This represents one of our most important programs at Ionis, particularly as we are getting ready to read out our phase III programs. We are 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. 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 a esteemed panel of experts that will help me and you lead the discussion on hypertriglyceridemia. We have Seth Baum. We have Dr. Seth Baum. We have Dr. Savitha Subramanian and Dr. Alan Brown. I'm going to allow them to introduce themselves in a little bit. First, let me just go over the agenda for today. We have four main objectives.
One is to learn about the pathophysiology of hypertriglyceridemia, especially severe hypertriglyceridemia, and its prevalence. 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. We are going to review the current standard of care for these patients and how they're 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. We are going to review the exciting new treatments that are coming forward for these patients. 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. 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. I'm going to start with Dr. Seth Baum first, who is online with us. Seth?
Yeah, thanks, Sam. 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. I'm also the chief medical officer of Flourish Research, which is a research company that has sites around the country conducting clinical research. I have a good deal of experience in clinical trials with severe hypertriglyceridemia. It's great to be here today.
Thank you, Seth. Dr. Subramanian?
Hi, 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. Anyone with any severe hypertriglyceridemia issues gets sent to us.
Great. Thank you. Dr. Alan Brown?
Hi. My name is Alan Brown. I am the Director of the Lipid Clinics for the large healthcare system in the Midwest, Advocate Medical Group. I actually am an interventional cardiologist, but have been interested in lipids since the mid-1980s when I started my first lipid clinic. I got labeled both a lipocrit and a balloonatic at that time. I have been doing it for 40 years. I also do clinical research, particularly in all different types of dyslipidemia. I am a past president of the National Lipid Association and Clinical Professor of Medicine at Rosalind Franklin in Chicago.
Great. Thank you, Alan. I think as you can see here, we have covered the expertise in lipidology, cardiology, endocrinology. This is very well-rounded in the discussion we're going to have today for severe hypertriglyceridemia because it spans both cardiovascular disease and metabolic disturbances. It really requires two sets of expertises, in a sense, to be able to deal with this issue. 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. I think that will help us kind of put in context what we do on a day-to-day basis and what our patients go through. I think that will frame the discussion on the various areas that we're going to discuss.
The first area that we'd like to discuss is to understand what the disease is, what its pathophysiology is, and what the prevalence is. We'll go through each one of those in a little more detail. I thought maybe I would 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? Put that in context in what we're going to talk about later for the patients.
Sure. That sounds good. First of all, it's important to know that triglycerides are fats, the most common fat that we consume, highly prevalent in the body. Triglycerides are carried in the blood in spherical lipoprotein particles. Blood is an aqueous solution. Fat and blood do not mix. 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 are stored as fat in adipose tissue. These lipoprotein particles are often atherogenic, meaning they cause vascular disease. In the highest triglyceride levels, those exceeding 880 mg/dL , there are also chylomicrons that are much larger particles filled with triglycerides and that are not atherogenic. 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 mg /dL . 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. That is about 1.3% of the population. When we get beyond 880, again, in that sphere where we're having chylomicrons, the prevalence falls significantly to maybe 0.2%-0.3% of the population. Genetics plays a huge role in hypertriglyceridemia, most of the patients having very, very small effect genetic abnormalities in multiple genes. There are 30-plus genes that can lead to hypertriglyceridemia, so many abnormalities having small effects. When you get beyond the 880, 1,000 mg /dL , we have larger effect mutations in a fewer number of genes. One or two may have a mutation.
Environment plays an enormous role as well. You have these either multiple small effect genetic abnormalities or these single or double large effect ones. The environment on certain medications, in overweight or obesity, diabetes out of control, alcohol, things like that can severely disturb triglyceride levels. That is basically the landscape of 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 880 or much higher than that.
Yeah. As Dr. Baum very elegantly mentioned, triglycerides are carried in these large particles which float in the blood called chylomicrons. They have to be digested. After you eat, triglycerides go up when there's fat in the food, which is pretty much most meals. There's a whole bunch of genes that help clear the triglycerides from the circulation. All these genes, and there's many, many genes. The primary gene for the clearance of triglyceride is lipoprotein lipase, or LPL. There are many cofactors that help lipoprotein lipase, or LPL, do its job. When there's any abnormalities in clearing your triglycerides, there can be issues with triglyceride clearance. Triglycerides accumulate in the blood.
In people with severe hypertriglyceridemia, which is what we're talking about here, you can, for the LPL, you get one gene from the mother and one from the father. If there's one gene that 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 where triglycerides range from 200-500, or they can be much higher. These are the single-gene heterozygous pathogenic variants. The other bucket that Dr. Baum actually mentioned is the small-gene effects. Sometimes you can have these very minor variations, single nucleotide polymorphisms, in many different genes. Again, these are also inherited. If you do a genetic test, you can't really pick them up. They're SNPs.
If you inherit more than one from either of your parents, you can have mild to moderate hypertriglyceridemia. 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. These are the two big buckets. Most people fall in the polygenic or the minor-gene variant groups.
