Arrowhead Pharmaceuticals, Inc. (ARWR) Earnings Call Transcript & Summary

Good morning, and welcome to the Arrowhead Pharmaceuticals Virtual Analyst and Investor Event. [Operator Instructions] As a reminder, this call is being recorded and the replay will be made available on the Arrowhead website following the conclusion of the event. I'd now like to turn the call over to Vince Anzalone, Head of Investor Relations.

Thank you, Tara, and thanks, everybody, for joining us today. We're here to talk about our Phase III data from the PALISADE study of plozasiran. The data were presented yesterday at ESC, and also simultaneously published in the New England Journal of Medicine. So before we start, I just want to make sure everybody is aware that we will be making forward-looking statements today, so please refer to our SEC filings. Here's what we're going to cover. So Chris Anzalone, our CEO, is going to talk about Arrowhead generally and how we're delivering on the promise of RNAi therapeutics. Bruce Given, our Chief Medical Scientist, will talk about our clinical plan and give a review of some of the non-PALISADE clinical results to date. Dr. Gerald Watts will give an encore presentation of the ESC data that we presented yesterday. Andy Davis, our Head of Commercial for the Cardiometabolic Franchise will talk about what we're doing to be commercial-ready to launch next year. And then Chris will come back and give some concluding remarks, and then we'll open up the call to questions. We also have Dr. Jennifer Hellawell, our Chief Physician for Cardiometabolic and Eleonora Goldberg, our Head of Medical Affairs, who are available during the Q&A portion of the call. So I just wanted to introduce Professor Watts. We're very fortunate to have him here today. He's the Winthrop Professor of Cardiometabolic Medicine at the University of Western Australia, Perth, and he gave a fantastic presentation yesterday at ESC. So we thank him for joining us today. So I'll turn the call over to Chris now.

Hello, everyone. Thank you for joining us today. We're developing a suite of RNAi therapeutics designed to treat a broad range of conditions across several verticals. Those verticals now are cardiometabolic, muscle, pulmonary, complement-mediated, liver and CNS. Within cardiometabolic, we are developing plozasiran and zodasiran. Olpasiran is being developed by our partner, Amgen, and we've got 2 obesity candidates, ARO-ALK7 and ARO-INHBE, both of which we'll be filing CTAs for by the end of the year. Within muscle, we are developing ARO-DUX4 for FSHD and ARO-DM1 for myotonic dystrophy. Within pulmonary, we're developing ARO-RAGE and ARO-MUC5AC for severe asthma and potentially COPD and ARO-MMP7 for IPF. Within complement-mediated, we have ARO-C3 and ARO-CFB, both being developed for complement-mediated diseases. Within liver, we have ARO-PNPLA3, a mass drug; fazirsiran, which we are co-developing with our partner, Takeda, against liver disease associated with alpha-1 antitrypsin deficiency. And we've got 2 compounds partnered with GSK. One against chronic hepatitis B and one against NASH. And then finally, CNS. We believe that we will be filing CTA by the end of this year for intrathecal administration and next year, we believe, will be in the clinic with subcu administration. So all of these are important, of course. However, cardiometabolic really is the key to our -- is our key near-term focus in Arrowhead. Cardiometabolic is the cornerstone of our commercial transition, which we believe is happening imminently over the next several quarters. Plozasiran is the cornerstone of our cardiometabolic presence, and FCS is the cornerstone of plozasiran's market entry. We truly believe that plozasiran could be a pipeline within a drug. However, it all starts with FCS. We believe that patients deserve a powerful, reliable and convenient therapy. Today, I think you'll -- you will hear about dramatic triglyceride lowering that we've seen with plozasiran, reduction in acute pancreatitis, convenient 4 doses per year dosing schedule and a favorable safety profile. But this is just the start. We are also studying additional populations to learn whether more patients may also benefit from plozasiran. We are interested in the severe hypertriglyceridemia population. These are patients with triglycerides above 500. We think there are around 3 million of those in the United States. And we'll also be studying the broader population of patients with triglycerides in the 150 to 500 range, we think there are about 20 million of those in the United States. This enables us to address the commercial opportunities in the staged manner, if studies warrant label expansion. So with that, I'd like to hand the call over to Bruce Given. Bruce?

