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

Good afternoon, 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 available on the Arrowhead website following the conclusion of the event. I'd now like to turn the call over to Vince Anzalone of Arrowhead Pharmaceuticals. Please go ahead, Vince.

Thank you, Tara, and thanks, everybody, for joining us today. We've got a lot to cover. We presented data at AHA on 3 of the studies for 2 of our cardiometabolic programs for plozasiran, formerly known as ARO-APOC3, and zodasiran, formerly ARO-ANG3. So before we start, I just want to let you know that we will be making forward-looking statements, so please refer to our SEC filings for risks. And we've got a really great panel today -- sorry, let me get to that slide. Sorry. We have Dr. Daniel Gaudet from the University of Montreal, Børge Nordestgaard from University of Copenhagen and Dr. Steven Nissen from the Cleveland Clinic. Here's the basic flow of what we're going to do. Jennifer Hellawell from Arrowhead will give a summary of the data that we presented today. Dr. Gaudet will talk about hypertriglyceridemia and the effects on acute pancreatitis risk. Dr. Nordestgaard will talk about remnant cholesterol, which is an important new way to view atherosclerotic cardiovascular disease risk. And so that's something I think we really need to pay attention to today. And then Dr. Nissen will talk about the potential for plozasiran in the treatment of ASCVD. And then Javier San Martin, our Chief Medical Officer, will talk about the future clinical development and why we should care, why it's important today. At the end, there will be a Q&A session where all panel members will be available. So just very quickly, who is Arrowhead? We are an RNAi therapeutics company. We've got a very broad pipeline of 14 clinical stage molecules, 9 of those are wholly owned, 5 of them are partnered. We've got a very diverse pipeline across stage, so there's early, mid- and late-stage clinical programs. We also have the drugs that are targeting ultra-rare diseases all the way to the most highest -- the highest-prevalence disease. All of these are built on a proprietary platform called targeted RNAi molecules or TRiM, and we've got a strong balance sheet to move all these programs through clinical development and toward commercialization. And the last is the -- we have an initiative called 20 in '25, which is our goal to have 20 individual drugs in either clinical development or marketed by the year 2025. So here's how our pipeline looks today. Again, it's across disease and therapeutic area. We have cardiometabolic programs, an emerging pulmonary platform, liver disease drugs, neuromuscular disease and then others that don't fit into those need buckets. Today, we'll be talking about the top 2 lines in this, plozasiran and zodasiran. And again, as I mentioned, these are all built on our proprietary technology platform called targeted RNAi molecules. It is -- the design of this to optimize -- is made to optimize for activity, specificity, versatility and simplicity. And one important thing to remember with a technology platform like this and with RNAi, in particular, is that clinical results are very predictable. And in our hands and in others, the safety profile has been very consistent across different drugs. The PD profile has been enormously translatable from animals into humans and the data that we see in early clinical results tend to be replicated very well in late clinical studies. So we feel like it's a platform that is relatively low risk. I mean, obviously nothing in drug development is low risk, but we -- it is a risk that we think that we're managing well. And knock on wood, the safety results have been very, very good to date and activity has been best in class against other RNAi competitors. So now I'll turn it over to Dr. Jennifer Hellawell, who'll talk about the data that we presented today.

Thanks, Vince. It's my pleasure to present a brief recap of data from 3 different Phase II studies that we presented at American Heart Association Scientific Sessions here in Philadelphia earlier today, the MUIR, SHASTA and ARCHES Phase II study. At Arrowhead, we recognize the unmet medical need associated with elevated triglyceride and triglyceride-rich lipoproteins and have identified several different targets in the biology that serve as attractive therapeutic target for these patients. On the left is APOC3. This is a protein that inhibits TRL metabolism and clearance through both LPL-independent and dependent pathways. And on the right is the schematic for ANGPTL3, a protein which regulates lipid and lipoprotein metabolism by inhibiting both lipoprotein lipase and endothelial lipase. Plozasiran and previously known as ARO-APOC3 is an investigational RNAi targeting APOC3. And zodasiran, previously known as ARO-ANG3 is an investigational [ RNA ] targeting ANGPTL3. Based on reassuring data from a first-in-human Phase I study demonstrating a reassuring safety tolerability, PK and PD profile, plozasiran was advanced into a Phase II study of subjects with mixed dyslipidemia. This is the MUIR study, a double-blind Phase II randomized placebo-controlled dose-ranging study. And the study population was subjects of mixed dyslipidemia defined as having fasting triglycerides between 150 and 499 and either an LDL-C of greater than 70 or non-HDL-C of greater than 100 subject for randomized in a 3:1 fashion to 1 of 4 different dose regimens of plozasiran versus placebo to NASH, 10, 25, 15 milligrams Q12 weeks and an additional 50-milligram cohort dosed Q24 weeks. Key endpoints included percent change from baseline over time in triglycerides as well as a variety of other lipoprotein parameters. So on the next slide are the top line results from this study, and of course, additional data from the study can be referenced from our presentations earlier today. And here, we saw that plozasiran demonstrated substantial and durable decreases in APOC3 and triglycerides, as well as remnant cholesterol at all doses tested. We saw reductions of APOC3 on the order of 74% to 80% at the 25 and 50 milligram Q12-week doses perspective. Triglycerides were reduced from 58% to 64% at those 2 doses. And finally, remnant cholesterol reduced to an unprecedented 54% to 53% level, respectively. Now turning our attention to our second study of plozasiran that was presented earlier today. This is in a slightly different patient population. This is SHASTA-2 study, a double-blind, placebo-controlled Phase IIb dose-ranging study of subjects with severe hypertriglyceridemia. These were subjects with a history of elevated triglycerides of greater than 500 and a fasting triglyceride level of 500 to 4,000 during the screening period. Here, subjects were randomized to 1 of 3 doses of plozasiran, 10, 25, 50 milligrams dosed Q12 weeks for 2 doses versus placebo to NASH. And key endpoints included change in triglycerides from baseline over time as well as changes across a variety of other atherogenic lipoprotein. And as shown on the following slide, again, as we've seen in the MUIR study in this study of subjects with severe hypertriglyceridemia, we similarly saw that plozasiran demonstrated substantial and durable decreases in serum APOC3, as well as serum triglycerides with reductions in APOC3 of 69% to 73% in the 25- to 60- milligram doses and upwards of 70% in the 25- and 50-milligram doses for triglycerides. Importantly, and again, further data can be referenced in our presentation from earlier today, we further saw that over 90% of subjects from the 25- and 50-milligram doses achieved serum triglyceride levels of less than 500, which is a clinically important threshold associated with increased risk of acute pancreatitis. And furthermore, about half of subjects on treatment with plozasiran had near normalization of their triglyceride levels to less than 150 mg per deciliter. I should further mention that in both of these studies, we saw a very reassuring safety profile. And finally, our third study presented today was the ARCHES-2 study. This was a double-blind placebo-controlled Phase IIb study to evaluate the effect of ARO-ANG3 in adults with mixed dyslipidemia with the study that's population defined as subjects with fasting triglycerides between 150 and 499 mg per deciliter and either an LDL-C of greater than 70 or non-HDL-C of greater than 100. Subjects here were randomized to 1 of 3 different doses of ARO-ANG3 50-, 100-, 200-milligram dosed Q12 weeks for 2 doses versus placebo to NASH. And the key endpoints were change in serum triglycerides, at least 24, with a variety of other supportive secondary and exploratory endpoints, notably including a sub-study of subjects wherein we assess liver fat fraction by MRI-PDFF over the treatment period. And as shown on the following slide, the top-level data, we saw that ARO-ANG3 demonstrated robust and sustained decreases in the target protein, ANGPTL3, as well as triglycerides in this patient population. At all doses tested for ANGPTL3, you saw that reductions were upwards of 60% to 70% at the 100- and 200-milligram dose. And for triglycerides, we saw greater than 50% to greater than 60% at the various doses tested. Once again, we saw a very reassuring safety profile with ARO-ANG3 or plozasiran in this study population. So in summary, we are pleased to report today that plozasiran, previously known as ARO-APOC3, significantly reduce triglycerides as well as a variety of other atherogenic lipoproteins across all dose levels tested in both subjects with mixed dyslipidemia, the MIUR study; and subjects with severe hypertriglyceridemia, the SHASTA-2 study with reductions in APOC3, the primary target of this agent of up to 80%. In the mixed dyslipidemia population, the MIUR study, we saw a mean reduction in triglycerides of 64% and a mean remnant cholesterol reduction of 54%. And in the severe hypertriglyceridemia population, we saw mean reductions in triglycerides at 74% with the majority of patients achieving that clinically relevant threshold of triglycerides less than 500. Across these 2 studies, we were further reassured to see that plozasiran has a favorable safety profile and that this is, indeed, the first RNAi molecule that has been demonstrated to show such substantial reductions in triglyceride, rich lipoproteins across both these patient populations. And finally, ARO-ANG3 in the ARCHES-2 study also showed significant lowering of triglycerides and ANGPTL3, as well as a variety of other atherogenic lipoprotein in patients with mixed dyslipidemia. So with these results in mind, I will hand it over to my colleague, Dr. Daniel Gaudet.

