Good afternoon, and welcome to the Arrowhead Pharmaceuticals Virtual Analyst and Investor event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a 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 three of the studies for two of our cardiometabolic programs, for Plozasiran, formerly known as ARO-APOC3, and Zodasiran, formerly ARO-ANG3. Before we start, I just want to let you know that we will be making forward-looking statements. Please refer to our SEC filings for risks. We've got a really great panel today. Sorry, let me get to that slide. Sorry. We have Dr. Daniel Gaudet from the Université de Montréal, Børge Nordestgaard from University of Copenhagen, and Dr. Steven Nissen from the Cleveland Clinic. Here's the basic flow, what we're gonna do. Jennifer Hellewell 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 Martín, our Chief Medical Officer, will talk about the future of 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.
Nine of those are wholly owned, five 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. They're 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 we have an initiative called 20 in 2025, 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 other others that don't fit into those neat buckets. Today, we'll be talking about the top two 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 octopus-inspired 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 tends 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 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 Hellewell, who'll talk about the data from that we presented today.
Thanks, Vince. It's my pleasure to present a brief recap of data from three 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 studies. At Arrowhead, we recognize the unmet medical need associated with elevated triglycerides and triglyceride-rich lipoproteins, and have identified several different targets in the biology that serve as attractive therapeutic targets for, 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. On the right is a schematic for ANGPTL3, a protein which regulates lipid and lipoprotein metabolism by inhibiting both lipoprotein lipase and endothelial lipase.
Plozasiran, 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, Zodasiran 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. The study population was subjects with mixed dyslipidemia, defined as having fasting triglycerides between 150 and 499, and either an LDL-C of greater than 70 or a non-HDL-C of greater than 100. Subjects were randomized in a 3:1 fashion to one of four different dose regimens of Zodasiran versus placebo to match: 10 mg , 25 mg , 50 mg to 12 weeks, and an 50 mg Q24W cohort to 24 weeks.
Key, key endpoints included percent change from baseline over time in triglycerides, as well as a variety of other lipoprotein parameters. Shown 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%-80% at the 25mg and 50mg 12-week doses respectively. Triglycerides were reduced from 58%-64% at those two doses. And finally, remnant cholesterol reduced to an unprecedented 54%-63% level, respectively. Now turning our attention to our second study of Plozasiran that was presented earlier today. This was in a slightly different patient population.
This is the SHASTA-2 study, a double-blind, placebo-controlled, phase 2b 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 500-4,000 during the screening period. Here, subjects were randomized to one of three doses of Plozasiran, 10mg, 25mg, 50mg dose to 12 weeks for two doses versus placebo to match. Key endpoints included change in triglycerides from baseline over time, as well as changes across a variety of other atherogenic lipoproteins.
As shown on the following slide, again, as was 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%-73% in the 25mg and 50mg doses, and upwards of 70% in the 25mg and 50mg 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 on the 25mg and 50mg doses achieved serum triglyceride levels of less than 500, which is a clinically important threshold associated with increased risk of acute pancreatitis.
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 very reassuring safety profiles. And finally, our third study presented today was the ARCHES-2 study. This was a double-blind, placebo-controlled phase 2b study to evaluate the effect of ARO-ANG3 in adults with mixed dyslipidemia, with the study population defined as subjects with fasting triglycerides between 150mg -499 mg per deciliter, and either an LDL-C of greater than 70 or a non-HDL-C of greater than 100. Subjects here were randomized to one of three different doses of ARO-ANG3, 50mg, 100mg, and 200 mg doses to 12 weeks for two doses versus placebo to match.
The key endpoints were a change in serum triglycerides at week 24, with a variety of other supportive, secondary, and exploratory endpoints, notably including a substudy of subjects, wherein we assessed liver fat fraction by MRI-PDFF, over the treatment period. 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, we saw that reductions were upwards of 60%-70% at the 100mg and 200mg dose. For triglycerides, we saw greater than 50%-60%, greater than 60%, at the various doses tested. Once again, we saw a very reassuring safety profile with ARO-ANG3 or Zodasiran in this study population.