Let me just summarize then what I heard. First of all, severe hypertriglyceridemia has levels at least 3x-20 x higher than what we consider normal. It is 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. It is a genetic disease, but it is not the typical genetic disease of a single gene knocking out. The other part of this that I wanted to clarify is that let's just make sure the audience knows there are two 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 two 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 8x-10 x the triglyceride level compared to the cholesterol. 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 to 1. In both cases, those large triglyceride-rich particles go through the capillaries where they're acted on by lipoprotein lipase.
The triglycerides are removed and broken down into fatty acids, for example, in the muscles to be used as energy. You can think of the cycle as whether it comes from the liver, 5 to 1 triglyceride to cholesterol, or the gut, 10 to 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. There are two different ways we get triglyceride-rich particles in the blood.
With all of this, Dr. Subramanian, is it fair to say that all of these influences are summated in one measurement, which is their 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, yeah. Triglyceride measurements are helpful. You can use non-HDL, which is part of a standard lipid panel. I think triglycerides are pretty reflective of what a person's status is.
Okay. Perfect. Okay.
Yep.
Dr. Baum, please.
Sorry. To Alan's beautiful commentary, those two different sources, the liver source is the atherogenic lipoprotein particle source. The gut source, the chylomicron source, is not. I just wanted to clarify that.
Thank you 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. Once those chylomicrons start to be metabolized into smaller remnants, they can be atherogenic. It is 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. As Seth pointed out, it is not the chylomicron. It is the breakdown particles that are participants in atherosclerosis.
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 two 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?
You know, I've had patients tell me they'd rather die of a heart attack than pancreatitis. 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. 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 150-500, I think 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. 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.
Dr. Subramanian, yes, please.
Can I add? In people who have severe hypertriglyceridemia, they also store triglycerides in the liver. It is an increased risk for metabolic-associated steatohepatitis, what used to be called NASH. I've forgotten the old term. It's called MASLD now. That is a risk. MASLD now we know is associated with increased cardiovascular risk, indirectly. Severe hypertriglyceridemia causes.
How do you identify those patients that they have in association with the 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. By looking at blood work, they may have a slight increase in liver enzymes, AST and ALT primarily. 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 just from whatever data you already have to see if they have fatty liver.
That's interesting. Not only is it a risk for atherosclerosis, but it's the number one cause of liver transplantation now. Steatohepatitis leading to cirrhosis. It's eclipsed alcoholism as the number one cause.
Yeah. Fantastic. 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 the other patients? Do you see them differently? Do they have different risks, different complications?
Yeah. So that group of the over 880, which by definition means they have chylomicrons in the circulation, or 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. As Alan said, many patients would prefer to have a heart attack rather than acute pancreatitis. 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 is a consequence of that pancreatitis. The mortality is very high.
The mortality rate is certainly 6% or greater. In severe hypertriglyceridemia-induced pancreatitis, mortality rates really do seem to be higher than they are for other forms of pancreatitis. That's our patient population we need to focus on.
It's interesting that the two cardiologists here both say they would rather 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, patient with long-term complications. Alan, I wonder what your thoughts about that. 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?
In the patients who have severe persistent hypertriglyceridemia, you know it is devastating in a number of ways. I always say those are the only lipid patients that keep lipidologists up at night because those patients, despite your best efforts, come in with recurrent episodes of pancreatitis. 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. You know that they're losing beta cells with each episode and that they're on their way to potentially diabetes. It is difficult for the physician because you feel like a failure in those patients who don't respond to traditional therapy. It is very frustrating for the patients who, despite their best efforts in many cases, still have episodes of pancreatitis.
I think we tend to think, oh, maybe they didn't follow the diet. Even the ones who are really good with their diet at times will have episodes.
Yeah, that's an important observation. Okay. 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. I would like to ask the other two panelists to tell us about their own healthcare 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. Dr. Baum?
Yeah. I'd say for just high triglycerides, meaning greater than 150, it's very prevalent, 25% of the population. 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. We're talking about, and our focus really, I think, today is that very vulnerable population, greater than 500 with a history of pancreatitis or greater than 880. It's probably in the order of close to a million people in the United States.
Okay. Great. Thank you. Let us know about your own healthcare systems and your own individual pool of patients that you see, each of you.
Do you want me to go?
Sure. Dr. Subramanian, sure.
Yeah. As I mentioned before, we have a tertiary referral center. Severe people with four-digit triglycerides, as they 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 internists, family doctors, mid-level providers, so ARNPs, PAs, 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 and management, especially because of their risk of pancreatitis. How many people with severe hypertriglyceridemia do I have under my care?
The ones with severe hypertriglyceridemia and pancreatitis, I'm going to say at least 30 patients in my panel. 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. I'm going to say 40% of my panel is severe hypertriglyceridemia.
Okay. Dr. Brown? We're going to give you a microphone to help there. Yep.
I know. I'm getting louder and softer. Yeah. I also have a tertiary care clinic for lipids. My catchment area is the suburban area and city of Chicago. We have two types of hypertriglyceridemic patients. Of course, the moderate ones, the 150-500, is about half the population. That's a huge group. Over 500, a smaller group, as Seth pointed out. Those with pancreatitis, even smaller and over 880, 0.2-0.3%, as Seth pointed out, in the population. I have a handful of patients with genetically proven FCS who have severe persistent hypertriglyceridemia and the classic genotype, and about three to four times as many persistent severe hypertriglyceridemic patients. I think we all see maybe a new onset diabetic patient who comes in with triglycerides of over 1,000.
