Ionis Pharmaceuticals, Inc. (IONS) Earnings Call Transcript & Summary

Today's webinar on severe hypertriglyceridemia. This represents one of our most important programs at Ionis, particularly as we are getting ready to read out our Phase III programs. So we're very excited to be able to present an educational session today with our world-renowned experts to review this topic. My name is Sam Tsimikas. I'm the cardiovascular franchise leader at Ionis. And I'm -- my background is as a cardiologist and very interested in the pathophysiology of cardiovascular disease, particularly as it relates to various lipid disorders. Today, we have an esteemed panel of experts that will help me and you lead the discussion on hypertriglyceridemia. And we have Seth Baum -- we have Dr. Seth Baum, we have Dr. Savitha Subramanian and Dr. Alan Brown, and I'm going to allow them to introduce themselves in a little bit. But first, let me just go over the agenda for today. We have 4 main objectives. One is to learn about the pathophysiology of hypertriglyceridemia, especially severe hypertriglyceridemia and its prevalence. Then we want to go over what these patients suffer from, how do they present, what kind of comorbidities do they have and review for you what they have -- what issues they have on a day-to-day basis. Then we're going to review the current standard of care for these patients and how are they currently treated and why they represent an unmet need and the unmet need that we've been working on for over a decade to get a new therapy for them. And then we're going to review the exciting new treatments that are coming forward for these patients. And so for the audience listening, we will also have a question-and-answer session at the end. You'll have an opportunity to ask questions. Please look at the bottom of your screen. There's a site that says ask a question, please type in your question, and we will be able to review those at the end of the question-and-answer session. So with that, I'd like to now have each of the panelists introduce themselves briefly and tell us what they do and their expertise and background in severe hypertriglyceridemia. And I'm going to start with Dr. Seth Baum first, who is online with us. Seth?

Yes. Thanks, Sam. So my name is Seth Baum. I'm a cardiologist, a preventive cardiologist and clinical lipidologist. I'm the past President of the American Society for Preventive Cardiology and the current Chairman of the Board of the Family Heart Foundation. And I'm also the Chief Medical Officer of Flourish Research, which is a research company that has sites around the country conducting clinical research. So I have a good deal of experience in clinical trials with severe hypertriglyceridemia, and it's great to be here today.

Thank you, Seth. Dr. Subramanian?

Good morning. My name is Savitha Subramanian. I'm an endocrinologist and lipidologist and a Professor of Medicine at the University of Washington in Seattle. I also serve as the Medical Director of the UW Medicine Lipid Clinic, where we serve to take care of patients with genetic lipid disorders, complex metabolic disorders. We are the only referral source for the whole state of Washington. So anyone with any severe hypertriglyceridemia issues get sent to us.

Great. Thank you. Dr. Alan Brown?

My name is Alan Brown. I am the Director of the lipid clinics for a large health care system in the Midwest, Advocate Medical Group. Actually, I am an interventional cardiologist, but have been interested in lipids since the mid-1980s when I started my first lipid clinic. And I got labeled both the lipocrit and a balloonatic at that time, and I've been doing it for 40 years. So I also do clinical research, particularly in all different types of dyslipidemia. And I'm a past President of the National Lipid Association and Clinical Professor of Medicine at Rosalind Franklin in Chicago.

Great. Thank you, Alan. Well, I think as you can see here, we have covered the expertise in lipidology, cardiology, endocrinology. So this is very well rounded, the discussion we're going to have today for severe hypertriglyceridemia because it spans both cardiovascular disease and metabolic disturbances. And so it really requires 2 sets of expertise's in a sense to be able to deal with this issue. And so we'll delve into some of those areas in more detail. I'd like to take the discussion through the view of a patient that we're seeing in clinic. And I think that will help us kind of put in context how -- what we do on a day-to-day basis and what our patients go through. And I think that will frame the discussion on the various areas that we're going to discuss. So on the first area that we like to discuss is to understand what the disease is, what is pathophysiology and what the prevalence is. And we'll go through each one of those in a little more detail. And I thought maybe I will start out with Dr. Baum, and he can maybe go for us briefly what is hypertriglyceridemia, what is severe hypertriglyceridemia, what's the cause of that and put that in context and what we're going to talk about later for the patients.

Sure. It sounds good. So first of all, it's important to know that triglycerides are fats, most common fat that we consume, highly prevalent in the body. It's carried. Triglycerides are carried in the blood in spherical lipoprotein particles. Blood is an aqueous solution, fat and blood don't mix. So we have these spherical lipoprotein particles that carry fats around, trafficking them from one place to the other. Triglycerides are used by various parts of the body as energy and they're stored as fat in adipose tissue. These lipoprotein particles are often atherogenic, meaning they cause vascular disease. Now when -- in the highest triglyceride levels, those exceeding 880 milligrams per deciliter, there are also chylomicrons that are much larger particles filled with triglycerides and that are not atherogenic. But most of the particles carrying these large amounts of triglycerides do lead to vascular disease. The normal triglyceride level that we consider is less than 150 milligrams per deciliter. And then elevated triglyceride or high triglyceride being greater than 150 occurs very frequently, about 25% of the population. As we exceed 500, we call it severe hypertriglyceridemia, and that's about 1.3% of the population. And then when we get beyond the 880, again, in that sphere where we're having chylomicrons, the prevalence falls significantly to maybe 0.2%, 0.3% of the population. So genetics plays a huge role in hypertriglyceridemia, most of the patients having very, very small effect genetic abnormalities in multiple genes. So there are 30-plus genes there that can lead to hypertriglyceridemia. So many abnormalities having small effects. When you get beyond the 880, 1,000 milligrams per deciliter, we have larger effect mutations in a fewer number of genes, so 1 or 2 may have a mutation. And then environment plays an enormous role as well. So you have these either multiple small effect genetic abnormalities or these single or double large effect ones, but then the environment on certain medications in overweight or obesity, diabetes out of control, alcohol, things like that can severely disturb triglyceride levels. So that's basically the landscape or the pathophysiology of hypertriglyceridemia and severe hypertriglyceridemia.

Okay. Great. Thank you, Dr. Baum. I want to go to Dr. Subramanian and maybe expand a little bit on the genetics. Perhaps you can give us a little more detail on what some of these issues are and especially how they differentiate patients with different levels of triglycerides, over 500 versus over 80 or much higher than that.

So as Dr. Baum very elegantly mentioned, so triglycerides are carried in these large particles which float in the blood called chylomicrons. And so they have to be digested. And so after you eat, triglycerides go up when they're fat in the food, which is pretty much most meals. So there's a whole bunch of genes that help clear the triglycerides from the circulation. All these genes -- and so there's many, many genes. And the primary gene for the clearance of triglyceride is lipoprotein lipase or LPL. And there are many co-factors that help lipoprotein lipase or LPL do its job. So when there's any abnormalities in clearing of triglycerides, there can be issues with triglyceride clearance and so triglycerides accumulate in the blood. In people with severe hypertriglyceridemia, which is what we're talking about, here, you can -- so for the LPL, you get one gene from the mother and one from the father. If there's one gene, there's a pathologic variant in one of the LPL genes, so a heterozygous pathogenic variant, this can lead to severe hypertriglyceridemia. That's one bucket of folks that have a genetic predisposition to have hypertriglyceridemia. These are folks who can fluctuate from mild to moderate levels for triglycerides range from 200 to 500 or they can be much higher. So these are the single gene heterozygous pathogenic variants. The other bucket that Dr. Baum actually mentioned is the small gene effects. So sometimes, you can have these very minor variations, single nucleotide polymorphisms in many different genes. And again, these are also inherited. If you do a genetic test, you can't really pick them up. They're SNPs. So if you inherit more than one from either of your parent, you can have mild to moderate hypertriglyceridemia. And then if there is a secondary factor, environmental factor, as Dr. Baum mentioned, if you have diabetes or you suddenly gain weight or you get put on a medication, it can really cause your triglycerides to fluctuate. So these are the 2 big buckets. Most people fall in the polygenic or the minor gene variant groups.

So let me just summarize then what I heard. First of all, severe hypertriglyceridemia has levels at least 3 to 20x higher than what we consider normal. So it's a very extreme form of hypertriglyceridemia. Second is that there are a lot of influences, but a lot of the genetics are not one specific mutation like FCS, where you have very specific biallelic knockouts, you have multiple contributors to that genetic risk. So it's a genetic disease, but it's not the typical genetic disease of a single gene knocking out. So the other part of this that I wanted to clarify is that let's just make sure the audience knows there are 2 sources of the hypertriglyceridemia. Alan, maybe you can comment on dietary-derived chylomicrons versus VLDL output from the liver.