So in summary, we're pleased to report today that Plozasiran, previously known as ARO-APOC3, significantly reduced triglycerides, as well as a variety of other atherogenic lipoproteins across all dose levels tested, in both subjects with mixed dyslipidemia, the MUIR 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 MUIR study, we saw a mean reduction in triglycerides of 64% and a mean remnant cholesterol reduction of 54%. In the severe hypertriglyceridemia population, we saw mean reductions in triglycerides of 74%, with the majority of patients achieving that clinically relevant threshold of triglycerides less than 500.
Across these two studies, we were further reassured to see that Zodasiran 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. Finally, ARO-ANG3 in the ARCHES-2 study also showed significant lowering of triglycerides and ANGPTL3, as well as a variety of other apolipoproteins lipoproteins in patients with mixed dyslipidemia. So with these results in mind, I will hand it over to my colleague, Dr. Daniel Gaudet.
So thank you. What I will do, in a few minutes is I'll share with you my experience as a clinician in a clinical trial that's treating patients with, both ApoC3 inhibitors or ANGPTL3 inhibitors, in the last years. ApoC3 inhibitors for 12 years and ANGPTL3 inhibitors for eight years. And of my knowledge, Arrowhead is one of the very, very few pharma developing both agents targeting these, agents. So, there are unmet needs in clinical lipidology, which covers 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 a target, despite available treatment.
Severe hypertriglyceridemia, meaning triglycerides above 500mg per deciliter or 5.7 millimoles per liter. Sustained chylomicronemia or extreme triglycerides above, let's say, 880mg or I'd rather prefer 1,000mg per deciliter. TG-related pancreatitis and other severe hypertriglyceridemia, hypertriglyceridemia-related morbidities. So, if you take both targets altogether, ANGPTL3 inhibition and ApoC3 inhibitor, inhibitors, they cover the spectrum of extreme, from extreme hypercholesterolemia to extreme hypertriglyceridemia. And regarding, 'cause what I have to share with you mainly is the association or the, 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 mg per deciliter, but it's the highest above 1000 mg 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 bioavailable. So if you look at the pancreatitis risk associated with chylomicronemia, this is a slide coming from data that was 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 familial chylomicronemia syndrome, which are the patients completely lacking the key enzyme associated with the triglyceride management in TG rich lipoproteins, had very... Well, they had a risk of pancreatitis, which was increased by more than 300 300 and 50 folds. Whereas those with multifactorial form, meaning those with some bioavailable LPL, but having very high TG, had a 15 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 high odds of being highly effective in patients with a multifactorial form, because these patients have some LPL bioavailable.
So, the ANGPTL3 inhibitor would work. And since, as previously 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 triglyceride in severe or extreme hypertriglyceridemia 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 ANGPTL3 blockade is LPL dependent and involves LPL receptor independent, but there are lots, lot of names of enzymes there. That doesn't matter really.
But the mechanisms by which ANGPTL3 blockade works involves some of the availability 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 refractory hypertriglyceridemia, acute pancreatitis, or cardiovascular morbidity. And again, there are very few pharma developing both the agents targeting both the ANGPTL3 and ApoC3.
Yeah. 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 try to show here is try to have people understand that there's really three causal 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), like I put it literally 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 then there's the third one, and as you can see already, I show here it's larger than the two other ones because it carries more cholesterol per particle than LDL, for example, but it also carries a lot of triglycerides. Remnants is what I call them. Others call them VLDLs. Some call them more complicated triglyceride-rich lipoproteins. I think there's a tendency in lipidology to complicate things and have all these different words. So I try to simplify what is the real important things. And you can see the NHANES data here for that, remnants actually carry quite a big fraction of cholesterol in the average American, 25 mg, but they say compared to LDL, 160 mg. So take-home message is really, it is cholesterol in these particles and not just triglycerides.
