Good morning. I'm Jennifer Capuzelo, Director of Investor Relations, and I'd like to welcome you to the Ionis 2021 Investor Day. Following our prepared remarks today, we will host a question and answer session. To participate, please use the Ask a Question function located on the left side of your screen. Please use the Help function for technical assistance at any time during today's presentation. Additionally, today's presentation is being recorded, and a replay will be available on the Ionis website shortly. Before we continue, please be aware that during today's presentation, we will be making forward-looking statements, which are based on our current expectations and beliefs. Please consult the risk factors discussed in our SEC filings for additional detail. With that, I'll turn it over to CEO Brett Monia.
Thank you very much, Jennifer. Most of all, thank you to everybody joining us for today, remotely out there, for today's Ionis Investor Day presentation. You know, we're very proud of some of our key strategic decisions that we've made over the last couple of years to bring Ionis to become a leading biotechnology company. We're also very proud of the fact that we made tremendous progress in achieving this vision for the company, and we're very excited to share with you today the great progress we've made over the last couple of years in achieving our vision of a top leading biotechnology company, and in the near future. Joining me today are five outstanding leaders from Ionis to present with me.
Sam Tsimikas, Senior Vice President Global Cardiovascular Drug Development and Franchise Leader for Cardiovascular Diseases. Onaiza Cadoret-Manier, Chief of Corporate Development and Commercial Officer. Ken Newman, Vice President of Clinical Development. Eric Swayze, Executive Vice President of Research, and Beth Hougen, our Chief Financial Officer. This is our agenda for today. It's a rich agenda, and it's an agenda we're very excited about presenting to you today. Following my opening remarks, I will hand it off to Sam. Sam Tsimikas, who will provide you with a summary and overview of what we believe is an industry-leading cardiovascular disease franchise. Following Sam, Onaiza will come on up and she's gonna present to you what our go-to-market strategy will be for two near-term very important commercial assets, eplontersen for TTR amyloidosis, olezarsen for patients with very high triglycerides.
Then following Onaiza, Ken Newman will come up on stage and present to you the phase II data, the results from donidalorsen in patients with hereditary angioedema. He'll provide you with his perspectives on why that data is so meaningful. He'll also shed some light onto what our phase III planning and strategy will be to bring donidalorsen to the market. Following Ken, Onaiza will come on back up, and she's gonna present to you our go-to-market strategy for donidalorsen in patients with hereditary angioedema. Following those presentations, we're gonna do a bit of a pivot, and we're gonna delve deep into the science.
Eric Swayze will come on up and present to you some of the most meaningful advancements we're making in antisense technology today, and more importantly, how that's gonna translate to very exciting new drugs for our pipeline well into the future and to extend our leadership position in RNA-targeted therapeutics. Following Eric, Beth will come on up and provide you a financial overview where we are today financially, but more than that, more importantly than that, how we see Ionis growing in the future from a financial perspective. I'll close it out with a few concluding remarks before opening it up for some questions from all of you. Let's start with the finish. What are the key takeaways from today's presentation? Let's cut right to the chase.
Ionis, here they are. Ionis has clear vision on how we are going to become a leading biotechnology company, and that is our vision, and we're well on our way to achieving that vision. Second, Ionis is positioned for substantial growth, and that growth is gonna come from our rich mid-stage and late-stage pipeline that is positioned very well to deliver a large number of new drugs to the market in the near future. Ionis is still the technology leader in RNA therapeutics, and not only are we still the leader, we're investing in all aspects of our technology to extend our leadership position in a rapidly growing competitive field. Fourth, Ionis has a compelling financial profile, a financial profile that allows us to invest in all aspects of the business that we need to invest in to achieve our vision for the future.
As many of you know, we have many dedicated, long-standing investors over many years, and you know that Ionis has made tremendous progress over the years. I mean, let's face it, we essentially created a new sector of the biotech industry called RNA-targeted therapeutics. We persevered and never gave up, and we've delivered very important drugs to the market already, and we're positioned to deliver even more in the future. But that history has really created a foundation, a strong foundation for the company that we're gonna leverage to take Ionis to even greater levels of success, to grow rapidly. That foundation is based on five pillars of strength, if you will.