Yes. The way to think about it is as these little spaceships called lipid particles carry cholesterol and triglycerides through the blood, they come from 2 different sources. One is the diet, and those are packaged into particles called chylomicrons, which are extremely high in triglycerides, 10 triglycerides to every cholesterol, which is why often when chylomicrons are in the blood, we see 8 to 10x the triglyceride level compared to the cholesterol. And the other source is what the liver makes endogenously, which is called VLDL. It's an analogous lipid particle. The liver makes VLDL. It has 5 triglycerides to every cholesterol, a ratio of about 5:1. But in both cases, those large triglyceride-rich particles go through the capillaries where they're acted on by lipoprotein lipase. And the triglycerides are removed and broken down into fatty acids, for example, in the muscles to be used as energy. So you can think of the cycle as whether it comes from the liver, 5:1 triglyceride to cholesterol or the gut, 10:1 triglyceride to cholesterol. Those particles go through the circulation and the triglycerides are extracted as fuel for energy as my colleagues have already described. But there's 2 different ways we get triglyceride-rich particles in the blood.

So with all of this, Dr. Subramanian, is it fair to say that all of these influences summated in one measurement, which is the triglyceride level? And do you need anything more than just measuring the triglycerides to take care of these patients?

I think just from a lab perspective, just measuring. Yes. So triglyceride measurements are helpful. You can use non-HDL, which is part of a standard lipid panel, but I think triglycerides are pretty reflective of what a person's status is.

Okay. Perfect. Okay. So, yes, Dr. Baum, sure please.

Alan's beautiful commentary. Those 2 different sources, the liver source is the atherogenic lipoprotein particle source, the gut source, the chylomicron source is not. And I just wanted to clarify that.

Thanks for that distinction. That's a very important one because we'll get into that issue a little bit later also.

Except for the remnants, chylomicron remnants. So once those chylomicrons start to be metabolized into smaller remnants, they can be atherogenic. And it's interesting that since that does come from the diet, if you do like a fat tolerance test and you give someone a fatty meal and measure how long it takes for them to clear their chylomicrons from the circulation, the longer it takes, the more likely they get atherosclerosis. But as Seth pointed out, it's not the chylomicron, it's the breakdown particles that are participants in atherosclerosis.

So what I'm hearing then, the risks in these patients are dietary-derived chylomicronemia that induces pancreatitis and then VLDL-derived hypertriglyceridemia that's associated with cardiovascular disease. Are these the 2 main risks that we worry about in these patients with severe hypertriglyceridemia? Or are you worried about other things that could be as a result of their underlying disorder?

I've had patients tell me they'd rather die of a heart attack than pancreatitis. So with severe hypertriglyceridemia, the first thought is to reduce the risk of acute pancreatitis, which has a significant mortality associated with it and tremendous morbidity. And then once you do that, you look at what's left in the blood. In other words, what are the circulating lipids and what's the risk for atherosclerosis. In the more mild hypertriglyceridemia patients, say, 150 to 500, I think we're -- those are almost always VLDL remnants. Those are almost always atherosclerotic in patients who are insulin resistant, for example, in today's world, it's obese patients with metabolic syndrome most often. So in that case, our focus is on reducing the risk for atherosclerosis, whereas in the severe hypertriglyceridemia, the first goal is to get the levels down below the pancreatitis levels.

So Dr. Subramanian, yes, please.

Can I add? So in people who have severe hypertriglyceridemia, they also store triglycerides in the liver. So it is an increased risk for metabolic-associated steatotic liver disease, what used to be called I have forgotten the old term. It's called MASLD now. So that's a risk. And MASLD now, we know is associated with increased cardiovascular risk, so indirectly. So severe hypertriglyceridemia causes.

How do you identify those patients that they have in association with hypertriglyceridemia liver steatosis, how do you diagnose them clinically?

Clinically, you can -- well, they're clinical phenotypes. If they have central adiposity, that clues you in. But by looking at blood work, they may have a slight increase in liver enzymes, AST and ALT primarily. or if they have some kind of imaging study, you can actually look in an old ultrasound and you'll see that their liver may be mentioned to be steatotic, which means there's fat in the liver and it's slightly enlarged. You can, of course, do specific tests for looking for this, but you can also look by just from whatever data you already have to see the fatty liver.

It's interesting that not only is it a risk for atherosclerosis, but it's the #1 cause of liver transplantation now. Steatohepatitis leading to cirrhosis. It's eclipsed alcoholism as the #1 cause.

Fantastic. So Dr. Baum, how would you differentiate the really high patients either that have triglycerides over 880 or patients that have over 500-plus pancreatitis versus other patients? Do you see them differently? Do they have different risks?

Over 500 with a history of acute pancreatitis, meaning once you have that first episode, your risk of having another episode is much, much higher. That's our real unmet need in management of patients with severe hypertriglyceridemia. These are patients who are at extremely high risk for acute pancreatitis. And as Alan said, many patients would prefer to have a heart attack rather than acute pancreatitis. And any of us who have taken care of patients with acute pancreatitis understand that it is a devastating disease. In fact, we've all seen patients with their first episode of acute pancreatitis come in absolutely destroy their pancreas end up with type 3C diabetes. So diabetes as a consequence of that pancreatitis. The mortality is very high. The mortality rate is certainly 6% or greater. And in severe hypertriglyceridemia-induced pancreatitis, mortality rates really do seem to be higher than they are for other forms of pancreatitis. So that's our patient population we need to focus on.

So it's interesting that the 2 cardiologists here both say they better have a heart attack than pancreatitis, which I think really should tell the audience that pancreatitis is not a benign issue, and it's a very serious issue, patients with long-term complications. And Alan, I wonder what your thoughts about that and you worry about -- what do you worry about when these patients come in with pancreatitis as you take care of them going forward in terms of follow-up?

Well, in the patients who have severe persistent hypertriglyceridemia, it is -- it's devastating in a number of ways. I always say those are the only lipid patients that keep lipidologist's up at night because those patients, despite your best efforts, come in with recurrent episodes of pancreatitis. And as Seth pointed out, they are really sick, really sick. They can get everything from fluid in their lungs to multi-organ failure and some of them don't survive it. And you know that they're losing beta cells with each episode and that they're on their way to potentially diabetes. So it's difficult for the physician because you feel like a failure in those patients who don't respond to traditional therapy, and it's very frustrating for the patients who, despite their best efforts in many cases, still have episodes of pancreatitis. I think we tend to think of maybe they didn't follow the diet, but even the ones who are really good with their diet at times will have episodes. And...

Yes, that's an important observation therapy.

Okay. Well, to finish this session, I'd like to just finish up on the prevalence. What I'd like to do is ask Dr. Baum to first kind of give us the big picture. And then I would like to ask the other 2 panelists to tell us about their own health care systems and their own care of their individual patients just in terms of so we get a sense of how many patients out there and what you're seeing on a day-to-day basis. So Dr. Baum?

Yes. So I'd say it's for just high triglycerides, meaning greater than 150, it's very prevalent, 25% of the population. But once you breach 500 and you're in that severe hypertriglyceridemia population, it's around, let's say, 1.3%. When you get above 880 or 1,000, it shrinks down to 0.2% or so. So we're talking about -- and our focus really, I think, today is that very vulnerable population greater than 500 with history of pancreatitis or greater than 880, and it's probably in the order of close to 1 million people in the United States.

Okay. Great. And let us know about your own health care systems and your own individual pool of patients that you see each of you.

You want to go...

Sure. Dr. Subramanian.

Yes. So as I mentioned before, we have a tertiary referral center. So severe people with 4-digit triglycerides, as I call them, people with triglycerides in the thousands, most will get referred to us for evaluation and management. If they have severe hypertriglyceridemia with pancreatitis, it's a SureFire referral. Numbers-wise, I did a search in our health system, and there's at least 1,000 people with triglyceride over 1,000 for one reading. Our referrals come from everywhere, primary care, so internist, family doctors, mid-level providers, so ARNPs, PA's, cardiologists and endocrinologists all refer people with severe hypertriglyceridemia to us because they need a certain kind of specific kind of focus and attention to evaluate in management, especially because of their risk of pancreatitis. So how many people with severe hypertriglyceridemia do I have under my care? So the ones with severe hypertriglyceridemia and pancreatitis, I'm going to say at least 30 patients in my panel. And including my colleagues, there's probably a total of 50 in our highly specialized clinic. Severe hypertriglyceridemia over 1,000, it's hard to really know. But it's -- I'm going to say 40% of my panel is severe hypertriglyceridemia.