Triglycerides can be important, but there's a tendency that too many people focus on triglycerides. Cholesterol is important, and I'll ask you why. Next one, please. So this is a human coronary atherosclerotic plaque, where you can see the lumen where the blood would usually flow, and there's a huge plaque, and one can see the yellow color within the atherosclerotic plaque. And it is really coloring from cholesterol, just like we know from echo, for example, and it is cholesterol that is deposited in the atherosclerotic plaque. It is not triglyceride. There's no triglycerides in there. I illustrate it from triglycerides and bacon, for example. So in my point of view, the target for these remnants is that you should target elevated remnant cholesterol, because that is what ends up being deposited in atherosclerotic plaque and cause eventually atherosclerotic cardiovascular disease.
But of course, it's also very nice to find the ones with high triglycerides because they are average would have high remnant cholesterol. And if you want to reduce it, the goal would be to 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, then you also want to make sure that non-HDL cholesterol go down, because then both remnants and LDL go down. It doesn't help to reduce remnant cholesterol if LDL goes up a lot, like we saw in the so-called PROMINENT trial. And then you also want to be sure that ApoB goes down a little bit because it also includes LDL.
If you get these three down, you have a really good chance of reducing atherosclerotic cardiovascular disease. So just try to say: What's the psychology of many clinicians when they look at things and why people keep talking about triglycerides all the time? That's from the lab report. People get the value plasma triglycerides, and as you can see, this is part of the remnants. They also have a lot of cholesterol, and therefore, people keep talking about triglycerides because that's what they see 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 them both triglycerides and cholesterol-rich lipoproteins and not just triglyceride-rich lipoproteins. Just try to illustrate for you.
This is the example of lung cancer, where we know from lots of science 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 statistical analysis, both of these will 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 touched and had in their hand, and it would be exactly the same association as the number of the cigarettes the person smoked. But it is the smoking per se that causes lung cancer, not the number of cigarette boxes you have in your hand. The analogy for remnants would be here that what causes atherosclerotic cardiovascular disease, exemplified with myocardial infarction, is the cholesterol.
People call it non-HDL cholesterol, but that's a composite of LDL cholesterol and remnant cholesterol. So again, it's the cholesterol in the two particles, remnant LDL, that cause atherosclerotic cardiovascular disease. But you could also do association and look at the triglyceride content, and you had the same association observationally. But from my point of view, as I see the totality of evidence, it is much more likely it's the cholesterol content that is here. Next one. So this is sort of like depicting the mechanism by which it drives atherosclerotic, or you could say, vulnerable plaques. So in plasma, you have both LDL remnants and also chylomicron content. The one Daniel Gaudet talked about, the chylomicron, they're too large to come into the arterial wall. That's why he'll be focused on pancreatitis.
But the LDL remnants, they can come into the arterial intima, where atherosclerosis is present, where LDL needs some sort of modification to drive atherosclerosis. Remnants are taken up directly by macrophages producing foam cells, and also further, lipoprotein lipase can degrade triglycerides, maybe in the intima, maybe at the endothelial surface, liberating free fatty acids, monoglycerol, that will be toxic, drive inflammation. So there's also chyle, but there's also the possibility of getting vulnerable plaques. So they committed again, for triglycerides and cholesterol-rich remnants, they cause atherosclerotic cardiovascular disease, and the evidence is overwhelming. It's as good as for as for LDL, as good as for LDL cholesterol. What convinced me as a young clinician was to seeing these patients in lipid clinic, something called remnant hyperlipidemia. It's very typical, just like familial hyperlipidemia, they have just remnants of plasma.
They don't have LDL, and they have these various xanthomas, tubereruptive xanthomas, or xanthelasma xanthomas, and they have accelerated atherosclerosis and premature cardiovascular disease. That's a genetic condition. Here's some epidemiology from our own studies in Copenhagen, where you can see just a simple, on the X-axis, measurement of non-fasting triglycerides, which is a marker of remnant cholesterol. It drives a hazard ratio for myocardial infarction, and you can see if you're just above 528 mg, literally, you have fivefold increased risk of myocardial infarction, compared to having less than 88 mg per deciliter. This is following people from two to maybe 40 years, so it's just one measurement of remnant cholesterol triglycerides.