Once their glucose gets under control, they get better, or someone who went on a drinking binge. There are 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 do not have the large gene mutations that we traditionally think of as FCS. They are polygenic, as was already pointed out by Dr. Subramanian. Those patients, despite traditional therapies, have persistent hypertriglyceridemia. The vast majority have had several episodes of pancreatitis.
Okay. What is your sense of the referral patterns and how many patients you're getting now? I know, Dr. Subramanian, you mentioned you have three 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?
Yeah. After three days of my clinical practice, two days are full lipids, one day is fully diabetes. I also run an electronic, an e-consult program. That e-consult program, our primary care providers can send electronic consults to us, and I do all the lipid consults. A big part of education and figuring out how they refer is through my these serve as an educational mode also. They learn when to start medications and who are the ones that need to be referred. That's a big way how I get information out into the local community. Beyond that, our clinic is a word-of-mouth clinic. If anybody with severe hypertriglyceridemia, especially over the 880 or 1,000 and with pancreatitis, 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.
Okay. Great. Alan?
Yeah. 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. We get referrals for almost everybody with high triglycerides that haven't responded to traditional therapy. We get referrals for triglycerides of 300 up to 5,000, 6,000. 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. We're the fifth largest healthcare system. We have a lot of primary care doctors. At the moment, just a couple of lipid clinics. It's also our 40th year.
Fantastic. This is a great wealth of experience. This first section, I think, took a little longer than we anticipated, but we did that on purpose just to make sure everybody was grounded on what we're dealing with in this. Let's go to the next section. We're going to talk about the patient now. We have a patient sitting in front of us, and we do our history and physical. Alan, what kind of things are you finding in these patients with hypertriglyceridemia? Maybe give us a sense of what those patients are like.
I think as a lipid geek, the first thing we ask is, why are the triglycerides high? We start thinking about particles. Is this a VLDL problem? Is it a chylomicron problem? A lot of it can be guessed based on the level of triglycerides, as Seth and Dr. Subramanian have already pointed out. That leads us to look at secondary causes of the high triglycerides. 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? 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. The first step is lifestyle modification.
That's more effective on triglycerides than it is on LDL, for example. We really focus on a low-fat diet, reducing simple sugars. The second step is to try to control any secondary causes. Thirdly, to determine, if possible, what the underlying genetics might be in that patient. Based on those approaches, we determine what the appropriate therapy would be for the patient.
Okay. Dr. Subramanian, from your perspective, how much has diabetes played into severe hypertriglyceridemia? What other kinds of things do they come in with in terms of hypertension, cardiovascular disease, other risk factors that worry you besides just the triglycerides?
Yeah. Sam, as you described, I put my people with severe hypertriglyceridemia in two buckets, those without diabetes and those with diabetes. There is a lot of overlap between the two because the metabolic syndrome, body type, central adipose tissue distribution, hypertension are all big contributors in both groups, 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. 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. These are pretty common ways that people present to my clinic.
Very good. We are going to talk about specifics for treatment in the next section. 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 am curious, Dr. Brown, what is your overarching treatment goals for these patients?
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? 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 zero, but it's significantly less. That would be a patient that I would get a calcium score and try and determine do they have subclinical atherosclerosis. The principal goal would be reduction in risk of pancreatitis. That's true for everybody over 500, as I mentioned earlier. Once the dust settles, once you get over the acute risk of pancreatitis. I might add, if you're over 500, a couple of beers gets you over 1,000.
It does not take much to push you into that threshold where the risk of pancreatitis is significant. We would, after those severe hypertriglyceridemic patients have their triglycerides controlled, take the next step to assess them for atherosclerosis. In your mind, again, you are trying to determine what is their diagnosis to help you decide what their risk for atherosclerosis would be. There is nothing better than a calcium score, which is $49 in my city. That is without insurance.
I want to focus a little bit on the acute pancreatitis risk. Maybe Dr. Subramanian and then Dr. Baum, how do you view that in these patients? What worries you the most? What's the kind of patient when they'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.
Yeah. 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. It's an impending risk. We don't understand who gets pancreatitis and who doesn't. You can't take that risk. That's important. Of the people who get pancreatitis, who gets pancreatitis? Anybody with triglyceride in the 4-digit range. Anything above 1,000, the cutoff point is that 880-1,000 because everything is saturated and you can't clear the triglycerides. What else did you want me to? I lost my train of thought here. Sorry.
Yes. No, that's fine. I think what you're reflecting is that the really high triglyceride patients are the ones that you worry about. Whether they had pancreatitis or not, they're still a very high risk. 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. As Dr. Brown mentioned, a person who's already had pancreatitis from high triglycerides is at significantly increased risk for developing another episode. They would, even though their triglycerides are 500 or 600, be 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.
Right. I want to just discuss the issue of cardiovascular disease. Dr. Brown, you already mentioned that a little bit. Dr. Baum, maybe you can expand on that a little bit in terms of that part of that equation in people with SHTG.
The cardiovascular disease? Could I address the pancreatitis?