Thank you, Chris. Good morning, everybody. Just in a way of a general beginning here, I have deja vu being where we are with triglycerides today. This reminds me of when I was at Janssen as we exploited at the beginning of the modern exploitation of atypical antipsychotics, and then in the PAH days, when people thought that was going to be a small market and it turned out to be an important big market in its own way. And here we are now with triglycerides, which in many ways, again, is a totally underappreciated opportunity that's going to become an important cardiovascular area of focus. So here we go. I'm not going to go into great depth on the role of APOC3 in lipid disorders here. I'm going to leave more of that to Professor Watts. But basically, to survive, humans need to be able to take advantage of nutrients that we eat, and this is the pathway by which we deal with fats that are available in the food we eat, which are critical for many, many physiologic functions, and the body evolved a quite sophisticated system for handling fats. And it turns out that APOC3 is central to that system. And when fat is brought into the body, it comes in, in the form of triglycerides initially in the form of chylomicrons. And Professor Watts will talk about chylomicrons and their importance. But that's just the start of the process. And then there is a very sophisticated set of physiologic steps that lead to the metabolism and ultimately, the utilization of this fat that's in our diet. And APOC3 really take place a central role in regulating that entire set of processes. And because of that, we wind up with a variety of disease states when this is disordered. But it also creates a tremendous opportunity for drugging the entire triglyceride pathway when it is appropriate using plozasiran. So this is going to be an important concept that we'll talk about. Just one other thing I'm going to say here, triglycerides is how we measure things with this pathway. And in some ways, it's the equivalent of measuring total cholesterol, which hides a great deal of metabolic complexity and importance when it comes to disease states that I think all of us will be explaining and learning about over the coming few years as people start to understand the importance of triglycerides in general. So this is a slide that we first introduced this last summer to try to place triglycerides in perspective. So for the last 5 or 6 decades, we've been very focused on LDL cholesterol, the so-called bad cholesterol, as a very important driver, obviously, of the atherosclerosis. But as we've gotten better and better at reducing LDL cholesterol, we've learned that there's still our ongoing heart attacks and strokes and chest pain and other things that really obviously can be fatal. It's still the #1 cause of death, cardiovascular disease is still the #1 cause of death despite the many decades that we've had statins available for instance. And the last 5 or 6 years, we've actually had an explosion of new drugs that are additive with statins. It's now almost hard to find a subject or patient, I should say, that you could not get to a goal LDL cholesterol, if you have the availability of all the agents that are available. And this is really the reason that we're not, at this point, continuing to invest as Arrowhead in ANGPTL3 because it really works in this side of the spectrum. And although we think it's a fantastic. We think plozasiran is a fantastic agent. It's just very crowded on that side. And it's very possible that as good a mechanism of ANGPTL3 is, it will just never be fully exploited in this space. But in our case, we are really excited about the triglyceride side because this has been an underappreciated, underdeveloped, low investment space up till now. And it turns out that with the age of modern genetics, we now understand that this side of the equation, the metabolites that come out of this fat metabolism process with triglycerides actually probably account for a significant amount of that residual risk that's not accounted for by LDL-cholesterol. And it turns out that there are important elements all along this access with respect to elevated triglycerides. So if we start in the middle with mixed hyperlipidemia, in the U.S. alone, we think this is maybe 20 million patients that have not only high LDL, which many times now is actually being effectively treated with statins, for instance, but also high triglycerides, for which the drug [indiscernible] is very limited and not very effective at this point. And we think plozasiran has a lot to offer here. We'll talk about that more in a few moments. But then as the dysfunction, if you will, in the metabolic process for dealing with the fact we absorbed from diet becomes larger as we get into severe hypertriglyceridemia. And if normal is 150 milligrams per deciliter, now we're talking about greater than 500 milligrams per deciliter to the thousands. And at the very end of this, a small subset of severe hypertriglyceridemia, now we're into a rare subset of patients with hypertriglyceridemia that have so much disorder here. Their triglycerides are so high that they have a problem with pancreatitis. And pancreatitis is a big problem. And just before pancreatitis, you have abdominal pain and could be very severe. And some of these patients that Dr. Watts will talk about, have daily abdominal pain, really have a miserable set of problems and they're always at risk for pancreatitis and the pancreatitis can be fatal as well as having just a number of complications that come along with it. So this triglyceride world is an important world that's very much underserved at this point and underappreciated. And as happens, it's often times a medical journals that understand the importance of what's coming as opposed to what physicians see today in front of them and certainly what investors see in front of them today. So it's no surprise that plozasiran has had not only late-breaking presentations and the major medical meetings this year, but also that New England Journal of Medicine and JAMA Cardiology have wanted to do simultaneous publications, expedited publications because they recognize, to quote Wayne Gretzky, "This is where the puck is going to be." It's not where the puck is today, but it's where the puck is going to be. This is going to be one of the most important frontiers in cardiovascular medicine over the next several years. And we think it's no accident for why plozasiran has been getting this treatment because the results have really been pretty impressive. So if we start at the bottom with mixed hyperlipidemia, we see the ability of plozasiran. Even on top of current medical therapy, the best medical therapy available today, we can still see a 60% reduction in triglycerides roughly from baseline. We see a very high percentage of patients that are taken from an abnormal triglyceride to now a normal triglyceride. And there's really nothing else available on the market for treating triglycerides that comes close to this kind of performance. We just haven't had the level of innovation in this area that's been needed. And as I mentioned, the geneticists are really understanding the importance of some of these triglyceride metabolites in driving atherosclerotic risk. And these include mouthfuls like non-HDL cholesterol, remnant cholesterol. These are terms that probably over half of cardiologists don't -- wouldn't even know what these terms represent. At this point, it just hasn't been taught, and it hasn't been something that people had to learn so that it's going to be an educational challenge, but we see large reductions. And based on the genetic work that's been done, the predictions will be that these will have substantial impacts on cardiovascular risk, has to be proven, but that's what the data is pointing to. SHASTA-2 was our study in severe hypertriglyceridemia. Now these patients with severe hypertriglyceridemia, the APOC3 impact is really high. So you see now, now you see reductions of triglycerides in severe hypertriglyceridemia or in that subset with FCS of 75% to 80% reductions from baseline, really very large reductions for baseline. And you see, again, high percentages of patients being taken from high-risk categories into lower risk categories because of the ability to move the triglycerides so greatly. And then you see improvements in other atherogenic lipids as well as you would expect. So just to review very briefly, SHASTA-2, a severe hypertriglyceridemia. Again, these are patients that could have triglycerides as low as 500, which is still quite a bit above the normal, to as high as 4,000. The average triglycerides in this study were around 900 or so. So really quite elevated triglycerides, but they were not allowed to come in with known FCS, and you'll hear more about FCS from Professor Watts. But we studied 3 doses of plozasiran here, 10, 25 and 50 milligrams. They got 2 injections, 3 months apart. And we measured the effect on the triglycerides in 6 months. So what would have been just before they would have gotten a third dose if they were going to be on chronic therapy, so what we would call trough, the lowest level you would expect to achieve. We, of course, measured a whole lot of other parameters that represent the metabolism of these chylomicrons and this absorbed dietary fat. And the results were really quite impressive as we talked about. On the top panel, you see the effect on APOC3. We are an siRNA. We are designed to very specifically and selectively knock down the production of APOC3 in the liver and hepatocytes. And as you can see at the 6-month time point, which is what would be the normal type for receiving another dose, APOC3 was quite suppressed, and this drove about a 75% reduction in triglycerides at the 25 or 50-milligram dose. 10-milligram dose is a pretty effective dose, but not as effective as we would like to see. So 25 milligrams is the dose that we're taking forward in requesting approval for plozasiran and FCS, and it's the doses in Phase III now for SHTG for instance, as well as mixed hyperlipidemia. And importantly here, in the open-label extension when everyone went back on to plozasiran, you can see they very rapidly drop their APOC3 and their triglycerides back down again and it's stable. There's no loss of effect over time. Remnant cholesterol is one of these key drivers in genetic studies of atherosclerotic risk, and you can see really remarkable reductions in remnant cholesterol of around 60%. HDL cholesterol is a bit controversial now. We used to call it the good cholesterol. It turns out it was probably just a marker for triglycerides. When HDL goes up, triglycerides tend to go down and vice versa. So patients that had low HDL and were thought to have insufficiency of the good cholesterol, it was probably just marking that they were the patients that had high triglycerides, and we were not understanding that the importance of triglycerides for atherosclerotic risk. But there's still a lot of research going on in HDL and trying to understand its function. And this is a space that I think is going to evolve over the coming years, and we'll learn more about whether these elevations that are produced by plozasiran are helping or not or are just a marker again that we've taken the triglycerides down so effectively. Turning to MUIR, which is our study in mixed hyperlipidemia, which was just published a couple of months ago in The New England Journal of Medicine, really a very similar design to what I just went over with SHASTA-2. 2 doses of plozasiran, 10, 25 or 50 milligrams again dose quarterly. And then we also had where we dosed 50 milligrams at 6-month intervals, just to see if we could stretch the dosing interval or not. And again, triglycerides at 6 months were the primary endpoint, and we measured all of those other important lipoprotein actors as well. And here again, repetitive theme, big reductions in APOC3 driving very large reductions in triglycerides and remnant cholesterol. You can see here the Q 6 month dosing did give good results, but we really felt that the peak to trough differences were larger than we wanted to have in a disease that we think deserves to have as deep and persistent reductions as we get. So we have decided not to do Q 6 months going forward, but to do Q 3 months and to have a steadier reduction in these lipoproteins of interest. Again, non-HDL-C, large reductions, which the genetics say should be important. You see here with LDL, this mechanism is not an important mechanism for LDL. This is very much a triglyceride drug, not an LDL drug. So LDL tends to not change much in either mixed hyperlipidemia or the more moderate levels of severe hypertriglyceridemia. ApoB goes down, which is important, and HDL-C again goes up. So now let's talk about where we're going from here. PALISADE is completed. FCS will be filed this year for approval in the U.S. and over the next first half or so of next year in other geographies. SHASTA-2, I just went over those results. They were published. Those are our Phase II. Now we are conducting SHASTA-3 and -4, which are our long-term pivotal efficacy studies for use in regulatory filings around the world for the broader severe hypertriglyceridemia market. We also have, what I think is going to be a landmark study in severe hypertriglyceridemia and extreme hypertriglyceridemia, which is SHASTA-5. I believe this will be the first purposely designed study to specifically look at pancreatitis as an endpoint. So the primary endpoint here would be the ability of plozasiran to reduce the incidence of pancreatitis when compared to placebo. So it's an outcome study. It's an event-driven study. And we don't really see this as a regulatory study so much as a key study for payers. We believe, especially at payers in some markets outside the U.S. And this will be important for some payers in the U.S. as well, that this study will be meaningful for them from the standpoint of reimbursement decisions. And it will be, I think, a landmark in the world of triglyceride research. And then finally, mixed hyperlipidemia. The MUIR study has already been published. The MUIR-3 study is a large Phase III study, 1-year double-blind treatment versus placebo. That's really largely to support SHASTA-3 and -4 by providing a large safety database. We divide these patient populations from regulatory indication standpoint, but the human body is just thinking about triglyceride and it's a continuum to the human body. So I think everyone recognizes that safety and tolerability, insights that we'll get from MUIR-3 read very directly SHASTA-3 and SHASTA-4 and on the severe hypertriglyceridemia space. And then finally, to achieve an approval of mixed hyperlipidemia, which is very much focused on atherosclerotic cardiovascular risk. The CAPITAN study will be probably one of the most awaited outcome studies in the industry over the next decade because with the genetics point and so strongly toward triglycerides being meaningful in cardiovascular risk, this is probably the best study that we can have to truly demonstrate an effect on cardiovascular outcomes because this is -- this drug has such a profound effect on triglycerides, while really not having much impact on the LDL side. So it's a very clean test of the hypothesis. So with that, it's my pleasure to turn the presentation over to a good friend and really wonderful lifelong student of lipid metabolism, Professor Gerald Watts.

