Good afternoon, and welcome to the Arrowhead Summer Series of R&D Webinars, Part Two. As a reminder, all participants are in a listen-only mode. This event is being recorded, and a replay will be made available on the Arrowhead website following the conclusion of the call. I would now like to turn the call over to your host, Vince Anzalone, Vice President and Head of Investor Relations. Please go ahead. Thank you, Sarah, and thanks, everybody, for joining us today. Just wanna remind everybody that we will be making forward-looking statements today, so refer to all the risks in our SEC filings. So as Sarah mentioned, this is Part Two of our summer series of R&D webinars. The first was for our muscle programs last month. Today, we'll be covering the cardiometabolic program, specifically plozasiran and an update on zodasiran. Next month, we'll be going over our pulmonary pipeline. In August, we'll talk about our growing obesity and metabolic disease programs, one of them, ARO-INHBE, we presented data on yesterday at the ADA meeting, and then an additional obesity target we will disclose in August. And then finally, September, we'll cover our CNS platform and pipeline. So the purpose of these summer series of R&D webinars is that our pipeline is very broad, and we don't often get an extended period of time to talk about just one area, one therapeutic area or one program. And so it gives us a focused time to cover parts of our pipeline more in depth. It also allows us to talk about advances that we're making on the TRiM platform that we think are important. Third, you're able to hear directly from the Arrowhead folks that have worked on these. And then lastly, and probably most importantly, you get an external physician perspective on the specific disease areas, the data, and then the studies that we're doing. So here's what we're gonna cover today. I'll give introductions and then give an update on the cardiometabolic pipeline. Bruce Given, our Chief Medical Scientist, will talk about Arrowhead's focus in cardiometabolic disease. Dr. Christie Ballantyne, who I will introduce in a moment, will cover where the unmet need in the triglyceride space is. And then Jennifer Hellawell, who's our lead physician on the cardiometabolic side, will talk about the different diseases that kinda cover the spectrum of triglyceride disorders. And then Bruce will talk about how we're meeting the challenge beyond FCS, which includes SHTG and atherosclerotic cardiovascular disease. Talk about some of the future of the cardiometabolic pipeline, and then I'll come back and talk about how we are getting launch-ready for FCS, and then beyond, where we see the opportunity here. And then the panel will all be available for a short Q&A session at the end. So as I mentioned, Dr. Christie Ballantyne is here joining us from the Baylor College of Medicine. This is a one-paragraph bio for somebody whose bio could be five pages long. He has insight into the cardiometabolic space and the lipid disorder space better than anybody we know. He's the Chief in the Section of Cardiovascular Research at Baylor College of Medicine, the director of the Center for Cardiometabolic Disease Prevention, and professor of medicine in Molecular and H uman Genetics and Integrative Physiology department. We are very fortunate to have him with us today. So just wanna spend a moment talking about Arrowhead, just to refresh for those who are new to our story. We are an RNAi therapeutics company. We use exclusively the RNA interference mechanism. We currently have 14 clinical stage programs across therapeutic area. We have a good mix of early, mid, and late-stage assets, and now, just a pre-commercial program with plozasiran as well. Our drugs target the ultra-rare disease, all the way up to the highest prevalence atherosclerotic cardiovascular disease, and we have a growing pipeline of two to three new programs per year. Our platform is called Targeted RNAi Molecule, our technology platform, or TRiM. It's designed to enable deep and durable silencing of target genes. And importantly, we are leading the field in addressing diseases outside the liver. As you'll see on the next slide, we have programs in multiple therapeutic areas, targeting multiple organ and cell types. Then lastly, we have non-dilutive capital and access to additional non-dilutive capital through partnerships, and the addition, or the possibility and the potential and the likelihood of doing additional platform, product, and structured finance deals to help us get to a point where commercial revenue will be the most significant source of capital in the future. Lastly, we hope to have 20 programs, either in clinical studies or at the market, in 2025. So again, our pipeline is large and growing. So here's what the pipeline looks like, and it's a lot. So here's what we're gonna focus on today is plozasiran predominantly, and an update on zodasiran, which is the top of the cardiometabolic therapeutic area. So before we go on, I just wanna give a quick update. We did, we did have a press release just before we started here, and I think one big takeaway here is that Arrowhead is now focusing very sharply on plozasiran. So let me just page forward. So at this point, when we get to late-stage clinical studies, and certainly when we get to commercial stage, capital allocation decisions for a company like us become much more critical than they are at earlier stages. We need to make sure that we are investing wisely, and that we're choosing the highest probability areas for us to commercialize ourselves. And that's our strategy, is that we wanna have our own drugs that our commercial sales force brings to patients. That's important. and in order to do that, we need to make sure that our lead commercial stage assets are fully funded, and that includes clinical development and commercial, and beyond. And that's critical at this stage, which means that we likely will partner or assess partnering opportunities for other similar high-value opportunities that we just won't be able to focus on ourselves. And we've kind of gotten to that decision point for cardiometabolic. So the process that we went through to select whether we were gonna move forward with cardiovascular outcome studies for plozasiran or zodasiran. We think we did a pretty exhaustive medical and scientific and clinical and regulatory, and then lastly, commercial and financial review of all the different options there. Those options were a cardiovascular outcome study for plozasiran alone, for zodasiran alone. As we mentioned in our New England Journal of Medicine papers last month, and we were also considering the idea of three-arm studies that look at both agents versus placebo, or lastly, no cardiovascular outcome study at all. All of those were on the table. Here's where we landed. We believe that the plozasiran data are very, very compelling across you know across the different disease areas. And, and you'll hear about more of that, more about that later today. But it is highly active in the FCS population, the SHTG population, and then, as our New England Journal of Medicine paper showed last month, also in the mixed hyperlipidemia population. So it's very compelling. And again, we are committed to fully funding all three of those for plozasiran. Next, the stage build-out of our commercial organization makes a lot of sense, with that progression from ultra-rare all the way to high-prevalence disease. We can build commercial in a staged fashion, to support these progressively larger indications. So what did we learn, that got us to that position? Bruce will talk about this in a bit, but kind of the LDL side versus the triglyceride side of cardiovascular disease is a much more crowded space, than it was when we started these programs. It's more challenging to compete in the LDL space than it is on the triglyceride space. Second, we have found through market research and physician and HCP and payer and patient, frankly, outreach, that the target product profile or the presumed target product profile of plozasiran is very attractive for a number of reasons. Next, we found that the SHTG opportunity is really wide open, and we think underappreciated in the investment community. And then lastly, we think that there's the possibility for significant short and midterm revenue as we go up that spectrum of larger diseases, from FCS to SHTG to ASCVD. So what about zodasiran? So I wanna make clear that the decision that we're making to focus on plozasiran was not based on data. The zodasiran data are, were very compelling. And I think we've said this many times, that we felt like there really wasn't a bad choice between all of those different options. The ANGPTL3 inhibition is a very compelling way to address mixed hyperlipidemia. But for us, as a company, it just did not make sense and wasn't feasible for us to fund two large phase III cardiovascular outcome study. And so again, it's the... That decision was not in a vacuum. That was the right decision for us. And then lastly, you'll hear why, how we got to that decision, what the data looked like for plozasiran, and Dr. Ballantyne will talk about the spectrum of diseases and why we're so excited about the future for plozasiran. I'll turn it over to Bruce. Thank you, Vince. So, we thought we'd start with a background of, you know, why, cardiometabolic is our most advanced franchise, here at Arrowhead. I think most of you know that despite the many, impressive advances in CB therapeutics and hypertension and, you know, LDL cholesterol management, atherosclerotic cardiovascular disease still is the number one cause of mortality in Western societies. It just stubbornly, stubbornly is staying there, and there's still a lot of, unmet need. We also, understand very clearly that cardiovascular diseases and metabolic syndromes are very closely linked. And in fact, you know, many patients with mixed hyperlipidemia, and by the way, that's synonymous with, mixed dyslipidemia, but the more modern term is considered mixed hyperlipidemia, so we're, we're converting over to that. But many patients with mixed hyperlipidemia and severe hypertriglyceridemia are obese and/or diabetic, so they're really sort of going hand in