentioned, give us an overview of the personal side of PSC. Mary, please.
Thank you so much. 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 this situation summarized so clearly. I, too, would like to start my talk with a less gray version of myself. We're going to go back 10 years ago. I am a proud and hopeful mom to a teenager, my firstborn, a 16-year-old super motivated swimmer, and an excellent student, and a generally nice person.
I get dragged out of bed at 5:00 A.M. daily by this energetic kid to give a 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 at the pool, regional championships. The swimmer has hit a personal best on breaststroke. The dream of swimming for a college team is looking really good. We are all exhausted and happy.
We've all gone to bed. We want to hear somebody rise. 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. After a year of tests, nothing has been found. I'm simply fed up. Enough with the pediatrician. Off we go 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 hospital they tested liver enzymes, which were sky high.
Within weeks, there was a diagnosis and lots of new vocabulary. What's involved in a diagnosis of PSC? Tests, lots of tests: blood tests, an ultrasound, magnetic resonance, MRCP, imaging of the bile ducts, liver biopsy in this case, scopes, all kinds of scopes, up and down, an ERCP, which was described, bile duct brushings, and bone density tests. After all of that, we get this diagnosis of PSC, autoimmune hepatitis, ulcerative colitis, and fibrosis stage 3. 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, could be 20 years, could be 30 years.
As was mentioned earlier, there's an organ allocation system that deprioritizes PSC patients. It is hard to get an organ for liver transplant. There is a chance of PSC returning post-liver transplant, up to about 30%. Then there are the daily symptoms. They are highly variable across the PSC population. In our case, weight loss, brain fog, debilitating fatigue. Fortunately for this patient, the awful pruritus, the itching, the entire body itching is not a problem. What do you do? I can tell you what I do. Everybody responds differently to a situation like this. 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. I learned everything I could about the liver and about PSC. 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. 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 de-risk 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. The organization is located in Denver, Colorado, with the Canadian affiliate in Toronto. 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. 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 Cholecystatic 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. We engage with the regulators. We had a critical path innovation meeting with the FDA around our real-world data collection. We have invested in our own research program. We have a scientific staff. We have a Chief Scientific Officer on staff. Some of the projects here are summarized here. One is the Wind Active 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. 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.
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. We just completed an acute cholangitis patient survey to understand the experience of patients living with this. 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 perspective, multi-center observational cohort with patients being followed for up to five years. We are looking to enroll up to 2,000 patients across North America and Europe by 2027.
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. It will create a large clinical and biomarker data set to establish individual and/or composite surrogate endpoints for eventual use in accelerated approval pathway. I'd like to go back to my story. It's not really my story. I'm a caregiver. I'm not a patient. I'd like to introduce Fred Sabernick.
He is a patient living with PSC. He, as Dr. Cohen said, is somebody who is heroic every day. Before we meet Fred, I just want to return to my story as a caregiver. It is now been 10 years. My teen is now a young adult. Their story is now about their health. It is their story. It is 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 do not know who it was. 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. The patient experience is, of course, much more important than the caregiver experience.
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. Hi, Mary. I live just outside of Atlanta, Georgia. I've been here close to 25 years now. I'm originally from Upstate New York. I never grew out of the hockey love there. I like to run. I love to make small furniture pieces.
Cool. Can you tell us how and when did you receive a PSC diagnosis?
Yeah. I was diagnosed in 2004. The process to get there was almost nine months with lots of different tests. The only reason that I was going through the process was abnormal liver functions on a regular physical. That started the process going.
I went through a number of different disciplines to finally get to the PSC diagnosis. When I finally got it, I just basically felt like, "Oh, OK, I've got it. So it's got a name. I'll see you." Yeah. Wasn't concerned because I had no symptoms.
What was it like for you living with PSC before transplant?
At first, it was nothing because I had no symptoms. Unfortunately, PSC is a progressive disease. As the years went by, I did start to develop symptoms. First, I developed pruritus. Pruritus is itching, for people who don't know. 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. That was really the worst symptom. While it could be partially controlled with medication, the medications that I was taking were quite uncomfortable to take. On top of that, they had some side effects of their own. Apart from pruritus, some other symptoms I experienced were fatigue. This can be almost mind-numbing. In my case, it was probably less of a concern than others. I know some PSC patients who simply can't get out of bed due to PSC fatigue. Another, I really experienced some strange mental side effects towards when the disease really came to a head.