Oh, yeah. 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. The higher the triglyceride, the greater the risk. We also know that triglycerides can rise very significantly with very minimal influence by diet, right? As Alan mentioned, two beers. 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. 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 eat, drinking out, whatever, those are people who really make us very, very afraid. 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. It is very concerning. Yes, pancreatitis is more frightening than even a heart attack, harder to deal with, quite frankly. 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. We have to understand that these people are at quite significant risk. Cardiovascular disease still remains the number one cause of death in the United States. We have to take these people very, very seriously and address their risk.
Right. I want to. Oh, Dr. Subramanian.
Yeah. Sorry. To Dr. Baum's very elegant explanation, I want to highlight that sudden risk of pancreatitis. 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. Those people can all of a sudden never have had pancreatitis and go into pancreatitis. 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? 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. Yeah. The people who have these fluctuations and who run in the 500,000 range, they have that genetic predisposition. Whereas the ones who do not have that, I do not believe, have that pancreatitis risk. Yes, absolutely.
Dr. Brown.
This was alluded to earlier. When your triglycerides are over 1,000, you've pretty much saturated your lipoprotein lipase receptors. All the lipase is busy and not available to pick up more particles. That is when a dietary indiscretion is really going to be an issue. It is also why our traditional drug therapy does not work too well in those patients until they drop below 1,000. Those people who hover persistently over 1,000 are particularly susceptible to dietary indiscretion, as we've all said in different ways.
Yeah. I think it's important for the audience to understand that when we're talking about these values of triglycerides, they're fasting. That's the best-case scenario. Most of the day, we're in the postprandial state. Once we eat, we typically don't measure postprandial triglycerides. They're much higher. The fasting level is the best you're going to get, is, in a sense, the way to think about it. We're now fluctuating up and down throughout the day depending on what we eat. 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 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?
What is the standard of care? Maybe Dr. Baum, you can start. Tell us what the standard of care is for these patients that are sitting in front of your clinic. What's in your toolbox? What do you have to offer them right now?
Yeah. 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. 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. Unfortunately, it turns out that these therapeutics are often inadequate to get our patients under 500 in a sustained fashion. 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.
Physicians are very, very afraid of acute pancreatitis.
Okay. Dr. Subramanian, how effective do you find statins, fibrates, omega-3 fatty acids in your patients? What is missing there, if anything, that you would like to have if you do not have it right now?
Statins are cholesterol-lowering drugs. They're not triglyceride-lowering drugs. They are not very effective in lowering triglycerides, maybe 20% if you're lucky. Fibrates are more potent. They work to increase beta oxidation. They burn up triglycerides, increase fat breakdown or triglyceride breakdown. You can get up to a 40%-50% based on studies. Do we get that? It depends. There is variability. They are the most potent of triglyceride-lowering drugs we have currently. Omega-3 fatty acids, again, or fish oil, you have to take at least up to 4 g a day to have a benefit. They can also, based on what we know from the literature, 20%-50% is what they claim for lowering triglycerides. I don't find them very effective. The one thing about fish oil is that in people who have very severe hypertriglyceridemia in the thousands, they don't really work.
Fish oil is also fat. It can increase hepatic or liver VLDL secretion. You need to exercise caution in people who have very severe hypertriglyceridemia. I do not use it very much.
Okay. Dr. Brown, your thoughts on current therapies?
I agree with it depends. The people in the moderate range, I would say under 880, they often have comorbidities, other issues that affect their triglycerides. Many of them will respond to fibrates. Statins, especially if you have a patient that you're worried about atherosclerosis, the higher your triglyceride level, the more reduction with the statin. It can be up to 30% in patients with over 500 triglycerides. If you're worried about atherosclerosis, many times we would start with a statin, especially if triglycerides are under 1,000. 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.
In my hands, you can get a 40%-50% triglyceride reduction, again, in those people with higher triglyceride levels. Fibrates to avoid pancreatitis because on top of statins, they have not shown a significant reduction in CV events. We have all had that group that is over 880, some over 500, that we have on all three of those therapies, and their triglycerides persist. It is not a trivial number of patients. I think I saw a paper by Dr. Godet saying that people episodically were over 1,000 might be as common as 1 in 500. About 1 in 5,500 had persistent severe hypertriglyceridemia. Certainly a lot more than 1 in a million that we quote for FCS. In those patients, we would often throw the kitchen sink at them, fibrates as well as fish oil and statins.
We no longer are using niacin, though in the past, we used high doses of niacin, probably caused some diabetics with that. Those patients are an unmet need for sure. They persist despite all of our currently available therapies, save one, which is now currently available.
Yeah. 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?
We certainly first get a nutritional consult, which I didn't mention, but that is a very important part of therapy. 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. As Dr. Subramanian pointed out, not everybody over 1,000 gets pancreatitis. We still lay awake waiting. We don't want them to get their first episode because they're more likely to get a second, third, and fourth episode. In general, over 500, I'm quite concerned for all the reasons we've already discussed. It doesn't take much dietary indiscretion to push them over the edge.
Let me just follow up on the diet issue. Dr. Subramanian, I know that you also have all your patients see a dietician. What is your experience with the patient's ability to keep their triglycerides low with diet, particularly with this genetic predisposition, the polygenic that we're talking about? Curious what your sense of that is. Of course, we have to do it. How effective is it?