hand. And it's also well known that patients with obesity and diabetes are at high risk for, you know, dying from cardiovascular events. So it's hard to separate these two, and in fact, you know, the obesity and diabetes epidemics that are, you know, running through Western society are driving, you know, this number one killer, you know, ASCVD. So you just sort of can't disconnect the two. We were an early entrant into cardiology, and we're gonna talk about that a bit with siRNAs. And we're now entering the obesity metabolic space to continue these efforts and really to get to the other side of this particular issue. And as was mentioned by Vince, we are gonna be having a separate webinar on August fifteenth. You know, so it's really gonna be important to visit that webinar too, if you can get the chance. You know, spoiler alert, I am gonna tease a little bit of the data from the obesity webinar, just a little bit, you know, at the end of the day today. So our cardiometabolic focus. Quick background, those of you who don't know Arrowhead's past, you know, we took the Roche assets in siRNA in 2011. With that came a very nice, you know, delivery system, which was unfortunately intravenous. But we started out in hepatitis B and alpha-1-antitrypsin disease, the liver disease associated with alpha-1-antitrypsin. You know, had very nice results, but we really... Our third choice, you know, the next product we wanted to do was Lp(a). This was really when Lp(a) wasn't very well known, but the genetics were quite interesting to us. But we reasoned that there was no way that an intravenous drug given monthly was going to be an effective, you know, marketed agent in cardiovascular disease, especially one of the mass that we thought that Lp(a) was gonna be. So we started working very hard, you know, this is back probably around 2013, to develop our GalNAc subcutaneous form. And early in 2016, we were getting close, and then finally, we had a major breakthrough in the summer of 2016. You know, hit our target, you know, for reduction in Lp(a), in primates. And we went and we talked to Amgen, and Amgen had actually been watching our program for a couple of years. They took one look at our primate data and said, "Yeah, we want that." And we very quickly wound up doing a deal with Amgen, and that was our first TRiM drug. You know, we went on and also brought TRiM to HBV and AAT, but then the question of where to go next, you know, arose. And now we're probably in, you know, late 2017, and we were very much drawn to these what we like to consider genetically proven targets. One type of target are what we call gain-of-function diseases, where, you know, you have mutations. You know, nature tries a mutation, and they wind up creating a disease, as with alpha-1-antitrypsin or PNPLA3, for instance, in NASH, where, you know, there are mutations that are in the population that actually increase disease, and and you can address those with siRNA. But my personal favorite are really loss-of-function mutations, and this is where nature tries an experiment of completely knocking out, you know, one of its proteins, and lo and behold, you get protection. And you know, oftentimes, when you knock out a gene, you get something like enzyme deficiency or something, and you get terrible diseases or even, you know, you know, just, you know, you know, make it to term. But, you know, there are these examples where loss of function seems to not create any disease, but actually offer protection. And examples of that include APOC3 and ANGPTL3, HSD17beta, again, protective in NASH, are examples, all of which we have drugged. But, you know, I'm gonna talk a minute about the genetic case for, apolipoprotein C3 and also angiopoietin-like 3. And in fact, you know, Christie will touch on some of this as well. So, you know, we, you know, we took note of, you know, the papers that were being published, you know, mostly in the last decade, you know, around APOC3 and ANGPTL3. You notice in that lower left, you know, the term familial combined hypolipidemia. You know, this is something that, you know, I studied in medical school, you know, 20-some years earlier. We knew that there was this familial syndrome that was clearly protective in families, but we didn't know what the genetic cause was. And with the genetic revolution and Human Genome Project, we're starting to understand, you know, these protective genetic experiments that nature has done. And, you know, this shows you just, you know, some of the data, you know, from these studies and, you know, here, just looking at patients where only one of their two genes is a loss-of-function variant, so they still have a normal gene. But you can see their lipids are, you know, favorable. You know, reductions in triglycerides and LDL, HDL is increased with APOC3 deficiency, you know, decreased with ANGPTL3 deficiency. But the cardiovascular risk is what catches the eye, where these families really appeared to have, you know, significantly reduced cardiovascular risk. And also very important to us, there are rare examples of patients that are homozygous for these, you know, loss of function genes, where they essentially have either undetectable or extremely low levels of, you know, circulating APOC3 or ANGPTL3. And of course, the lipid profiles are even more profound. But more importantly to us, in this case, was, you know, they didn't seem to be paying any price for this. They had no apparent penalty, you know, by nature for having knocked out these hormones. And in fact, that matters a lot to us because, you know, siRNAs, you know, done right, can produce very profound knockdown. We don't tend to obliterate, knock down all the, you know, obliterate a gene altogether, but we'll often, you know, knock the protein down 80%, 90%, 95%. So it mattered to us that there was not gonna be a clear payment to be made for addressing these proteins. So we were faced with a bit of a conundrum because, you know, we were basically developing both of these in parallel at the same time, often in the same disease model. And you know, the question was, well, which one to develop? And in fact, you know, we opted for and rather than or, and the reason for that was because there were subtle differences in the lipoprotein and lipid effects, between knocking down APOC3 or ANGPTL3. And, and because of that, we thought that they translated to different clinical opportunities. And this is a spectrum you might say. It's one way of looking at atherosclerotic cardiovascular disease, with, you know, the long-dominant, you know, view of bad cholesterol, going all the way back to Framingham, you know, whatever, 40, 50 years ago, with LDL being the bad cholesterol. And, you know, this is a silent disease mostly, you know, asymptomatic and silent, but was the silent killer. Especially with the advent of statins, you know, we started to make real strong progress over on the LDL side of the world. But there is another side, and that was the triglyceride side. And, you know, this is a side that really is seldom talked about, seldom thought about. Triglycerides are not even measured by a lot of physicians on a routine basis. And I think the biggest reason for that is physicians tend not to measure what they can't really do much about. And the drugs, you know, available for triglycerides have actually tended to be pretty poor and, you know, not produce very dramatic results. But the triglyceride side, as you're gonna hear from Dr. Ballantyne, is also an important source of atherosclerotic risk. But in addition to that, when the, when the triglycerides get high enough, these patients are, you know, don't have silent disease. They actually have a lot of abdominal pain, a lot of other symptoms, and are prone to pancreatitis, and pancreatitis can be fatal. You know, so this is a serious, this is a serious illness. So at the, at the far end of, of this disease is, is a very, you know, symptomatic, you know, issue with respect to abdominal pain and pancreatitis. But, you know, be- you know, once, you're below a level of, let's say, 800 mg per, per deciliter, it tends to again, be more asymptomatic, similar to, to LDL. You know, as you can see, you know, we considered ANGPTL3 by virtue of its effect on LDL and ApoB and other things to be a compound that could be quite helpful in patients who were not getting enough LDL therapy from their statins. You know, again, in the 2016, 2017 timeframe, we didn't have PCSK9s, we didn't have the Regeneron antibody against ANGPTL3. We didn't have bempedoic acid. We really were pretty much having statins, and the result was there were still quite a lot of patients who were not reaching, you know, goal LDL and were continuing to have residual risk. But when we get to 2024, now we're in a different scenario. Now there's actually a lot of, a lot of drug availability over on the LDL side, a lot of competition for these patients. And when patients are serious about dealing with their LDL and their payers cooperate, most of them can get to quite low levels of LDL and, you know, lower LDL-related risk. But over on the triglyceride side, it's still, you know, a relative desert with respect to the ability to really treat high triglycerides. And we think APOC3 is a huge game changer in that environment, you know, both for the symptomatic piece, you know, with the pancreatitis, but also for the asymptomatic atherosclerotic piece in, you know, in the mixed hyperlipidemia right through the severe hypertriglyceridemia. So with that set up, you know, the decision was made to put our efforts firmly behind, you know, plozasiran and to make zodasiran available, you know, for licensing to, you know, hopefully somebody with deep enough resources and, you know, large enough commercial apparatus that they could actually go compete in that LDL space. There are a lot of drugs over there, but they're not perfect. We do believe zodasiran, in a perfect world, if you could snap your fingers and make it available, would be a big contribution in that space, but it's really beyond our capabilities at this time to prosecute it. So with that, I'm gonna turn the presentation over to Dr. Ballantyne to talk about this large cardiovascular frontier, you