I had a first transplant.
How has it been for you since transplant?
A transplant, and I've had two now, transplant is a balancing act. Once you've had transplant and you've developed PSC again since, now I'm balancing transplant with PSC. The two treatments are kind of opposing each other. 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. I developed something called PTLD, which is a form of lymphoma. That presented as internal bleeding in my colon. In one instance, it was so bad that I almost couldn't step off, take two steps without falling to the ground. 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. Just other aspects. In my case, I developed PSC again. PSC then went again towards transplant again on the second try. The effects that I felt there were just constant infections. I was hospitalized before my second transplant, probably five of the eight 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. It's just 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.
I can't thank you enough for sharing your experience with us. Can you share what gives you hope for the future?
Yeah. PSC Partners, in conjunction with different pharmas and scientists, have all come together. We are all pointing towards finding real treatments and potentially a cure, something that really was not available when I was diagnosed. When people are diagnosed today, I like to tell them that this is the best time ever to be diagnosed with PSC.
I love that. Thank you.
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. Thank you again. OK, 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 PSC. 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 multi-component 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 the multifaceted component of the different biochemical outcomes of ACLY activity. We propose a rationale for its inhibition, again, touching multiple pathways that have been demonstrated and validated across a spectrum of different cell types. 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. The question is, where do we even start? We understand the problem. We have a sense of the pathophysiology. Etiology is a bit unknown. We have a really good understanding of the pathways for ACLY that are relevant to the pathophysiology of PSC and related liver diseases. 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. We took a very, very comprehensive, broad approach. We wanted to make sure we could deliver these fully optimized novel inhibitors. 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, its binding sites, the potential ligands that we could build off of. 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, 8 million plus compounds is where we start. 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 are small hydrophobic binding pockets where amenable to binding by small ligands with drug-like properties. 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. 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. The next thing we need is a custom high-quality screening cascade to begin optimizing these compounds. We took this multifaceted, multi-tiered approach. I won't go too much into details.
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 vitro screens, PK/PD studies, and rodents, and finally, disease models. You'll see a little bit of those data today. 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.
This is just an example of kind of the profile that we aim for early on in the discovery process. I talked about the multi-parameter optimization process. This is one of the leads themselves. We optimize on molecular properties. We optimize on potency, pharmacokinetics, off-target liability. Just as an example, when we start with compounds, we see lots of red and yellow. Actually, after years, now we're at a profile here where we've got greens. This is a profile that's desirable and really gives us confidence with really no signs of liabilities. 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.
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. We dose high. Then we look, using transcriptomics in this case, what are the pathways it's 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 were engaged with our molecule ESP-1336. 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, much higher than the effective pharmacological dose. Again, looking at the liver transcriptomics on the left-hand side, you can see the enriched reactome pathway analysis, top 10 analysis on the left-hand side. 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. On the right-hand side is just a clustering of these pathways so that we can 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 in this, I think, connects very well with what Dr. Mantzoros painted in terms of the mechanism.
That is this new link between ACLY and fibrosis in the context of metabolic disease. These are primary human liver microtissues. These are essentially just assembled using primary hepatocytes, epithelial cells, Kupffer cells, stellate cells. They form small little spheroid liver spheroids. We can stimulate a MASH-like phenotype in these spheroids by just essentially adding fat, sugar, and some inflammatory stimuli. We can induce fibrosis. It is a very relevant model system, very reproducible, and considered to be highly translatable. In the graph, you can see on the right of the schema describing the model that we can induce, as you look at the open circles versus the black circles, the MASH phenotype as marked by collagen composition score.
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 a DNL pathway. This is really just to highlight the difference in the mechanisms inhibiting at the point of acetyl-CoA carboxylase and ACLY. That is kind of depicted on the schema on the right-hand side. Pharmacological inhibition of either of those targets ultimately results in reciprocal regulation of acetyl-CoA. It is this component of the mechanism that links to the epigenetic mechanism we talked about and the impact on the pathways that we have elucidated as being novel to ACLY.