We have validated a platform technology, antisense technology, and we're using that technology to deliver new drugs to the market. The second pillar is a rich mid and late stage pipeline from this technology that we invented. The third pillar is our financial strength, which, as I said earlier, allows us to invest in all aspects of the business that we need to invest in to achieve our vision. Fourth, commitment to innovation. We've always been committed to innovation. Despite the fact that we're now moving to commercialize products of our own, we're still committed to innovation, and we're even more committed to innovation than we ever have been. We are committed to being the leaders in the field that we helped create. Finally, we have the people.
We have a tremendous workforce, dedicated employees who persevere and are right behind our vision to be a leading top tier biotech company. They're all on board and ready to take the company to the next level of success. As I said, that foundation we will use to leverage and bring Ionis to even greater success and grow the company. There are three strategic imperatives that we are 100% locked in on. We're 100% focused on to achieve that success. First is to build out our pipeline and bring products to the market and to commercialize those products on the market successfully ourselves. Second is to extend and expand and diversify our technological capabilities, as I already touched on.
All of this, the foundation and these two strategic new imperatives all feed into the third strategic imperative, deliver the drugs, get them to the market, an abundance of new drugs to reach the market, and not only reach the market, but be successful in the market. Those are them, and that's how we're going to achieve our vision. That vision is based today on two very important two leading industry therapeutic franchises that we're very proud of here at Ionis that we've created. The first is our neurological disease franchise. In our neurological disease franchise, we are addressing all many major neurological diseases, whether neurodegenerative diseases, neurodevelopmental diseases, and so on. We have three ongoing phase III studies in progress and 10 drugs in clinical development across the neuro pipeline and more coming.
Second, our cardiovascular franchise, again, a leading franchise in the industry, in the cardiovascular space. We're essentially addressing all the major risk factors that still create unmet need for the millions of patients suffering from cardiovascular disease. We have four ongoing phase III studies in progress and nine drugs in our cardio pipeline that are progressing very nicely across the pipeline. As I said earlier, we have a very rich mid- and late-stage pipeline. Our late-stage pipeline is one of the best in the industry, bar none. Today, we have six medicines in phase III development that are being evaluated and tested across eight different indications.
Three drugs from our neurological disease franchise, four drugs from our cardiovascular franchise, and then donidalorsen for hereditary angioedema, emerging and in phase III development from a rapidly growing specialty rare franchise that's, as I said, is growing and gaining a lot of momentum here at Ionis. These drugs are being developed for different patient size patient populations. We have several of these drugs are being developed for severe rare diseases where there is a tremendous unmet medical need, and we're going to deliver these drugs to the market to meet that need. Other drugs, particularly from our cardiovascular franchise, are positioned very well for very large markets in the millions of patients suffering from these diseases, and then, of course, donidalorsen for hereditary angioedema.
Furthermore, what you can also see on this slide is the fact that there's gonna be a steady cadence of phase III data readouts every year for as far as we can see into the future. In some years, we're gonna have several different phase III readouts all within the same 12-month span. Of course, that's a great phase III pipeline, but what's also important to know is the fact that that pipeline will continue to grow, and they're gonna continue to expand because of our rich midstage pipeline, our phase II and phase IIb pipeline. Today, we have 14 drugs in phase II inpatient studies for a variety of different diseases, all of which, if successful, any of which that are successful, have the potential to move into phase III pivotal clinical trials.
Of course, that's really important for obviously, because that signals that we have the ability and will continue to replenish our phase III pipeline as the current phase III drugs reach the market. It's a very long-term successful late stage and midstage pipeline. Of course, what matters most are what are the products that are gonna reach the market? What's our vision for products to reach the market in the near term and in the longer term? As a reminder, we have three products on the market today led by SPINRAZA. SPINRAZA is the foundation of care for all forms of spinal muscular atrophy, and it is performing as a multibillion dollar blockbuster, and we expect it to continue to perform as a multibillion dollar blockbuster for many years to come.
In the near term, we're expecting quite a number of drugs to potentially reach the market for rare, principally for rare diseases, but also for some for large indications, even within the near term. Seven drugs expected in the near term to potentially reach the market. As I said, drugs even for very large indications such as olezarsen for severe hypertriglyceridemia. Then looking beyond that period, you can see how many drugs have the potential to reach the market, in the future, following these other drugs that we're positioning to reach market. There you can also see that, there are many drugs that are targeted to very large patient populations. Today, we're gonna focus on three near-term commercial opportunities with multi-billion dollar potential.