know, which is how we view the triglyceride space. Christie? Thanks, Bruce. So let's start off with some definitions. And Bruce, you talked about the Europeans use millimoles. So basically, the severe, the really top of this pyramid is where we talk about chylomicronemia, and that's 10 millimoles, which is 85, or it could be a thousand. They go with a simple number, 10 millimoles. We use a simple number, 1,000 mg per deciliter. But usually, you're having these large chylomicron particles, and in fact, if you were just to look at the blood and spin it down, you can see it looks a little bit creamy, with it, 'cause the triglycerides are such high concentrations. And the very top of this peak is what we call familial chylomicronemia syndrome. And we'll talk a bit more about these individuals who have chylomicronemia. Now, what's larger is the population that's over 500, but less than 885, and that's called severe hypertriglyceridemia. And the reason that that is called severe, I trained at UT Southwestern, and Scott Grundy was the first set of these ATP guidelines, and it's because we measure triglycerides in the fasting state. So if someone has a triglyceride of 600 or 700 in the fasting state, what can end up happening is, you know, basically, you're talking about, here, not a receptor, and this issue of lipolysis, but they're kind of on the very edge of what you can handle. And after a bad weekend, what we know is triglycerides go up a lot in the postprandial state. So if you're running 200 and you eat a really high-fat meal, you in four-six hours can go up to 600. Now, think about if you have breakfast at McDonald's and eat something fatty. What happens four-six hours later? Lunch. And what happens four-six after that? Dinner. And if you wanna really jack up the triglycerides, try doing what's done in Houston every Friday night, is you have some cervezas and margaritas along with the enchiladas and the, you know, the fried chips. And you can now skyrocket into the 1,500, 2,000, 3,000 with one bad weekend. So Grundy wanted to keep it in this range because the people who are in this range can drift off very easily into the range of getting pancreatitis. What about 150-500? Well, that's even bigger, and if you're less than 500, you're probably not gonna have pancreatitis. What we'll talk about, in fact, is that you have increased risk for cardiovascular disease. So what we know is, is the higher the triglyceride, the greater the risk for pancreatitis. And as I mentioned, triglycerides fluctuate tremendously, so somebody who's running at 800 may have, and we've seen this in some of the trials, if you look at the time, triglycerides over time, there's huge fluctuations that people have. Once you're over 1,000, that person coming in fasting might be 1,200, but two weeks later, they might be running 3,000 or 4,000 and end up in the hospital with pancreatitis. So in general, we use the, the level of over 500 as severe. Remember, that's fasting. The postprandial is gonna be higher. It's, it's fairly common. It's about 3.4 million people in the United States, so about 1% of the population with it. We know there's increased risk for acute pancreatitis, also for cardiovascular disease. Particularly, the higher the level of triglyceride, the greater the risk. This is a problem of inability to clear these triglyceride-rich particles out of the circulation. Lifestyle is very important, and the drugs that are commonly used are generic fibrates. We have omega-3 fatty acids. It turns out the generic ones are as for triglycerides, just as good as EPA alone in terms of lowering severe triglycerides. And so we try lifestyle, cessation of alcohol, exercise, along with some of the medications that are mentioned here. Now, it turns out when we talk about this chylomicronemia, people who have these really high triglycerides, FCS is a-... We used to call this autosomal recessive, and now we talk about biallelic, but you have to have two defective copies of a gene, or you have one defective copy of one gene and one chromosome, another person, another one, defective copy of one of these other genes here, could be a compound heterozygote. So this is much less common than what we call, you know, multifactorial chylomicronemia syndrome. And it turns out now we have the same genes, but also lots of polygenic variants. So it's a much broader set of genes, and in fact, I think this is some of this nomenclature is really a bit antiquated. You know, we spent a lot of time. That all of these genes are involved with lipolysis, so it's the ability to have these triglyceride-rich lipoproteins. What typically happens is, so this is the way you transport energy, and Bruce talked about this link between triglycerides, obesity, and diabetes, and its fundamental biology is our two major energy substrates are glucose and fatty acids. The people who tend to have defects in both of these things, and unfortunately, people with diabetes accelerates the problems they have with clearance of these triglyceride-rich lipoproteins. It's part of the metabolic syndrome. So there's been a lot of focus in terms of how do we define familial chylomicronemia syndrome, and it's, we have the ability to do genetic testing. We do this routinely in our clinic, and, and what happens is it turns out that most of the people who have these severe triglycerides and pancreatitis, they don't have biallelic. What they have is a pathogenic variant. They have a bad polygenic risk score. There, there's other things, for example, partial lipodystrophy with an LPL, you can have a severely high triglyceride. Turns out all of these people respond to APOC3 knockdown. So one of the things that comes up is, and I think we're gonna be evolving toward this, I'm working on a manuscript with a colleague right now, is in terms of the clinical issue, it's really not an issue of FCS versus MCS. It's simply an issue, is someone not responding to your treatment? It turns out... I hate the nomenclature. If you have a pathogenic variant in LPL, that's hereditary. If you had a bad polygenic risk score, that's hereditary, so it's familial. It, we didn't-- we made these terms up before we understood the genetics. So the I don't like the term because it somehow implies, perhaps to an insurance company, that this is just somebody who's on a bad diet and drinking alcohol. That's not the case at all. These are people who have, the vast majority, have a genetic disorder leading to extremely high triglycerides. The average person, no matter what you eat or drink, cannot get a triglyceride of 2000. And so you have to have a genetic predisposition for this, or you can have some type of other rare thing that happens where you develop antibodies to lipoprotein lipase. However it happens, if you cannot control triglycerides, you've got a serious problem. This is very simple clinically, is if somebody's not responding to diet or exercise, and they still have triglycerides that are over 10 millimoles or 1000 mg, that's it. They've got chylomicronemia, and it's sustained or persistent, and if they've had pancreatitis, they need to be treated. So I do think that the clinical picture is actually quite simple here, and it's something that we'll need to do some more work in terms of education and in terms of this, but I do think this is not uncommon. It's still infrequent. This is not gonna hurt any insurance companies to treat these people 'cause they're not real common, but it's a lot more common than the rare biallelic genetic FCS. Okay, that's just these are my personal opinions with it, but I do think that's the clinical scenario. You talk to any lipidologist, they'll tell you the same thing. Now, what about the cardiovascular side of things? So this is data from Copenhagen, and what ends up is if you look at the pancreatitis risk, it goes up as your triglycerides go up. Same thing as... Now they're using 443, which is 5 millimoles, similar to our 500, and you can see the risk for pancreatitis has gone up over eightfold compared to people with low triglycerides. That was adjusted for age and sex, and on the right-hand side, it's multivariable adjustments, and it doesn't really change much. Myocardial infarction, it's a fourfold increase in this range of over 443, and as you can see, after multivariate adjustment, didn't change much. Now, these were non-fasting levels, so that would, you'd have to, for fasting, you can move that down some, because as I said, in the non-fasting state, your numbers go up considerably. This is showing the association for individual events. The risk goes up for myocardial infarction, the broad term of ischemic heart disease, ischemic stroke is increased, and in fact, all-cause mortality is also increased. So this is. Yeah, Bruce had talked about genetics, and I did a postdoc in genetics after finishing cardiology. My wife thought I was crazy to do that. I said I've had a choice of interventional cardiology or doing a postdoc in genetics. But anyway, I thought the future would be genetics. I was right about that. She was right about the salary. But basically, if we take a look at this, it ends up is that we've known LDL, big focus on LDL, and the genetics have consistently shown that genetic variants that increase LDL or reduce LDL, we see the risk going in that direction. Where the big surprise is that we see this triglycerides had also a very strong signal, but we didn't see it for HDL cholesterol. So this really, at the same time, we were doing lots of trials focusing on raising HDL that didn't work, and there was a shift, and it's interesting, the shift actually has happened now, but when I first started, there were two, Wolfgang and Josef Patsch, working at Baylor, and they were stating that really, that HDL cholesterol, low HDL cholesterol was a marker of postprandial triglyceride increases. So they felt that going back, and this is in the, you know, late eighties, early nineties, that in fact, it was really your levels of triglyceride lipoproteins in the postprandial state causing the disease, and that HDL cholesterol is just the marker, kind of like a hemoglobin A1C. So it's interesting, a couple of decades later, they look pretty smart, as we, you know, see this other data. So it