It is this pathway, and it 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 multi-prong mechanism that we talked about. On the left-hand side is really just the gene enrichment analysis. Yet you can see there are lots of gene sets that have been modified via ESP-1336. On the right-hand side, we have just bucketed them into the mechanisms that we have described already. Multiple pathways are linked to fibrosis, wound healing, myofibroblast proliferation, multiple mechanisms that fall within the inflammatory immune component of the mechanism, NF-k B signaling, TNF-alpha interleukin signaling, chemotaxis signaling for immune cell recruitment, and then those markers of liver injuries.
Those mechanisms link to TCA cycle, cholesterol biosynthesis pathways that show that on the substrate level and the mitochondrial level, these pathways are engaged with ESP-1336. We want to look in vivo disease models. Here with PSC, there is not really one disease model that can recapitulate the disease that occurs in humans. As Dr. Cohen had highlighted, I think the etiology is still a little unknown. We can capture different pathophysiological aspects of the disease. One of the first in vivo models, we use this as a tried-and-true model that has been around for decades, highly reproducible and highly interpretable, where you just administer carbon tetrachloride to mice. This causes kind of a nonspecific hepatic inflammation, ultimately resulting in fibrosis. 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. In the presence of ESP-1336, you can see that this is reduced. A quantitative assessment in the upper right. 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. 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 these small interductoral porphyrin plugs, which eventually lead to the accumulation of bile acids in the liver and then injury, inflammation, and fibrosis. 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. 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 that's also another food additive.
This one is not a model necessarily of primary obstruction, but more a model that induces inflammation in the bile ducts, ultimately leading to fibrosis. You can see, again, the same comparison. The addition of ANIT, this additive that causes inflammation, results in increased collagen content in the liver. The addition of ESP-1336 reverses this. 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. The final data set we will show here is a model called BDL bile duct ligation. This is a surgical model in which the common bile duct is tied off. This leads to a very rapid and severe cholestasis. As you can see, 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 multi-component 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, essentially reversed by the treatment of ESP-1336 when we 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. Again, even in the severe model, we can pick up changes in markers of fibrosis.
I just want to summarize where we're at now. 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're many risk. They're highly potent, nanomolar potency against ACLY. And we've demonstrated good pharmacokinetic properties that support daily oral dosing.
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 of 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 mechanism 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. We're feeling very confident in the leads that we've selected to pull forward. I just want to highlight again, there's no approved therapy for PSC, no therapy proven to slow, reverse, or cure PSC. This multi-component 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, about 30,000 patients. Together, U.S., EU, we're looking at a total of 76,000 patients.
This, we think, is somewhere north of a billion-dollar market opportunity. 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 healthcare 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. I just want to mention, I think, with what Sheldon started out with, this is an Esperion discovered internally developed program and wholly owned globally. With that, I think we're off to a really strong start.
Just to give you some guidance on the timelines, we're in a stage now where we're nominating the final candidate. We're on track to do that kind of mid-year. This is where we initiate our preclinical de-risking 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. We're looking at starting phase I studies sometime in 2026. We have to, of course, meet with the FDA. 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. 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. Thanks. I'll welcome up Dr. Mantzoros and Dr. Cohen.
Thank you.
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. 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. 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 these data and how drug developers view them.
Sure. We can go in as much depth as the audience needs, right?
We have been relying on genetic studies for a long time. In the past, we used to rely on the tip of the iceberg. Say the knockout mutations, right, that would create a hugely prominent phenotype. 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 kg when he was three years old. It led to leptin discovery, leptin development. This child was 30 kg when he was seven years old. PCSK9 inhibitors, we can give these examples. These were rare mutations found in laboratories of prominent scientists. This led over time to the development of a more systematic approach.