Very tough. As we've talked before, a main source of triglycerides is food. For most people, food is really important. Focusing on what kind of foods are good for individuals with high triglycerides. Usually, when I see these folks, I do a quick diet screen for less than five minutes, kind of figure out what their eating patterns are. 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 fat? That is all going to go into the triglyceride pool. For someone who is constantly running in the thousands, a lot of this is food. Really counseling them is really important.
What I do is I refer to my lipid clinic dietician who has the skill set to kind of 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 dietician is another important part of the management process. 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 just weighs them down. Sometimes they fall off the wagon. That's when the folks who are predisposed to pancreatitis can get pancreatitis and recurrent pancreatitis. It becomes a cascade.
Yeah, I think diet and lifestyle is 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. You are seeing what the physicians are worried about. They are referring the patients to you. What would you characterize as kind of their major concerns when they are sending you patients to put in trials for hypertriglyceridemia?
Yeah. First, they're typically horrified by the numbers. They just don't like seeing these numbers in their clinics, right? When it gets right down to it, they're afraid of the acute pancreatitis. That's definitely their biggest fear. They also do understand the connection with cardiovascular disease, though. That's not nothing, right? It's not inconsequential. 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. That's really the kind of message we get.
Interesting. Okay. What I'm hearing is we have diet. We have three classes of drugs. There is still a lot of unmet need. We just do not have anything very, very potent to get you to say, okay, I gave you this prescription. Your triglyceride is now under 500. I am not going to worry about you anymore, at least for pancreatitis. With that, there is a fourth drug, GLP-1 receptor agonists. We have an expert endocrinologist here. I wonder if you could tell us how that fits into your treatment paradigm for these patients.
Yeah. 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. They also help with diabetes management. They have direct, and now we now know that GLP-1 receptor agonists, like the drugs that end with tide, semaglutide, tirzepatide, liraglutide, et cetera, have direct effects on the liver to decrease triglyceride production. Indirect effects are through weight loss. When you lose weight, the triglycerides will come down.
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 which say that increase the risk of pancreatitis. We will not get into that. I will use these drugs to help with weight loss and severe hypertriglyceridemia or in people with diabetes who also have the severe hypertriglyceridemia. There is a decent effect that I have seen.
If I could follow up to your analysis, the patients that we're focusing here with the very high triglycerides, over 880, you're suggesting that the role for those patients for GLP-1 receptor agonists is not as much as the ones for lower. Could you maybe explain that a little bit more?
No, I didn't say that.
Okay. I just wanted a clarification.
Yes, yes.
Yeah. Go ahead and clarify that. I'm just curious how you see the two differences.
Yeah. So if you have someone who we know is at risk for pancreatitis or has had pancreatitis from severe hypertriglycerides, 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. I do use GLP-1 receptor agonists in people who have severe hypertriglyceridemia, even in the thousands, not maybe like in the 4,000-5,000 range. If they're hovering even in the 1,000 range, I will use them because we do get a triglyceride-lowering effect. It'll get them off of the pancreatitis range. In the community, clinicians are usually nervous about using them in people with severe hypertriglyceridemia because of this risk of pancreatitis. I use them off-label for lowering triglycerides because that's all we have after you've maxed out on everything else.
That's why we really need drugs to address the.
That really speaks to the unmet need, I think. You now have to go on four drugs, and you still have this nervousness. Dr. Brown, I wonder what your experience is in that regard.
I don't have nearly as much experience. 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 the A1C and a drop in triglycerides. I personally have no experience using it for a non-diabetic with severe hypertriglyceridemia. I also would be nervous with someone with pancreatitis. I would send that patient to Dr. Subramanian if I was nervous.
You could use the weight indication for these folks and use them because you can use them for weight loss. 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 on that.
Okay. 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 moderately effective, but we still have this unmet need? What would the future look like for you to take care of these patients?
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. Having more drugs available with efficacy and well tolerated would be a wonderful thing for all of us.
Great. That is a nice segue to our last segment, which is to think about the future and the near future, really. I think the audience obviously knows that donidalorsen is approved for FCS. 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 of post-approval.
Yes. I have two 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 do not have any follow-up labs on her. I know what her results were when she was in the study. They were amazing. This is a woman with genetic LPL deficiency who has always run in the 2,000-3,000 range. For the first time, she saw triglycerides in the 500s. She was just so thrilled. My second patient is also another genetically diagnosed. I just started him on it. I do not have any follow-up. I am 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'll look forward to more of those going forward. Dr. Brown?
I have three genetically proven FCS patients that are currently on olezarsen. Two of them were in the BALANCE trial. One just showed up in the office in the clinic a couple of weeks ago. I do not have follow-up on that patient. The two that are on olezarsen had been in Balance and then the open-label extension trial. One of them had 30 episodes of pancreatitis from the time she was three until I met her when she was pregnant at 28 years old. Since she has been on olezarsen, she has not had a single episode. 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. It has been a few years where she has not had an episode.
I haven't seen her follow-up labs either because she just came out of the trial. All three of mine, just like Dr. Subramanian, are relatively new on the drug. They're very happy to be on it, especially because of their experience during the clinical trials.
Fantastic. 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.