Thank you very much, Bruce. Ladies and gentlemen, my name is Gerald Watts, and it's nice to be broadcasting this result from Center of the University in London as it was, actually, which my home town and where I rendered medicine practice for many years before relocating to Australia, and quite near where we are is where I had my clinics at St. Thomas and [indiscernible] managed a lot of these patients in [indiscernible] that were very difficult to treat really. And it's nice to see that we now have a therapeutic tool that can address those problems. A little bit later in the day, but we're here. And so thanks very much for providing the evidence really that lowering triglycerides, excessively triglycerides can influence not only the biochemistry and the metabolism, but the importance of the PALISADE trial is that you have a clinical outcome, and that's quite unique. And it's also a first in class siRNA, the first drug to show this in a formal way because statistically, you have shown quite -- we have shown quite clearly that there is benefit. So moving on to the background to persistent chylomicronemia. For those of you who are not aware, the lipoprotein system is compared to a whole range of particles. These are the largest particles. These particles chylomicrons are about 1 -- or at least 100x larger than LDL, as we know that causes cholesterol. They're also lightest particles, they're ultralight, not high density like proteins, not low-density protein, not very low density, but ultra low density particle. So they just flip to the top of the test tube and they're large, and they're milky and you can't really see through them. So if someone has chylomicronemia, plasma or serum is totally white. As white as [indiscernible]. You can't actually see through it at all. But because they are large, they also have large sequelae as we'll talk. So when we talk about persistent chylomicronemia, we refer to an extremely high plasma concentration of triglycerides. And I should indicate that over 95% of the chylomicron particle is triglyceride. When we say that triglycerides are elevated, we really mean that the particle concentration is elevated. Above 880 milligrams per deciliter for those who like millimoles per liter, more than 10. So in simple terms in which the fat that you eat and then is absorbed and packaged as a particle called a chylomicron particle that cannot be cleared from the circulation. So it's a traffic chylomicron particles trying to get out of the system, trying to get off the motorway. And you can't get out because there's a big traffic jam. So I suppose to say therapeutically, what this is all about is putting the policemen in there and really even the traffic cap. The transportation defect has to be corrected. So for the geneticists, it's also -- not only is it an ultra-low density lipoprotein, but it's also an ultra-rare, but important genetic disorder in which you inherited 2 alleles, 1 from 1 parent and 1 from the other, that's recessive and therefore, it expresses as pure familial chylomicronemia syndrome, that's the big term, FCS, or more commonly as a polygenic disorder or heterozygous disorder or disorder in which the genes haven't been identified called the multifactorial chylomicronemia syndrome, which is about 100x more frequent than FCS. And the important point that whether it's bi-allelic recessive or whether it's polygenic or anything else or a combination of polygenic and recessive heterozygous that the final metabolic defect is an impairment in lipolysis or fat breakdown in the central station called lipoprotein lipase, this enzyme is the business end of clearing fat from the system. So when does this fat particle accumulate for primarily genetic reasons and environmental reasons, too, it causes multiple symptoms, physical, cognitive, emotional, social, economic consequences. But undoubtedly, the most severe one is acute pancreatitis. This is a massive inflammation of the pancreas in which it may hemorrhage. And it's an acute medical emergency. And with recurrent episode of pancreatitis in each individual who inherits FCS of an 80% lifetime risk of developing acute pancreatitis, 60% of recurrent pancreatitis and its other consequences, diabetes, malabsorption and [indiscernible] some poor quality of life. So the current, as Bruce indicated, the current therapeutic agents that are in guidelines. So treating severe hypertriglyceridemia beyond diet, which is difficult to adhere to our fibrates, omega-3 fatty acids or fish oils, if you wish, statins, if there is a background risk of coronary disease and niacin. But we don't -- we know that they're not effective. There's almost a diagnostic test if you don't respond to these current therapies, then you have persistent chylomicronemia. Most likely, they're bi-allelic recessive disorder. So that's what we call the unmet need in clinical practice and as a practitioner of internal medicine, but with particular interest in cardiometabolic disorders and within that particular interest in lipid disorders. I mean this is one of the greatest unmet needs in lipidology. Even lipidologist -- even endocrinologists can't handle this. Even lipidologist miss it really. It's interesting that on average, it takes about 5 to 6 doctors or clinical specialists and general practitioners to actually make the diagnosis because we're just simply not aware of it. So one of the important aspects of the program here is that these clinical trials would lead to increased awareness of these disorders and better clinical practice. So this is the unmet need. How do we address it? So we address it by thinking about what's causing the problem in the system and trying to get that system, get that bug out of the system, if you wish. So on the left-hand side, we have to think about APOC3, which is you don't want APOC3 as you all those lines going to LPL dependent and LPL independent pathways and other sectors. Once it gets into the system, it is released from the liver, it blocks receptors. It down regulates enzymes and inhibits the enzyme lipoprotein lipase, the policemen that keeps the traffic going, and you basically don't want it. And we do know that it's not good for you at all, actually. So in terms of getting rid of APOC3, the way we can address this is by silencing the APOC3 mRNA within the liver in the cytoplasm. The metaphor is shooting the messenger, and that's a very good metaphor because that's what we're doing. And the messenger is a nasty person in this particular instance. So when you remove lipoprotein lipase, those inhibitory mechanism on the left-hand side are released. And then the chylomicron particles, there are remnant products and also VLDL, very low-density lipoprotein is cleared. So the motorway is completely devoid of the traffic jams and policemen. The therapeutic agent plozasiran is a specific silencing RNA, the policeman really has allowed the traffic jam to relieve and there's a nice flow all the way home and triglycerides formed. That's in simple terms. And that what I'm trying to describe to the audience here, that lipids are just not static things. They are kinetic things. They're like particles and vehicles that move. And what plozasiran does is just keeps the movement going by relieving the blockages in the road. So as you heard from Bruce, the study support particularly SHASTA, SHASTA-2, very effective triglyceride reduction also seen in the Phase I. So now it's going to be put to the test. This is the solution. Let's look at the evidence. So the evidence is a trial, and this is the PALISADE trial, a randomized placebo-controlled Phase III trial of plozasiran in patients with FCS. 75 patients that were randomized to 3 groups, the placebo, 25 and 50 milligrams of plozasiran, and they had quarterly injections every 3 months and followed up for 10 to 12 months, a 12-month study. So they -- the trial was conducted in several countries and many centers to increase generalizability. The -- we're going to report mainly here on the primary end point, the so-called placebo adjusted median percentage change in triglyceride in 10 months and a number of multiple endpoints, most importantly, #4, which is the incidence of acute pancreatitis. Because to have a trial where you have a clinical event as an outcome really increases the importance of the trial. And this is the value of this particular one. So now we go to the selection of patients. PALISADE importantly, defined FCS in clinical and genetic terms. So everyone had multiple measurements of triglycerides that were averaged about 11.3 millimoles per liter, 1,000 milligrams per deciliter. Importantly, despite best standard of care and at least one of the following as agreed with the regulator, a genetically confirmed diagnosis of FCS, although that wasn't essential or recurrent episodic pancreatitis or recurrent hospitalization for severe abdominal pain for which no reason was identified, a history of childhood pancreatitis or a family history of hypertriglyceridemia, of course, acute pancreatitis. So pretty broad criteria that allow both genetic and clinical diagnoses to be employed, and that was with agreement with the regulator and an important move to increase a generalizability. Perhaps the correct word is equity care. So importantly, as you see there, the bottom genetic testing was done in all patients without prior testing for FCS and the importance of that as an inclusion in the protocol and also as a prespecified endpoint will become evident shortly. So that's selection criteria. And now these are the characteristics of the people. So they were mainly middle age on average, similar proportion of male and female, whites, mainly. BMI not obese at all, respectable BMI. Severe hypertriglyceridemia as we can see here, averaging 2,000 milligrams per deciliter or 22 millimoles per liter. According to best standard of care of at least 60% to 70% on other agents, statins, fibrates, omega-3 fatty acids, 40% of them had diabetes genetically confirmed on average 60%. I mean it's almost quite interesting that close to -- there was a 50-50 split and that was [indiscernible] too. And this is important that there was a very high incident [indiscernible] history of acute pancreatitis, I mean, close to 90%. And that's important because again, we might have been lucky here, but people had 90% pancreatitis, it gave you something to bite into. So an increased the chance really of finding something. And also in the group that was quite sick have recurrent -- 90% of the group with pancreatitis or recurrent pancreatitis signifies the group that requires this type of treatment. So that's -- those are the so-called baseline characteristics. Now let's go on to the results. We've got second slides with the results. This is the primary endpoint on the left-hand side. And you can see that with the plozasiran 25 and 50 on average, there was a 80% reduction in triglycerides at 10 and 12 months. If you turn to the right, you can see the median fall in APOC3 at 90%. This fits in. You knock down APOC3, get the bug out of the system, traffic jam is released and triglycerides fall very nicely, down by 80%. And ipso facto, the chylomicron concentration is down by 80%. So moving on to the time dimension. It's important to look at metabolic changes in the time space. And here, you can see on the left-hand side of the median fall in triglyceride that occurred within the first 4 weeks. And notwithstanding natural variation in triglycerides with the 3 doses that were sustained up to 12 months, much tighter than APOC3. This was an important result and was prespecified that, that reduction in triglycerides and hence, chylomicron concentrations was uniform and independent of the presence or absence of the gene variant, the bi-allelic pathogenic gene barrier shown in white compared with the variant in other colors really. So irrespective of the presence of a genetic mutation, I could use that term, the impact on triglycerides was clear up and seen with no significant difference in those changes. So patients with genetically defined FH, nongenetically FH, clinically defined FH have the same percentage response. So the other way to look at reductions is how many people actually have achieved therapeutic targets. And please focus on the left-hand side, that's easier to look at the first instance here that being absolute triglyceride levels mean plus interquartile ranges on average, they fell below -- well below 10 millimoles per liter or 1,000 milligrams per deciliter. And perhaps more meaningfully because we can look at the waterfall plot, these are individual patient results. Placebo in gray. Turquoise, I think, for the 25 milligrams and navy blue for the 50 milligrams. And the interrupted line within the waterfall plot is a 50% reduction in triglycerides or 50% reduction in large chylomicrons. So you can see that -- the very few people on placebo whose triglyceride fell, but that's expected in the clinical trial and a good support really for the design of the trial actually, placebo-controlled trial, that's why we do it. But in the intervention groups, with plozasiran over 80%, over 80% of patient subjects in the trial drop their triglyceride below 50%. So that therapeutic goal was met. The other way to look at therapeutic goals is in terms of the proportion of people whose triglycerides fell below a recommended level threshold or goal 10 millimoles per liter, that's get below 10 millimoles per liter, risk of pancreatitis will fall. So 3/4 of the individuals in the 25 milligrams plozasiran group drop their triglyceride below 10 millimoles per liter, and a half of them dropped the triglycerides below 5.5 millimoles per liter, 500 milligrams per deciliter. So that's seen at that stage for a good evidence that we should see a reduction in the incidence of pancreatitis as demonstrated in this slide. So this slide is a so-called survival analysis. It's called a Kaplan-Meier curve after Kaplan Meier, who used it to represent a survival over time. It's the time to first event of pancreatitis in navy blue in plozasiran and in gray in placebo. So these are people who have pulled from both groups to increase statistical power. So we can see here that 20% of the placebo group developed pancreatitis compared with 4% of 50 individuals in plozasiran. And that was statistically significant relative odds 0.17, effectively meaning an 83% reduction in the incidence of acute pancreatitis, which is actually more severe in the placebo group than the plozasiran group. So that's a very gratifying result. And these reductions in triglycerides reported in this drug. You don't see that with oral agents. And this is the first time that the outcome of acute pancreatitis has been shown to be statistically significant in an intervention group with plozasiran siRNA compared with placebo. So we went beyond just the numerical report to statistically testing the null hypothesis. And here, null hypothesis is upturned, and it's very positive. So summarizing now the adverse events here in this table and a summary on the right-hand side. I'll read the writing because it's much easy to take you through it. A greater proportion of placebo-treated patients experienced serious adverse events, no surprise because they had recurrent abdominal pain and acute pancreatitis. There were fewer premature discontinuations with plozasiran. No surprise because there was less pancreatitis. There was no reduction in platelet count. No surprise actually because these are ligand conjugated agent. Hyperglycemia with plozasiran was confined to those with prediabetes and diabetes but could be overcome by minor adjustments in antiglycemic therapy. That wasn't a big problem. And there were no fatalities during the trial. So coming up to the conclusions now that is a very positive trial. It met all its trial endpoints after they were subjected to alpha control systems or hierarchical step-down procedures. Very lucky to get them all being positive. It's -- even in the sample size, this size, it was a remarkably positive readout. Because I think the trial was well designed, actually, exceptionally well designed, and had a group of patients that were enriched with acute pancreatitis. So in summary, plozasiran significantly reduced triglycerides in patients with persistent chylomicronemia, FCS or FCS-like syndromes at 10 months, that was the primary endpoint and over half of the patients that I showed you in the waterfall plots achieved triglyceride treatment levels. Reductions in triglycerides and APOC3 received early and sustained thereafter, with comparable efficacy in triglycerides and APOC3 genetically defined and clinically defined patients. And there is this impressive reduction, statistically significant reduction in acute pancreatitis at 12 months. The safety and tolerability profile was favorable and similar to placebo. So I suppose the bottom line here is plozasiran is a novel therapeutic candidate reducing plasma triglyceride levels and chylomicron concentrations and the associated risk of acute pancreatitis in patients with persistent chylomicronemia. So we're very grateful to the sponsors and grateful to the investigators and participating patients and their families for being in this trial. This sort of PALISADE, I think of PALISADE as a metaphor for a bulwark, or a defense against acute pancreatitis -- hypertriglyceridemia, so there hypertriglyceridemia, a defense PALISADE against the development of acute pancreatitis. So congratulations to the sponsors and investigators for a very successful study. So on that note, it's Andrew Davis, is that right?