The systematic approach is the huge databases, right? The U.K. 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 U.S.A. Pharma, and your analysts and the audience may know that they have moved on to create their own databases. 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, and I'm sorry. This is where the field is moving, right? We leverage data. We live in a big data era, right? We leverage the data from huge numbers of people. As I said, all of us are randomized by nature to the extent that we can isolate exposures.
In this case, the exposure is high versus low levels, right, of a gene or the product. We have a lot of outcomes to correlate it. This is causal. It's not just an association. It's causal. It gives us a lot of confidence that what we see there is true. To make sure that what we see is not a fluke, we confirm it with a second database, right? Now, as an Editor in Chief, I don't accept papers that do not have two databases. We have confirmed it in a second database. If we zoom in now to 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. I think you provided excellent evidence for the causal associations of ACLY with liver disorders and liver diseases. I'm curious also, can you derive anything about the safety, on-target safety of?
Yes, right. This is something we did not have time to present, right? The paper is not out yet. Of course, we have data on potential side effects. We went systematically over each and every side effect that we could think or could have been recorded in the electronic health records. We did not see any red flags.
Okay. 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.
Given the data set in the outcome of your analysis, I mean, what can you say more broadly about the target and maybe about the state of NAFLD-NASH current therapies and sort of how you see the future?
I'll try to be brief. I could be talking for hours or days, 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? But 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. We talked about other organs and other diseases.
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. I see this as a potentially unlimited drug development effort. 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.
Yeah, that's fantastic. Thank you. Then, Dr. Cohen, 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.
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?
Yeah. In terms of ACLY inhibition per se, I mean, to your point that I think just needs to be driven home is that certainly PSC is a confluence of the activity of multiple cell types in the liver. To the extent that BA is hepatocyte-specific, that could be an important driver and mazzel because we know that therapy in the lipid accumulation phase of the disease is probably among the most effective mechanisms now. That's encouraging there.
Really, the cholangiocyte and the stellate cell and 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. To be able to target multiple activities with the newer generation molecules that can penetrate these cells, I think is going to be very impactful in that space. The other aspects, what's in development, there is not a lot. There are emerging ideas about PSC being, is there certainly some gut-liver axis communication. There are, and certainly fibrotic mechanisms are important. There are molecules called integrins that you can approach and modify 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. There are therapies in that space.
Also, the other aspect that integrins have is that one of the common problems that as the liver is injured is that the liver has the blood vessels in the liver, the capillaries are very porous. That allows the liver to communicate with the plasma. As they become less porous in an injury setting, that is thought to be detrimental as well. Other mechanisms are potentially impactful in that bile acid, reducing bile acids. None of them really has the opportunity to span multiple mechanisms. I think that certainly all that drug development should be prosecuted. I think like IBD, like hypertension, like other complex diseases, I think in the end, we are probably looking at combination approaches for successful mechanisms. Again, a lot of these are speculative and really need to be borne out in human models.
No, that's great. Thank you.
Yeah. You see a variety of patients. 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. I just wanted to give you the opportunity to talk a little bit more about your clinical personal experience with PSC and anything else you might want to add.
Yeah. Again, as we think we've seen, I mean, the human cost of this is very high per patient. There is a lot of cost to the families, the caregivers, the health system. One thing we did not talk about, the ongoing complications, it is not just the tests. As the patient talked about with the infections, these are infections that are typically due to bile ducts stricturing.
They lead to a problem called cholangitis, where when the bile ducts become so narrow, the bile can't flow, infection follows. It is very hard to clear. It is repetitive. The healthcare burden and the costs to the healthcare system really expand quite dramatically. It is a very intensive relationship with patients and patients with their families. I think that they have different manifestations. I think there is a clear opportunity, even in a disease where we don't know the specific mechanism, to intercede and to measure that intervention.
Because 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, yeah, I had my first transplant. And then when I had my second transplant." That is the kind of disease trajectory. He was diagnosed in 2004. That is 20 years. He has already had two transplants. Whatever we are going to be measuring and impacting, it should be clear, I think, in the course of structured trials that we are getting someplace.
Yeah. Okay. Great. We will just end things here, I think, on a positive note. I will open it 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- 10 years?