Eplontersen, olezarsen, and donidalorsen. Eplontersen, of course, is indicated for... is being developed for TTR amyloidosis, a prevalence that's estimated to be 300,000-500,000 patients worldwide. Our first phase III readout projected for 2022 next year in polyneuropathy. We believe based on the profile of eplontersen that this drug has the strong potential, we expect it to change the standard of care for patients living and suffering with TTR amyloidosis. Olezarsen for the treatment of patients suffering from high triglycerides, severe high triglycerides. Millions of people suffer from this disease around the globe and millions right here in the United States. Our first phase III data readout for olezarsen is expected in 2023, and this drug is positioned as a first-in-class medicine for the management of patients with high triglycerides and the best-in-class medicine at the same time. Donidalorsen.
Based on the data that we reported out from phase II, we expect donidalorsen to be a best-in-class medicine for the prophylactic treatment of hereditary angioedema, with our phase III data projected to read out in 2024. Now to close, I'd like to just highlight four questions we plan to really drill down on and answer today in our through our presentations. We selected these questions because they were the questions that came from you, our investors. Since our announcement last year that we were gonna move Ionis to become a commercial organization of excellence to match our excellence in research, development, and in our business, questions came such as, what near-term products will you prioritize for commercialization?
What is our go-to-market strategy, and how will that strategy allow you to win on the market? How will we extend our technology leadership position? Will your pivot to commercialization come at the expense of innovation? I'll tell you that answer now. It's no. We're continuing to invest in innovation and in our science while we still build out a commercial organization. Finally, do we have the resources to achieve our vision, to invest in all aspects of the business to achieve that vision, and what are our growth expectations for the company from a financial perspective? We're setting out to answer all these questions for you, so sit back and here come the answers. Now I'm gonna hand it over to Sam Tsimikas, who's gonna provide us with an update on our leading cardiovascular franchise.
Great. Thank you, Brett. Good day, everybody. Well, on behalf of all the hardworking people at Ionis, on my team, I have the privilege to present to you the exciting developments, excuse me, in the cardiovascular program. This has been flying a little bit under the radar, but I hope in the next 15 minutes I can convince you that you need to get very excited about our cardiovascular programs. This little clock represents what we have in development for phase II and phase III programs. ION904 and factor XII are not on this slide, but the other seven drugs that we're developing in phase II and phase III, I'll just briefly review them here for you and then show you the details. A couple of concepts from this slide.
One is that this is a very, very comprehensive program. When you look at cardiovascular disease and what the risk factors are, what you can see here is that we have all the lipid disorders covered. In fact, Ionis was the first to identify the targets that we're treating. So for Lp(a), for example, we're several years ahead, APOC3, angiopoietin-like 3. We have hypertension covered. That's a very common risk factor globally in billions of people. We have heart failure covered, both through AGT and through eplontersen. We have thrombosis covered through fesomersen and with a very unique mechanism that I will describe for you. Now we have a best-in-class PCSK9 inhibitor.
When you look at this wheel, you'll see that we really address probably 80%-90% of the cardiovascular risk factors. Now, the other part of this is that these are not me too drugs. We're not developing another drug just to develop it. All of these drugs are best in class, first in class, or have that potential. And this really implies the innovation at Ionis, where we've identified the targets, done all the hard work to validate them, and now have taken a big risk in doing development in those in the clinical trials. With that background, let me just briefly go over each one of these, and then I'm gonna come back to each one with a couple of slides from each one for some details.
If we start at seven o'clock and eplontersen, today is gonna be a big eplontersen day. You'll hear a lot about it. We're in phase III with two trials, and those are going very well, and we believe we can bring novel therapies to unmet need. Fesomersen, Factor XI. One of the holy grails of cardiovascular disease is to develop an anticoagulant where patients don't bleed. That might seem like an oxymoron. How can you have anticoagulation, but patients don't bleed? The natural history of Factor XI tells us that that can happen because patients that have Factor XI deficiency are anticoagulated naturally but don't bleed. This drug is gonna try to replicate that natural history, so we can have a safer anticoagulant because a lot of our patients can't tolerate those.