Thank you, Professor Watts. Since yesterday, Professor Watts, when you presented this data at the ESC Congress here in London, and that data was simultaneously published in the New England Journal, the feedback from physicians and patient societies has been incredibly swift and very, very encouraging. So what I'm trying to do here is summarize for you the value proposition of plozasiran in FCS, and it really spans 5 key pillars that we've talked about throughout the course of the discussion this morning. The first one on the left-hand side relates to triglyceride reduction. And the 2 words we like to use here are deep and durable. So the depth of that triglyceride reduction of 80% and that occurring really as early as 1 month into the study. And then durable, the durability of those reductions maintained truly throughout the 12-month treatment period. The second pillar related to value proposition is what we call goal attainment, and Professor Watts spoke to this in his presentation. You would note that over 2/3 of the plozasiran-treated patients reached levels less than 880 milligrams per deciliter and nearly half less than 500 milligrams per deciliter. These are acute pancreatitis risk thresholds that are recognized in clinical guidelines around the world, spanning multiple specialties, including endocrinology, cardiology and beyond. The third pillar is the consistent effect. And this is a consistent triglyceride reduction, irrespective of whether the patient was genetically confirmed or clinically diagnosed for FCS. And this really does support the potential value of plozasiran in patients with clinically diagnosed disease, regardless of genetic status. The fourth pillar here is around risk reduction. And as Professor Watts indicated, this truly is the most important outcome of the study, and this study demonstrated a statistically significant reduction in the risk of developing acute pancreatitis, 83% risk reduction. That truly is important for all stakeholders, including not just patients, but also physicians and payers as well. And lastly, what we call an attractive profile. This includes both a favorable safety and tolerability profile. But also the convenient dosing, which is every 3 months. Again, we believe this is important for the health care system, for physicians and for patients, and that it truly reduces the treatment burden on all of these stakeholders. So our conclusion as it relates to these 5 pillars is that this molecule does deliver on what is important to patients, physicians and payers. So let's talk for a moment about our commercialization efforts. And really, the conclusion here is that we are exactly where we need to be at this moment in time. In order to support this highly differentiated profile that I talked about on the previous slide, we are building a best-in-class medical affairs and commercial organizations. Our leadership team is solidly in place. And it's worth noting that the team that we have assembled has incredibly deep experience in not just the cardiometabolic space, but in the lipid space specifically. Our leaders across medical and commercial have done this before, and I have tremendous confidence in our commercial strategy and the team's ability to execute. In fact, our medical science liaisons are presently in the field, conducting scientific exchange, and our hiring plans for future personal promotion should we find ourselves in that position, those plans are in place and will be executed at the appropriate time. I'll just say lastly, that our best-in-class patient and caregiver support program continues to take shape, with the aim of ensuring that patients can easily start and stay on therapy when it becomes available. Lastly, we're incredibly excited about the future. PALISADE, of course, is our first Phase III study to report out, and the key stakeholders with whom we talk to this -- talk about this study with are incredibly impressed with the results. Being here at ESC provides almost instantaneous feedback from physicians amongst the hallways of the forum. We know that the addressable FCS population is ultra rare, you see that on the right-hand side of this slide. But the potential to address larger populations, as Chris had indicated at the beginning of the address today, those populations are on the horizon. You can see the severe hypertriglyceridemia patient population between 500 and 880 of roughly 3 million and a population above 880 of roughly 800,000. Significant unmet need does exist in these populations, including on the far left here in the 20 million U.S. adults, with triglycerides between 150 and 500. And I do look forward to talking to you more in the future about how we see the commercial market opportunity developing across these indications and how we intend to bring plozasiran to the many patients who could benefit. Chris, I'll turn it back over to you.