Yeah. I think I said it, and I spoke maybe too much earlier. It is an unmet clinical need, not only PSC, but liver disease in general, unmet clinical need. A huge number of people. It is like an iceberg, if I can, or a pyramid, if you can. There are a few people like PSC, right, that have a huge need for an effective medication, right, solution. There are more and more with liver disease like MASH, right, MASLD, just starting, right, which may need a milder approach. For all of them, I think, and I will come back to this. 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, right, an approach. We need an association with the patients. I would applaud you for what you have done. You 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. Not just from clinicians.
Right. I can, right. 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? They will give you different answers. You can ask the doctors there who treat the patients, right? What I can see here is that you have managed to put together a village. The patients, the doctors, right, winning molecules, the rationale. This is what makes me optimistic at the end of the day.
I would add to that that these multi-pronged mechanisms that we're excited about because PSC is really a perfect storm of that. 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 that's a lot of the difference between health and disease. You have got an enzyme that's at the nexus of that. Here we have got an unmet need. I do not think that anyone would contest. If you think about other fibrotic diseases, even adjuncts in fibrosis and inflammation is an important part and drivers and enablers of any number of c ancers, I think that developing this will lead to insights that I think are applicable to other disease processes.
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 and driving most liver cancers. 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. We have nothing that treats it. None of our anti-inflammatories and autoimmune can address this problem. It's a great place to start. I think that's just the start.
Great. I think that's a great start. This is a great place to end. I just want to thank you.
I can't thank you both enough for your partnership, your collaboration, your help here today, and everything you do in your clinics every day. Again, thank you to Mary for sharing your experience and everything that PSC Partners does. With that, I think we'll close this panel discussion. Then we'll open it up to questions more broadly. Sheldon.
This is an opportunity to take questions from the audience now. For those of you that have questions, I guess just raise your hand and ask. Hey, Joe.
Thanks, everyone. Thank you for all the feedback. Looking forward to more data from this program. Joe Pantginis, H.C. Wainwright, right? 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?
The second aspect of that question is very forward-looking for the company. Any potential for lifecycle management with bempedoic acid in the future as patents expire?
Okay. I'll take the first one. Yeah, great question, Joe. Thank you. 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. 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? This is not where our focus is. We've been really dialed in and trying to extract the lipid-independent effects of this mechanism.
LDL metabolism, HDL metabolism, just lipoprotein metabolism in general in rodent species is just not, at least without genetic modification or extreme dietary modification, going to be relevant. We do not measure those specifically for that purpose. I cannot really necessarily comment on that. If the question really is getting at the 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 first-generation inhibitors can accomplish.
I will take the second question, Joe. I think it is important to note that ESP-1336 is really being developed specifically for PSC. I think it is also a gateway of other, as you can see, modalities from a hepatic perspective.
As it relates to bempedoic acid and ESP-1336, 1336 is a completely different scaffold and molecule than bempedoic acid. As it relates to lifecycle management for bempedoic acid, we've talked about, and I mentioned it today, the triple therapy, triple therapy combination, which we'll be discussing more. I would put that in the lifecycle basket as we move forward.
No, thanks for that. My second question, and thanks for taking it, is obviously this is very early. First, we'd love to get the physician's 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. Thank you.
David, yeah.
Yeah. That's a very good question. Because as you can see, there's heterogeneity in the disease.
There is not a consensus that there is a good biomarker for PSC, which is what is so helpful in LDL trials in that you can really correlate a single response. There is pretty good evidence that certain alkaline phosphatase, which is very helpful in primary biliary cholangitis, sort of related, also a cholestatic disease. I would not call it related because we do not 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 tests that can be done.
Now, elastography, these are parameters that would be expected to follow in a 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. There are a lot of clinical events in this disease. I think early trials would be difficult to think about using clinical events in early phases. 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 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. In the MASH thinking, we think about intervening in sort of late F2, early F3 patients so that we can prevent the progression. In PSC, he talked about his presentation, "Oh, I just have liver enzymes at the time, so I've got PSC." That would probably be a good time because you see it did not take him very long to turn into a patient with symptoms and progression. That is 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.
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 does not get done that it should, you will likely start picking up more of this pre-symptomatic than otherwise.