turns out that all of these genes involved with lipolysis turn out to be important in regards to genetic studies with cardiovascular risk. And Bruce had talked about, it's very interesting, that the data on APOC3 goes back a while. This was done in the Amish, 2008. They were looking at postprandial lipemia, and look at the difference between people who are heterozygous, very low levels of triglycerides, and notice overall, the Amish have low levels. But look how blended it is in the postprandial state compared to the people who, you know, do not have these variants. So in addition to postprandial lipemia, that, you know, you expect heterozygotes to have a half normal. They'd have one inactive, so it's 50% levels of APOC3, but also their whole lipid profile looked better, and other things, non-HDL, LDL, the HDL particles, and they had reduced coronary calcium score, so they had less coronary atherosclerosis. And this has been followed up later on, and he showed this, but this was a big, you know, 110,000 people, 14 studies, and it shows that basically, loss-of-function mutations reduced triglyceride levels by 39% and reduced the risk of CHD by 40%. So genetic by Mendelian randomization confirmation. Now, there's lots and lots of epidemiological study that when we look at the bad cholesterol, so we talked about non-HDL cholesterol, but that's basically your LDL and the remaining cholesterol or the remnant cholesterol. HDL cholesterol is not atherogenic. So this remnant cholesterol is associated with increased risk for coronary events, increased cardiovascular mortality. There's also increased other mortality for these individuals with it. So remnant cholesterol has become something of a lot more focus in that when we use a statin, we lower the levels of LDL cholesterol very effectively, but we don't lower triglycerides and remnant cholesterol as much as we lower LDL cholesterol. So there is this concept of residual risk, and a lot of that has to do with this, these particles that are having still containing cholesterol and triglycerides, so-called triglyceride-rich lipoproteins. Now, another way of looking at this, so this is the... it's the. As you get into very large datasets, and you look at SNPs, where you can look at, you know, hundreds of thousands of SNPs. So this is data out of a U.K. Biobank, and they looked at SNPs associated with triglyceride-rich lipoproteins. So we can look at the level of basically ApoB or, you know, remnant cholesterol to LDL cholesterol, different ways of doing this, but in blue, this was looking at 1,100 SNPs. This was the individuals who had more high triglycerides versus just high LDL, and you can look at these clusters of SNPs. Notice the top one up there in blue is APOC3. Right next to it is LPL. We know that APOC3 plays a critical role in lipoprotein lipase. Lipoprotein lipase, gain of function, has less heart disease, APOC3, loss of function. And then what do we see is when they look at these particles, and kind of look at the amount of ApoB, is that the CHD risk per standard deviation of ApoB particles for these triglyceride-rich particles was 1.76. For the other particles, was 1.33. Now, to put this in perspective, if someone has a high LDL, you have a very large number of LDL particles. So we're not saying, I'm not saying LDL is not important. LDL is the most common phenotype for these people because there's lots and lots of particles, but if after you use a statin, you still have a lot of these atherogenic triglyceride-rich lipoprotein particles, which are a problem with it. Well, so what's the unmet medical need? I mentioned you've got familial chylomicronemia syndrome, where none of the drugs work at all. So this is really a very, very tough problem for people. It's all lifestyle, and it's a super strict lifestyle. And then we've got people who have this persistent chylomicronemia, which is, I consider to be equally problematic. And then we also have people with severe high triglycerides, and now you have a risk for both potentially pancreatitis and heart disease. And below that was this mixed hyperlipidemia group, who have high triglycerides and high levels of remnant cholesterol. Okay, now, what about fibrates? You know, these are the main triglyceride drugs. It's very interesting, you know, we go back to a long time ago to the Helsinki Heart Study, which was actually the only trial that was enrolled, not by LDL cholesterol, by the levels of non-HDL cholesterol. So that includes the atherogenic cholesterol and triglycerides and stuff with that. And we see that as we go toward the more modern studies, the background statin therapy kept getting higher and higher. And what happened to the results of these trials? Well, the Helsinki Heart Study showed benefit, but as we move along, there's less and less benefit, and finally, there's no benefit. You know, ACCORD was unsuccessful, and PROMINENT was unsuccessful. Very disappointing study. Let's look a bit more at the PROMINENT study, 'cause it's highly relevant. So this, this was a group of people who had triglycerides of 200-500, and as you'll hear coming up here, this is what we call mixed hyperlipidemia. The focus at that time was on dyslipidemia, so they included low HDL, and these people were looking at that. We don't think that that's necessarily the issue, to try to raise HDL, although, it's really to lower the atherogenic triglyceride lipoprotein particles. And they were randomized to placebo or to pemafibrate, and there's no benefit. So quite disappointing in terms of this, the results of the study here. So what happened to the lipoproteins and lipids? Well, triglycerides did go down. They went down 26%. Now, the remnant cholesterol, if you look at the absolute change, it only changed by 7 mg per deciliter. So it was. You know, this was the on treatment, was 39 versus 32. So very modest percent reduction, 18%. The absolute reduction was even smaller. Non-HDL cholesterol, the, you know, on treatment, it's 122 versus 125, so no difference, actually slightly higher non-HDL, and ApoB actually went up, which is the number of particles. So the results on remnant cholesterol were very modest. Some increase in LDL, non-HDL, no benefit, ApoB, some increase. So the impact on atherogenic lipoproteins was really disappointing. All right, so in conclusion, targeting APOC3 mRNA has been; we'll see more data coming up here, but it really works well with FCS, it works with SHTG. It's more effective than available therapies. Fibrates added to statins, and statins are the mainstay, as Bruce has already talked about. They have shown to have lead to any reductions in cardiovascular events. Only modest reductions in remnant cholesterol, non-HDL cholesterol, no benefit added to statins, and then actually some increase in ApoB and LDL-C. So you'll see coming up, the phase II studies with plozasiran. So remember those numbers I was talking about, and you'll see what was shown in the similar patient populations. And the nice thing here, as compared to a fibrate, these were based upon Mendelian randomizations that shown that a loss-of-function mutation in APOC3 is associated with reduced cardiovascular events. I will stop there and turn it over to Jen. Thank you, Dr. Ballantyne. I always learn something new hearing you speak, and I'm glad that you prevailed over your wife in believing that the future was and is genetics, 'cause we certainly believe that here at Arrowhead. I'm Jennifer Hellawell. It's my pleasure to provide a brief overview of our plozasiran clinical development program today. So the SUMMIT program describes our overall development program of plozasiran across the spectrum of elevated triglyceride disorders, as was described to you in greater detail by Dr. Ballantyne. Today, I'll be presenting some top-line results from our PALISADE phase III study in familial chylomicronemia syndrome or FCS, as well as a brief review of the completed SHASTA-2, phase II study in severe hypertriglyceridemia and the MUIR study, phase II study in mixed hyperlipidemia. To begin with, the PALISADE study, our phase III study in FCS, was a randomized, double-blind, placebo-controlled study of plozasiran, where eligible subjects or patients with both a genetically or clinically confirmed diagnosis of FCS, underwent a screening period of up to eight weeks for stabilization of diet and other medications, and then were randomized in a 1-to-1-to-1 ratio to receive one of two different doses of plozasiran, dosed quarterly, 25 mg and 50 mg, or placebo to match. The primary endpoint was placebo-adjusted median change in triglycerides at month 10, and there were a number of multiplicity-controlled key secondary endpoints, which were tested in a hierarchical manner, and these included% change from baseline at months 10 and 12 in fasting triglycerides, as well as% change from baseline in month 10 and month 12 in ApoC-III, and finally, incidence of positively adjudicated events of acute pancreatitis during the randomized period. Shown here are the baseline characteristics for the patients, the 75 patients that were enrolled in the PALISADE study. I should note that more detail on the demographics and baseline characteristics of this patient population will, of course, be shared at a forthcoming scientific congress. You can see, as is reflective of what we know of the phenotype of this rare disease, subjects enrolled had a mean age in the mid-40s. They were about half male, female, and median triglycerides at baseline were considerably elevated over 2,000. Importantly, in light of our eligibility criteria, about half the subjects had a genetically confirmed diagnosis of FCS, and the others were clinically confirmed, and almost 90% of subjects enrolled had a prior history of pancreatitis. Shown here, at both doses tested, we saw that plozasiran induced deep reductions or knockdown in the primary target, ApoC-III, approaching 95% at month 10 and at month 12. And not surprisingly, given this deep reduction in ApoC-III, this also led to a deep reduction in triglycerides at both the primary endpoint at month 10, as well as at month 12. Patients treated with the quarterly doses of 25 and 50 mg of plozasiran achieved median triglyceride reductions of about 80% at