Thanks very much, Andy. So we are excited to bring plozasiran to FCS patients. As I mentioned early on in the presentation, we believe these patients deserve a powerful reliable and convenient therapy. And I think what you've seen today suggests that plozasiran may just provide that solution. What you've seen today is a dramatic reduction in triglycerides. We see TGs reduced by around 80% from baseline. We are seeing triglycerides reduce to levels that lower the risk of acute pancreatitis, for instance, at the 25-milligram of plozasiran cohort. 83% of patients got below 1,000 milligrams per deciliter. 75% of patients got below 880, and 50% of patients got below 500. We've seen a substantial reduction in pancreatitis. We see reduced risk pancreatitis by about 83%. We see a near-complete suppression of APOC3, a convenient administration schedule of 4 subcutaneous doses per year. And finally, a favorable safety profile. And as Andy mentioned, we believe this is attractive to patients, physicians and payers alike. So this is a key step for us to be sure, but it's only the first. But that -- as I mentioned earlier in the presentation, we didn't believe that plozasiran could be a pipeline within a drug. We hope to be serving the FCS patient population in 2025 with a planned NDA towards the end of this year. We're studying plozasiran in SHTG patient populations in multiple Phase III studies. Our goal is to be fully enrolled in 2025 and complete the studies in 2026. We plan to study plozasiran for ASCVD in the broad populations of patients with mixed hyperlipidemia. And with that, we'd like to turn the call over to questions.