Pelacarsen. Ionis has been in the forefront of this. We're several years ahead of the competition. This is a risk factor. It has no therapy, but it's extremely common and underdiagnosed. So there are about 1.4 billion people at risk, and we're in the midst of phase III now with Novartis to have the first drug on the market for that. Angiotensinogen is another target. This is impacting the whole RAS pathway from the top down, and it has the ability to have fundamental benefits in that system without affecting kidney function. This is another one of these unique aspects of this drug development that will hopefully bring additional benefit to our patients. PCSK9, we have several PCSK9 inhibitors approved. However, there's still an unmet need.
This collaboration with AstraZeneca, with ION449, as I'll show you, is really the best-in-class agent for lowering LDL cholesterol. Vupanorsen, we'll go over that. This reduces both triglycerides and other atherogenic lipoproteins, and it's a target for mixed dyslipidemia. Finally, you're gonna hear quite a bit about APOC3 because this is one of our most advanced programs with several indications, and we'll review that in more detail as we go forward. Now even though Ionis has been around a long time, the technology has evolved quite a bit. As you can see here from this slide, the publication world, which is the arbiter of, you know, what's important and what's good, is really caught up.
You see here we're averaging about one paper per year in the New England Journal of Medicine. As most academicians know, it's extremely difficult to publish in the New England Journal of Medicine. This is a really good stamp of approval that we're providing novel, unique information to the field and all these different targets that you see on this slide. Now, we have nine drugs, some of which have multiple indications. The point here I wanna make is that we have three in phase III. Currently, we have four in phase II, and we have two in phase I. These drugs, I'm gonna go through them in detail, but as I mentioned earlier, they target these unique aspects of the biology that so far has not been addressed.
We believe we can bring additional therapies to patients that have continued needs despite what's currently available. They do in many ways represent unique indications that have not had approvals for them in some cases. In other cases, like PCSK9 inhibition, we'll be able to provide clinicians with a very, very potent drug to get most patients to goal. For this talk, I'm only gonna focus on the phase III and phase II programs, and I'll go through each one of them now in a bit of detail. Let's start with TTR amyloidosis. In the clinical world, this is really emerging. Everybody now has to learn about TTR amyloidosis. What is it? Transthyretin is a protein that's made by the liver.
It helps to carry vitamin A and thyroid hormone, but it comes as a tetramer, and either for genetic reasons or through aging, those tetramers dissociate, form fibrils, and accumulate in the body. Where do they accumulate? If you look at the slide there on the right side, the main manifestations are peripheral neuropathy and cardiovascular disease, which presents as heart failure. There are also other parts of the body that get impacted, but those are the two key ones. Now, why do we care about this? If you look at the prognosis, particularly when somebody has heart failure, it's only two to five years, and that's as bad as any cancer currently. These are very, very high morbid diseases that lead to death unless they're treated.
Where we come in is we can inhibit the TTR from being made in the liver and prevent these fibrils from forming and allow the body to heal. We can do this because the pathway for this is redundant. You don't need any significant amount of TTR to carry these two particles that I mentioned earlier. The awareness is increasing. It's estimated that it could be as many as 300,000-500,000 patients with cardiomyopathy. There are less patients with polyneuropathy, which is the genetic version. There's a large indication here that's growing as patients are getting diagnosed with ways that we can do that fairly easily now. Eplontersen is the drug that we're gonna use for cardiomyopathy and neuropathy.
This represents the phase I study that led to the phase III studies that are ongoing right now. Notice here that the doses are quite low, 45 mg, which is the phase III dose. Notice here we're getting in the 90% reduction of plasma TTR. The drug was very well-tolerated, and it really has allowed us to proceed very rapidly in the development in this program to now be in the middle of two phase III programs. You'll hear a lot more about the commercial aspects of that program in a little bit. Now, we think we've developed the best phase III trial for the cardiomyopathy indication. It's called CARDIO-TTRansform. Why is that? First of all, it's the largest trial in terms of patients.