Dr. Brown? We're going to give you a microphone to help there.

I'm getting louder and softer. Yes. So I also have a tertiary care clinic for lipids and my catchment area is the suburban area and city of Chicago. And we have 2 types of hypertriglyceridemic patients. Of course, the moderate ones, the 150 to 500 is about half the population. So that's a huge group. Over 500, a smaller group, as Seth pointed out, and those with pancreatitis, even smaller and over 880, 0.2% to 0.3%, as Seth pointed out, in the population. So I have a handful of patients with genetically proven FCS who have severe persistent hypertriglyceridemia in the classic genotype and about 3 to 4x as many persistent severe hypertriglyceridemic patients. So I think we all see maybe a new onset diabetic patient who comes in with triglycerides of over 1,000. And once their glucose gets under control, they get better or someone who went on a drinking binge. But then there's several, I think I have between 25 and 30 just in my Chicago suburbs practice of people that persist over 1,000 despite our best efforts, who genetically are negative for FCS. In other words, they don't have the large gene mutations that we traditionally think of FCS, they're polygenic as was already pointed out by Dr. Subramanian. And those patients, despite traditional therapies have persistent hypertriglyceridemia and the vast majority have had several episodes of pancreatitis.

Okay. So what is your sense of the referral patterns and how many patients you're getting now? I know Dr. Subramanian, you mentioned you have 3 full days of a clinic. How are you guys seeing what's happening out there from the referring doctors and all the other issues with awareness of hypertriglyceridemia? How are you finding that in your practices?

So yes, so after 3 days of my clinical practice, 2 days are full lipids, 1 day is fully diabetes. I also run an electronic -- an e-consult program. So -- and that e-consult program, our primary care providers can send electronic consults to us, and I do all the lipid consults. And so a big part of education and figuring out how they refer is through my -- these service and educational mode also. So they learn when to start medications and who are the ones that need to be referred. So that's a big way how I get information out into the local community. Beyond that, our clinic is a word-of-mouth clinic. So if anybody with severe hypertriglyceridemia, especially over the 880 or 1,000 and with pancreatitis, they -- I mean, that's just our local area. They know to send to the lipid clinic because our clinic has been around for over 45 years.

Great. Alan?

Yes. So we have a community-based clinic in the sense that we're at a teaching institution but not at a university in several locations around the Western suburbs. So we get referrals for almost everybody with high triglycerides that haven't responded to traditional therapy. So we'll get referrals for triglycerides of 300 up to 5,000, 6,000. So we do see all comers and they don't necessarily have to have pancreatitis. Certainly, if they have severe hypertriglyceridemia, their primary care doctors get concerned and send them to us. And we're the fifth largest health care system. So we have a lot of primary care doctors. And at the moment, just a couple of lipid clinics. But it's also -- it's our 40th year.

Fantastic. Well, this is a great wealth of experience. This first section, I think, took a little longer than we anticipated, but we did it on purpose just to make sure everybody was grounded on what we're dealing with in this. So let's go to the next section. We're going to talk about the patient now. So we have a patient sitting in front of us, and we do our history and physical. And Alan, what kind of things are you finding in these patients with hypertriglyceridemia? Maybe give us a sense of what those patients are like.

So I think as a lipid geek, the first thing we ask is why are the triglycerides high. And we start thinking about particles. So is this a VLDL problem? Is it a chylomicron problem? And a lot of it can be guessed based on the level of triglycerides as Seth and Dr. Subramanian have already pointed out. And then that leads us to look at secondary causes of the high triglycerides. So is the patient a diabetic? Are they drinking? Do they have hypothyroidism or renal disease, anything else that could be leading them to have those high triglycerides. And then based on that, we make a decision with regard to genetic testing to look for large gene mutations and if we're lucky to look for SNPs that might be associated with hypertriglyceridemia. So the first step is lifestyle modification that's more effective on triglycerides than it is on LDL, for example. So we really focus on low fat diet, reducing simple sugars. And then second step is to try to control any secondary causes. And thirdly, to determine, if possible, what the underlying genetics might be in that patient. And then based on those approaches, we determine what the appropriate therapy would be for the patient.

Okay. And Dr. Subramanian from your perspective, how much does diabetes play into severe hypertriglyceridemia? And what are the kinds of things do they come in with in terms of hypertension, cardiovascular disease, other risk factors that worry you besides just the triglycerides?

Yes, Sam. So as you described, so I put my people with severe hypertriglyceridemia in 2 buckets, those without diabetes and those with diabetes. There is a lot of overlap between the 2 because the metabolic syndrome, so body type, so central adipose tissue distribution, hypertension are all big contributors in both groups, so with or without diabetes. The folks with diabetes, the severe hypertriglyceridemia often manifests if they're newly diagnosed or if their diabetes for some reason has become suboptimally managed. So they've become, as we say, uncontrolled. That's a big reason. Sometimes medications, they may have been put on a medication that may have caused their triglyceride to go up. So these are pretty common ways that people present to my clinic.

Very good. So just -- we're going to talk about specifics for treatment in the next section. But just in terms of treatment goals, what is the big picture? What would you like to -- when you get done with your visit, what would you like to achieve with that patient in terms of overall prevention of various things? I'm curious, Dr. Brown, what is your overarching treatment goals for these patients are?

Well, one of the reasons I think about particles is to determine in my own mind, what disease does this patient have? And is it a risk for atherosclerosis or isn't it? So treatment goals differ depending on the situation. If they're over 880 and it's primarily a chylomicron problem, as Seth has already pointed out, the risk for atherosclerosis is not 0, but it's significantly less. And that would be patient that I would get a calcium score and try and determine do they have subclinical atherosclerosis, but the principal goal would be reduction in risk of pancreatitis. And that's true for everybody over 500, as I mentioned earlier. Then once the dust settles, once you get over the acute risk of pancreatitis. And I might add, if you're over 500, a couple of beers gets you over 1,000. So it doesn't take much to push you into that threshold where the risk of pancreatitis is significant. So we would -- after those severe hypertriglyceridemic patients have their triglycerides controlled, the next step is to assess them for atherosclerosis. And in your mind, again, you're trying to determine what is their diagnosis to help you decide what their risk for atherosclerosis would be. But there's nothing better than a calcium score, which is $49 in my city, and that's without insurance.

So I want to focus a little bit on the acute pancreatitis risk. And maybe Dr. Subramanian and Dr. Baum, how do you view that in these patients? What worries you the most? What's the kind of patient when you're sitting in front of you, what's the one thing that worries you about the pancreatitis? What are the characteristics of those patients?

Should I go first.

Yes.

So one thing I do want to point out, which hasn't been mentioned is not everyone with severe hypertriglyceridemia over 880 or in the thousands will get pancreatitis. But it's an impending risk. We don't understand who get pancreatitis and who doesn't, but you can't take that risk. So that's important. Of the people who get pancreatitis -- so who gets pancreatitis. So anybody with triglyceride in the 400 -- 4-digit range. So anything above 1,000, the cutoff point is that 880 to 1,000 because everything is saturated and you can't clear the triglycerides. What else did you want me? I lost my drain of though here.

No, that's fine. I think what you're reflecting is that the really high triglyceride patients are the ones that you worry about. And whether they had pancreatitis or not, they're still a very high risk and you worry about them and you need to find a way to deal with that.

Right, absolutely.

What about the patient that has a triglyceride of 600, but they've had pancreatitis in the past. Would you put them in the same category or a different category?

Yes. And as Dr. Baum mentioned, a person who's already had pancreatitis from high triglycerides is at significantly increased risk for developing another episode. So they would -- even though their triglycerides are 500 or 600, they are at significantly higher risk. They know how to manage themselves lots of times, but that is still putting them at very high risk for pancreatitis.

I want to just discuss the issue of cardiovascular disease. Dr. Baum, you already mentioned that a little bit. But Dr. Baum, maybe you can expand on that a little bit, that part of that equation in people with sHTG.

The cardiovascular disease, can I address the pancreatitis.