Great. Thanks, Chris. So at this time, we will be conducting a question-and-answer session with our speakers. [Operator Instructions] So our first question comes from Eli Merle from UBS.

Congrats on the data. For Dr. Watts, in SHTG and mixed dyslipidemia, how do you think the average cardiologist is thinking about the importance of triglyceride lowering and the urgency to treat within SHTG and mixed dyslipidemia? And then for Arrowhead, from a commercial perspective, how are you planning to highlight differentiation from Ionis in FCS?

Eli, thanks very much, it is a really important question. I have to say really being quite honest really, that the awareness of severe hypertriglyceridemia is pretty low amongst cardiologists and it has been amongst many physicians. And this is something that we need to raise awareness really in order to increase -- improve the care of these patients. But that's concerning cardiologist. So there's much greater awareness of the importance of hypertriglyceridemia amongst endocrinologists. And also some other burgeoning, growing field of awareness of hypertriglyceridemia is against amongst hepatologists to say. Even in the gastroenterology community, there's quite a lot of good awareness among pancreatologists. These are doctors who actually look after patients with pancreatic disorders. So within gastroenterology, the hepatologists has good awareness and the pancreatologist has great awareness. So we really have to put into place improved awareness of triglyceride's moderate hypertriglyceridemia amongst cardiologists. There is no doubt. I mean, center stage to all of this -- and also of severe hypertriglyceridemia, the chylomicronemia that I referred to. It is an unmet area of need. And I think it's been documented that on average, it may take at least 5 clinical encounters with a specialist before the penny drops. In addition to that, many patients are admitted to -- as acute emergencies with abdominal pain and label as having -- being alcoholics, which is not the case. So there's a lot of injustice going on concerning the care of such patients, which I think this trial and the subsequent trials is going to put right. I should like to end up by saying is that the model of care, the patients that have hypertriglyceridemia is a multifactorial integrated model. I mean, [ center stage ] should be the family doctor because they're the people who knows the family well, and this is in part a genetic disorder. But the family doctor has to be supported by the endocrinologists. It has to be supported by the pancreatologist, by the liver expert, by the cardiologist. Cardiologists was mainly going to deal with the coronary consequences of hypertriglyceridemia, and by and large will not be managing these patients with acute pancreatitis. But outside the medical model, there are multiple health care professionals really who will be aware of this and are involved in care, the dietitian, the diabetic educator for FCS geneticists because this is an inherited disorder is important that the family be counseled on average. 1/4 of such a family with FCS will have the condition, the other 1/4 will not, and the 50% of them will be heterozygous for the gene defect. Interesting enough, and that's a group that may be at risk of coronary artery disease. So I think genetic counseling is important. And then, of course, awareness is important in pregnancy. As the obstetricians need to work, I'm going back to my hometown at the moment, and I've got 2 sisters who are about to get pregnant and they've got severe hypertriglyceridemia. First thing that we're doing is they're seeing the dietitian and I'm contacting and setting up an integrated care with the obstetrician and center stage that would be the GP and the nurse practitioner. And also psychologists for severe cases. But for the -- let me -- I've said a lot here, but in terms of management of moderate hypertriglyceridemia, garden grown hypertriglyceridemia, the trial is that, that you're doing down the tracks, that would be the province or the concern of the cardiologist and the general practitioner. For this severe type of chylomicronemia and the mixed hyperlipidemia, the multifactorial chylomicronemia, that is beyond the cardiologist that would be within cardiometabolic services, endocrinology, dietetics, genetics and therapeutics. But I mean this therapy is simple enough that it could be provided safety is assured that could be instituted almost within -- as soon as the diagnosis has been made. So a long answer, but there are complex patients. I mean hypertriglyceridemia is a gateway to many other conditions.

Yes. I think nothing drives awareness like a high-quality therapeutic. You don't monitor what you can't change. And now we have something that can really alter, triglyceride levels. So the second question was related to differentiating our product with competitors. Look, the way we have always viewed this is we can't affect the competition. And what we can do is try and make the best drug that we can. And I think we achieved that. Our goal was to have something that's best in class, and it appears that we have that. It's not clear to me where our openings are, to be honest, with competition. We have something that is well tolerated, something that is convenient to administer, something that just nukes triglycerides and something that decreases pancreatitis risk. We think that we are well positioned to meet any sort of competition. Andy and [indiscernible], anything else to offer in that?

No.

Our next question comes from Ted Tenthoff at Piper.

Great. And congratulations on the data. I mean really impressive, and I was particularly impressed by the reductions in pancreatitis, I mean, that's really showing just the power of these changes in the trends. My question is a little bit more broad. And I think you've done a good job laying out the increasing or growing opportunity from FCS to severe hypertriglyceridemia to even mixed lipidemia with the [ outcome ] study. How do you envision marketing to those different and growing populations? Is this something you think Arrowhead could do yourselves? Is this something that maybe you want in FCS and then partner as you get to the bigger opportunities? Just curious to see sort of how you plan on marketing plozasiran over time as you grow in patient numbers.