Here we try back-to-back in our Copenhagen Young Population Study to look at the same increase in LDL cholesterol, with the same increase in remnant cholesterol, and then we also Lp(a) cholesterol. It's at 1 millimole or 39 mg 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 for myocardial infarction, and it is even higher for Lp(a). I'm not implying that Lp(a) it's a cholesterol content that drives disease, but I'm just putting on the same scale.
Genetically, you can see that all of them, that's the, with the wide confidence, and there to the right of the observation, one telling that they are all causal. When you adjust from each other, which we did here, they're completely independently, three 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 guidelines for non-HDL cholesterol. Non-HDL cholesterol is LDL plus remnant cholesterol. That's the two that comes into it. You see here, so like main guidelines from Canada, 2021, Europe, 2019, or U.S., 2018.
For secondary prevention of ASCVD on top, they all say, Let's bring LDL down, but then they also all say, Let's also bring non-HDL cholesterol down. And what they say is, Let's bring remnant cholesterol down. And the Canadian Europeans further have the ApoB. Familial hyperlipemia in the middle, that's only LDL cholesterol, but in primary prevention, it's the absolute ten-year risk-based diabetes or chronic kidney disease. They all say, LDL, let's get it down, but Canadian Europeans say, Let's also get non-HDL and ApoB down, meaning it's not enough to get LDL down, you 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 in JAMA in 2007, and it took some years before the others picked up, but now you can see there's a lot of publication on it.
So finally, people have understood that this is a very important causal risk factor for ASCVD. So for ASCVD risk, it is cholesterol, not just triglycerides. Triglycerides can also, because of inflammation plaques, make vulnerable plaques, but cholesterol content, of course, 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 come back to me and say they heard me give a talk eight years ago, and they remember one slide, this one. So the good, the bad, and the ugly. HDL being the good one, now not good anymore. We just know some LDL, 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 of plasma. 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 a really lucid presentation. First of all, we're delighted to be working together with Arrowhead Pharmaceuticals on the Plozasiran cardiovascular outcome trial. I'm gonna 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 revascularization, 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 what I want to show you are two 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 a million people, so they're very convincing evidence. Next slide, please.
So why have previous studies of triglyceride-lowering therapies not succeeded? Well, of course, they focused primarily on triglycerides, and as you heard from Borg, 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 you know more than four years, there was a hazard ratio of 0.99. These curves were virtually superimposable, but the triglyceride reduction was only 19%, and the actual reduction in the other fractions that he that Borg talked about, like ApoB and non-HDL, was even less impressive.
Next slide, please. Then more recently, my colleague, Dr. Paul Ridker, published this study with Gemfibrozil. 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 four years of treatment. Next slide, please. So why are we enthusiastic about the Plozasiran 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%-20%, ApoC3 in the range of 60%-70%. Non-HDL, 5%-8%, it with niacin and fish oil, 17%-29% with ApoC3. The increase in HDL is modest with niacin and fish oil, but it is large with ApoC3, 42%-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. ApoC3, 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 ApoC3.
So this is a study of 18,000 genes, 3,007 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, my last slide, and thank you so much for your attention.
This is Javier San Martín. 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 syndrome, where still we have a significant unmet medical need. I wanted to walk you through the plan that we have on the clinical development program, both from clinical trials perspective and from the regulatory next steps. As most of you know, the PALISADE study, which is a study in patients with familial chylomicronemia syndrome or FCS, we completed enrollment in April of this year. It's a one-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 pancreatitis is an event of concern, is ongoing. We completed the phase II study. We presented at this meeting the full results. A few weeks ago, we had our end of phase II meeting with the FDA. We agree upon the next steps, which is the phase III program, where we had two phase III studies, the SHASTA-3 and the SHASTA-4. Both studies will involve patients with TG greater than 500. It would be a one-year study with four 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. All right. Now I wanted to provide some guidance about the cardiovascular study, cardiovascular outcome trial with Plozasiran or ApoC-III. You heard today very interesting data on how this field is evolving with regard to the remnant cholesterol as an important risk factor, that this part has not been addressed with any other treatment. So we are, of course, we completed the phase II study we presented here, and we are right now working with Dr. Nissen on the design and the specifics 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 the ApoC-III, addresses the spectrum of diseases driven by elevated triglycerides, including the hypertriglyceridemia syndrome, FCS and SHTG, and the residual risk associated with cardiovascular diseases driven by atherogenic TRLs or remnant cholesterol. The recent phase II data demonstrated unique pharmacodynamic profile of Plozasiran that reducing TG and TRLs in a majority of the patients with a very convenient dose scheduling interval of every three months subcutaneous 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 three indications. That I will turn over 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. And just to be clear, we'd like to take one question from each analyst. And if you need to follow up, we can do that, but let's limit it to one question please.