both doses, with a maximal reduction of close to 98%. Whether we accounted for changes in triglycerides over time using mean or median measures of central tendency, we saw that the reduction in triglycerides at both dose levels was rapid, with near peak reduction occurring by one month after first dose, and it was sustained throughout the three-month dosing interval. Shown here is the safety profile of plozasiran in the PALISADE study, and you can see that it was fairly consistent with what we have already reported for plozasiran in other phase II studies. Notably, the treatment-emergent adverse events were comparable across treatment groups versus placebo. The number of severe and serious TEAEs occurred with greater frequency in the placebo group relative to the two plozasiran groups. There were no deaths on study, and the most common treatment-emergent adverse events were abdominal pain, COVID-19, nasopharyngitis, headache, and nausea. So that rounds out our top-line review of the results from the PALISADE study. Again, we look forward to sharing the broader results at an upcoming congress. These results come in the context of recently reported final results from our phase II studies across the spectrum of triglycerides, including the SHASTA-2 study in severe hypertriglyceridemia. Just to note that these full data from the SHASTA-2 study of subjects with severe hypertriglyceridemia were presented this year at the American College of Cardiology and published contemporaneously in JAMA Cardiology. This was a study of patients with severe hypertriglyceridemia, defined as triglycerides greater than 500, with fasting levels between 500-4,000 during screening. Eligible subjects underwent a six-week screening period for diet run-in and stabilization of background therapy, and then they were randomized in a 1-to-1 to 1-to-1 ratio to one of three doses of quarterly-dosed plozasiran versus placebo to match 10 mg, 25 mg, or 50 mg. The key primary endpoint in this phase II study was% change from baseline over time in triglycerides, and we, of course, assessed a variety of other key lipoprotein parameters, as well as safety in this study. Eligible subjects or interested and eligible subjects could opt into an optional open-label extension at the completion of the double-blind period. Similar to what is known about severe hypertriglyceridemia and what was described to you by both, Dr. Given and Dr. Ballantyne, these patients had mostly a metabolic phenotype, if you will. The mean age of the patients enrolled in this study was in the mid-50s. They were predominantly white men, and mean baseline ApoC-III levels were elevated in the 30s, with median triglyceride levels in the 600s. In this study, we once again saw that plozasiran lowered ApoC-III, its primary target, as well as triglycerides, in a deep and robust fashion. Whether we looked at mean change in triglycerides over time or in the open-label extension, we saw that there was robust knockdown that occurred within the first month. These results were consistent throughout the treatment period and then on into the open-label extension period, with minimal variability seen across patients in dose groups. We also saw that plozasiran induced considerable decreases in remnant cholesterol and also increased HDL. I'll highlight here, for example, at the 25 mg quarterly dose, at the week 24 primary endpoint, plozasiran induced a reduction in remnant cholesterol in this patient population of over 60%. And once again, we saw a reassuring safety profile in the SHASTA-2 study, with the treatment-emergent adverse events observed in this study, reflecting the comorbidities of this patient population and their underlying metabolic dysfunction. The most common treatment-emergent adverse, adverse events, not surprisingly, included COVID-19, given the time course of enrollment of the study, upper respiratory tract infection, headache, and type 2 diabetes-related adverse events. However, when we further interrogated that signal of increased adverse events related to type 2 diabetes, we saw that across treatment groups relative to placebo, there was minimal change in hemoglobin A1c in this patient population. Moreover, as can be referenced in our published manuscript, we saw no changes over time, no meaningful changes over time in HOMA-IR to suggest worsening insulin resistance. Finally, at the other end of the spectrum of triglyceride-related disorders, we've also recently completed, published, and shared publicly the results of the phase II MUIR study in patients with mixed hyperlipidemia. This study enrolled patients with mixed hyperlipidemia or previously referred to as mixed dyslipidemia, as Dr. Given highlighted, defined as fasting triglycerides between 150 and 499 mg per deciliter, and either elevated LDL-C greater than 70 or non-HDL-C greater than 100. Eligible subjects were on stable background statin therapy and underwent a six-week screening period with diet run-in and stabilization of other medical therapies. Then, they were randomized to one of four doses of plozasiran versus placebo to match. The 10, 25, and 50 mg dosed quarterly, and a single 50-mg arm dosed every 6 months to explore potential increasing of dosing intervals. The key endpoint here was% change from baseline in triglycerides at week 6, and we did, of course, evaluate a number of other lipoproteins over time. The baseline characteristics of this study are also reflective of what we know of these, patients that people like Dr. Ballantyne treat in the clinic, patients with mixed hyperlipidemia, and that the mean age at baseline was around 60. Here, there was a better balance between male and female participants, predominantly white and other features of metabolic syndrome, including an elevated BMI at baseline. These subjects also had a more moderately elevated triglycerides at baseline in the 250 mg per deciliter range, and an attendant increase in remnant cholesterol on the order of 45-48 mg per deciliter. And once again, we saw that treatment with plozasiran in this patient population induced robust and consistent and durable lowering of ApoC-III, the primary target, as well as triglycerides, with change from baseline in triglycerides at month 6 of about 60% at both the 25- and 50 mg dose. And as well, we saw considerable decreases in remnant cholesterol, with changes at month 6, ranging around 54%-53% at the 25- and 50 mg quarterly doses. And to provide a little bit of further context, of course, we looked at a variety of other atherogenic lipoproteins, and we similarly saw decreases, a more modest reduction in LDL-C, which is perhaps not surprising, given the physiology of triglyceride metabolism and an increase in HDL-C. To put these results in further context, and to furthermore highlight some of what Dr. Ballantyne shared earlier, if we look at the results in terms of reductions in remnant cholesterol, at the 25 mg quarterly dose, which is our dose selected for further testing in phase three studies, we can see that the reductions in remnant cholesterol at the lowest tertile were about 15 mg in terms of absolute reductions or 41% relative reduction, and at the highest triglyceride tertile, that change was closer to 44 mg/dL, an absolute change with a 68% change. I believe, if I can recall the numbers correctly from Dr. Ballantyne's presentation, with the PROMINENT trial, dosing with pemafibrate induced an absolute reduction of just 7 mg/dL at 4 months, so considerably greater reductions in remnant cholesterol. The same was true with non-HDL-C. When we look again at the 25 mg quarterly dose, we see that there's a stepwise increase in reductions or the magnitude of reductions in non-HDL from the first to the second to the third tertiles. At the very highest tertile, we see a 23% relative reduction with an absolute reduction of closer to 35 mg/dL, whereas in the PROMINENT study, they essentially saw no change overall. Finally, not surprisingly, and once again, consistent with what we have seen in previous studies, the safety profile for plozasiran in the MUIR study, phase II study of mixed hyperlipidemia, was reassuring. Treatment-emergent adverse events again reflected comorbidities of these patients afflicted with multiple comorbidities and the metabolic dysfunction. Importantly, we saw no changes in platelets. There was an observation of worsened glycemic control that was more pronounced in the 50 mg dose. But as we had seen with the SHASTA study, when we further reviewed those data in detail, overall, we saw minimal change in hemoglobin A1c and similarly, no meaningful change in HOMA-IR to suggest worsening insulin resistance. So with that, having presented an overview of our phase II and phase three studies of plozasiran and how we are treating the spectrum of triglyceride disorders, I will turn it back over to Dr. Given to tell you how we look to meet the challenge moving forward. Thanks, Jen. That's great. So let's talk about what we're working on now, in addition to, of course, looking to file our FCS NDA, you know, hopefully in the somewhat near future. The continued SUMMIT program now addresses severe hypertriglyceridemia as well as atherosclerotic cardiovascular disease in that mixed hyperlipidemia population. Although here you'll see, we actually stretch beyond that, you know, into that larger sort of bottom of the pyramid that Dr. Ballantyne showed of severe hypertriglyceridemia as well. So SHASTA- 3 and 4 are the two pivotal studies in SHTG in phase III. They're really designed to replicate what we showed in phase II, just with a longer treatment duration. The key thing in phase III, generally in SHTG, is that the recently sort of updated ICH guidelines in a population like this looks to have 1,500 patients treated with your active drug for at least a year against placebo. And of course, the previous trial, they got two doses, you know, at day one and 12 weeks. You know, the agency, the FDA and the EMA, you know, now, after that ICH change, you want a full year of therapy. So both of these are designed to provide that. MUIR- 3, which is in the mixed hyperlipidemia population, is just to help build that safety database. The regulatory authorities have accepted that the safety really between