Yes, sure. Go ahead. Yes, please.

I was going to say that we do understand that the risk of pancreatitis is very tightly correlated with the level of triglyceride. So the higher the triglyceride, the greater the risk. So -- and we also know that triglycerides can rise very significantly with very minimal influence by diet, right, as Alan mentioned, 2 beers. So those individuals who are at very, very high risk, obviously, the ones who've had pancreatitis already, the ones who are sitting at 880 to begin with or over 1,000. But when you have somebody who's got some dietary indiscretion, let's say, and you know they're going out and eating things they shouldn't need drinking out, whatever, those are people who really make us very, very afraid. So I think we need to pay attention to those people even more so. With regard to cardiovascular disease, we do know, as we mentioned early on, that many of the particles that carry triglycerides, these VLDL-derived particles in particular, are atherogenic. They cause vascular disease. And so it is very concerning. Yes, pancreatitis is more frightening than even a heart attack, harder to deal with, quite frankly. And I was a former interventional cardiologist. So I used to deal with those people as well. We have a greater comfort level dealing with them. So -- but we have to understand that these people are at quite significant risk and cardiovascular disease still remains the #1 cause of death in the United States. So we have to take these people very, very seriously and address their risk.

I want to...

Yes, sorry. So to Dr. Baum's very elegant explanation. So I want to highlight that sudden risk of pancreatitis. So the people who run constantly in the thousands, they may not get pancreatitis, but that impending pancreatitis risk, I just want to highlight this, any situations of celebrations, holidays, vacations where their standard lifestyle has changed, where they're eating out, where they're celebrating, where they went to a wedding and ate over a weekend, and they can't clear their triglycerides, so those people can all of a sudden, never have had pancreatitis and go into pancreatitis, and that's really something.

Is it fair to say that the person that doesn't have that genetic predisposition will be able to clear them and not have an issue, but the patients that you're dealing with in your clinics they're much more likely to have significant fluctuations because they have that genetic predisposition.

Absolutely. Yes. The people who have these fluctuations and who run in the 500,000 range, they have that genetic predisposition, whereas the ones who don't have that, I don't believe have that pancreatitis risk. So yes, absolutely.

Dr. Brown?

This was alluded to earlier, but when your triglycerides are over 1,000, you've pretty much saturated your lipoprotein lipase receptors. All the lipase is busy, not available to pick up more particles. So that's when a dietary and discretion is really going to be an issue. It's also why our traditional drug therapy doesn't work too well in those patients until they drop below 1,000. So those people who hover persistently over 1,000 are particularly susceptible to dietary indiscretion, as we've all said in different ways.

Yes. And I think it's important for the audience to understand that when we're talking about these values of triglycerides, they're fasting and that's the best case scenario. Most of the day, we're in the postprandial state. So once we eat, we don't -- actually, we typically don't measure postprandial triglycerides, they're much higher. So the fasting level is the best you're going to get is, in a sense, the way to think about it. And then we're now fluctuating up and down throughout the day depending on what we eat. And so it's kind of a little bit deceiving from that perspective to try to understand that the baseline triglyceride is probably much higher during the day than it is in the first thing in the morning. Okay. Why don't we go ahead and move on to the next section, which is what are our current therapies? What is the unmet need? And what is the standard of care? So maybe Dr. Baum, you can start. Tell us what the standard of care is for these patients that they're sitting in front of your clinic. What's in your toolbox? What do you have to offer them right now?

Yes. So I would say standard of care would be in individuals who have triglycerides over 500. Obviously, we deal with dietary issues and exercise and therapeutic lifestyle changes. That's always fundamental in any patient we're dealing with, frankly, with any lipid disorder or cardiovascular disease, we always address that. But then we have a few therapeutics that we can prescribe, statins, fibrates, omega-3 fatty acids are really the mainstay of therapy. I would say most people end up on statins, a bit fewer on fibrates and fewer still on omega-3 fatty acids. And unfortunately, it turns out that these therapeutics are often inadequate to get our patients under 500 in a sustained fashion, and I will tell you from a research standpoint, we're sent many patients for clinical trials because they're on therapeutics like this. Their triglycerides don't fall below 500 and the physicians are very, very afraid of acute pancreatitis.

Okay. So Dr. Subramanian, how effective do you find statins, fibrates, omega-3 fatty acids in your patients? And what is missing there, if anything, that you like to have if you don't have it right now?

So statins are cholesterol-lowering drugs. They're not triglyceride-lowering drugs. So they are not very effective in lowering triglycerides, maybe 20% if you're lucky. Fibrates are more potent. They work to increase beta oxidation. So they burn up triglycerides, increase fat breakdown or triglyceride breakdown. You can get up to 40%, 50% based on studies, do we get that? It depends. There is variability, but they are the most potent of triglyceride-lowering drugs we have currently. Omega-3 fatty acids, again, you -- or fish oil, you have to take at least up to 4 grams a day to have a benefit. They can also, based on what we know from the literature, 20% to 50% is what they claim for lowering triglycerides, but I don't find them very effective. The one thing about fish oil is that in people who have very severe -- the severe hypertriglyceridemia in the thousands, they don't really work because -- and fish oil is also fat. So it can increase hepatic or liver VLDL secretion. So you really -- you need to exercise caution in people who have like very severe hypertriglyceridemia. So I don't use it very much.

Okay. Dr. Brown, your thoughts on current therapies?

Well, I agree with it depends. So the people in the moderate range, I would say, under 880, they often have comorbidities, other issues that affect their triglycerides and many of them will respond to fibrates. And statins, especially if you have a patient that you're worried about atherosclerosis, the higher your triglyceride level, the more reduction with the statin. So it can be up to 30% in patients with over 500 triglycerides. So I think if you're worried about atherosclerosis, many times we would start with a statin, especially if triglycerides under 1,000. And then the question is, what are we trying to avoid? Are we trying to avoid pancreatitis or are we trying to avoid a cardiovascular event? If we're trying to avoid a cardiovascular event, we would use Icosapent ethyl, which is the only omega-3 fatty acid that's been shown to reduce cardiovascular events. And in my hands, you can get a 40% to 50% triglyceride reduction, again, in those people with higher triglyceride levels and then fibrates to avoid pancreatitis because on top of statins, they haven't shown a significant reduction in CV events. But we've all had that group that's over 880 and some over 500 that we have on all 3 of those therapies and their triglycerides persist, and it's not a trivial number of patients. I think I think I saw a paper by Dr. Gude saying that people episodically were over 1,000 might be as common as 1 in 500, but about 1 in 50, 500 had persistent severe hypertriglyceridemia. So certainly a lot more than 1 in a 1 million that we quote for FCS. And in those patients, we often throw the kitchen sink at them, fibrates as well as fish oil and statins, and we no longer are using niacin though in the past, we used high doses of niacin probably caused some diabetics with that, and those patients are an unmet need for sure. They persist despite all of our currently available therapies, safe one, which is now currently available.

Yes. So for these patients that are on multiple drugs and they're still persistently elevated, how do you view them in terms of their risk profile for pancreatitis?

Well, we certainly first get a nutritional consult, which I didn't mention, but that is a very important part of therapy. And then we lose sleep over those patients. Again, once you've seen a patient come in with pancreatitis, you don't ever want to see it again. So as Dr. Subramanian pointed out, not everybody over 1,000 gets pancreatitis, but we still lay awake waiting, and we don't want them to get their first episode because they're more likely to get a second, third and fourth episode. But in general, over 500, I'm quite concerned for all the reasons we've already discussed. It doesn't take much dietarian discretion to push them over the edge.

So let me just follow up on the diet issue. Dr. Subramanian, I know you that you also have all your patients see a dietitian. What is your experience with the patient's ability to keep their triglycerides lower diet, particularly with this genetic disposition, the polygenic that we're talking about. I'm curious what your sense of that is. Of course, we have to do it, but how effective is it?