Great. Thanks, Vince. So our first question comes from Luca Issi from RBC. Please go ahead, Luca. Luca, you may be on mute.
Oh, great. Can you guys hear me okay?
Yes, we can.
Great. Apologies. Maybe two quick questions here. So maybe the first on glycemic control, Javier, if I may, on ApoC-III. I think we're seeing some worsening in glycemic control in some patients. I think it was 22% in SHASTA-2 versus 11% for placebo.
... Can you just maybe offer some numerical color on what magnitude of the A1C elevations have you seen, and maybe whether the elevations were sustained or transient? Just try to think about the severity of the signal rather than 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 the powering assumptions for such trial? Again, appreciate APOC3 has a much higher impact on lipids versus prior molecule, but obviously, patients will also have access to GLP-1 , and obviously, we've seen the impact on cardiovascular outcome 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 will take the first question about the A1C or the glycemic control in the SHASTA-2 study. So look, as we, we did see this signal in the first interim analysis. The signal clearly was in the patients on the, that had pre-existing diabetes, and particularly those with poorly controlled diabetes. In this study, we have an exclusion criteria on patients with more than 9% A1C, but really we did that based on one single assessment, and we did observe high variability throughout the study in general. We did not see any increase in patients with newly diagnosed diabetes, and this finding was mainly on the highest dose of 50 mg compared with the, with the 10 mg and the 25 mg.
There were very few patients that have an excess or any increase greater than, let's say, 1% twice, or 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 poorly controlled diabetes and in the highest dose. So that's how we're thinking about this. The phase 3 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 of, of, of more the sample size, of the program, maybe we can pull more color and maybe the signal goes away.
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 will ask Dr. Nissen.
Yeah.
Go ahead.
Yeah. Let me just respond to the question about the powering of the outcome trial. You know, we're not prepared yet to tell you exactly the size and the powering assumptions, but let me just tell you how we go about this. We try to understand what degree of reduction in the 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, you know, we don't use the exact values that we had in the last study that we did. We look at, you know, 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, nor 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, you know, we'll post it on clinicaltrials.gov, and everybody will get to see exactly, you know, what we've postulated and how we're going to go about it.
Got it. Thanks so much.
Thanks for the questions, Luca. Our next question comes from Prakhar Agrawal from Cantor Fitzgerald. Please go ahead.
Hi, thanks for taking my questions. 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. Thank you.
Daniel Gaudet here. The LDL cholesterol increase was expected, because when you hydrolyze triglyceride and VLDL particles through the LPL-dependent and LPL-independent mechanisms, at the same time, you rapidly form LDL particles. But in the context of the phase two 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, the remnant particles are cleared also more rapidly due to the APOC3 inhibition. But again, this is kind of a signal of the high efficacy of APOC3 inhibition on VLDL particles management, but it's easily manageable.
I just want to add about the comment on the clinical, on the phase three 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, and patients should be allowed to be treated with the best possible standard care to manage their LDL cholesterol.
Thank you.
So our next question comes from Mani Foroohar from Leerink. Please go ahead, Mani.
Hey, thanks for taking the question for this, very insightful, presentation. I guess a broader question on treatment paradigm. Presuming-
... The asset in question continued to produce a profile suggested by the data we have in hand. Can you sort of walk us through patient population? Who's the right patient for Plozasiran, who's the right patient for Zodasiran, the role of existing, approved or other potentially approvable late-stage oligotherapies and FCS and elsewhere? Just help us understand where in the paradigm and amongst which patients each asset is the best suited in your mind.