Yeah. I have a number of patients who are in the study. I have the same experience that you've just heard. They're very happy to be on the medication because they understand the effectiveness. It's not just something that has helped them reduce triglycerides. Certainly, we believe reduce the incidence of recurrent pancreatitis. It actually is reassuring and comforting to them. On an emotional level, there's a lot of power to the drug as well. I don't think we should ignore that.
Fantastic. Dr. Brown?
One other comment. One of my colleagues, who's a former fellow of mine, now runs the lipid clinic at Cook County. 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. She got her triglycerides back on olezarsen, and it was under 300. She said she cried. The doctor cried. That's how emotional we get about these patients. 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 continued to have morbidity despite our best efforts. I just thought that was a great story. I think everyone in the room knew exactly how she felt as the physician.
Apparently, the patient was crying too when she saw her results. It was very nice to hear that story.
I think what all three of you 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. They keep coming back. 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. This hopefully will continue to progress. 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. Until APOC3 inhibition came around, we really didn't have a way to treat the chylomicronemia. The patients that we worry about, the overweight 80, the history of pancreatitis.
I'm curious what your general sense is, all three of you, about APOC3 inhibition as a new mechanism and how that might impact the disease versus what we've had in the past. Maybe we can go with Dr. Subramanian, and then we'll go around to the rest.
I think these drugs hold tremendous promise. How I see myself using them is if when approved for severe hypertriglyceridemia, I'll start, I mean, in a tiered approach. I'd probably start with my severe hypertriglyceridemics with a 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." 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. A drug like this would really keep these people safe, improve their quality of life. That's where I would start and then go down the tier depending on the degree of severe hypertriglyceridemia.
I would be curious to see what the cardiovascular disease risk with these agents would be as the data comes out. Then we would go down that pathway of treating more and more people with severe hypertriglyceridemia.
Fantastic. Dr. Brown?
Yeah. 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, how would it work in a person with broken lipoprotein lipase? Removing inhibition on a broken enzyme theoretically shouldn't work. But it did. It is 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. There is a separate pathway that the liver uses to pick up the chylomicrons. I think that's fascinating. 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.
For whatever reason, gets upregulated in people who wouldn't want it to, like obese people with prediabetes. 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. 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. There is a whole lot of reasons to get excited about APOC3. 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. Having this therapy has been a godsend for the patients, but also for those of us who treat these patients.
Great. Dr. Baum, you're involved in a lot of clinical trials. I wonder what your perspective is on this new mechanism and the new approach to treating these patients.
Yeah. First of all, the answers we just heard were phenomenal. I don't have that much to add. 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. The approach also is easy to deliver patients. It's well tolerated. These are all very, very good things. I'm particularly excited. It's always nice to see side benefits to drugs. If a side benefit has a cardiovascular one, that's really, really great. When we look at APOC3 and its relationship to cardiovascular disease and we inhibit it, we can get very, very excited potentially. Yeah.
Fantastic. All right. This is going to come this is the end of our four groups. Let me just summarize what I heard. Then we're going to have a question and answer session. Just to remind the audience, please type in your question. Then we'll address those as they come through. What I heard is that severe hypertriglyceridemia is fairly common as far as diseases go, but not super common, maybe 1% of the population. 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. Really, APOC3 inhibition is the only one that more specifically addresses these high-risk patients for pancreatitis. There's an unmet need.
There are a lot of new therapies coming down the road that will broaden the indication from FCS to severe hypertriglyceridemia. We are looking forward to some new data coming out later this year. Thank you very much to the panel. Dr. Wade Walke is our Director of Corporate Communications, and he is going to take our question and answer session and help facilitate that. Wade?
Thank you very much, Dr. Tsimikas. 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. We'll take your questions as they come in. We've had a couple that have come in already. 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? 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?
Yeah. We may have a slightly different perspective depending on whether they go to the endocrinologist or the cardiologist. Let me have both of you answer that question. Dr. Subramanian, you can start. Yeah.
Yeah. Mine have a lot of comorbidities. Absolutely. They all fall under the multifactorial group. Meaning they have many different factors feeding into their severe hypertriglyceridemia, like, as I said, central adiposity, hypertension, prediabetes, diabetes, maybe medications. 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. Yeah.
Yeah. I would say that I see probably the majority have comorbidities. There is not a trivial minority that do not. Those are the ones I remember. I can remember every single one of them. There are somewhere between 15 and 20 of those patients I am 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 do not have diabetes. They are not alcoholics. They do not have any other significant disease. Yet, their triglycerides are over 880. The majority of them have had at least one episode of pancreatitis. They are not responding to traditional therapy. Again, now that we are doing genetic testing, we are finding out there are a bunch of these people that do not fit the FCS category that I like to call functional FCS patients.
Speaking to some of my colleagues in Canada, anywhere from 30%-50% of their patients that present just like FCS are these types of patients. That is a severe hypertriglyceridemia that does not have FCS by genotype. Definitely, even without comorbidities, it was an unmet need. We are grateful that genetic testing is not absolutely necessary in terms of an option for olezarsen for those patients. As Dr. Subramanian said, we see a whole slew more of 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. Those patients often get better with control of their comorbidities and currently available therapy. It is a spectrum. I am curious. I am sure Seth has something.