I agree. I'll 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. The lessons that we can learn by designing this study, right, and doing the study. The biomarkers, I would call them NITs, non-invasive tests. I do not want to make the same mistake and mention names.
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. We are going to learn a lot and set the stage for the next stages of development, if it makes sense.
Yeah. 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. In other disease states, even in atherosclerosis, I mean, certainly patients are motivated. 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." You have registries and patients. You're not going to have to go out and build that infrastructure. It's there. The idea is to partner with it and intervene.
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 is one investigator in particular who 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." Hopefully that will help with any trial conduct.
And compliance and everything that goes with the trial.
Yeah. You have done the groundbreaking work with the FDA. I mean, this is amazingly important, in my opinion.
Thank you.
Hi. This is Kristen Kluska at Cantor. Thanks for hosting this. 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. Based on all the work you've done, if you believe ESP-1336 might have any potential to address this.
Pruritus is still a mysterious entity in the setting. It typically occurs in cholestasis. It is a feature also of primary biliary cholangitis and other things that obstruct bile flow. There is some evidence that bile acids have to do with pruritus, but they probably are not solely responsible. There are therapies that are being developed called ileal bile acid transport inhibitors or IBAT inhibitors that prevent reabsorption of bile acids in the intestine and lower the levels. Because invariably the bile acid levels are high in pruritus.
That is almost a biomarker for intensity of itching. These inhibitors have been developed for even rarer diseases of childhood that are associated with intense itching. They have been demonstrated in PSC patients to have positive effects on pruritus. To the extent that ACLY inhibitors will modulate bile acid synthesis and balance, there is some hope that they could have some intrinsic activity on pruritus themselves. In terms of evaluating pruritus, there are very well-validated tools for understanding intensity of itching, frequency of itching, and things like that. In the trials that have those IBAT inhibitor trials, there are very quantitative scales for measuring that. That could be quite readily incorporated into a clinical trial and measured as an outcome.
Great. Okay. Thank you for that. Second question.
You've demonstrated that ACLY was upregulated in certain liver disorders and that also lower gene expression correlates with greater protection. 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.
Thanks again. Yeah, it's a good question. That's what we're working on in the lab. We're trying to make specific genetic modifications in 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.
Great. Thank you.
Hi. This is Dennis [Thane] with Jefferies. Thanks for taking my questions. Two questions for me. One for Sheldon, perhaps big picture.
As you think ahead over the next 5- 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? My second question is just around the ACLY target. Why 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? Thank you.
Stephen, I'll do the first one and then turn it over to you for the second one if that works. 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 a very big focus for the organization. This is a $1 billion-plus opportunity in the United States alone, and we see it that way. 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 Stephen's question, but we have a lot of faith and confidence in our laboratories and what we've developed on our own. I view it as something that eventually makes our company bigger, makes it a larger organization.
Over the next five years, we still have patent protection going till June of 2031. That's our base case for bempedoic acid. We talked about the timing for this molecule would come in sometime right around there when we potentially could lose patent exclusivity. One, it's more related to keeps Esperion going but grows as to a bigger company. 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 III development, soon to be approved, etc. We've been very active from a business development perspective. 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'm not a scientist, but as you can see, it's very sophisticated.
We have said this before, this is also an opportunity for partnerships and development. I think there are a lot of organizations that are very intrigued and interested in what we have been doing from a fibrosis perspective. I think today further cements that we are one of the leading experts in that area. This is just initially scratching the surface. We talked about liver today. There are other areas such as kidney, oncology maybe later. To me, it is a very big opportunity overall for the organization for Esperion. Stephen?
Yeah. Great. Yeah. I think it is a great question about the mechanism. It is one I am very passionate about. I can maybe offer a first response, but then I would be very curious to hear what Dr. Mantzoros and Dr. Cohen have to say regarding comparison and relative confidence versus other therapies in development.