Very tough. So as we've talked before, a main source of triglycerides is food. And for most people, food is really important. We really -- so focusing on what kind of foods are good for individuals with high triglycerides. So I usually -- when I see these folks, I do a quick diet screen for less than 5 minutes, kind of figure out what their eating patterns are. And some simple principles are avoiding very refined sugars and carbohydrates, switching to complex carbohydrates, decreasing the amount of fat, are they consuming a lot of animal fat, saturated fats. That's all going to go into the triglyceride pool. And for someone who's constantly running in the thousands, a lot of this is food. So really counseling them is really important. So what I do is I refer to my lipid clinic dietitian who has the skill set to kind of tell them -- teach them about what kind of fats where they're coming from and how much fat they need to include in their diet. Additionally, if they have diabetes, sending them to the registered dietitian is another important part of the management process. So however, because this is food and most people love their food, and they have to constantly be vigilant, there's a significant disease burden because they have to constantly think about what they put on their plate during Thanksgiving, when they go to a wedding, when they go on vacation. It's really -- it just weighs them down. And so sometimes they fall off the wagon, and that's when the folks who are predisposed to pancreatitis can get pancreatitis and the recurrent pancreatitis. So it becomes a cascade. So yes, so I think diet and lifestyles are a huge part of managing people with severe hypertriglyceridemia, whatever the range is.

Great. Dr. Baum, you see a lot of these patients. You do a lot of clinical trials and you're seeing what the physicians are worried about, they're referring the patients to you. What would you characterize as kind of their major concerns when they're sending you patients to put in trials for hypertriglyceridemia?

Yes. So first, they're typically horrified by the numbers. They just don't like seeing these numbers in their clinics, right? But when it gets right down to it, they're afraid of acute pancreatitis. That's definitely their biggest fear. They also do understand the connection with cardiovascular disease, though. So that's not nothing, right? It's not inconsequential. But definitely, the big driver is, oh my God, I have this patient with a triglyceride level of whatever, 500, 1,000, 1,500, can't do anything about it, tried everything, on an appropriate diet, can't get it down, please help. So that's really the kind of message we get.

Interesting. Okay. So what I'm hearing is, we have diet, we have 3 classes of drugs but there's still a lot of unmet need. We just don't have anything very, very potent to get you to say, okay, I gave you this prescription, your triglyceride is now under 500. I'm not going to worry about you anymore, at least for pancreatitis. So with that, there's a fourth drug, GLP-1 receptor agonist, and we have an expert endocrinologist here. I wonder if you could tell us how that fits into your treatment paradigm for these patients.

Yes. So the folks who have, as you mentioned, are on all available medications. They're maximized on what lipid-lowering therapies that are available. Again, they fit in the diabetes and no diabetes buckets. GLP-1 receptor agonists are good for people with diabetes as well as for people who don't have diabetes with weight management issues. These are the drugs that are now widely available. They help with weight loss, they suppress appetite. They make you feel full, and they also help with diabetes management. So they have direct -- now we now know that GLP-1 receptor agonists like the drugs that end with tide, semaglutide, tirzepatide, liraglutide, et cetera they have direct effects on the liver to decrease triglyceride production and indirect effects are through weight loss. So when you lose weight, the triglycerides will come down. So when I have someone who's still kind of hovering in the severe hypertriglyceridemia range, that can be in the 500, 600 I won't go to the over 1,000 range because there is a black box warning on these drugs would say that increase the risk of pancreatitis. We will not get into that. But I will use these drugs to help with weight loss and severe hypertriglyceridemia or in people with diabetes who also have the severe hypertriglyceridemia. And there is a decent effect that I have seen.

So if I could follow up to your analysis, the patients that we're focusing here with a high -- very high triglycerides over 880, you're suggesting that the role for those patients for GLP-1 receptor agonist is not as much as the ones for lower. Can you maybe explain that a little bit more?

No, I didn't say that.

I just want a clarification. Go ahead and clarify that. I'm just curious how you see the 2 differences.

Yes. So if you have someone who we know is a risk for pancreatitis or has had pancreatitis from severe hyper triglycerides -- high triglycerides, as I said, there is a black box warning on these drugs, which say you have to exercise caution because the side effect is pancreatitis. But that -- if -- so I do use GLP-1 receptor agonist in people who have severe hypertriglyceridemia, even in the thousands, not maybe like in the 4,000, 5,000 range. But if they're hovering even in the 1,000 range, I will use them because we do get a triglyceride lowering effect. And it will get them off of the pancreatitis range. So there are -- in the community, clinicians are usually nervous about using them in people with severe hypertriglyceridemia because of this risk of pancreatitis. But I'm -- I use them off-label for lowering triglycerides because it's all we have after you've maxed out on everything else. So that's why we really need drugs to address the...

That really speaks to the unmet need, I think, you have to go on 4 drugs and you still have this nervousness.

Yes.

Dr. Brown, I wonder what your experience is in that regard?

I don't have nearly as much experience. So I would just say that I agree with the fact that in patients with diabetes, severe hypertriglyceridemia, it's a no-brainer. You get cardiovascular benefits as well as weight loss and improvement in A1c and a drop in triglycerides. I personally have no experience using it for a nondiabetic with severe hypertriglyceridemia. And I also would be nervous with someone with pancreatitis, but I would send that patient to Dr. Subramanian if I can.

So you could use the weight indication for these folks and use them because you can use them for weight loss. So yes.

Dr. Baum, do you have any thoughts about this? I want to ask you a question if you don't as a follow-up, though.

No additional thoughts.

Okay. So you're looking at your crystal ball here. What would you like to see considering the fact that we have a lot of drugs that are modelly effective, but we still have this unmet need, what would the future look like for you to take care of these patients?

Well, I would love to have a new drug available to be able to manage these patients, a new effective drug because clearly, the unmet need is substantial. I mean we've heard a lot of stories from each of us. Some of them are quite scary. I've seen these patients be in very, very scary circumstances and have, for example, recurrent acute pancreatitis, which is devastating. So having more drugs available with efficacy and well tolerated would be a wonderful thing for all of us.

Great. Well, that's a nice segue to our last segment, which is to think about the future and the near future really, and so I think the audience obviously knows that TRYNGOLZA is approved for FCS. And I maybe start with Dr. Subramanian and Dr. Brown, your experience with FCS patients, both in the trials and maybe if you had some recent experience post approval.

Yes. I have 2 patients now on olezarsen. One is a woman who has FCS and she transferred from the BALANCE study and is now on the drug. I don't have any follow-up labs on her, but I know what her results were when she was in the study. They were amazing. And this is a woman with genetic LDL deficiency who's always run in the 2,000, 3,000 range. And for the first time, she saw triglycerides in the 500s, and she was just so thrilled. My second patient is also another genetically diagnosed. I just started him on it. So I don't have any follow-up, but I'm just glad that these folks have a drug that will keep them safe and give them some flexibility on what they can eat and avoid the pancreatitis and take some of the disease burden away.

Great. Those are great stories. We look forward to more of those going forward. Dr. Brown?

So I have 3 genetically proven FCS patients that are currently on olezarsen. They -- 2 of them were in the BALANCE trial and one just showed up in the office in the clinic a couple of weeks ago. So I don't have follow-up on that patient. But the 2 that are on olezarsen had been in BALANCE and then the open-label extension trial. And one of them had 30 episodes of pancreatitis from the time she was 3, until I met her when she was pregnant at 28 years old. And since she's been on olezarsen, she's not had a single episode, and that included -- she was originally on Volanesorsen and then switched over because of some side effects and got into BALANCE and the open-label extension. So it's been a few years where she hasn't had an episode. So I haven't seen her follow-up labs either because she just came out of the trial. So all 3 of mine, just like Dr. Subramanian are relatively new on the drug. But they're very happy to be on it, especially because of their experience during the clinical trials.

Fantastic. And Dr. Baum, I know you were actually, I think, our first site that opened up for BALANCE and you put in the first patient. I'm wondering what your insights are into what you've been seeing during that process.

Yes. So I have a number of patients who are in the study, and I have the same experience that you've just heard. They're very happy to be on the medication because they understand the effectiveness. So it's not just something that has helped them reduce triglycerides and certainly, we believe, reduce the incidence of recurrent pancreatitis, but it actually is reassuring and comforting to them. So on an emotional level, there's a lot of power to the drug as well. So I don't think we should ignore that.

Fantastic. Dr. Brown.

One other comment. One of my colleagues who is a former fellow of mine now runs the lipid clinic at Cook County, and I was just at a journal club meeting with her. She was talking about a patient who was getting admitted monthly there with pancreatitis who had genetically proven FCS. And she got her triglycerides back on olezarsen, and that was under 300. And she said she cried, the doctor cried. That's how emotional we get about these patients. Again, they keep us awake at night. We worry about them. We felt like a failure in the past despite all of our best efforts because many of them continue to have morbidity despite our best efforts. So I just thought that was a great story. And I think everyone in the room knew exactly how she felt as a physician. Apparently, the patient was crying too when she saw her results. So it was very nice to hear that story.