Who wants to start? Steve?
Well, happy to jump in. We've never had an agent like this. You know, we have nothing out there that can produce, as 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, you know, 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. You know, 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, you know, very high levels of triglyceride-rich lipoproteins.
So, you know, as a clinician, and I see prevention patients, you know, every week, I have very little to offer these patients. You know, fibrates haven't worked, fish oil hasn't worked, and so we need something to treat those patients. And at least, you know, you know, in this case, we think this would be a very, very big addition to the therapeutic armamentarium.
Yeah, but also I'd like to also add in. I mean, again, trying to keep it simple. You want to recruit patients with high remnant cholesterol. You 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.
Thanks, guys. That's really helpful.
Just to add something here. So when you add up, and that's the, my opinion, a huge difference from what we had previously. When you have the possibility to silence the ANGPTL3 and or ApoC3, when you silence the ANGPTL3, you decrease circulating ApoC3, by the way, significantly. With both agents, you cover all the spectrum of lipid disorders from extreme LDL cholesterol elevation, from extreme triglyceride elevation, including the middle remnant particles. So, it's an interesting paradigm to decide the algorithm for the future, and the treatment of lipid disorders is shifting.
Great. So our next question comes from Jasmine Grewal from UBS. Please go ahead, Jasmine.
Hey, this is Jasmine on for Ellie Merle. So, your 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? Thank you.
Sure. Thanks, Jasmine. 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 are, that have no other agents. And from a commercial standpoint and from a 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 ultra-rare 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 you know, 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 step edits . So we make it easy for patients to fill 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 outcomes study in a larger population, I think it's critical that we select the right patient populations for the clinical development in a way that we can also grow into and support. So I would say partnering right now for Zodasiran, maybe ex-US, 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 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, you know, that's a harder question to answer because it's really a case-by-case basis. It...
There are certain areas that have more strategic importance to us as a company, and I would say cardiometabolic, broadly, you know, 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 diseases, neuromuscular diseases that have no treatment or degenerative diseases that have no treatment. So I would say those three areas, we would be less likely to seek partners. And if we do, they would be at later stages of development.
Awesome. Thank you so much.
Thanks, Jasmine. Our next question comes from Brendan Smith, from Cowen. Please go ahead, Brendan.
Hi, guys. Great, thanks for taking the questions. Congrats on all the great progress here. First question I wanted to ask, just on pricing, I know everybody's favorite question. But obviously you'd be positioned to launch in FCS, first, but then, you know, I think SHTG shortly 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 CVD 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 for, like, a newly diagnosed patient or maybe it's the physician who are with us. For a newly diagnosed patient who comes in, I mean, and is 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 Zodasiran? Just trying to understand the kind of real-world commercial opportunity there. Thanks, guys.
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 that innovative drugs that provide a solution have value.
And so we need to, we need to define what that value is, and do the background research and surveys and interact with payers before we can kind of put some meat around those bones. So the second question.
Yeah, let me comment on that for just a moment. You know, look, patients present to our clinics or in our coronary care unit, and a lot of these people we see for the first time with the abnormalities when they come in with a myocardial infarction. You know, patients present whose primary problem is control of their LDL cholesterol. Their triglycerides 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 their primary problem is high levels of triglycerides, remnant cholesterol, non-HDL, where the conventional LDL-lowering agents are insufficient.
We are leaving those patients now at considerable residual risk, and so we need agents, an agent or agents that we can use to treat those patients. You know, we've got all the wonderful PCSK9 inhibitors, and we have, you know, 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.
Yeah. I'd like to add in actually, Bob and Scott, it's when you try to do surveys of how clinicians treat patients with hyperlipidemia, then it's very simple to see lots of data showing that they are all focusing on bringing LDL down. And there's lots of patients that have residual risk due to the high remnant cholesterol, high non-HDL cholesterol when you already have LDL down, which is basically the same. So there's lots of patients out there, and they are, as I see it now, they're simply not being addressed by the average clinician.
... mainly because there's no good drugs for it.