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 and a cholesterol biosynthesis pathway, a statin-like mechanism resulting in a very similar compensatory response that yields that LDL-lowering effect. Through all of the efforts that we presented today, we've got very good confidence that this is at a metabolic nexus. 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. For an example, we understand very well what happens in the hepatocyte. That's essentially what we can achieve with bempedoic acid. 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 ACLY inhibition in immune cell, you downregulate overactive immune, several immune functions. The same as Dr. Cohen discussed, in hepatic stellate cells, the fibrotic processes or pro-inflammatory processes in macrophages. I think that's extremely unique to this mechanism. ACLY is at a nexus. It's expressed ubiquitously but upregulated under dysfunctional conditions. I would really want to turn it over to you .
I would agree with that. 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 maladaptive 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. That gets into a condition of you don't know what you don't know is occurring. 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 feed forward degrade cholesterol. Many other things happen, and you just don't even know what they are. Here, we know what's happening. Acetyl citrate is being activated to acetyl-CoA, and there's where it is. If you think, what other instance of that? Statins. Statins targeted a specific enzymatic step. Here we are 40 years later, and another shoe has never dropped in statins.
I think this is targeting in as clean a way as you can the nexus between health and disease. That's what's attractive about it from my standpoint.
Great. Thank you.
D id you want to add anything ?
No, I fully agree. I fully agree. That's what history teaches us about transcription factors.
[Jessica I] JP Morgan. I have three questions. First, I think you said you expect you could secure a 2030 approval for this next-gen HB citrate lysis inhibitor in PSC. I guess that would mean filing in 2029 and registrational data maybe in 2029. If you're entering the clinic in 2026, can you talk about how you see the development path between 2026 and kind of delivering fillable data in 2029? 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. Third, for Esperion, have you investigated this mechanism preclinically in PBC, and would you consider development there?
Do you want to start with the scientific?
Sure. Yeah. Maybe I'll start with the last question first. Regarding PBC, and 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 injury related to bile acid inflammation, fibrotic processes, these are all sitting at that nexus that we're talking about in these different cell types. I would certainly expect that to also apply. I think that kind of is in line with the way we think about this program moving forward. There are clearly multiple opportunities in the future. I do not know if David, you would want to add?
Yeah. 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, from a clinical perspective, PBC, even in my own career, has evolved from a disease that I used to see in later stages. It would present later. There was not a lot of management prior to IRSO.
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 antimitochondrial M2 fraction, are very sensitive and specific. You don't even need a liver biopsy anymore. We catch it at an early stage. When placed on IRSO, in my clinical experience, most patients respond. It's a very rare patient that I meet with PBC that ever goes on secondary therapy. That being said, OCA was secondary therapy, but now there are two PPARs that are probably more potent secondary therapy. What's left on the table in PBC, thankfully, I don't think is a lot. I think that there could be crossover for a new mechanism like this.
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. I do know colleagues who just use them because there's not a lot else to offer, and you're probably not doing harm with the ones that are more established. To my knowledge, the efforts are the mechanism's more limited. Again, there's a lot of pleiotropy in agonizing nuclear hormone receptors. It's important. Yeah, 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. When alpha. Alpha for 50 years, right? Yeah. Or combinations there. Right. PPAR gammas, 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, never go up to the highest approved dose because of side effects. We use it. We love it, but we cannot maximize them. Now we're trying to get some conclusions from MASH, which is related. We recently analyzed all the data from clinical trials on PPAR gammas for NASH. The maximum we can see is and we published it.
You can find it is 30% placebo-subtracted. It's like 25-30%, if I remember well, of the population improves over a couple of years. 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. Even if they work, they work for a relatively small percentage of the population. That leaves huge room for other compounds, either alone or in combination with a low-dose PPR gamma. I hope I did not make it too complicated. Very good.
Okay. To your regulatory question. In the slide, we actually said early 2030s. We did not say 2030 specifically. The point there, and we kind of made a joke about it on the stage, I think it is Dr. Mantzoros was saying this. You're going to hear that, like, how can we move faster?
How can we move faster? That's a question Stephen gets all the time. How are we going to move faster? Obviously, there's such an unmet need here with this disease. We're looking on how we can move as quickly as possible. 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.