Sure. Thanks, Ted. So first, I don't want to get ahead of ourselves too much here. Where we are is we have a drug that appears to work very well in FCS, and we are laser-focused on that population in the near term. We hope to file our NDA, as we mentioned, by the end of this year, and we hope to be bringing this to patients next year. Look, we will see how this drug fares in the current Phase III studies against SHTG and the future ones against mixed hyperlipidemia. We are optimistic that those will work. But let's not get ahead of ourselves with respect to expectations, I guess, of broadening that legal [ outlook ]. We do, however, believe that we can handle those. We are building out our commercial presence in the United States to be sure. We will likely need help internationally. And what is really attractive about this drug to us is that it allows us to leg in our commercial presence, if you will. We can start with something that is bite size that we can certainly handle ourselves. And as we institutionally get used to being a commercial organization, we can grow into these larger markets sequentially.

It makes a lot of sense.

Chris, if I may just add that with this evidence, I mean [ it's inclusion ] in clinical pathways for diagnosis and therapy. I mean that will have an enhancing effect on awareness and societies, and expert bodies really will automatically help the process of increasing awareness and things will change over time, I wouldn't be surprised, in 5 years, there will be more cardiologists will be talking about hypertriglyceridemia. It's happened with the gastroenterologist, I mean they never thought about [indiscernible] reduction, no sooner have they identified liver factors a cause of hepatic fibrosis. So then they're writing actually the risk reduction pathways for obesity action. So it's interesting how it's going to expand and cascade out over time. This is the start. This is absolutely -- this is a paradigm shift.

Gerald, I couldn't help but notice at ACC in the spring, not much discussion at all about triglycerides. Here at ESC a few months later, a whole bunch of sort of major plenary presentations talking about triglycerides, talking about the genetic data. It was really interesting to me how much was going on without any industry effort behind that at all, just people now starting to see the data, see the research. I saw both zodasiran and plozasiran data being shown from The New England Journal of Medicine articles, et cetera, that just with people that we don't even have contact with at this point is largely people from all over the world, not out of the U.S., it's already happening because they're noticing that there are actually drugs coming a lot that can really make a difference, and they've never had that before. So it's happening even now.

Yes, it certainly feels like where we are now with triglycerides is where we were with LDL cholesterol 30 or 40 years ago.

It sure is.

So our next question comes from Mayank Mamtani of B. Riley.

Congrats on the results. So could you please touch on the importance of this comparable efficacy noted within clinically confirmed versus inadequately defined FCS? And specifically, any learnings regarding the AP event rate that -- really interested in how that data may evolve over time as you have patients rolling over to open label. There are metrics like time to AP analysis, quality of life metrics that could be important to regulators and clinicians. Just at the high level, trying to understand your confidence level in securing label for both subpopulation and getting [ APO ] label, which could be important for peers. And I do have a follow-up for Dr. Watts.

Well, Look, I think one of the interesting elements going into the analysis is, we, of course, didn't know if there was going to be a difference in response in patients that essentially would be potentially nulled for lipoprotein light base versus patients who will have had some problems in lipoprotein wide base, but may not have been now. We didn't know what we were going to see until we have the data and analyzed it. It was a prespecified analysis. And lo and behold, you really couldn't see a difference between the response in the patients that were either classical genetically confirmed FCS or those that were phenocopies you might say, of genetic FCS. So it was no surprise to us actually then when we had seen that, it was no surprise to us when we looked at the patients that did have pancreatitis in the study. And basically, it was kind of an even split there as well of those that had genetic FCS and those that had the clinical FCS because clinically, they looked the same going in. So it wasn't really a surprise that they responded the same. As far as this notion of the timing of pancreatitis, at this point, these studies are so small. It's -- I just don't think we could really say anything responsibly. SHASTA-5 will be the first purpose-designed, really well, well-designed outcome study for pancreatitis that's ever been done in this disease, and we may learn some more from that. We won't learn -- I don't think we won't learn much of anything from the open-label extensions because they're not placebo-controlled. So I just don't think they're going to tell us much. I mean we know from both our study and the [ BALANCE ] study that we're not able to prevent 100% of pancreatitis happening. These are patients that had recurrent pancreatitis mostly. They've had a lot of damage to the pancreas. Their pancreases are very vulnerable. They -- you can't blame them for being human if they occasionally just try something in their diet that maybe they shouldn't. And they can be very vulnerable to having a pancreatitis episode happen. Clearly, effective reduction of APOC3 reduces the risk of pancreatitis, but it doesn't eliminate it. So I'm not quite sure where this question is coming from, but I don't think it's particularly germane. And if it is, it's going to take SHASTA-5, I think, to tease it out anyway.

Yes. I mean the risk of -- I may just add, I mean, the risk of pancreatitis is linearly related to the level of chylomicronemia to triglyceride. And it's not only linearly to the concentration, but duration at the hypertriglyceridemia has been above 20 millimoles per liter or 30 millimoles per liter, 3,000 milligrams per deciliter, irrespective of whether you've got FCS or MCS. The lifetime risk of acute pancreatitis in MCS is probably 30% or 50% less than an FCS patient. But there happens to be far much more greater number, almost 100 times. So I mean if you did -- we're going to do the estimates, right, a world calculation, majority of the pancreatitis related to chylomicronemia actually comes from the MCS population. And these individuals are quite sick too. So I mean, intuitively, by extension, the implications of this trial goes to that group. But as Bruce has indicated, really, it strictly would need to be confirmed in a clinical trial may be actually. But it depends how the regulators are viewing the top of the data that is presented to.

Well, payers oftentimes [indiscernible].

For payers [indiscernible].

Yes, for the payers. Yes, no, I agree. I think physicians will be pragmatic about it, but the payers oftentimes want something that they can consider definitive. I've become quite excited by SHASTA-5. I think it's going to be a landmark study.

I mean I have to say in my experience, is doing this particular trial, I mean the worst pancreatitis from the people that I consented were not a pure FCS bi-allelic [indiscernible] variants, but for those who are heterozygotes and slightly off-target glycemic control, which they continue to have pancreatitis until they were treated in the open-label extension rate. So I mean it's not incredible really to think of treating chylomicronemia acute pancreatitis just in the domain of having 2 allelic genetic mutations. Look, it's as a parallel here with other genetic disorders of lipid or cholesterol metabolism, heterozygous and homozygous FH. You don't withhold the treatment if you haven't confirmed the diagnosis, you actually go on the clinical impression the so-called phenotype.

That's super helpful context. And just maybe piggybacking on that last comment about -- I noticed that the background therapy used at baseline seemed a little higher than prior trials. I was curious, applicability of this data set to plozasiran activity being evaluated with additional hypertriglyceridemia indication where such background therapy use may not be as high as we pointed to a lot of other triglyceridemia are not using too much sand of care triglyceride-lowering therapy. So if you could comment on that point, that would be very helpful.