Thank you. What I will do in a few minutes is I'll share with you my experience as a clinician and the clinical trial is treating patients with both APOC3 inhibitors or ANGPTL3 inhibitors in the last years, APOC3 inhibitors for 12 years and ANGPTL3 inhibitors for 8 years. And of my knowledge, Arrowhead is one of the very, very few pharmas developing both agents targeting these agents. So there are unmet needs in clinical lipidology across -- which cover a lot of lipid disorders that the Arrowhead ANGPTL3 inhibitor or APOC3 inhibitor would cover eventually: homozygous FH and refractory hypercholesterolemia, statin-intolerant patients and these are the kind of patients that I've treated over years with these agents through clinical trials; individuals with cardiovascular disease not at target despite available treatment; severe hypertriglyceridemia, meaning triglycerides above 500 milligram per deciliter or 5.7 millimoles per liter; sustained chylomicronemia or extreme [ triglyceridemia ] above, let's say, [ 880 ] or I would rather prefer 1,000 mg per deciliter; TG-related pancreatitis; and other severe hypertriglyceridemia-related morbidities. So if you take both targets altogether, ANGPTL3 inhibition and APOC3 inhibitor, they cover the spectrum of extreme -- from extreme hypercholesterolemia to extreme hypertriglyceridemia. And regarding what I have to share with you mainly is the association or the importance of these agents in preventing pancreatitis or treating patients with severe hypertriglyceridemia-related pancreatitis. The risk of pancreatitis is linearly associated with the population of chylomicrons, which are the largest lipoproteins transporting fat after a meal. The risk starts at the level of 500 milligram per deciliter, but it's the highest above 1000 milligram per deciliter or approximately 10 millimoles per liter. ANGPTL3 inhibitors will cover all the spectrum of these lipid disorders, whereas APOC3 inhibitors will cover the spectrum of hypertriglyceridemia-related phenotypes, including mixed dyslipidemia, remnant diseases and including chylomicronemia provided there's some lipoprotein lipase, which is a key enzyme associated with the management of triglycerides, are available. So if you look at the pancreatitis risk associated with chylomicronemia, this is a slide coming from data that we have collected almost 15 years ago when we were assessing gene replacement therapy, LPL gene replacement therapy, for patients with extremely severe hypercholesterolemia. When we have looked at 1,000 people approximately, we have observed that patients with chylomicrons has highly, highly increased risk of pancreatitis and those with chylomicronemia, which are the patients completely lacking the key enzyme associated with the triglycerides management in TG-rich lipoprotein had very -- well, their risk of pancreatitis, which was increased by more than 360-fold, whereas those with multifactorials meaning those with some bioavailable LPL, but having very high TG has a 50-fold risk of pancreatitis. So when you look now at the potential of the Arrowhead ANGPTL3 inhibitor or APOC3 inhibitor in preventing that, it's clear that both agents would be [ at the odds ] of being highly effective in patients with multifactorial form because these patients have some LPL that bioavailable. So the ANGPTL3 inhibitor would work, and since previously we presented the APOC3 inhibitor works even in absence of LPL, this agent will work whatever the underlying cause. So in conclusion, both the ANGPTL3 and APOC3 blockade reduce plasma triglycerides in severe or extreme hypertriglyceridemic patients and thus have the potential to reduce acute pancreatitis risk. APOC3 inhibition involves LPL-dependent and LPL-independent mechanisms covering all the spectrum of hypertriglyceridemia from moderate to extreme, including patients completely lacking lipoprotein lipase bioavailability. Whereas the ANGPTL3 blockade is LPL-dependent and involves LDL-receptor independent [indiscernible] does not matter really. But the mechanism by which in ANGPTL3 blockade works involves some of the bioavailability of LPL, at least a little bit, but it covers a large spectrum of lipid disorders from extreme hypercholesterolemia, including homozygous FH or refractory hypercholesterolemia to severe or extreme hypertriglyceridemia. So ANGPTL3 or APOC3 blockade agents are highly promising tools in the treatment of patients with severe or refractory hypertriglyceridemia at risk of recurrent acute pancreatitis or cardiovascular morbidity. And again, there are very few pharmas developing both -- the agents targeting both the ANGPTL3 and APOC3.