Yeah. 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. I do not even know that we want to go there. We know from other diseases like FH, familial hypercholesterolemia, that there are times where people clearly have FH and do not have the mutation identified. We are still learning a lot about mutations. They are still not all identified. This distinction between functional FCS and FCS, to me, is a little arbitrary. I prefer to just call them all FCS and leave it at that.
OK. Great. 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 risk? And why?
Maybe we'll ask that for the cardiologist. Dr. Brown, you can start. Yeah.
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. Once you start getting and maybe up to 880. Over 880, as Seth and Dr. Subramanian both said, they have some sort of a chylomicronemia syndrome. They can have other lipoproteins in their blood. 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 to 1 ratio. Their remnants have anywhere from 3 to 1 to 1 to 1. They do not tend to get triglycerides quite that high when they have the more atherogenic lipoproteins.
If you see over 1,000 triglycerides, the ratio of triglyceride to cholesterol on the lipid profile is often right about 10 to 1, which is almost always chylomicrons. It is when you have both, then you can have cardiovascular disease on top of severe hypertriglyceridemia. I think it is the mid-range, 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?
Yeah. I agree. It's the lipoprotein particle that's carrying the triglyceride that's going to let us know whether there's risk for ASCVD. Frankly, the majority of these patients we're talking about today in the 500 up range have a lot of those atherogenic lipoprotein particles. When you breach the 80, you know you have chylomicrons. That doesn't mean you don't also have VLDL and VLDL remnants. I'm optimistic, I would say, that by reducing these triglycerides, we will be reducing cardiovascular risk.
Great. Thank you.
We do not have to guess because we have the ability to do non-invasive imaging and determine whether the patient has atherosclerosis. A calcium score, again, is an extremely helpful tool. 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. It is nice to be able to look at a person's heart. If they have a zero, they have a surprisingly good prognosis. We do not 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. If there's a family history, many of these folks will have other family members who have mild to moderate hypertriglyceridemia. Family history of cardiovascular disease can be extremely helpful. That's what I use. I do use some imaging. As an.
That makes sense because, for example, familial hypertriglyceridemia, which is a VLDL disorder, is not associated with much increased risk for cardiovascular disease. They do not have too many particles. They have large VLDL particles. And they have family history of smattering of pancreatitis with five times the cholesterol. Their triglyceride level is five times the cholesterol. But it is a dominant trait. So a parent is going to have similar triglycerides. And there will be pancreatitis. But very little family history of heart disease as opposed to familial combined dyslipidemia or other triglyceride disorders associated with cardiovascular disease. Taking a good history, examining a patient is still important.
Thank you. All right. The next question is directed to Dr. Subramanian. You have 50-plus patients with a history of pancreatitis but only two on commercial therapy. What's the holdup in getting more patients on olezarsen?
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 two gene defects, so meaning they're homozygous LPL deficient, meaning they have no enzyme clearing capability. 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. olezarsen is not approved for that yet.
Just one clarification. The label for olezarsen doesn't require genetics. It's the clinical. I just want to make sure the audience was, yeah. Your patients have the genetics. But they don't need to have that to be on olezarsen.
Fair. The folks that are not treated with olezarsen are the multifactorial folks who have polygenic etiology and have many different contributors.
The kind of patients we're talking about today.
Today. Yes. Exactly. Exactly.
I'm putting a plug in for the North American scoring system. This was an issue for us because we do not lose any less sleep over those patients with negative genotypes for large gene mutations that act exactly like patients with a positive genotype. I think we can all agree on that, right? 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. As Seth pointed out, it would be the people we all would have said had FCS before we had genetic testing available. Those are patients that we would consider for olezarsen. I have already heard of several of my colleagues who have used that scoring system and been able to get patients on therapy.
Oh, that's fantastic. I was going to ask you for some feedback. They're finding you useful to use that in lieu of genetics when they're not available or they're not done.
Yeah. We had a get-together during the ACC of several lipid geeks. Several of them said they've been able to use that to get their functional FCS. In other words, persistent severe hypertriglyceridemia 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.
OK.
Thank you. The next question deals with the percent 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. Yeah. 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.
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. I guess Seth will probably know the numbers here. Once you're over 1,000, it could be somewhere between 8% and 15%.
Yeah. Something like that. 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. It might be more pertinent if we reframed it to say, what percent of patients on statins and fibrates and omega-3s do not get their triglycerides below 500? That is really the issue because those drugs independently do not reduce the risk of acute pancreatitis. It is the number. It is the triglyceride that is critical. 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. It is the inadequacy of the treatments that is really at issue here.
Yeah. Yeah. 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 5,500 patients. It is 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. They're not extremely rare, certainly not 1 in a million. 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. We sometimes have to stop the omega-3s because we've had a few patients get pancreatitis on them, as Dr. Subramanian pointed out. Otherwise, they're on everything. We're treating ourselves as much as we're treating the patients in that situation.
A related question, I think, is 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 in that condition than those that haven't yet had pancreatitis? 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. We can't predict which one of those patients would be the one that's never going to get it. After the first episode, they're more likely to get more, as we've all stated. We don't want them to get the first episode. I think if they're 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. The triglyceride levels are part of the score. Having pancreatitis is part of the score.