Two, we're allowing standard of care. As Wayne Gretzky would say, "You have to skate where the puck is going, not where it is." This field is changing very rapidly. We've allowed standard of care to be part of this trial. If you restrict standard of care, by the time your trial reads out, your trial may be irrelevant. We don't think we're gonna have that issue. The physicians can do whatever they want. They're gonna now randomize their patients to eplontersen versus placebo. As you see here, the duration is adequate to get our endpoint. The primary endpoint here is gonna be a combination of cardiovascular death and cardiovascular events. This is now actively recruiting very fast, and we anticipate to have a read of this trial in 2024. Now, let me switch over now to APOC3.
Ionis is the APOC3 company. We developed volanesorsen. We first identified this as a pharmaceutical target. It was discovered already before that that it was a genetic determinant of triglyceride levels, and it does it at really three levels. One is in this very rare indication, familial chylomicronemia syndrome, at which you see here the numbers are quite small, probably one in a million, but these patients are very sick. At their young age, they start having pancreatitis, and they can't eat any fat, otherwise they have abdominal pain. These patients have no therapy right now except volanesorsen in Europe, and the patients that we're now treating with expanded access in the U.S. and Canada. There's another version of this, which is severe hypertriglyceridemia. These patients have triglyceride levels over 500.
This is a very large indication. In the U.S. alone, there's at least 3 million people. It's a very common disorder, and those patients get the same thing. They get pancreatitis. We have a very potent drug to address both of these, and this is where our initial focus is gonna be. However, at lower levels, between 150 and 500 triglycerides, it's also associated with cardiovascular disease, and I'll show you one of the trials that we did in phase II, where we had those kind of patients in our trial. Our focus right now is gonna be on the two triglyceride indications for pancreatitis. That's what we're gonna focus on our commercial activities and our trials. This is the phase II trial I just mentioned.
This had patients that had triglyceride levels 2- 500, not at the FCS or SHTG level. Nonetheless, you see here at the doses that we're using, the 50 mg dose gives us a 60% reduction in triglyceride levels, which is very potent. The drug was extremely well-tolerated. We saw no liver, platelet, renal issues. The next steps is we have two phase III trials ongoing in FCS, in SHTG, but because those patients have higher triglycerides levels, we're gonna use a 50 mg dose and an 80 mg dose, and this will allow clinicians to personalize therapy depending on where the patients start with their triglyceride levels. Now, switching to Lp(a), Lp(a) is an independent risk factor for both cardiovascular disease and aortic stenosis.
Of all things I'm gonna mention, this is the one that has no therapy right now, and everybody's desperate to have a therapy for elevated Lp(a), particularly because one in five patients have high levels, the vast majority of which don't know it. This is a field that's growing along with the therapy. The HORIZON trial is ongoing now. If you look at the population at risk, if you have cardiovascular disease and Lp(a) level that's elevated, there's a minimum of 8 million patients. I think this is a significant underestimate, but we'll see how it goes out as more patients get tested. Now Lp(a) is a unique lipoprotein. It has a LDL component, it has the apo(a) which is prothrombotic, and it has oxidized phospholipids which are pro-inflammatory.
It has all the three worst things you want in a lipoprotein. Because of that, it really requires a way for us to address that. Now, we've already published our phase II data with pelacarsen, and to summarize it, at the cumulative 80 mg a month dose, we had 80 mg/dL reduction or 80% reduction, which is about three to four times more than you can get with current therapies. For example, PCSK9 inhibitors can get you maybe 20 mg/dL reduction. We're already at eighty with that. And what that does result in, and notice here that 98% of our patients got to goal, which is, in this case, less than 50 mg/dL. So we have the most potent and the most efficacious drug as the very, very first drug of its kind in the field. We're several years ahead of the development of this compared to a competitor.
I really feel if this trial is positive, this will be a transformative drug in cardiovascular disease. It's not just me, I think the whole field is getting that kind of excitement as we proceed. The Lp(a) HORIZON trial you see here, it's very robust. I give Novartis a lot of credit for designing it in a way that's gonna most likely give us the answer we need. These are patients that have prior cardiovascular events. It's not a primary prevention trial where a lot much larger population exists. Patients have to have an event to get in the trial, and they have to have Lp(a) levels at about two and a half times above normal. Okay? It's gonna be 70 mg/dl or higher. They're gonna be randomized to pelacarsen, or they are being randomized to pelacarsen versus placebo.