Yes. Hello, everybody. My name is Børge Nordestgaard, I'm Professor and Chief Physician at University of Copenhagen and Copenhagen University Hospital. I will be talking about remnant cholesterol. So what I've tried to show here is try to have people understand that there's really 3 cholesterol lipoproteins that drive atherosclerotic cardiovascular disease. And LDL -- and where we focus on the cholesterol content, LDL cholesterol has been known for a long, long time and there's fantastic evidence both from genetics and also from randomized trials. And then we have Lp(a), lipoprotein (a), in the middle where we have huge genetic evidence now that it is a cause for atherosclerotic cardiovascular disease, maybe not atherosclerosis, but the disease itself. And this is the third one. And you can see already as shown here it's larger than the 2 other ones because it carries more cholesterol particle than LDL, for example. It also carries a lot of triglycerides. Remnants is what I call it, others call it VLDL, some call them more complicated triglycerides [indiscernible] I think there's a tendency [indiscernible] to complicate things and have all these different words. I try to simplify what is the real important things. And you can see the NHANES data, therefore, that remnants actually carry quite a big fraction of cholesterol, the average American 25 milligrams. [ This then compares ] to LDL 150 milligram. So take-home message is really it is cholesterol [indiscernible] and not just triglycerides. Triglycerides can be important, but there's a tendency that too many people focus on triglycerides, cholesterol is important. Next one, please. So this is a human coronary atherosclerotic plaque, where you can see the lumen where the blood will usually flow and there's a huge plaque. And one can see the yellow color within the atherosclerotic plaque. And this is really coloring from cholesterol, just like we know from egg yolk, for example. And this is cholesterol that is deposited in the atherosclerotic plaque. It is not triglycerides. There is no triglycerides in there. I illustrate from triglyceride from bacon for example. So in my point of view, the target for these remnants is that we should target elevated cholesterol because that is what ends up being deposited in atherosclerotic plaques, and of course, eventually atherosclerotic cardiovascular disease. But of course, it's also very nice to fight [ the monster ] hypertriglyceridemia because they, on average, would have a high remnant cholesterol. And if you want to reduce -- the goal would be not reduce triglycerides, that's what we just heard from Daniel Gaudet. If you want to prevent pancreatitis, that's what you want to do. But if you want to prevent atherosclerosis, make sure remnant cholesterol goes down. And that means also that you also want to make sure that non-HDL cholesterol go down because then both remnant and LDL will go down. It doesn't help to reduce remnant cholesterol if LDL goes up a lot like you saw in the so-called [ prominent slide ]. And then you also want to make sure that ApoB goes down a little bit because it also includes LDL. If you get these 3 down, we have a really good chance of reducing atherosclerotic cardiovascular disease. So just trying to say what's the psychology of many clinicians when they look at [ patients ]. People keep talking about triglycerides all the time. That from the lab report, people get the value of their triglycerides. And as you can see, this is part of the remnant. They also have a lot of cholesterol. And therefore, people keep talking about triglycerides because that's what they've seen in the lab reports. But I have chosen, let's focus on the cholesterol content because that's what's clinically important for atherosclerotic cardiovascular disease calling it remnant cholesterol. So I call them remnant, sometimes now I call it both triglycerides and cholesterol if you put in -- it's not just triglycerides if you put in. Just try to illustrate for you, this is the example of lung cancer where we know from lots of signs that lung cancer, there's a direct cause for that, namely, smoking or it could also be a lot of air pollution. You can say inhaling non-clean air. If you do a statistical analysis, both of these would be highly correlated with higher risk of lung cancer. But you could also choose to look at the number of cigarette boxes that an individual person has actually [indiscernible] and It will be exactly the same as we see as the number of the cigarettes a person smoked. But it is the smoking per se that causes lung cancer, not the number of cigarette boxes you have in your hand. And the analogy for remnants would be here that what causes atherosclerotic cardiovascular disease is the fact [indiscernible] is the cholesterol. People call it non-HDL cholesterol, but that's a composite of LDL cholesterol and remnant cholesterol. So again, it's a cholesterol in the 2 parts, it's LDL here that causes atherosclerotic cardiovascular disease. But you could also do association and look at the triglycerides content and you have the same association observationally, but from my point of view, as I see the totality of evidence, it is much more likely the cholesterol content that is here. Next one. So this is all like depicting the mechanism by which it drives atherosclerotic or you can say vulnerable [ flat ]. So in pathway you have both LDL remnants and also like chylomicrons. The one Daniel Gaudet talked about the color, I can say it's too large to come in [indiscernible] here we focus on pancreatitis. But the LDL remnants, they can come into the [ endothelial ] where atherosclerotic is present. Where the LDL needs some sort of modification to drive atherosclerosis, remnants are taken up directly by macrophages producing [indiscernible] and also further protein lipase can be creating triglycerides maybe at the endothelial surface liberating free-fatty acid more than [indiscernible] that will be toxic by inflammation. So there's both the cholesterol, but there's also the possibility of getting vulnerable plaques. So take-home message again, for triglycerides and cholesterol-rich remnants, they cause atherosclerotic cardiovascular disease and the evidence is overwhelming. It is as good as [indiscernible] cholesterol. What convinced me as a young clinician was to seeing these patients exhibiting something called remnant hyperlipidemia. It's very typical, just like [indiscernible] they have just remnants of [ plasma ]. They don't have LDL. And they have these various xanthomas, tuberoeruptive xanthomas or palmar crease xanthomas that they have accelerated atherosclerosis and premature cardiovascular disease. That's a genetic condition. Here's some [indiscernible] from our own studies in Copenhagen, where you can see just a simple, on the age factors, measurement of nonfasting triglycerides, which is a marker of remnant cholesterol. And it drives -- it has ratio for myocardial infarction. And you see, if you're just above 528-milligram per deciliter, you have fivefold increased risk of myocardial infarction compared to having less than 88-milligram per deciliter. And this is following people from 2 to maybe 40 years. So it's just one measurement of remnant cholesterol triglycerides. Here, we tie it back to back in our Copenhagen general population study to look at the same increase in LDL cholesterol with the same increase in remnant cholesterol and maybe also lipoprotein (a) cholesterol. It's at 1 millimole per liter or 39 milligrams per deciliter increase and then what is the hazard ratio or in genetic terms causal risk ratio for myocardial infarction. And first, you can see that for the same cholesterol content on top that's for LDL cholesterol. But if you look in the middle, it's for remnant cholesterol, it's actually a higher risk of myocardial infarction and it is even higher for Lp(a). I'm not implying that Lp(a) is a cholesterol content that drives the disease, but I'm just putting on the same scale. And genetically, you can see that all of them, if that's with the wide confidence compared to the right of the observation [ on ] telling that they are all causal. And when you adjust from each other, which we did here, they're completely independent. It's 3 different causal risk factors that drive the disease. Guidelines on lowering remnant cholesterol. They haven't come to put in directly, but now they talk about the guidance on non-HDL cholesterol. Non-HDL cholesterol is LDL plus remnant cholesterol. That's the [ thought ] that comes into it. And you see here like the main guidelines from Canada 2021, Europe 2019 or US 2018 for secondary prevention of ASCVD. On top, they all say just bring LDL down, but then they also all say let's also bring [ non-HDL ] cholesterol down. And what they say is [ just ] bring remnant cholesterol down. And the Canadian, Europeans further had the ApoB. Familial hypercholesterolemia is the method that's only LDL cholesterol. But the primary prevention is the absolute 10-year risk-based, diabetes or chronic kidney disease, they all say LDL, let's get it down, but Canadian and European say let's also get non-HDL cholesterol level down meaning it's not enough to get LDL down, we have to get remnant cholesterol down also. So this is just to illustrate historical development. I first used the term remnant cholesterol in a publication, JAMA, in 2007 and it took some years for the others to pick up. But now you can see there's a lot of publications and so finally people have understood that this is a really important causal risk factor for ASCVD. So for ASCVD risk, it is cholesterol, not just triglycerides. Triglycerides can also, because of inflammation [ packs ] can make vulnerable [ packs ]. But cholesterol content is what causes atherosclerosis. This is just my last slide, the good, the bad and the ugly. I made it first in 2011 and then I stopped showing it because I got so tired of it. But then people will come back to me and say they heard me give a talk 8 years ago and they remember one slide, this one. So the good, the bad and the ugly [indiscernible] Western. HDL being the good one -- or not good anymore, [ which is LDL ]is the bad one. But the ugly one, if you have a lot of it, remnant cholesterol. It's even worse than LDL, it does a lot [indiscernible] . Thank you so much.