Thanks, Sheldon. Paul Choi with Goldman Sachs. My first question is for the KOLs on the panel. 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 agonists? Would it potentially open up additional populations that may have comorbidities like IBD and so forth?
Then two quick ones for the company. First, just in terms of the market, can you maybe just inform us as to how many patients are sort of managed in academic versus community settings and just sort of what diagnosis rates are versus the estimated prevalence? 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 two-year or 96-week study will ultimately be required with an endpoint like a one-point change in fibrosis? Currently, is that sort of where the agency's thinking is? Maybe just your thoughts on where the regulatory framework is.
I'm going to start with the science first, and we'll go to the regulatory.
Yeah. I mean, I would actually probably defer the, I think, to the KOLs, I think, on the. Yeah.
I just want to, could you just restate your question?
Oh, sure. Are there any particular patient types or subgroups that you think would benefit from an ACL approach versus other targets or modalities? Or would it open up additional populations like who may have comorbidities like IBD or something like that?
Yeah. Considering the multifaceted potential benefit, and in our we really don't have a lot to subcategorize the patients with PSC as opposed to at a certain point in 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. 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 UDCA, that there are some patients, those who respond more robustly with certain metrics with alkaline phosphatase, for example, will go on to potentially have a modifiable clinical course. You could say perhaps you can imagine a thought experiment where you try to induce some alkaline phosphatase response with something available like UDCA. You identify a population that responds and then put your eggs in that basket as a pretrial. Other than that, I mean, that's just an opinion based on clinical experience. I think, again, I would try to get patients, 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 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. Is that sort of about your question?
Great. To your question regarding regulatory and where we are as it relates to market dynamics, for lack of better words. Currently, we show 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, etc. That's something that we'll be working on in the future. This is more of a, as we said, an 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 being 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. 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. That's what we'll be focusing on and then focus on the study necessary to achieve that. Hi. Jason.
Hello. Jason Zemansky with B of A. 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?
Yeah. We actually, and I showed in my second slide our guidance. Our guidance is very similar to, as Ben would say before, we gave guidance going into 2025. No surprise, 2025 looks very similar to 2024. We do not see any type of additional expenditures, etc., necessary. 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.
As we continue growing those products, it's also going to help us fund these other programs that we are currently engaging in. Right now, for this year, for 2025, our guidance remains unchanged.
Thank you.
Hey, good morning. Serge Belanger from Needham. Two questions for the ESPR team. The first one, another one on the development path. It sounds like it's too early to talk about the late-stage part of it. In the early stage, I think you highlighted a phase I study starting in maybe 2026. Would that be in healthy volunteers or patients? Just trying to get an idea when we could see proof of concept for 1336. Secondly, Sheldon, you talked about the company being active on the BD front. Is the focus there to leverage the commercial infrastructure or add on to the pipeline?
Yep.
I'll go first, and then Stephen, have you answer the second one? It really is from a BD perspective, it's 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. I think that's really the beauty of 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 as a real organization to effectively launch a product. We've had companies actually come to us and talk to us about this as well as we've proactively reached out to several companies.
The point being, though, is we don't want to bring in anything that's in the clinic. We're not going to take that risk. Honestly, we just can't afford that. We can afford this, but we can't afford that. It's really, again, just leveraging our infrastructure. I'll have Stephen answer the question regarding healthy volunteers and proof of concept.
Sure. Yeah. We can make this one quick. I think LeAnne or probably Ruth would probably agree with me, but I'd 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, Stephen. Thank you, Dr. Mantzoros. Thank you, Dr. Cohen. Really just an amazing session. Mary, every time I see patients and hearing your story, that's why we all are here.
I think it is forgotten sometimes, us and company and even those of you in Wall Street. It is a good reminder to see really what we are working on and what our goals are. Really, again, why will we succeed? We have a patient-focused strategy. We've talked about what we're trying to do here as an organization with our current franchise. Today was really focused on the future. We have a scientific edge. I mean, what you heard today was deep science. Thank you, Stephen, again, for all the work that you've been doing in 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 is 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. Again, it's an opportunity, I think, for strong partnerships and research collaborations. We're always open to that, always. 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. Thank you again and have a great day.