The trial is 4.25 years median follow-up, which is about twice as long as PCSK9 inhibitor trials, and that's on purpose not to miss the cardiovascular mortality endpoint. The typical MACE endpoint is there. There are gonna be two co-primary endpoints, the entire trial, for MACE, and also a subset of patients who probably at least half of them with Lp(a) levels over 90. This is recruiting very rapidly. As of August, we already had half of the trial recruited, and this should read out in early 2025, for the main endpoint. Now, this slide shows you what we expect to see in the trial. On the left side, you see the typical distribution of the population. The green is what's optimal.
The sort of orangey is kind of borderline, and the red is really the patients at high risk, which is about one in five. In the middle panel, it shows you the patients in HORIZON. They're gonna have that red color, and those are the patients that have the high-risk events plus high Lp(a), and our drug is gonna be able to get everybody or mostly everybody into green. The drug is basically gonna be very clean from the perspective, you start with a very high Lp(a) with an event, you end up with a normal Lp(a), what kind of benefit do you get? We anticipate a very clean answer from this trial with very few other confounding variables.
Now, angiopoietin-like 3, as I mentioned earlier, affects both triglycerides and it affects LDL. There are natural loss of function mutations of that, but they're not that many patients, but it gives us an idea that these patients have lifelong low levels of both of those. If you inhibit angiopoietin-like 3, a couple of things happen. One is you inhibit the VLDL output from the liver, and that leads to less LDL cholesterol downstream, and you also activate lipoprotein lipase, which degrades triglycerides into free fatty acids for energy. It also affects endothelial lipase, which affects LDL cholesterol. So a large proportion of patients can get the goal with their LDL and have high triglycerides, and this would be the indication for those patients as well as you can also use it for patients that have only high triglycerides.
Now, with our partner Pfizer, the top-line data of vupanorsen was presented. I want you to keep in mind that this study was designed to be a dose-ranging study, and on purpose, very large doses were given that may not necessarily be used in the phase III trial. This was really meant as a discovery of where is the optimal dose and efficacy safety. The trial met its primary endpoint, a non-HDL cholesterol. It's met all its secondary endpoints. The serious adverse events were similar, but there were two things that were noticed that were somewhat unexpected. With the very high doses, we noticed LFT increases and some liver fat increases. This is top-line data. We don't have any more details on that at this point.
Pfizer is looking through this very carefully, and we'll be working with them on this, and we anticipate they will report more details on this study as we go forward. Now, to finish up with the last two targets, Factor XI, as I mentioned earlier, the key for this target is that we can anticoagulate patients with a lower risk of bleeding. It's already been shown with a non-GalNAc version where patients had knee surgery and did very well when they were fully anticoagulated. But one of the issues we have clinically, of course, is we can't anticoagulate a lot of patients, or if we do, they bleed. This is gonna hopefully address that. In end-stage renal disease, this is a particularly high-risk population that both has thrombosis and bleeds. Our emphasis is that right now on the phase II trial.
This is the phase I data. Notice a very nice reduction in both the antigen and the activity of Factor XI. The trial was very well performed. It had no side effects that we noticed that were significant. The phase II-B trial in end-stage renal disease was recruited six months early. We anticipate an answer for that in the next few months in early 2022. Finally, to finish up with PCSK9, for those of you that don't know, Ionis actually developed the very first PCSK9 inhibitor in 2007. Here we are now with what we think is the best-in-class PCSK9 inhibitor.
There is still a need for LDL lowering 'cause a lot of patients still don't get to goal despite the fact that we have antibodies and in the U.S. may have inclisiran down the road. Their efficacy is about 50%-60% in LDL lowering. What you see here from ION449 is that we get a 95% reduction in PCSK9, and we have a 73% reduction in this multiple ascending dose cohort in the study. It's very potent. It's well-tolerated to date. There are phase II studies that are just about completed and will be reported next year. We look forward to moving forward with our partner AZ on this program with additional reports of phase II data coming forward.
I want to kind of leave you with the final take-home message, which is that we have a very robust program. We have 9 drugs with multiple indications. We should have six drugs in phase III next year. We're gonna have thousands of patients, tens of thousands of patients in trials going forward, and we anticipate having three approvals by 2026. I think our pipeline is industry-leading. I think we provide patient needs that are currently not addressed, and we look forward to working with our partners for the drugs that are partnered and for the drugs that we own to develop them ourselves to bring this new value to our patients.