We'll now turn it over to Dr. Steven Nissen.

Well, thank you very much, and Børge, as always, that was just so really lucid presentation. First of all, we're delighted to be working together with Arrowhead Pharmaceuticals on the plozasiran cardiovascular outcome trial, and I'm going to tell you just a little bit about it. Next slide, please. So the primary objective will be to evaluate whether treatment with ARO-APOC3, now plozasiran, can reduce the risk of myocardial infarction, ischemic stroke, unplanned coronary vascularization, cardiovascular death or major adverse limb events in subjects with mixed dyslipidemia at high risk for future cardiovascular events. Next slide, please. You've heard a lot about this issue of remnant cholesterol and I want to show you our 2 recent genetic studies. These studies, these Mendelian randomization studies, are considered the highest quality evidence available on the causality relationship between a biomarker and outcome. And you see, of course, for LDL cholesterol, every millimole difference is about 37% increase in risk. This is from the UK Biobank. But triglyceride-rich lipoproteins, remnant cholesterol, the risk, if anything, is substantially higher, it's 2.59. And this kind of data is very convincing to us, that remnants are more atherogenic than LDL, and we already know that lowering LDL cholesterol is of great benefit. Next slide, please. This is the second Mendelian randomization study. And again, in this study, you see it's a little bit more similar. The LDL cholesterol risk is 1.45%, 45% higher risk, but it's 51% higher for the total remnant cholesterol. Both of these have been published relatively recently in very good journals. They involve very large populations. This is nearly 1 million people. So they're very convincing evidence. Next slide, please. So why are previous studies of triglycerides-lowering therapies not succeeding? Well, of course, they focus primarily on triglycerides, and as you heard from Børge, that may not be the best strategy. But let me show you what we know about them. Next slide, please. So this is a trial that we did. I was the study chair. We used a very potent fish oil developed by AstraZeneca, known as Epanova, and we studied it in a very large group of people. And at the end of the study after more than 4 years, there was a hazard ratio of 0.99. These curves were virtually superimposable. But the triglycerides reduction was only 19% and the actual reduction in the other fractions that Børge talked about, like ApoB and non-HDL, was even less impressive. Next slide, please. And then more recently, my colleague, Dr. Paul Richter, published this study with pemafibrate. It's a fibric acid derivative, also a triglyceride-reducing agent. It reduces some of the associated lipoproteins, but it doesn't reduce them very effectively. The reduction was 26% for triglycerides and was even less impressive for remnant cholesterol, non-HDL, et cetera. And the hazard ratio was 1.03, no benefit whatsoever after 4 years of treatment. Next slide, please. So why are we enthusiastic about the plozasiran and cardiovascular outcome trial? And I can't say this any more clearly: we have seen unprecedented reductions, and you heard them today, in triglyceride-rich lipoproteins. Let me show you. Next slide, please. So this is the various classes of drugs that have been tested. You can look at fibrates, niacin and fish oil. The reductions in triglycerides in the range of 18% to 20%. Plozasiran in the range of 60% to 70%. Non-HDL, 5% to 8% with niacin and fish oil, 17% to 29% with plozasiran. The increase in HCL is modest with niacin and fish oil. But it is large with plozasiran, 42% to 63%. And very importantly, we know that ApoB is a very important factor in the development of atherosclerotic cardiovascular disease. These other agents didn't do a whole lot. Plozasiran, a 13% reduction. Next slide, please. So what about patients that have a loss of function mutation? This is a way of looking at people who would look like what our patients would look like during the administration of plozasiran. So this is a study of 18,000 genes, 3,700 participants evaluating coronary heart disease risk in 110,970 persons. Mutations in the APOC3 gene which is, again, mimicking what we will see with plozasiran was associated with a 39% lower triglyceride level and 46% lower APOC3. But most importantly, risk of coronary heart disease with these mutations was 40% lower, an odds ratio of 0.6. In medicine, when we can achieve odds ratios like this, this represents a very attractive target. Next slide, please. Plozasiran lowers APOC3 by more than 75%. And so we have the mutations that tell us that lower activity of APOC3 is associated with less coronary heart disease, and that's exactly what we intend to do with plozasiran in the clinical outcome trial. I believe that's my last slide, and thank you so much for your attention.