It might not be that we might not be interested in using it in those patients. It'd be harder to get approval for it.
Thank you.
About that first episode of acute pancreatitis, it occurs at some point in time, obviously, right? We've all seen it occur with people in their teens. We've all seen it occur with people in their 40s and 50s. That's their 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. We always have to treat these people as though they will have pancreatitis. If the triglycerides are that high, we look at them. 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. They die a horrible death. That is why we're also fixated on trying to avoid pancreatitis.
Thank you. The next question is asking about the symptoms that patients who have very high triglycerides, so patients above 880 mg /dL . What kind of symptoms do you see? Because you mentioned that in FCS patients, besides acute pancreatitis, there may be abdominal pain. You 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. 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. They see the numbers, and they're like, oh my god, this is so high. It's usually asymptomatic. If someone's 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. Eventually, that dips 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. Most just don't have any symptoms.
They just don't, not for this group of people we're talking about. The brain fog, I mean, it can happen when there's very, very high numbers. Like we're talking about like 3,000-4,000 in some people. 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.
Yeah. There's no warning. This gentleman who's had recurrent pancreatitis, for him, it's all food. He's a chef. It kills him to not be able to eat the kind of foods he wants to eat. The last time he had pancreatitis, he said it just came on all of a sudden with severe upper abdominal pain radiating to the back.
Yeah. 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. 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. In addition to that, that general feeling of malaise and brain fog. We certainly see it in the FCS patients and in that group of patients that act like FCS but have a negative genotype. The ones that are a little more episodic, I think, often, as Dr. Subramanian said, are asymptomatic. I've thought about this a lot. I don't know what Seth's experience is.
Yeah. It's really the same. Nothing to add there. Yeah.
Thank you. The next question we actually get a lot. It has to do with the clinical trials we're conducting because the primary endpoint in the phase III studies is triglyceride reduction. One of the key secondaries is looking at acute pancreatitis. 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? Does it require you to show a statistically significant reduction in AP events and have that in the label in order to use it or for you to want to use it?
You mean to get that indication?
No. Just, I mean, to use it in patients with SHTG, how important is it just to hit the primary endpoint of TG reductions versus also seeing a statistically significant reduction in acute pancreatitis events?
Seeing 11 episodes in a placebo and one in a treatment arm is pretty encouraging. I would just point out for the last four 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. Fibrates, omega-3s, et cetera, none of them have had a statistical reduction in pancreatitis. The reason is they weren't studied in populations with a high enough prevalence of pancreatitis to be able to show it. 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.
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. I think all of us believe that we will soon have statistically significant reductions in pancreatitis in larger trials.
Yeah. I would just say it certainly would be nice to see the statistically significant reduction. We do understand the relationship between hypertriglyceridemia and pancreatitis. The higher the triglyceride, the greater the risk of pancreatitis. We do understand that. Triglyceride-induced pancreatitis is not a small issue. It is the third most common cause of pancreatitis. It is something that we need to deal with. I would say at this point, seeing the triglyceride reduction will give us all enough comfort to use the medication. Certainly, in the absence of seeing a statistically significant reduction, if that remains the case, we will still feel very comfortable that we are doing a very good job at trying to reduce that risk of acute pancreatitis. Yeah.
Thank you.
Can I add something to that?
Yes.
Yeah. 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 the hospital. If they land up in the hospital, it's nothing by mouth, bowel rest, pancreatic rest. That is what will bring the triglycerides down. They're out of the pancreatitis range. 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. Yeah.
Thank you. I think we have time for one more question because we're running out of time. These have all been great questions. The last one is a little complicated. I'll go through it here. For the more milder patients, those with triglycerides between 500 and 880, the milder of the severe, how motivated are they to seek or use treatment to lower their triglyceride levels to avoid a fatal event like pancreatitis? Part two of that question is, in your experience, how compliant are patients with taking other potential medications like fibrates and omega-3 fatty acids? 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. I think there were many parts to that question. How effective are fibrates in lowering triglycerides? I think that was the last part. They're effective in mild to moderate hypertriglyceridemia. They will lower triglycerides. However, 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. 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, yeah, they're pretty well tolerated. Most people will take them. There's always adherence issues in some people who have side effects on medications. If you educate the individual, it works. Fish oil, I will defer to Dr. Brown because I'm not a big fan of fish oil, except for maybe for cardiovascular risk reduction with icosapent ethyl.
For lowering pancreatitis prevention, I don't really use it very much. I will defer. I think, yeah.
Yeah. I go back to the days when we only had over-the-counter fish oil. For persistent severe hypertriglyceridemia, we used it. 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. I would use traditional fish oil, EPA, DHA combinations, prescription brand. 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. Taking two big capsules twice a day makes the omega-3 a little harder. Some people get GI side effects from it. 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. That remains to be seen. Adherence for hypertriglyceridemia is an area that I just don't know the data on it. I know that after someone has an acute MI and they're taking a statin, that a year later, only half of them are still taking their pill. 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. In terms of effectiveness in that over 500 group, they're fairly effective in some patients.
There is a subset of patients that we've all discussed where, despite those efforts, they still need additional therapy.
Thank you. 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 helped 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, 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 mid-year 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. We want to thank everyone.