Well, I mean, I think that was a strength of the trial, that it was done against best standard of care with -- I think it's 67% of individuals having lipid-lowering therapy, dietary therapy, an antidiabetic therapy with a BMI that was not in the obese range at all and a placebo group that were clearly receiving good therapy because some of the 2 individuals had triglyceride fell less than 50%. And that's good. That's an ethical trial actually. I'm worried about placebo groups going off target and doing whatnot really. So I think it's what it is, a trial done against best standard of care. And that has to be the optimal -- in the guidelines, they will definitely say that you have to be on the best diet, weight regulating diet, a statin, if there is a history of coronary artery disease. Remember, some of these patients are not diagnosed in [indiscernible], but they're diagnosed in middle age and may have coronary artery disease for other reasons. Maybe they will. The guidelines will say try a fibrate, fenofibrate or gemfibrozil. See what you get and if the triglyceride hasn't fallen below a certain level, which I can guarantee with those agents, it may improve with an improvement glycemic control, then I think this is used plozasiran. Well, look, it would be interesting to see how the guidelines developed because these guideline-directed therapy is what clinicians will follow and they'll have to be aligned with the FDA. The payers will be different maturation.

Due to time constraints, we kindly ask our analysts to limit themselves to one question. So our next question comes from Patrick Trucchio at H.C. Wainright.

Congrats on the data today. Just a follow-up on the concept of genetically and clinically confirmed FCS. I'm just curious if one group or the other is considered more difficult to treat? And then separately, if you can talk about the implications of the PALISADE data for potential FDA label, specifically for potential to include language around genetically confirmed and clinically diagnosed FCS? And how important is it have language around is in the FDA label upon potential approval from a competitive and as well as commercial perspective?

Yes. Okay. So I'll leave the question of the FDA up to Bruce actually because, I mean, you've been directly involved. The management of FCS is a pure FCS, bi-allelic gene defect is very difficult. Many of them are not responsive universally, and they're not responsive to standard triglycerides therapies that I referred to. And the diet in less than 20-gram fat diet. This is as a murderous diet to be on, particularly from an early age. And the early way people come out of it is as we know, certain patients who actually can change they're life entirely actually with support of their families. But it is totally disruptive to a number of things, leads to a lot of anxiety and depression a lot of anger with society. There's a high increased rate of [indiscernible] disharmony, pregnancy is a problem. It is difficult actually, particularly when diagnosed early, actually, and this is a lifetime management. With MCS is usually a secondary factor, excess weight, uncontrolled diabetes, alcohol, high refined carbohydrate diet. And I mean you could at least tackle that and do something about that. Putting someone with MCS on insulin, for example, can make a great difference with diet, with follow-up with the diabetes educator and you may be frequently, you can get the triglyceride below 10 millimoles per liter, 1,000 milligrams potentially. Just so you can do quite a bit about that, but there is and hence, the lifetime risk is 20% for acute pancreatitis. [indiscernible] those factors, those factors that I referred to. But beyond that, of course, it's 80% with FCS, which is much more difficult to treat from a dietary perspective. It almost can be viewed as a nutritional disorder because that's all we've had so far. And that's where this drug actually plozasiran comes in. But I mean, I don't want to give you the impression that the high risk of acute pancreatitis in the MCS group will be addressed solely by plozasiran. One would have to target it at treating the secondary factors: diet, weight regulation or glycemic control, alcohol and then definitely, there is a residual risk that is inherent there, having to a genetic predisposition to chylomicronemia and hypertriglyceridemia as well also due to a genetic predisposition to acute pancreatitis. We do know there are certain genes affecting trypsinogen and other proteins that makes the pancreas much more susceptible. I should say just one last thing in relation to the chylomicronemia is the third most common cause of acute pancreatitis. The first -- the most common cause is gall stones followed by alcohol and then pancreatitis. But the point of differentiation -- sorry, and then chylomicronemia, the differentiating point it is that the severity of the acute pancreatitis is much worse and it's much more costly because the length of hospital and in particular, in intensive care departments is much more severe and extensive. To the extent that the cost of managing acute pancreatitis in the hypertriglyceridemia induced episode is substantially greater. I mean it's been posted at the order of that $40,000 really for one case of acute pancreatitis compared with, I think, $30,000 with lesser acute [indiscernible] function. It's actually cheap have a [indiscernible] in the case of that TG induced acute pancreatitis. So that's where the health economics we need to work further on that and scope that out. I hope I have answered the first part of your question, sir. So the second part of the question was related to payers, Bruce? After the FDA.

So first of all, you don't enter lately discussions with regulatory authorities until they've decided that your drug is approvable. So we're not at the point of having discussions with the agency about how they're thinking about labeling. So I can't answer that question. I can say that I think the agency was comfortable with our protocol design because they had the opportunity to weigh in on and give the feedback. And I do believe that they were comfortable with us enrolling both genetic FCS and clinically diagnosed FCS. And my suspicion is that they'll be comfortable with our data showing that the results were similar in those 2 groups. I can't imagine that, that would be disappointing in some way. So I'm as comfortable as you can ever be from the standpoint of submitting the NDA. But ultimately, we submit the FDA reviews, the FDA decides. And if we're lucky enough that we're labeling discussions at some point in the near future, that's when we'll know more specifically about what the FDA thinks. But I can't tell you right now where things are going to go. I'm very comfortable with where we are scientifically how that translates into labeling -- I can't say at this point.

Would not be equitable to -- not alter this to MCS as the recurrent pancreatitis. That wouldn't be a good medicine and not meeting your principal domain of quality health care.

We're at the bottom of the hour so we only have time for a couple more questions. So Tara, let's get to 2 more, and then we have to close it up.

So our next question comes from Farzin Haque at Jefferies.

This is Farzin on for Maury. So I have a question on the waterfall plot. You're showing very nice consistent reductions in APOC3 across all the patients. But the triglyceride reduction is a bit more variable. So a question for Dr. Watts is for these patients that are getting the suboptimal levels, is there more that can be done? And what would you do in clinical practice?

Well, I mean, we are knocking down APOC3 and you can knock it down and it is quite -- it's easier and less variable than triglycerides. I mean, triglycerides are variable per se for a variety of reasons, actually. I mean, when you measure triglyceride, it's mainly [indiscernible] microns in this setting, but there's also competition with very low-density lipoproteins. It's a fact of life that the biological variability of triglycerides is much greater than LDL and much greater than APOC3, given that you've actually knocked the APOC3 done, that's not unexpected. I mean that the therapy is graded at APOC3. It's directed at APOC3, knocked it down. The triglyceride is the consequence of that knockdown. So in these people with primarily like a protein line-based deficiency owing to 2 gene variants, most of the gene variants were in the lipoprotein lipase gene, they were split between homozygosity and heterozygosity and the rest in other proteins that enable the clearance of triglyceride type proteins, the lipase maturation [ VapoC2,3GPH1 ]. They've all got funny names, but it's complex depending on the gene defect that you have, you'll have much more variable, less variable hypertriglyceridemia and responsive therapy. It just so happens that [ APOC2 ] and LPL mutations, no mutations are more difficult to treat. So I mean the synergy of the genetic defect does have a response.