SHTG and the regular HTG or mixed hyperlipidemia population really would be no different. You see SHASTA-5 there. This is not a study really being done for the regulatory authorities per se. This study is actually being done more for the payers, especially in Europe. And this will be, to my knowledge, the first study ever conducted where the primary endpoint is actually pancreatitis. So it's designed to provide very convincing and definitive proof that lowering triglycerides in these patients will actually reduce the incidence of pancreatitis. And then finally, you know, CAPITAN, which is our outcome study, which I'll describe in greater detail in one of the next slides. So first of all, for SHASTA, SHASTA-3 and SHASTA-4, they're very similar to the SHASTA-2 design with a run-in period, randomization. In this case, the randomization is two to one, active to placebo, because again, the biggest drive here is to build up that safety database. They'll receive four active doses, so the primary endpoint is at month 12, so you get that one year of full, you know, treatment exposure. You know, from an efficacy perspective, you know, the primary endpoint is again triglycerides at 12 months. However, in this case, you know, we are, you know, very highly overpowered, because we're really, we're really here to build up the safety database. You know, the SHASTA-2 study was already, you know, highly statistically significant, with a smaller patient population. And this is only the 25 mg dose, by the way, versus placebo. So three and four are basically the same, and it's two studies, so they get 2 adequate and well-controlled trials, which is also the regulatory standard. MUIR-3 is essentially a copy of MUIR-2, but, you know, as with the SHASTA-3 and SHASTA-4, it's a full year of dosing. Again, 25 mg versus placebo. Here, the randomization is three to one. But this patient population, rather than being greater than 500, is now 150-499, which is, you know, a much larger patient pool. And again, the purpose here, even though the primary endpoint is% change in triglycerides, the real purpose here is to demonstrate safety versus placebo, you know, for regulatory filing. Sorry, got to go back. And then, finally, talking about CAPITAN. You know, that this trial is, you know, comparing 25 mg of plozasiran versus placebo. There's two populations here. There's a secondary prevention cohort, which will be about 80% of the patients. Here you see, these are patients who have already had a cardiovascular event in the past. So they've already, you know, have demonstrated cardiovascular disease, you know, with an event in the past or more than one event in some cases. Triglycerides here will be 200-800 mg per deciliter. So we're stretching beyond, you know, that normal 200-500 or 150-500 definition, you might say, up into the pre-chylomicronemia, you know, fasting triglycerides. So 200-800, and their non-HDL cholesterol has to be greater than 100 mg per deciliter. So they have to have enough non-HDL cholesterol that we could have a substantial reduction. The primary prevention cohort here is about 20% of the patients. Here, their triglycerides have to be higher, 250-800. Their non-HDL-C also has to be higher, greater than 130 mg per deciliter, because, you know, these patients have to have a high enough risk since they have not had a prior event. However, it's important to note that they also have to have some other risk factor, such as diabetes or, you know, a high calcium score on coronary CT, for instance. And the primary endpoint here will be a five-point MACE, so a major adverse coronary event. So five-point MACE, either cardio, cardiovascular death, MI, stroke, coronary revascularization, or, major adverse limb events. And, this has been discussed with, with the FDA. They have accepted, this design. It has not yet been discussed with EMA or the Japanese authorities, but that will happen in the near term here. So that is the, you know, phase III program for both SHTG and also for the larger mixed hyperlipidemia, ASCVD population. Now, I'm going to give you a brief look into the future for Arrowhead's cardiometabolic disease. So this is a couple of teases just to give you something else to chew on. First, yesterday, there was a poster presented at the American Diabetes Association about our Inhibin E program. Now, Inhibin E is again one of those experiments that nature conducts, and with loss of function in Inhibin E, patients tend to be lighter, have less fat mass, but still normal lean, you know, lean mass, and they tend to have better glucose tolerance as well. And here, we're showing results in DIO mice. You can see the saline treated mice are quite obese, a lot of fat, especially abdominal fat. And if you look to the far right at tirzepatide, these mice are essentially starved. With the doses of tirzepatide that are used in these studies, the mice essentially stop eating, and they lose all their fat, but they also lose a good deal of lean body mass. And that's probably one of the biggest concerns people have right now with the GLP-1s, that the weight loss is associated with lean body mass loss, not just fat. And the Inhibin E-treated mice have very substantial loss of body fat, but they don't lose their lean mass. They don't lose their muscle. And that's considered to be a pretty intriguing proposition. That's all I'm going to tell you today. There's more in the poster, if you'd like to read it, but there will obviously be a good bit more discussed on August fifteenth. And there, we'll also talk about our new, you know, as yet still undisclosed adipocyte target, which we think you'll enjoy hearing about as well. The second tease is that we're not done on the cardiovascular side. We actually think that combining, you know, deep reductions in LDL and deep reductions in triglycerides could actually be a really great combination in patients across the spectrum. So we have combined a PCSK9 siRNA with an APOC3 siRNA into a dimer, so into a single molecule. And this slide shows you what happens with just a single injection in primates with the dimer in the blue versus the individual monomers in the black. You can see that, essentially, the dimer mimics the monomers, but in a single molecule, this would be a single injection and, you know, we would anticipate quarterly therapy and would be likely, based on what we understand about both agents in humans, to give deep reductions in LDL and triglycerides with a single every quarter injection. So just a tease for where we're going now in the future. With that, I'll turn it back over to Vince. Thank you, Bruce. Let's move forward. Okay, I'll go quick through this. So I just wanna talk about what we think about plozasiran broadly from a commercial perspective and what we're doing to be launch-ready in 2025. So this slide shows you basically what we see as a potential value proposition for plozasiran. The activity and durability of response are really encouraging. So again, as other folks mentioned, we're seeing TG reductions in the FCS population approaching 80% from baseline, ApoC-III reductions in the 90%-94% range, so essentially near full suppression of the liver production of that protein and also a long duration of effect. As Jen showed in the plots, we were getting basically steady state. There's some variability, obviously, with TGs, but once we get down to the bottom, once every three-month dosing gives us consistently low TG levels. Second, we achieved statistical significance for the reduction in acute pancreatitis in the phase III PALISADE study, which is important. Infrequent dosing, which is very patient-friendly, and as you'll see in one of the next slides on physician requirements for this, not only is that convenient, but it may help with adherence and compliance, which is always an issue, you know, for new medicines. And lastly, safety and tolerability. We are confident that we have a, we've demonstrated a good safety and tolerability profile to date. And then on the bottom bar, we see APOC3 or plozasiran, as kind of a pipeline in a molecule. You know, I know that's an overused term, but there are clearly different patient populations and different diseases, that we have shown activity against, very encouraging activity. And, and, and we see the, that as a very attractive thing, with this particular target and molecule. So what do those look like? What do those different patient populations look like? If you look, this is a spectrum of triglyceride level, and patient population. So go to the far end on the bottom right. That little sliver, little blue sliver, that's genetic FCS. Less than 1,000 patients, in adults in the U.S., and they typically have the triglycerides in the thousands range. If you go down the spectrum of triglycerides over 880 mg per deciliter, there's somewhere in the range of 800,000 patients in the U.S. with trigs at that level. You go down even further, the severe hypertriglyceridemia population, or SHTG, with trigs in the 500-880 range, you're talking about approaching 2 million potential people in the U.S. And then we're talking crazy numbers when you go all the way on the left side. They're patients with trigs in the 150-500 mg per deciliter range and ASCVD. There's estimated to be around 20 million of those. It's very large. And again, as I mentioned, this kind of pipeline and a molecule idea, we think really fits for plozasiran. And then importantly, we talk about a couple different areas. Dr. Ballantyne talked about cardiovascular disease risk when we're looking at FCS and also for SHTG. Acute pancreatitis is a concern. And as you go up the spectrum or the scale of triglycerides, AP risk increases with triglyceride level. So here's kind of how we view the market, and we've done some background work with patients, HCPs who treat their patients, and then payers, and tried to figure out what's important to those three audiences. So for patients, and this is, you know, roughly, in order of importance for each group. Patients have said that they want something that can reduce abdominal pain and the incidence of acute pancreatitis. Second, it has to be safe and tolerable. They want a minimally burdensome dosing regimen. They don't wanna think