I want to -- this is Javier San Martin. I want to thank you all the speakers for such a good presentation, clear clinically oriented mechanistic understanding of the role of hypertriglyceridemia in different relevant clinical syndromes where still we have a significant unmet medical need. I want to walk you through the plan that we have on the clinical development program, both from a clinical trial perspective and from the regulatory next steps. As most of you know, the PALISADE study, which is the study in patients with familial chylomicronemia syndrome or FCS, we completed enrollment in April of this year. It's a 1-year study, so the study will be completed in April of 2024. We're going to have an interaction with the FDA after that completion and data evaluation, and we are aiming to file for this indication at the end of 2024. The Phase III program to develop this drug for severe hypertriglyceridemia, which again the goal of therapy here is to decrease TGs below the threshold at which heart attack is an event of concern is ongoing. We completed the Phase II study, we presented at this meeting the full result. A few weeks ago, we had our end of Phase II meeting with the FDA. We agreed upon of the next steps, which is the Phase III program where have Phase III study with SHASTA-3 and the SHASTA-4. Both studies will enroll patients with TG greater than 500. It would be 1-year study with 4 doses during that year and then patients will transition to an open-label extension. So we aim to initiate these studies in the first quarter of this coming year. All the execution component is already ongoing, and we will provide more details soon. And now I wanted to provide some guidance about the cardiovascular study, cardiovascular outcome trial with [ zodasiran or ARO-ANG3 ]. You heard today very interesting data and how this team is evolving with regard to the remnant cholesterol as an important risk factor that this part has not been addressed with any other treatment. And so we are, of course, we completed the Phase II study and we presented here and we are right now working with Dr. Nissen on the design and the specific of the Phase III cardiovascular outcome trial. We are planning to have an interaction with the FDA in the first quarter of 2024 and initiate the study soon thereafter. So to conclude, plozasiran, by silencing APOC3 addresses a spectrum disease driven by elevated triglycerides, including the hypertriglyceridemia syndrome, FCS and SHTG and the residual risk associated with cardiovascular diseases driven by atherogenic TRL for remnant cholesterol. The recent Phase II data demonstrated unique pharmacodynamic profile of plozasiran of reducing TG and TRLS in a majority of the patients with a very convenient dose [indiscernible] interval of every 3 months [indiscernible] administration, again, for now with a very positive safety profile. And of course, these results justify the initiation of a Phase III program across all these 3 indications. Now I will turn on to Vince to guide the Q&A session.

Thanks, Javier, and thanks to all the speakers today. Tara, if you want to bring up the Q&A session.

[Operator Instructions] So our first question comes from Luca Issi from RBC.

Oh great. Can you guys hear me, okay?

Yes, we can.

Great. Apologies. Maybe 2 quick questions here. So maybe the first on glycemic control, Javier, if I may, on APOC3. I think we're seeing some worsening in glycemic control in some patients. I think it was 22% in SHASTA-2 versus 11% of placebo. Can you just maybe offer some numerical color about magnitude of the A1C elevations that you see and maybe whether the elevation to sustain or transient just try to think about the severity of the signal of rather just the frequency of the signal. So again, any thoughts there are much appreciated. . And then maybe for the cardiovascular outcome trial, Dr. Nissen or Javier, how are you thinking about powering assumptions for such trial? Again, appreciate APOC3 has a much higher impact of lipid versus prior molecule, but obviously, patients will also have access to GLP-1. And obviously, we're seeing the impact on cardiovascular come over the weekend. So how many patients do you think will be sufficient to potentially show a benefit here? Do you think you need more or less than 10,000?

All right. So I would say the first question about the A1c of glycemic control in the SHASTA-2 study. So look, we did see this signal in the first interim analysis, the signal clearly was in the patients on the -- that have pre-existing diabetes and particularly those with fully-controlled diabetes. In this study, we have an exclusion criteria in patients with more than [ 90% ] of A1c, but really, we did that based on one single assessment, and we did observe higher variability throughout the study in general. We did not see any increase in patients with newly-diagnosed diabetes and this filing was mainly on the highest dose of 50 milligrams compared with the 10 milligram and the 25 milligram. So there are very few patients that have an excess or any increase greater than, let's say, 1% twice of more than 2%. Once we amend the protocol enable investigators to see that A1c data and take action. Most patients return to baseline. So this seems to be a transient phenomenon. It happened mainly on those patients with fully controlled diabetes and in the highest dose. So that's how we're thinking about this Phase III study. We have a more precise approach of how to manage both the selection of patients and how to manage changes in glucose control over time. And I think when we triplicate or more the sample size of the program, and maybe we can put more color and maybe the sigma goes away. So we discussed this again with regulators, and there is no concerns about it with regard to how we move forward on the Phase III program. Maybe I'll let Dr. Nissen -- go ahead.

Let me just respond to the question about the powering of the outcome trial. We're not prepared yet to tell you exactly the size and the powering assumptions. So let me just tell you how we go about this. We try to understand what degree of reduction in a hazard ratio would be clinically meaningful, large enough that physicians would want to prescribe a drug. And we work back from there. We always look at event rates with the understanding that medical therapy improves over time. And so we don't use the exact values that we had in the last study that we did. We look at values for the event rates that are a little bit lower than that, so that we are adequately powered nobody on this team, not my team here at C5 Research in our Arrowhead has any interest in doing a trial that's not adequately powered to answer the question. when we're ready to finalize the protocol, we'll post it on clinicaltrials.gov and everybody will get to see exactly what we've postulated and how we're going to go about it.

Our next question comes from Prakhar Agrawal from Cantor Fitzgerald.

So firstly, on -- can you talk about the LDL increase seen with ARO-APOC3 in SHASTA-2, reasons why this is happening mechanistically and why this level of increase is not concerning to you? And anything that you may be doing proactively in Phase III to mitigate these LDL increases?