Well, I think what all 3 are reflecting is that this approach gives patients hope. They've had this disorder for all their lives. They have had a very difficult time dealing with it. You have had a lot of difficult time taking care of them. and they keep coming back. And all of a sudden, there's a whole new way that we're treating this disease with a different approach with RNA therapeutics and olezarsen. And this hopefully will continue to progress. So from that perspective, what we know is in terms of our current landscape, statins are not very effective, fibrates and omega-3 fatty acids tend to work on the VLDL component, the liver-derived triglycerides. But until APOC3 inhibition came around, really had -- didn't have a way to treat the chylomicronemia. So the patients that we worry about, they're over 880, the history of pancreatitis. And so I'm curious what your general sense is all 3 of you about APOC3 inhibition as a new mechanism and how that might impact the disease versus what we've had in the past. So maybe we can go with Dr. Subramanian and then we'll go around to the rest.

I think these drugs hold a tremendous promise. How I see myself using them is when this -- if when approved for severe hypertriglyceridemia, I'll start, I mean, in a tiered approach. So I'd probably start with my severe hypertriglyceridemics with the history of pancreatitis. Again, pancreatitis from severe hypertriglyceridemia, as you've heard, is no joke. People can die from severe hypertriglyceridemia induced pancreatitis. As you've heard many stories now, one of my patients just recently said, I thought I was going to die in the hospital when he went in with pancreatitis from high triglycerides. So that's where I would start. I mean, these people, they really do struggle. It's a daily thing. They're constantly thinking about this. So a drug like this would be really would improve -- would keep these people safe, improve their quality of life. So that's where I start -- I would start and then go down the tier of -- depending on the degree of severe hypertriglyceridemia. And of course, I'd be curious to see what the cardiovascular disease risk with these agents would be as the data comes out and then we'd go down that pathway of treating more and more people with severe hypertriglyceridemia.

Fantastic. Dr. Brown?

Yes, I don't have a whole lot to add to that. I think I'm a metabolism geek, and I tried to understand initially since APOC3 is an inhibitor of lipoprotein lipase, why -- how would it work in a person with broken lipoprotein lipase, removing inhibition on a broken enzyme theoretically shouldn't work, but it did. So it's fascinating to me to understand a little more about how it actually works and causes the LDL receptor and LDL remnant receptor to increase their affinity for chylomicrons when you remove APOC3. So there's a separate pathway that the liver uses to pick up the chylomicrons. So I think that's fascinating. But the more you learn about APOC3, the more fascinating it is. It does so many things from causing peripheral insulin resistance to particularly -- maybe causing beta cells in the pancreas to have apoptosis to affecting triglyceride metabolism and for whatever reason, gets upregulated in people who wouldn't want it to like obese people with pre-diabetes. So -- and when we look at those people who have knockout mutations of C3, we see some things that are encouraging, like reduced risk of atherosclerosis, lower triglycerides, lower LDLs. And though there is a little bit of a glucose increase, it doesn't appear to be due to insulin resistance. It looks like it may just be release of glucose from the liver. So there's a whole lot of reasons to get excited about APOC3. But again, these patients with severe hypertriglyceridemia, they're the ones that we have felt helpless in the past because we didn't have a therapy and having this therapy has been a godsend for the patients, but also for those of us who treat these patients.

Great. And Dr. Baum, you're involved in a lot of clinical trials, and I wonder what your perspective is on this new mechanism and a new approach to treating these patients.

Yes. So I -- first of all, the answers we just heard were phenomenal and don't have that much to add. But I do love this new approach. It's opened the opportunity to manage the patients, as you point out, with regard to chylomicrons as opposed to VLDL. But the approach also is easy to deliver patients, it's well tolerated. So these are all very, very good things. I'm particularly excited. It's always nice to see side benefits to drugs. And if a side benefit has a cardiovascular one, that's really, really great. So when we look at APOC3 and its relationship to cardiovascular disease and we inhibit it, we can get very, very excited potentially. So yes, all good.

All right. This is going to come -- this is the end of our 4 groups. Let me just summarize what I heard, and then we're going to have a question-and-answer session. And just to remind the audience, please type in your question and then we'll address those as they come through. But what I heard is that severe hypertriglyceridemia is fairly common as far as diseases go, but not super common, maybe 1% of the population. But the ones that we really worry about are the ones that have dietary-derived chylomicronemia with triglycerides over 880. We have several drugs to treat more of the VLDL-mediated hypertriglyceridemia, but really APOC3 inhibition is the only one that more specifically addresses these high-risk patients for pancreatitis. There's an unmet need, and there's a lot of new therapies coming down the road that will broaden the indication from FCS to the severe hypertriglyceridemia. And so we're looking forward to some new data coming out later this year. And thank you very much to the panel. Now Dr. Wade Walke is going -- is our Director of our Corporate Communications. and he's going to take our question-and-answer session and help facilitate that. Wade?

Thank you very much, Dr. Tsimikas. So just as a reminder, as Sam said, there's a section on the webcast where you can submit your questions if you click on that link, and we'll take your questions as they come in. We've had a couple that have come in already, so we'll kick it off with those questions. The first question that we have is, do all of the patients that come in with sHTG have comorbidities? And if so, which comorbidities do you have the most concern about? In other words, is there a priority in how you treat patients with sHTG based on their comorbidities?

Yes. We may have a slightly different perspective depending on whether they go to the endocrinologist or the cardiologist, but let me have both of you answer that question. Dr. Subramanian, you can start?

Yes. Mine have a lot of comorbidities, absolutely. They all fall under the multifactorial or group. So meaning they have many different factors feeding into their severe hypertriglyceridemia, like as I said, central adiposity, hypertension, prediabetes, diabetes, maybe medications, but these are the most common comorbidities that I see in my practice. Almost -- I'm going to say 90% of my people with severe, very severe hypertriglyceridemia have these comorbidities.

Yes. I would say that I see probably the majority have comorbidities, but there's not a trivial minority that don't. And those are the ones I remember. I can remember every single one of them is somewhere between 15 and 20 of those patients I'm following now that look like they have FCS that in my earlier years before we did genetic testing, we would say they have FCS. They don't have diabetes. They're not alcoholics. They don't have any other significant disease, but yet their triglycerides are over 880. The majority of them have had at least one episode of pancreatitis, and they're not responding to traditional therapy. And again, now that we're doing genetic testing, we're finding out there's a bunch of these people that don't fit the FCS category that I like to call functional FCS patients. And speaking to some of my colleagues in Canada, anywhere from 30% to 50% of their patients that present just like FCS are these types of patients. So that's a severe hypertriglyceridemic that doesn't have FCS by genotype, but definitely even without comorbidities was an unmet need. And we're grateful that genetic testing isn't absolutely necessary in terms of an option for olezarsen for those patients. But then as Dr. Subramanian said, we see a whole slew more patients that do have comorbidities, consultations in the hospital sometime with new admissions for uncontrolled diabetes and severe hypertriglyceridemia, often presenting with pancreatitis as their first presentation to the hospital and those patients often get better with control of their comorbidities and currently available therapy. So it's a spectrum.

I'm curious, I'm sure Seth has...

Dr. Seth?

Yes. Not too much to add. That was quite the exhaustive response and beautiful. I would say the only one thing I would say is, and this is on FCS. So I don't even know that we want to go there. But we know from other diseases like FH, familial hypercholesterolemia that there are times where people have -- clearly have FH and don't have the mutation identified. And we're still learning a lot about mutations. They're still not all identified. So this distinction between functional FCS and FCS to me is a little arbitrary, and I prefer to just call them all FCS and leave it at that.

Okay. Great. So the next question that we have is looking specifically at patients with sHTG and cardiovascular disease, do you think that decreasing their triglycerides substantially will decrease their cardiovascular and why?

Maybe we'll ask that for the cardiologist. Dr. Brown, if you could start?