I want to actually pose this to Dr. Gaudet as well. So, if a patient came into your clinic now with SHTG, so their TGs are 500-1,000. What would be, you know, in a world before Plozasiran and in a world after Plozasiran, what would be the process of what you would look for to figure out how to treat these patients?
You know, when we were trying to treat patients with mixed dyslipidemia or severe hypertriglyceridemia, and as Børge raised, it probably is an issue when you ask for a lipid profile. Triglycerides, LDL cholesterol, HDL cholesterol are provided, not remnant cholesterol. It was not in the picture to provide this information. Fibrates didn't work. Well, we didn't know, but it didn't really. Statins, there are limitations. We know that APOC3 is an independent cardiovascular risk factor. So it's a little tricky to discuss the world before APOC3 inhibition, because we are 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 remnant particles, severe hypertriglyceridemia, and you increase LDL cholesterol by treating it, treating him, you just raise the point that it's... We have the toolbox to manage these, this elevation in LDL 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 hypertriglyceridemia, 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 in ANGPTL3 inhibition as well.
Yeah, I said this before, I think that we are actually dealing with, it's a very, very exciting for the patients. We have in hand a toolbox which is in development, advanced development, 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, Dan Gaudet said, they'll typically get an LDL cholesterol, HDL cholesterol, total cholesterol, total triglyceride. In my country, and in Copenhagen, particular, we have simply introduced, if you order one of these four, we will automatically calculate remnant cholesterol, and we will automatically calculate non-HDL cholesterol because it doesn't, 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, so.
All right, great. Super helpful. Really appreciate it.
Thanks, Brendan. Our next question comes from Maury Raycroft from Jefferies. Please go ahead, Maury.
Hi, thanks for hosting this event, and congrats on the progress. I just had a quick one. I was going to ask about the high placebo response and the proportion of patients who can get triglycerides less than 500, which is below the acute pancreatitis 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 at all, or is there a way that you can minimize this in the pivotal?
Yeah, that's a good question. You know, the patient TG in this population was about 650, and yes, about 30%-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, you know, 1,000 or 1,500. So I think that we need to present the data in more detail, looking at this type of sub-analysis to provide more guidance on how the placebo rate looks like. And similar to today, once in the phase III study, we're going to have more precise and more than one TG baseline, because as you know, triglyceride fluctuates a lot more than other lipoproteins.
So we're going to have more precise baseline assessment of the TG to make sure that we're not enrolling patients who may have significant fluctuation. At the same time, it's true that once the patient gets into clinical trials, oftentimes they have more control, they behave better. The clinical trial per se asks for best possible care, both from the point of view of diet and exercise, 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 it's part of the variability, it's part of all the patients were treated. And one more point about the phase three studies is we will enhance that population for patients at higher risk for pancreatitis as well.
I think we're going to take 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 triglyceride from baseline at different time points.
Also, Maury, I just want to add one more thing. So keep in mind that the magnitude of effect here, we're not talking about a moderate effect on APOC3 and a moderate reduction in triglycerides in these SHTG patients. The numbers that Jennifer was talking about earlier are really impressive.
... Those were week 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, when you have a magnitude of effect like that, powering becomes very easy.
Yeah, makes sense. Thanks for the perspective.
Thanks for the questions, Maury. Our next question comes from Patrick Trucchio from H.C. Wainwright. Please go ahead, Patrick.
Great. Thank you so much, and, good evening, and congrats on all the progress on these programs. I guess 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, 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 have 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. You know, I think we can't think about what we're going to do a decade or two 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, you know, injection that's less satisfying for patients, involves much closer follow-up.
One of the nice things about, you know, 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, you know, your triglycerides or triglyceride rich lipoprotein. So I think it fills a void due to the very high efficacy and relatively infrequent administration without necessarily editing someone's genome.
Allow me just to echo, I fully agree with Steven Nissen that gene editing is very exciting. We all like it. We go to meetings, and it's in the news, but it's way... It'll take a long, long time before this will be something that will be used widely. Whereas what we see here, the siRNA, this is already in clinical practice, is much, much closer. So I agree with that.