Daniel Gaudet here. The LDL cholesterol increase was expected because when you hydrolysis triglyceride the VLDL particles through the LDL-dependent and LDL-independent mechanisms at the same time, you rapidly form LDL particles. But in the context of the Phase II study, we were not allowed to modify the lipid lowering regimen of the patients. But in the real life, through the open label extension, it's easy to manage. Having said that, all the remnant particles are cleared also more rapidly due to the ANGPTL3 inhibition. But again, this is kind of a signal of the high efficacy of ANGPTL3 inhibition on VLDL particles management, but it's easily manageable.

And I just want to add about the comment on the clinical and the Phase III clinical trials, nothing in particular. This was a topic that specifically was discussed with the FDA, and they made pretty much the same comment Dr. Gaudet made, which is this is expected patients should be allowed to be treated with the best possible standard care to manage the LDL cholesterol.

Our next question comes from Mani Foroohar from Leerink.

Very insightful presentation. I guess a broader question on treatment paradigm, presuming with the [ APOC ] continue to produce a profile suggested by the data we have in hand, can you sort of walk us through patient population, who is the right patient for Plozasiran, who's the right patient for Zodasiran? They're all existing approved or other potentially approval late-stage oligo therapies and FCS and elsewhere. Just help us understand where the paradigm and amongst which patients, each asset, is the best student in your mind?

We wanted to pass. Steve?

Well, I'm going to just -- I'm happy here to jump in. We've never had an agent like this. We have nothing out there that can produce as -- so I try -- hope I made clear that could reduce triglyceride-rich lipoproteins to this extent. That's what provides a unique opportunity here. We see these patients. We do treat them with other effective agents, but we are leaving on the table these very high levels of remnant cholesterol and triglyceride-rich lipoproteins. And so that is the ideal patient population. And one observation is, if anything, this problem is getting worse. We have a global obesity epidemic and only a very small fraction of these patients are actually being treated with GLP-1 agonists. So and even treated with GLP-1 agonists, they still have very high levels of triglyceride-rich lipoprotein. So as a clinician and I see prevention patients every week. I have very little offer to these patients. Fibrates haven't worked, fish-oil hasn't worked. And so we need something to treat those patients. And at least in this case, we think this would be a very, very big addition to the therapeutic armamentarium.

Yes. Børge Nordestgaard, I would like to also add in, I mean, again, trying to keep it simple, you want to recruit patients with high [indiscernible]. We want to measure that directly. And then at the same time, those that have high atherosclerotic cardiovascular disease risk that could be people already with the disease. And where do you find them? The easiest place, well, it is people that are obese and severe overweight and at the same time, maybe for starting having atherosclerotic cardiovascular disease, that's a really, really good candidate.

Just to add something here. So when you add up, and that's the -- my opinion, a huge -- huge difference from what we had previously. When you have the possibility to finance ANGPTL3 and ARO-APOC3, when you finance ANGPTL3, you decrease theoretical leading APOC3 , by the way, significantly. With both agents who cover all the spectrum of lipid disorders from extreme LDL-cholesterol elevation from extreme triglycerides validation including in the middle remnant particles. So it's an interesting paradigm to decide the algorithm for the future in the treatment of lipid disorders is shifting.

So our next question comes from Jasmine Fels from UBS.

This is Jasmine on for Ellie Merle. So after potential strategy regarding partnerships, are Plozasiran and Zodasiran programs that you would commercialize on your own? Or are you considering partnership options? And then just broadly, how do you think about your strategy across the pipeline for partnerships versus keeping wholly owned?

Sure. So I would say for Plozasiran, it's a very attractive product for us to maintain rights to -- through commercialization. And I think because what you've heard today, the profile looks fantastic, and the safety has been very encouraging, and it addresses parts of lipid disorders that just that have no other agents. And from a commercial standpoint and from a -- the corporate strategy standpoint, it's an attractive way for us to build out our commercial organization kind of in a stepwise fashion. So for FCS, it's an ulterior disease, maybe 1,000 patients, maybe more in the U.S., and we'll be filing that NDA a year from now. That's something that we can manage certainly in the U.S. ourselves and in certain parts of Europe ourselves. And the goal for commercial there is to make sure that patients who get this prescribed get access to the drug and we take away any kind of [indiscernible]. So we make it easy for patients to build a prescription. The next step up from that would be the SHTG population. And from a clinical development standpoint, again, that's also very attractive because there's a biomarker triglycerides that are approvable and the time frame for that is a year, and so from now until Phase III readout, it's really an execution story. And so as we build out commercial for FCS, we can slowly build that out to support an SHTG launch. And then beyond that, with the cardiovascular outcome study and a larger population, I think it's critical that we select the right patient population for the -- for clinical development in a way that we can also grow into and support. So I would say partnering right now for Plozasiran, maybe FCS would be something that would make sense. Ultimately, I think right now, it's not necessary. For Zodasiran, for ANGPTL3, as a company, we need to focus on where we invest scarce capital. And what we've decided to do is to invest more heavily into the APOC3 program than ANGPTL3. That doesn't mean that we see ANGPTL3 being a less attractive target. It's just a decision that companies have to make. So we are looking at the HoFH population because there's clear opportunities there. And Zodasiran has been very active in that population. But there are ways to make that drug more available to more patients who need it. And we're looking at the best way to do that. That might be through partnering that might be through other structures or other strategies. But at this point, we're focusing more to invest more heavily in APOC3. The second part of your question about partnering broadly, that's a harder question to answer because it's really a case-by-case basis. There are certain areas that are -- that have more strategic importance to us as a company. And I would say cardiometabolic broadly described would be there, the pulmonary, the emerging pulmonary platform also is there and potentially CNS also. We have a lot of opportunities with our technology to address neurovascular diseases that have no treatment or degenerative diseases that have no treatment. So I would say those 3 areas, we would be less likely to seek partners. And if we do, they would be at later stages of development.

Our next question comes from Brendan Smith from Cowen.

Congrats on another great progress here. First question I wanted to ask just on pricing and a very bigger question. But obviously, you've positioned to launch in FCS. First, but then hyperTG is really thereafter. But kind of given the timing to launch for some of your competitors, I mean, how are you kind of thinking at this point about pricing and kind of navigating that shift from orphan to broad CBD pricing and kind of just what's your plan to navigate that as of now? And then if I could, just really quickly, kind of a follow-up to Mani's question earlier. I guess, maybe more to the point, so like a newly diagnosed patient for maybe just the physician to work with us, for a newly diagnosed patient, who comes in, I mean it's just starting therapies, maybe which therapies do you think patients would need to first fail before your average cardiologist would then reach for something like Plozasiran? Just trying to understand the kind of real-world commercial opportunity there.