The right answer is it depends. It depends on why their triglycerides are high. If they have atherogenic lipoproteins in their serum, the answer would be yes. I think that the majority of those patients hover between 150 and 500. And once you start -- and maybe up to 880. Over 880 as Seth and Dr. Subramanian have both said, they have some sort of a chylomicronemia syndrome. They can have other lipoproteins in their blood, but the majority of cardiovascular risk that we see in the country is in that metabolic syndrome group that has more modest hypertriglyceridemia because, again, VLDL particles have a 5:1 ratio and their remnants have anywhere from 3:1 to 1:1. So they don't tend to get triglycerides quite that high when they have the more atherogenic lipoproteins. And if you see over 1,000 triglycerides, the ratio of triglyceride to cholesterol and the lipid profile is often right about 10:1, which is almost always chylomicrons. And it's when you have both, then you can have cardiovascular disease on top of severe hypertriglyceridemia. So I think it's the midrange, the moderate range that we really worry about cardiovascular risk with a few exceptions, which are diabetics, for example, uncontrolled that are going to have atherogenic lipoproteins and chylomicrons in their blood.

Great. Dr. Baum, do you have anything to add to that?

Yes. I agree. It's the lipoprotein particle that's carrying the triglyceride that's going to let us know whether there is risk for ASCVD. And frankly, the majority of these patients that we're talking about today in the 500 up range have a lot of those atherogenic lipoprotein particles. When you breach the 880, you know you have chylomicrons. That doesn't mean you don't also have VLDL and VLDL remnants. So I'm optimistic, I would say, that we're doing -- that by reducing these triglycerides, we will be reducing cardiovascular risk.

And we don't have to guess because we have ability to do noninvasive imaging and determine whether a patient has atherosclerosis. So a calcium score, again, is an extremely helpful tool. And I always point out that not everybody who crosses the street with a red light gets hit by a car. Not everybody with dyslipidemia of any type gets atherosclerosis. That includes familial hypercholesterolemia patients. Some for whatever reason, get none. So it's nice to be able to look at a person's heart. And if they have a 0, they have a surprisingly good prognosis. But we don't have to guess anymore whether the dyslipidemia needs to be aggressively treated for cardiovascular disease as well as for pancreatitis.

Can I add something?

Yes, please.

As a non-cardiologist, chief endocrinologist, you can actually just get a simple family history. And if there's a family history, many of these folks will have other family members who have mild to moderate hypertriglyceridemia. So family history of cardiovascular disease can be extremely helpful. That's what I use. I do use some imaging, but as...

Yes. That makes sense because, for example, familial hypertriglyceridemia, which is a VLDL disorder, is not associated with much increased risk for cardiovascular disease. They don't have too many particles. They have large VLDL particles. And they have family history of smattering of pancreatitis with 5x the cholesterol. Their triglyceride level is 5x the cholesterol. But it's a dominant trait. So a parent is going to have similar triglycerides and there'll be pancreatitis, but very little family history of heart disease as opposed to familial combined dyslipidemia or other associated with cardiovascular disease. So taking a good history, examining a patient is still important.

Thank you. All right. So the next question is directed to Dr. Subramanian. You have 50-plus patients with a history of pancreatitis, but only 2 on commercial therapy. What's the holdup in getting more patients on olezarsen?

Yes, so the people who are on olezarsen are the ones who are genetically diagnosed familial chylomicronemia syndrome, which is what the drug olezarsen is approved for as of now. These are the people who have 2 gene defects, so meaning they're homozygous LPL deficient, meaning they have no enzyme clearing capability, and they've had this condition since they were kids or adolescents. The rest of my population is all what we put in the polygenic or the multifactorial severe hypertriglyceridemia who don't have this genetic defect and olezarsen is not approved for that yet.

And just one clarification. The label for olezarsen doesn't require genetics. It's the clinical -- I just want to make sure the audience -- your patients have the genetics, but they don't need to have that to be on olezarsen.

Yes. So the folks that are not treated with olezarsen are the multifactorial folks who have polygenic etiology and have many different contributors.

That's kind of patients we're talking about today.

Today, yes, exactly. Exactly.

Right. So I'm putting a plug-in for the North American scoring system. This was an issue for us because we don't lose any less sleep over those patients with negative genotypes for large gene mutations that act exactly like patients with a positive genotype. And I think we can all agree on that, right? So we did develop a clinical scoring system that allows us to come up with a diagnosis of FCS in the absence of a genotype, which would be those functional FCS or as Seth pointed out, it'd be the people we all would have said had FCS before we had genetic testing available. So those are patients that we would consider for olezarsen. And I've already heard of several of my colleagues who've used that scoring system and been able to get patients on therapy.

I was going to ask you some feedback. So they're finding you useful and -- to use that in lieu of genetics when they're not available or they're not done.

Yes. We had to get together during the ACC of several lipid geeks and several of them said they've been able to use that to get their functional FCS. In other words, persistent severe hypertriglyceridemic patients that didn't respond adequately to traditional therapy through the scoring system, they've been able to get the therapy and get it approved.

Okay.

Thank you. So the next question deals with the percent of patients of your sHTG patients that are taking statins, fibrates or omega-3s, how many of those patients or what percent of those patients end up having an acute pancreatitis event?

That's a hard question. Yes, we don't know who gets pancreatitis. Those numbers, we just don't know. That's the best answer I can give you. Unfortunately, I don't know.

Yes. I don't know the denominator. I don't know how many didn't get acute pancreatitis because most of the ones that get referred that we hear about have come in with an episode of pancreatitis. So I guess Seth will probably know the numbers here, but once you're over 1,000, it could be -- somewhere between, what, 8% and 15%.

Yes, something like that. But I wanted to reframe that question because I think maybe the question would have been more -- nothing against the question. It was a good question, but might be more pertinent if we reframed it to say what percent of patients on statins and fibrates and omega-3s don't get their triglycerides below 500. That's really the issue because those drugs independently don't reduce the risk of acute pancreatitis. It's the number, it's the triglyceride that's critical. And so we know from what we see in clinical trials where most of the people coming in are on multiple therapeutics to reduce triglycerides, they still remain over 500. So it's the inadequacy of the treatments that's really that issue here.

Yes. I think that's been guesstimated if you take the whole population and look at those that are persistent despite aggressive therapy, somewhere around 1 in 50, 500 patients. So it's still a fair number of patients as opposed to maybe 1 in 500 who've had triglycerides over 1,000 episodically, the ones that persist, they're more rare, but they're not extremely rare, certainly not 1 in a 1 million. And I would say if the question is how many of our patients are on all of those, virtually all of those patients over 1,000 are on all of those therapies. And we sometimes have to stop the omega-3s because we've had a few patients get pancreatitis on them, as Dr. Subramanian pointed out. But otherwise, they're on everything, and we're treating ourselves as much as we're treating the patients in that situation.

So a related question, I think, is, so you have these patients, they're on all these different therapies to try and manage the triglycerides they're still above 500 and had a history of acute pancreatitis or they're above 880 or 1,000 and they're refractory to these treatments, they still have these high triglycerides. Do you treat patients who have had acute pancreatitis differently than those in those -- in that condition than those that haven't yet had pancreatitis? Or do you treat them all the same if they're refractory and they still have high triglycerides?

If they're over 1,000, it would be a no-brainer to me. If I could get them approved for olezarsen, I would use it, because as we've all stated, none of us want to see the first episode. It is true that some patients never will get pancreatitis, but we can't predict which one of those patients would be the one that's never going to get it. And after the first episode, they're more likely to get more as we've all stated. So we don't want them to get the first episode. I think if there are over 500, but less than 1,000 on maximal therapy and never had pancreatitis, we would have a harder time getting approval for it. We'd have to go through the scoring system again. And the triglyceride levels are part of the score and having pancreatitis is part of the score. So it might not be that we might not be interested in using it in those patients, but be harder to get approval for it.

About that first episode of acute pancreatitis, it occurs at some point in time, obviously, right? So we've all seen it occur with people in their teens, and we've all seen it occur with people in their 40s and 50s, and that's the first episode. When they're between their teens and their 40s and 50s and beyond, we never know when they're going to have or if they're going to have their first episode. So we always have to treat these people as though they will have pancreatitis. If the triglycerides are that high, we look at them and we go, you are at great risk for acute pancreatitis. We need to address you seriously so you can avoid that because your first episode could truly, truly be the end, people do die with their first episode of acute pancreatitis, we don't want that.

The number is about 6%. That means 1 in 12 or 1 in 13 people die. I don't think folks realize the magnitude of the risk there, and they die a horrible death. So that's why we are all so fixated on trying to avoid pancreatitis.