about taking their medicine all the time. And lastly, and this is a quality-of-life issue that we don't always appreciate, but they wanna live their life with fewer restrictions. They don't wanna always have to think about diet and fat content and medicine. They wanna live, they wanna live their life with less restrictions. And I have a quote here that I wanna just go through. So one patient told us, "Pancreatitis is what happened that led to all this. One time I was really, really ill. It was worse than childbirth. It hurt so bad." I think, you know, it, it's... You know, when we do these kind of events, we talk about patients, and we talk about data, and we talk about drug genes, and we forget that each one of these patients is a person, and this is a very serious disease, and these patients just have nothing that really helps them right now. And so we think that plozasiran gives some hope here. The next population or the next audience is HCPs, physicians and caregivers who treat these patients. And again, this is roughly in the order of importance from some of the work we've done, survey work. HCPs have said they wanna have an agent for FCS that gets deep and durable triglyceride lowering to a level that would be predicted to be low risk for acute pancreatitis. You know, that's roughly below that 500 mg/dL level. Second, they wanna have something that can show statistically significant reduction in acute pancreatitis in a phase three clinical study. Next, and then there's some overlap here. Obviously, physicians want a safe and tolerable drug. And lastly, as I mentioned before, infrequent dosing that can help with compliance and adherence for their patients. And here's a quote that also we got from a treating physician: "I think we need help with current treatments. It'd be great if there was something specific, but anything that's easy for the patient, anything that's better access, anything that would help these people in the future would be great." So we've heard similar things like this all along the way, that there's kind of a helplessness with physicians that treat patients with FCS. There's just nothing out there that helps them. And again, we think that the plozasiran product profile could provide some hope in the future. Lastly, payers. What do payers want in order to give coverage and access? First, they wanna see a reduction in the incidence of acute and chronic pancreatitis, and a reduction in ER visits and admissions. And again, I think that showing that in a clinical study is important. There's that overlap with safety again. Payers also want safe and tolerable drugs. And lastly, they want something that can reduce the cost of care and has a manageable impact on their overall budget. Here's an interesting quote that we got from a payer that we did some survey work with. They said, "We are responsible for patients' long-term medical care, so we're looking for a long-term outcome. We want to see impact in decreased episodes and total cost of care." That's important. So here's where we are. Here's what we're doing to be commercial ready. You see the rows in green are ones that we have, we are already on our way towards. First, on the medical side, we have medical education and communication strategy that's developed, and we're in the process of deploying field medical right now. Commercial strategy and the go-to-market strategy is solidified. We're looking at marketing and market access, and we're also executing on that go-to-market strategy now. We have selected a patient hub provider, and we're trying to get those service offerings up and running. And then these bottom three are ones that are still in process. So the regulatory side, we need to have regulatory interactions, which are planned in the near future. We need to get the commercial field force ready, which typically happens four to six months or so ahead of launch. And then lastly, we wanna have the patient, provider, and all the payer work done. So on day one, we are ready to launch this, effectively. So that's it. And I wanna just say thank you to Dr. Given, Dr. Hellawell, and Dr. Ballantyne. That was, you know, we really appreciate all the work on this. And now we will compile some questions from the audience. And the way we're gonna do this, I will... I'll read the questions out loud, and then tee up the various panelists. Okay, our first question is from Prakhar Agrawal at Cantor Fitzgerald, and he is asking about the plans to finance the cardiovascular outcome study. And then the second question is: will the trial be powered? What will the trial be powered to show, and what is that based on? So I'll let Bruce answer the second question first, and then I'll go, I'll go after. I don't think I can divulge the power at this point, partly because, you know, we haven't, you know, finalized the design with the executive committee. You know, I think I know what the answer is, but it's always based on estimates of what it's expected to happen in the placebo group and what reduction you're powered for, clinically. And at this point, you know, I don't feel comfortable sharing that, other than to say, you know, that, you know, we have a absolutely spectacular executive committee. The trial will be run out of, you know, the Cleveland Clinic C5 group, and, you know, they've got a just a raft of experience with doing these studies, seeing the trends, understanding what the trend is, you know, in the placebo patients. But I don't think we're ready yet to... I don't know if we'll ever be ready to talk about how we've powered the trial. That may be, that may be a step too far, just from a competitive perspective, I'm not sure. But the five-point MACE helps us. It gets us more events. We're comfortable with all components of the five-point MACE, but at this point, I think I can't give you a lot more detail than that. I don't know, you know, Christie, whether you'd have any comment beyond what I just said there? I think until it's finalized with it and all that, it is a very experienced committee. CCF, Steve Nissen and the group have tremendous experience, have worked with him on multiple studies, and he's got a powerhouse steering committee. So, you know, it's and it's all thought through very carefully. So I just supportive what you were saying, and I think till the final protocol has been developed and approved, it would be better not to try to answer any further. Okay, thanks. I'll take the first question on finance. So we intend to finance this as well as the future of the company in the same way that we have financed in the past. And I know this is a not a satisfying answer for people, but if you look at the access to capital, it's across I would say four distinct buckets, and it will be five in the near future. So we have done a good amount of business development. As I mentioned, our pipeline is very large, and our platform is very productive. And so we brought in somewhere in the range of $1 billion in cash or so over the last handful of years and through business development. We have also done somewhere in the $700 million range in equity. So we've accessed the capital markets. We've done around $300 million or so in this time frame through kind of creative or royalty-based or structured finance. And then, you know, at some point, we will look at some smart strategies to add debt to the balance sheet. And then the fifth bucket will be commercial revenue. You know, we think that will, at some point, be the sole need to access capital. We're obviously not there yet, but we have kind of a view to getting there. And so I think that we will finance this study as well as the rest of the company through those same types of means. Next question is from Will Pickering at Bernstein, and his question is: In the segment of FCS patients you will be initially focused on commercially, does genetic FCS make up the majority or minority of those patients versus clinical FCS? What's your latest thinking on the number of addressable patients in the U.S.? Let me take that second part first, and then I'll give it to the panel after that. That's a challenge to identify the total number of addressable patients across genetic and non-genetic. I would say the genetic FCS or the traditional FCS, as Dr. Ballantyne has talked about, is somewhere in the area of 1,000 or less patients. But if you talk about MCS or less, you know, not using those antiquated terms, it's somewhere between 1 and 10 per million. And so it's not a super well-defined number there. Then I will pass to the panel on the relative sizes, genetic FCS versus clinical FCS, the relative size. Yeah, I just think you have to be a little bit careful only because the labeling is going to matter. And, you know, the one thing I never do is get ahead of the FDA on what they're going to allow in labeling. You know, if the label, you know, covers basically the patient population, which was genetic FCS and patients who phenotypically look like genetic FCS, you know, that expands the population and, you know, to a significant degree, that's hard to quantitate. If the label is confined to FCS, and all this predicates on being approved to begin with, you know, that's a smaller population. So, you know, we think whatever the label is, you know, assuming we are approved, you know, that's how we're likely to be, you know, managed by the payers. So it's pretty complicated mix to answer that question. You know, again, Dr. Ballantyne, I, I don't know if you have anything to add to that, but, but that's kind of the, the take I would have. Well, I think one of the things that's interesting is that, you know, your study allowed clinical FCS to come in. So I think that is an important distinction, and it was a conservative approach with plozasiran, and he was all genetically confirmed, and you had about half and half. So I think that gives some idea that there are lots of people who have clinical FCS who may not meet the biallelic traditional genetic criteria. I think the more important question is, first question is: What is the FDA gonna do? The second question is: What are the payers gonna do? You know, I think this is quite interesting because what we're talking about is something very different than PCSK9. I