Okay. So pricing is going to be quick. There's not a lot we can say about that at this point. So for FCS, obviously, it's an ultra-rare disease. So the plan would be orphan pricing, but that -- we still need to work that out. We still need to see the data from the Phase III before we can make those kind of assessments and have those interactions with payers. Our goal with this is really to make this broadly accessible to as many patients who need it. It's a very severe disease with no treatment. The quality of life for patients with this disease is not good, and we have something that can help them. And so I think the innovative drugs that provide a solution have value. And so we need to define what that value is. And do the background research and surveys and interactive payers before we can kind of put some meat around those bones. So the second question.

Let me comment on that for just a moment. And look, patients present to our clinics or in our coronary carrier. A lot of these people we see for the first time with the abnormalities, when they come in with myocardial infarction. And patients present whose primary problem is control of their LDL cholesterol. Their cholesterol are not particularly high. They don't have a lot of remnant cholesterol, and those are people we're going to treat with the LDL-lowering agents for which we have many and they're very effective. but we also see a very substantial fraction of patients, where the primary problem is high levels of triglycerides, remnant cholesterol, non-HDL, where the conventional LDL-lowering agents are insufficient. And we are leaving those patients now at considerable residual risk. And so we need agents and agent or agents that we can use to treat those patients. We've got all the wonderful PCSK9 inhibitors, and we have statins, and we have ezetimibe and we have bempedoic acid. But for this population, these patients with high non-HDL triglycerides and remnant cholesterol, we really don't have a very good therapy.

Yes. I'd like to add in, actually, Børge Nordestgaard, it's when you try to do surveys of how clinicians treat patients with hyperlipidemia, then it's very simple to see lots of that we're showing that they are all focusing on bringing LDL down and there's lots of patients that have the secure risk due to the high remnant cholesterol, high non-HDL cholesterol when you already had LDL down, which is basically the same. So there's lots of patients out there. And there, as I see it now, it's simply not being addressed by the average clinician, mainly because there's no good drugs for it.

And I want to pose this to Dr. Gaudet as well. So the patient came into your clinic now with sHTG. So their TGs are 500 to 1,000 what would be in a world before Plozasiran and in a world after Plozasiran, what would be the process of what you would look for to figure how to treat these patients?

When we -- in the old world, when we were trying to treat patients with mixed dyslipidemia or severe hypertriglyceridemia and as a words raises, probably is an issue. When you -- as for lipid profile, triglycerides, LDL cholesterol, [ HDL ] cholesterol, are provided not remnant cholesterol, was that in the picture to provide with this information. Fibrates didn't work well, we didn't know, but is in trailing, statins is our limitation. We know that APOC3 is an independent cardiovascular risk factor first. So a little tricky to discuss the world before APOC3 inhibition because we aren't dealing with this target for now. Several years, and we know the importance of it. What we have to manage, however, and someone raised the issue, if you treat a patient with a lot of random part of severe hypertriglyceridemia. And you increase LDL cholesterol by treating him. You just raised the point that we have the toolbox to manage the severe hypotriglyceridemia cholesterol, which is already available. It would just push on the capacity to treat adequately this component of the risk of the patient with the available toolbox, but we will eventually be able to treat patients with severe hypotriglyceridemia, which are representative of those patients with a lot of remnant particles in circulation adequately. So I think that there is a world before and after APOC3 inhibition and eventually ANGPTL3 inhibition as well. I said this before, I think that we are actually dealing with -- it's very exciting for the patients. We have enhanced toolbox, which is in development, advanced development, which might be very -- which will facilitate the life of the majority of the physicians in managing lipid disorders of any kind.

Can I just add one thing about what the laboratory typically give like any liquidation, they will typically given an LDL cholesterol, HDL cholesterol, total cholesterol, total triglycerides. In my country and in Copenhagen, in particular, we have simply introduced. If you order 1 of these 4, we will automatically calculate remnant choles, and we will automatically calculate non-HDL choles, because they don't cost anything. It's free of charge. It's just the computer, and then it becomes so obvious, which patients have the high residual risk due to high remnant cholesterol and high non-HDL cholesterol with LDL is low.

Our next question comes from Maury Raycroft from Jefferies.

Congrats on the progress. I just had a quick one. I was going to ask about the high placebo response in the proportion of patients, who can get triglycerides less than 500, which is below the [indiscernible] highest threshold. How do you think about that for the pivotal study? And I know you talked about powering assumptions earlier. Does this factor into powering it all? Or is there a way that you can minimize this in the pivotal?

Yes, it's a good question. They based on [ TG ] and this population was about 650 -- and yes, about 30% to 40% of patients in the placebo went below 500. But when you look at the distribution, those were mainly those patients who were close to 500, not the ones that were in 1,000 or 1,500. So I think that we need to -- I think we need to present the data in more detail, looking at this type of [indiscernible] to provide more guidance on how the real placebo rate looks like. And similar to A1c in the Phase III study, we're going to have more precise and more than one TG baselines in because as you know triglycerides fluctuated a lot more than other lipoproteins. So we're going to have more precise base than assisting on the TG to make sure that we're not enrolling patients, who may have significant fluctuations. At the same time, it's true that once the patient get into clinical trials, oftentimes, they have more control, they behave better. The clinical trial per se as for best possible care both from the point of view of value than extra [indiscernible] but also concomitant therapy, we enable and allow every single approved therapy to treat hypertriglyceridemia in this study and a sizable number of patients were treated with those drugs. So we think despite of the viability is first of all the paper where patients were treated. And one more point about the Phase III status is we will enhance that population for patients at higher risk of pancreatitis as well. So I think we're going to try care to some degree. The power of the study is, of course, sufficient to show difference both in response rate and in the mean changes in triglycerides from patient at least that time.

And also, Maury, just want to add one more thing. So keep in mind that the magnitude of effects here, we're not talking about a moderate effect on APOC3 and a moderate reduction in triglycerides in these sHTG patients that the numbers that Jennifer was talking about earlier are really impressive and unprecedented. And frankly, those were weak '24 figures. And so there was a moderate return during that time frame. I think the mean maximum reduction in APOC3 was above 90%. And the mean maximum TG reduction in the sHTG population was approaching 90%. I mean it's -- when you have -- when you have a magnitude of effect like that, powering becomes very easy.