Thank you. So the next question is asking about the symptoms that patients who have very high triglycerides. So patients above 880 mg per deciliter, what kind of symptoms do you see? Because they mentioned that in FCS patients, besides acute pancreatitis, there may be abdominal pain, described brain fog, symptoms like that. Do you see those kind of symptoms in patients with sHTG who are greater than 880?

I can take that. So many folks who have severe hypertriglyceridemia have no symptoms, especially the group of people we're talking about today. It's incidentally picked up by a lipid panel, by whoever they're seeing like maybe a primary care provider and then they see the numbers and they're like, oh my God, this is so high. So it's usually asymptomatic. If someone is really in what I call the pre-pancreatitis range, if they've really gotten their triglycerides high and there's impending pancreatitis, they may have this increasing heartburn. They feel really tired and fatigued, some joint aches and that just not feeling right and then eventually, that tips over to pancreatitis. That is usually the folks who have either had pancreatitis before. That's what I call the pre-pancreatitis prodrome or the symptoms that lead up to that. But most just don't have any symptoms. They just don't, not for this group of people we're talking about. The brain fog. And I mean, it can happen when there's very -- like very, very high numbers, like we're talking about like 3,000, 4,000 in some people. But many don't feel it. I had a guy last week, 4,000 triglycerides. He doesn't feel anything.

Does that make you more worried or less worried?

Totally more worried, yes, because...

There's no warning.

Yes, there's no warning. And this gentleman who's had recurrent pancreatitis, for him, it's all food. He's a chef. And he -- it kills him to not be able to eat the kind of food he wants to eat. But the last time he had pancreatitis, he said it just came on all of a sudden with severe upper abdominal pain radiating in the back.

Yes. I don't know the secret to that. I have had the same experience that many of the patients with severe hypertriglyceridemia are asymptomatic. Certainly, that isn't true about FCS patients or the FCS-like patients, and it probably has something to do with the persistence of that severe hypertriglyceridemia. It gives you hyperviscosity of the blood. You can even have strokes with really high triglyceride levels because the blood just gets thick. But in addition to that, that general feeling of malaise and brain fog. So we certainly see it in the FCS patients and in that group of patients that act like FCS, but have a negative genotype. But the ones that are a little more episodic, I think often, as Dr. Subramanian said, are asymptomatic. And I thought about this a lot. I don't know what Seth's experience is?

Yes, it's really the same. Nothing to add there, yes.

Thank you. So the next question we actually get a lot, and it has to do with the clinical trials we're conducting because the primary endpoint in the Phase III studies is triglyceride reduction. But one of the key secondaries is looking at acute pancreatitis. So the question we often get is, in the clinical trials, how important is it to observe a statistically significant reduction in acute pancreatitis events? Will significant and sustained reductions in TG be enough for a new agent to get approved or adopted in practice? Or does it require you to show a statistically significant reduction in AP events in order -- and have that in the label in order to use it? Or for you to be want to use it?

You mean to get that indication?

No, just -- I mean, to use it in patients with sHTG, is it -- how important is it just to hit the primary endpoint of TG reductions versus also seeing a statistically significant reduction in acute pancreatitis events?

Well, seeing 11 episodes in a placebo and 1 in the treatment arm is pretty encouraging. But I would just point out for the last 4 years that I've been doing this, 40, I'm getting old. We've been using drugs to lower triglycerides with absolutely no data that they reduce pancreatitis because we made the assumption that they probably would since we knew severe hypertriglyceridemia led to pancreatitis. So fibrates, omega-3s, et cetera, none of them have had a statistical reduction in pancreatitis. And the reason is they weren't studied in populations with a high enough prevalence of pancreatitis to be able to show it. So I think we're on the brink of being able to see that. We certainly numerically saw a remarkable reduction in pancreatitis in the BALANCE trial. And I think the reason is we were finally studying a group of patients that had enough episodes of pancreatitis to be able to see that. But I think all of us believe that we will soon have statistically significant reductions in pancreatitis in larger trials.

Yes. So I would just say it certainly would be nice to see the statistically significant reduction, but we do understand the relationship between hypertriglyceridemia and pancreatitis. And the higher the triglyceride, the greater the risk of pancreatitis. We do understand that. And triglyceride-induced pancreatitis is not a small issue. It's the third most common cause of pancreatitis. So it's something that we need to deal with. And I would say at this point, seeing the triglyceride reduction will give us all enough comfort to use the medication with -- certainly in the absence of seeing a statistically significant reduction, if that remains the case, we'll still feel very comfortable that we're doing a very good job at trying to reduce that risk of acute pancreatitis. So...

Thank you.

Can I add something to that?

Yes.

So this just goes down to pathophysiology of hypertriglyceridemia pancreatitis, very high triglycerides, pancreatitis. You bring the triglycerides down because that's how they treat in a hospital. If they land up in a hospital is nothing by mouth, bowel rest, pancreatic rest. And that is what will bring the triglycerides down and they're out of the pancreatitis range. So if you have a drug that does that effectively, I mean, I would not hesitate to use it in this population because these people are sick and they need something.

Thank you. I think we have time for one more question because we're running out of time. These all been great questions. The last one is a little complicated, so I'll go through it here. So for the more milder patients, those with triglycerides between 500 and 880, the milder and the severe. How motivated are they to seek or use treatment to lower their triglyceride levels to avoid a fatal event like pancreatitis? And then part 2 of that question is, in your experience, how compliant are patients with taking other potential medications like fibrates and omega-3 fatty acids? And how helpful are they in the real world? What's been the actual triglyceride lowering that you're seeing? I think you answered that during here, but kind of related to the first part.

Sure. So I think there are many parts to that question. So how effective are fibrates in lowering triglycerides. I think that was the last part. They're effective in mild to moderate hypertriglyceridemia. Well, they will lower triglycerides. However, there's no -- if we're -- it depends on what we're using it for. If we're using it for cardiovascular risk reduction, there's no clinical trial evidence that they're beneficial. But if we're using it for pancreatitis prevention, sure, it will lower triglycerides. How often do the patients take them? If they don't have side effects, yes, they're pretty well tolerated and most people will take them. There's always adherence issues in some people who have side effects on medications. But if you educate the individual, it's always -- it works. Fish oil, I will defer to Dr. Brown because I am not a big fan of fish oil, except for maybe for cardiovascular risk reduction with Icosapent. So for lowering for pancreatitis prevention, I don't really use it very much. So I will defer I think...

Yes. I go back to the days when we only had over-the-counter fish oil for persistent severe hypertriglyceridemia, we used it. And I currently try to segment my patients into those I'm worried about cardiovascular risk, in which case I use Icosapent ethyl. I have some young individuals in their teens and 20s with severe hypertriglyceridemia where the risk is more pancreatitis and then I would use traditional fish oil, EPA/DHA combinations, prescription brand. And they're effective in lowering triglycerides in those patients. Once you get over 880, none of those things are uniformly effective. Adherence to a pill, unfortunately, the more pills you take, the less the adherence. So taking 2 big capsules twice a day makes the omega-3 a little harder and some people get GI side effects from it. But any pill daily is a problem. I have to tell my patients, rubber band your pills to your toothpaste, so you don't forget to take it. On the other hand, I think the once-monthly injectable is just an example where hopefully, we're going to see better adherence with a little bit less having to remember everything every day, but that remains to be seen. So adherence for hypertriglyceridemia is an area I just don't know the data on it. I know that after someone has an acute MI and they're taking a statin at a year later, only half of them are still taking their pill, and that may be because of all the superstitions around statins and misguided information about side effects. I don't have that data for fibrates and omega-3s. But in terms of effectiveness in that over 500 group, they're fairly effective in some patients, but there's a subset of patients that we've all discussed where despite those efforts, they still need additional therapy.

Thank you. Well, that brings us to the close of our program today. I want to thank Dr. Tsimikas for moderating this panel today and especially to our experts on the panel for joining us for this lively and I think very informative discussion. I think your insights really help to illustrate the risks that are associated with severe hypertriglyceridemia and the remaining unmet need for people living with this disorder. We also appreciate our online audience for submitting questions and joining us today. As Sam noted at the beginning of this event, this is -- today's webinar marks the beginning in a series of events this year that are focused on olezarsen. We are eagerly anticipating the Phase III data from our ESSENCE study in midyear and also from the CORE and CORE2 Phase III studies in the second half of this year, both key milestones as we advance toward potential sHTG indication for olezarsen. Today's discussion was a great way to kick off this year's great events and exciting year, and we want to thank everyone.