mean, PCSK9, you know, FH is one in 250, but people with cardiovascular disease and LDLs over 70, you're talking millions of people. And so there was a tremendous concern that you were gonna be breaking the bank for that. You know, if you were to go and take a look at. If you were to say there's, you know, the estimates are one in a million to maybe 1 in 250,000, so it's, that might be 1,000 to 4,000. But if you were to say, well, what if you were-- there were 10,000 people, that's one out of 30,000 people who might need a drug like this. I mean, when you're talking about, you know, in terms of a payer, if you've had people with pancreatitis and they have persistent chylomicronemia, and it's one in 50,000 people in your plan, this is not the same thing as, you know, approval of something for everybody who has heart disease. So I do think it's gonna be the issue of value, and then, you know, what is the cost of pancreatitis, and what is the likelihood of these things? I think there's other pragmatic issues that need to be thought through with it. I think the issue of—and it'll be challenging, so I—I think there's two separate issues. One of them is, of course, regulatory. You have to get approved. You have to have a label. The second one is, what do payers consider to be a good value? The label was wide open for PCSK9, but it was very restricted. If you're starting off with something that's much, much less common and has very big expense associated with it, we'll have to see what ends up happening. There's a lot of work to be done to get that worked out, though. Thank you. Next question is from Ellie Merle, from UBS, and this is probably for Dr. Ballantyne. How do you think about the landscape in SHTG, particularly given other mechanisms like FGF21 analogs are being investigated here? Where specifically do you see the opportunity for plozasiran in SHTG? So, I, you know, I think the first thing is that, probably FGF21 is not gonna work for FCS. I, I'm doubtful. I think you have to have some LPL activity probably for that to work. So, and we'll have to see how that program proceeds with it. It's a little bit further behind. It's a promising therapy. It's, I think, too early to evaluate. I do think is that, there's gonna be a lot more confidence in having a big program that's also doing an outcome study, in terms of what's the benefit of this drug for, you know, potentially for high-risk people who are at risk for both pancreatitis and heart disease versus, smaller programs with it. But it's a little premature. I think FGF21 is a promising target. I don't think it's gonna work in FCS, which is the most severe part of it. And so right off the bat, in terms of that, you know, the first goal of this approval process, where I think you've got - you have the FDA giving an expedited approval, right? It was similar to... Do you wanna comment on that, Vince or Bruce, what your position is in terms of the FCS indication? Well, we have fast track. Fast track is what I meant, yeah. We have fast track, and you know, so we, again, I don't know what the FDA will do with respect to the review process, but- FCS has unmet clinical need more than severe HTG. So I think it's what we're talking about with FGF21 is a different ballgame in terms of when would it first come to market. So it's a little too early to, I think, speculate what it will look like. Mm-hmm. Thank you. Okay, I know we are bumping up against a, a deadline here, so I'm gonna try to get to a couple more questions. So this is from Maury Raycroft at Jefferies. For Palisade, are you saying how many patients continued in the OLE portion of the study, and how much OLE data you'll include in the regulatory filing? And then an update on the status of the EAP study, which I'll take that right now. We're not, we're not disclosing anything about the EAP program at this point. So I'll turn it to Bruce and Jen, to talk about the OLE. Yeah, I suspect there will be minimal OLE data in the original filing, but there, you know, will be, you know, a good bit of OLE data in the 120-day safety update, you know, that's a part of the NDA process. You know, that's when I think more of the OLE data will come in. But I don't think we'll have a lot of OLE data. It depends on when the submission is going to happen, and that's gonna depend on our discussions with the FDA. You know, the earlier the submission, the less OLE data there'll be. The later the submission date, the more OLE data that probably makes it in. As regards, you know, you know, how many patients have gone into the OLE, you know, I think at this point, I'm probably not comfortable hovering, you know, on that point. And I'm not sure, you know, that whether or not that will go into the, you know, the first presentation we make. Generally, you know, we'll stick to the blinded phase early and then you'll bring the OLE data in later, you know, to show durability. Thank you. And again, we probably have 30 questions in here, so apologies to all the analysts that we're not gonna be able to get to them. But I can ask one. We can go one more question, and this is from Pat Trucchio at H.C. Wainwright, and the question is regarding next steps for the plozasiran program. When would you anticipate in having the feedback from FDA on the NDA in FCS and getting the NDA filed, and will this be standard review? Is there a potential for accelerated review? Let me give, you know, the philosophical answer, and then, you know, Bruce can give the real answer. So here's our goal is to figure out the path that gets us to filing as quickly as we can, review, and as quickly as possible, and launch as quickly as possible. Which means that we need to have some regulatory interactions to figure out what that is. And I did mention earlier that our goal, and we're confident that we can launch in 2025. Now, when in 2025, who knows? And as far as the process for regulatory interaction and filing, I'll turn that to Bruce. Well, now that we have the top-line data, we can approach the FDA about, you know, talking about, you know, filing matters. You know, that will generally have a 60-day clock. So once we ask them, yeah, well, we should have our answer in about 60 days, would be my guess. So we're probably, you know, on the order of a quarter of a way, you know, from knowing internally. With respect to, you know, what sort of review, that only comes after you submit the NDA that the FDA, you know, makes that determination. And, you know, we have nothing. Yeah, we ask, but, you know, the FDA decides. I have no way of saying, you know, what kind of review it will be, you know, until such time as we've submitted the NDA, and the FDA has accepted that NDA, which they don't have to. They can refuse to file, you know. So there's always, you know, a waiting game, you know, before you know the answer to that. Thanks for this. I'm sorry. I want to slip in one more, actually, 'cause there was multiple people that were asking this same question. We didn't go over this much on the call. So this was from Jason Gerberry at BofA Securities and others. "How would you characterize your appetite to partner zodasiran? Is it pretty important in the near term, or will it take a backseat to prioritizing other assets, for example, advancing obesity and other potentially partnered assets?" So I'll take that. So what we've said is that the data for zodasiran, again, were extremely compelling. And it was a very difficult decision that we had to make to prioritize internal development of plozasiran over zodasiran or even both of them together. But, you know, that we are. We are a development stage biotech company, and we are a cash-consuming company, and so we have to make those decisions, sometimes, when we don't want to. So what I would say on partnering is that we will, at least today, our plan is not to move forward with other phase III studies for zodasiran independently. And I don't think we're alone in thinking that those data are compelling. And so we certainly will consider partnering or licensing of that particular asset for somebody that, you know, may wanna take it into a larger study. It's impossible to characterize priority because we don't drive that. You know, that would be based on external folks, and the timelines for these types of deals are very, very long. And so I couldn't give any kind of timeline guidance on that. You mentioned obesity and other metabolic programs. We do feel like the INHBE, and then the second adipose-targeted program that we'll disclose in August, we think those fit pretty well, with our own internal development in the cardiometabolic pipeline that we have. And so we feel good about moving those into clinical studies ourselves. We'll give timeline guidance on those. We did say for INHBE, at least, that we're on schedule to file a CTA this year to begin clinical studies, and we'll give timeline guidance on the adipose program, which is not too far off from that also. So I think that we are. We can do both of these things. We can look at maximizing the value of assets that we're not taking forward ourselves, and we can also prioritize development of additional pipeline programs that may fit from a portfolio standpoint. So we can do both of those. That's my- Hey, Vince, can I say one thing? I sure hope someone picks up zodasiran to partner, 'cause I would love to have that drug available for patients. Yeah, that. And again, I— It's honestly, that's why in one of my slides, I wanted to say, "Here's the process we went through. Here was the different options." And the decision is not based on the strength or weakness of the data. It's very, very compelling, and that was. It's a hard process, an exhaustive analysis that we did with folks like Christie and many others in the field that, you know, see a lot of hope for ANGPTL3-targeted programs. And, you know, we think that that is a, you know, that is a potential solution. But it's not one that we can make for both. We couldn't make a decision to move forward to large phase III studies. It just wasn't in the cards for us today. That's all. So again, I wanna thank everybody for joining us, the panelists and Christie, especially. We always appreciate your input. And thanks to everybody for watching today.