Our next question comes from Patrick Trucchio from H.C. Wainwright.

Thank you so much, and good evening, and congrats on all the progress on these programs. Just my follow-up is for the KOLs and for the company as well. If you can discuss the advantages of Plozasiran and Zodasiran as compared to some of these other approaches, whether it's antibodies, ASO, gene editing, et cetera, in terms of dosing or safety or efficacy. How clinicians would decide to administer these novel compounds to patients over some of these other modalities?

I'm going to jump in for just a second and say, I actually presented on Sunday in a session, where some of the early gene editing data was presented. I have to tell you that gene editing is really interesting, but it is a long way off. And I think we can't think about what we're going to do a decade or 2 from now. We need to know what we're going to do in the next decade. So that's important. And monoclonal antibodies are also potentially effective, but their duration of effect tends to be modest, and so they require much more frequent injection that's less satisfying for patients. It involves a much closer follow-up, the -- one of the nice things about the ARO-APOC3 is that it lasts a long time. And so you don't have to get very many injections a year in order to control your triglycerides or triglycerides rich lipoprotein. So I think it fills a void due to the very high efficacy and a relatively infrequent administration without necessarily editing someone's genome.

Just allow me, just to anchorite, fully agree with Steve Nissen that gene editing is very exciting. We all like it. We go to meetings and it comes in news, but it's way -- it will take a long, long time before this will be something that will be used widely. Whereas, what we see here, IRNAi this is already in clinical practices much, much closer. So I agree with that.

Yes. And I wanted to add something like from the perspective of drug development kind of historically. You think about the antibodies in this field, they didn't out there for a few years. And they're about to be replaced by this IRNAi as we speak. And if we fast forward 5- to 10-year, maybe the 4 key letters that you want to address to prevent cardiovascular is it would be all is IRNAi. They would address lipid A, they would have this LDL with PCSK9, APOC and ANGPTL3. So beyond starting, it seems to me that this therapy similarity that is relatively new is taken in mainstream as we speak, and it might be the way that will be treated this disease in 5- to 10-year from now timeline.

If I may add something here. Yes. On the imaging, I think it's for -- it's developed for very long term. If you has any side effect, it would be for a long-term as well. So there is a question of efficacy for the question of very well evaluated the risk of safety. We're not there for the moment. Having said that, combining treatments of a couple of IRNAi patient is easily feasible. It's a little bit more complicated with gene editing, if you want to target 2 or 3, and at the same time, the same treatment. Again, we're not talking in 2023. I'm just projecting myself in 10 years from now. So clearly, we to deal with the advantage of the treatment, which is effective and speak, highly say, I mean, in the trials, I'm impressed by the safety profile of the [indiscernible], and impressed by efficacy as well. I mean 90% reduction in TG levels is huge, remnant cholesterol because everything decreased significantly, except LDL cholesterol. But again, it's easily manageable.

Our next question comes from William Pickering from Bernstein.

At your earnings call in August, you said that SHASTA-3 and SHASTA-4 would serve slightly different purposes. With SHASTA-3 being 12 months long, triglycerides cutoff at 500 and kind of looking at triglyceride lowering is the main endpoint, whereas SHASTA-4 was going to be, I believe, a 2-year study with a higher trig cutoff looking at pancreatitis risk reduction in addition to trig lowering. Can you give a bit more color on how your interaction with the FDA changed your plans, if at all? And what's your current plan for generating outcomes data assessing pancreatitis risk reduction to support your engagement with payers?

Sure. Very good question. So you're right. Our plan initially was to have 1 Phase III study in patients with hypertriglyceridemia decline of greater than 500. The study initially was designed to be 600 patients, and in parallel, we were running this high-risk study in patients with [indiscernible] and pancreatitis smaller study, but longer in duration to enable enough time to see events, pancreatitis and its statistical significant difference. So that was our initial proposal, when we went to the FDA and have the end of Phase II meeting, they were very clear that we need to follow the guidance and the guidance are for to well control randomized studies and 1 single study will not be sufficient. So we decided then to do 2 studies similar to the first one we proposed because if we will wait to file with a high risk pancreatitis study that will last 2 years and we'll expand the time to another 1 or 2 years, and we will prepare us to file on the time line that we want to file. So that changed the strategy. That's why now we had 2 Phase III studies that are similar, we are planning to enrich these studies with a cap of minimal number of patients, with [indiscernible] pancreatitis to be able to show pancreatitis risk reduction. So that's the way we try to mitigate that risk. But essentially, we need to follow the guidance and the guidance call for 2 randomized Phase III study. And we think that we need to finish this on time to get the drug approved as early as possible and not wait fully long study.

So I'll add one more thing. So I think of the current SHASTA-3 and 4 as the prior SHASTA-3 just broken up into 2 separate studies. They'll essentially have the exact same design with a smaller number of patients in each study that was originally contemplated. So that doesn't -- the endpoints and basic sizing and the design of the study doesn't really change. It's just broken up into 2. And also, I think, importantly, our time line for getting the studies up and running and the way that we're projecting now as long as we're making correct assumptions, our time line to NDA doesn't change either.

And do you think that the number of patients in that subpopulation with higher pancreatitis risk will be sufficiently large for you to be powered to show a statistic benefit in pancreatitis risk reduction?

We're doing the work right now to maximize the chances to see pancreatitis reduction. Yes.

Our final question comes from Keay Nakae from Chardan. [Operator Instructions]

Can you hear me now?

Yes.

Yes. Sorry about that. Vince, just wanted to follow-up on your early comments on the plans for Zodasiran. You're still committed to advancing it into the Phase III for HoFH on your own?

Yes. That's what we're working towards that now. But I think, I guess I want to talk more broadly on this. Our goal is to find a way for that particular molecule to get to as many patients that need it, frankly. And as I mentioned before, as a company, you need to sometimes make decisions on investment, and so we're looking at ways to structure that or strategize around how that would happen. And so I'm not -- I guess it's a nonanswer, that's not going to be very satisfying, but we are focusing right now on HoFH. There are other opportunities for that program, and we're trying to figure out the best way forward for it. I think that was our last question. Is that right, Tara?

Yes.

Okay. Great. Thanks, everybody. I appreciate all the time today. We are really excited about these 2 programs, and thank you to the panelists. That was a really interesting talk and a really interesting discussion. Thanks to Javier and Jennifer for the data and the clinical development plans. Again, we're really excited about the future of these, and we appreciate everyone signing in today.