Yeah, and I wanted to add something, like, from the perspective of drug development, kind of historically, you think about the antibodies in this field, you know, they've been out there for a few years, and they're about to be replaced by this RNAi as we speak. And if we fast-forward five to 10 years, maybe the four key letters that you want to address to prevent cardiovascular disease will be all siRNA. They will address Lp(a), they will address LDL with PCSK9, ApoC3, and ANGPTL3. So beyond statins, it seems to me that this therapeutic modality that is relatively new, is taking in mainstream as we speak, and it might be the way that we, we'll be treating this disease in five, 10 years from now, I think.
If I may add something here. Yeah, the gene editing is for; it's developed for very long term. If you have any side effects, it will be for a long term as well. So, there is a question of efficacy, but a question of very well evaluated the risk of safety. We're not there for the moment. Having said that, combining treatments of couple of RNA in a patient is easily feasible. It's a little bit, little bit more complicated with gene editing if you want to target two or three things at the same time, the same treatment. Again, I'm not talking in 2023. I'm just projecting myself in 10 years from now. So, clearly, we have to deal with the advantage of a treatment which is effective and safe, highly safe.
I mean, in the trials, I'm impressed by the safety profile of the Plozasiran and impressed by the efficacy as well. I mean, the 90% reduction in TG levels is huge than in cholesterol because everything decreased significantly, except LDL cholesterol, but again, it's easily manageable.
Got it. Thank you so much.
Thanks, Patrick. Our next question comes from William Pickering, from Bernstein. Please go ahead, William.
Hi, good afternoon. Thanks so much for the question. 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, triglyceride cutoff of 500 and kind of looking at triglyceride lowering as the main endpoint. Whereas SHASTA-4 was going to be, I believe, a two-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 the outcomes data assessing pancreatitis risk reduction to support your engagement with payers? Thank you.
... Sure. Well, very good question. So you're right. Our plan initially was to have one phase 3 study in patients with hypertriglyceridemia, defined as TG 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 pre-existing pancreatitis, smaller study, but longer duration, to enable enough time to see events, pancreatitis, and a statistically significant difference. So that was our initial proposal. When we went to the FDA and had the end of phase II meeting, they were very clear that, you know, we need to follow the guidance, and the guidance asked for two well-controlled randomized studies, and one single study would not be sufficient.
So we decided then to do two studies similar to the first one we proposed, because if we will wait to file with a high-risk pancreatitis study that will last two years, then we'll expand the time to another one or two years and we will prevent us to file on the timeline that we want to file. So that changed the strategy. That's why now we have two phase III studies that are similar. We're planning to enrich these studies with a couple minimum number of patients with pre-existing pancreatitis, to be able to show pancreatitis risk reduction. So that's the way we try to mitigate that risk. But, you know, essentially, we need to follow the guidance, and the guidance call for two randomized phase III study.
We think that we need to finish this on time to get the drug approved as early as possible and not wait for a long study, so.
So and I'll add one more thing. Think of the current SHASTA-3 and SHASTA-4 as the prior SHASTA-3, just broken up into two separate studies. They'll essentially have the exact same design with a smaller number of patients in each study than was originally contemplated. So it doesn't. The endpoint and the basic sizing and the design of the study doesn't really change. It's just broken up into two. And also, I think importantly, our timeline for getting the studies up and running, and the way that we're projecting now, as long as we're making correct assumptions, our timeline to NDA doesn't change either.
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 risk reduction. Yes.
Thank you.
Thanks for the question, William. Our final question comes from Keay Nakae from Chardan. Please go ahead. You might be on mute.
Try to activate his line, his line again. I'm not seeing it, Tara.
Can you, can you hear me now?
Yeah.
Yes.
Yeah, sorry about that. Vince, just wanted to follow up on your, your early comments on the plans for Zodasiran. You're still committed to advancing it into the phase III for HoFH on your own?
Yeah, that's what we're working towards that now. But I think, you know, 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 that, you know, to not answer that's not going to be very satisfying, but we're 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.
Okay. Thanks for that.
So there's-
Okay. I think that was, 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 two programs, and thank you to the panelists. That was a really interesting talk and a really interesting discussion. And 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.