I wanna thank you very much, and I now wanna invite Onaiza to the stage, and she will give you the commercial aspects of our drugs. Thank you, Onaiza.
Thank you, Sam. That was great. Thank you, Sam, for a great review of our very deep cardiovascular franchise. I am excited to be here today to share our commercial strategy with you. As you know, I joined Ionis to carry forward Brett's vision for commercializing what we innovate and discover here at Ionis. It is an exciting vision. It's inspiring, it's bold, and it's near-term. I continue to be very, very excited about the pipeline that we have in front of us and the plethora of opportunities we have to choose between it. I'm also very excited about how we were able to, in 2021, really start building the team that's gonna bring these great medicines to market, transformational at its best. Let me begin with our commercial vision.
I will get to our product strategies and walk through each one of the three that Brett outlined in his opening. But I'd like to begin here. Our commercial vision is really to maximize the value of our innovation, and it goes hand in glove with really serving the patients out there with unmet needs. I believe firmly that if we do that well, the commercial success will follow, and we will create shareholder value. As I said to you last year at Investor Day, we will be focusing on two core franchise, Cardiovascular and Neurology. This makes a lot of sense, right? This is where the strength of the R&D organization has been.
We not only have products in the near term to populate these franchises, but we have a sustainable set of products that are coming in to create these as core franchises for durability in the future. We are also going to be very opportunistic about products that are coming in from our specialty rare franchise. You will see that we've already made the decision to take one of these forward. Why? Because the clinical data is great, and the market is commercially attractive. With that, we will be moving forward our specialty product of donidalorsen as well into our set of three near-term opportunities. Now, it's great to have a vision, it's great to have a strategy, but you got to have the people and the capabilities to bring them to market.
We have been building that through in 2021, and we expect to rgeally scale that in 2022, particularly with our partnership with AstraZeneca. We will leverage those capabilities for our other products, olezarsen, as well as donidalorsen to bring to market. As Beth will go through later, we are well capitalized. We're financed, we have a strong balan ce sheet, and we will be investing in building these capabilities that are needed to be successful in the marketplace. Taking a look at the journey line we've been on, I joined at JPM 2020. Six months later, we formed the initial commercial team at Ionis. We then did the Akcea merger, which brought in a lot of great commercial talent into the organization. We've been integrating that talent in.
We did two transactions with Sobi to take the focus of that team towards our future for eplontersen and olezarsen. As a result of that freed up their time, their capacity, and those resources, and we quickly followed that up with the formation of the first brand team at Ionis, eplontersen. That was done in the spring of this year. This was then rapidly followed up in the summer with the creation of the olezarsen brand team. We also formed for the neurology commercial team in the interim as well. As you just heard this week, hot off the presses, we announced a co-development and co-commercialization agreement with AstraZeneca. This is a really important endeavor to really realize the full opportunity for eplontersen in hereditary and wild-type ATTR.
Talk a little bit more about how that really builds into our commercial build and our commercial strategy in a bit. As we've made the decision to really move donidalorsen forward, we will be forming that brand team in January 2022, just a few weeks away. As I said, we started to build the organization out this year. This was really fueled by the talent that we got from the Akcea team. We've got some foundational skills and capabilities in place. With eplontersen, we will be participating in the U.S. co-commercialization with AstraZeneca, and we'll be building out obviously the core capabilities that are required, such as brand planning and analytics. We will also be taking the lead on certain key activities, such as our patient hub and support services. We know this rare disease population really well.
This is what we do really well, and we will bring that to the partnership. In addition, we've also built out our field medical team, as well as our KOL connections and our publications team, and that will also be a place where we will participate very actively with AstraZeneca in bringing eplontersen to market. As we think about how we're gonna move our capabilities forward in the organization, as eplontersen is being built out, we will also be looking to olezarsen, and we know that we will have to scale up our capabilities around pricing, contracting, distribution, and other customer-facing resources. At which point, we will be actually pretty fully built out for donidalorsen. However, we know that every market that we get into requires some real customization of capabilities.
For donidalorsen here, we know this is gonna be, by the time we get to market, a switch market. We will be amplifying our access hub and some of our field reimbursement services as well. With eplontersen, olezarsen, and donidalorsen, we have these three near-term opportunities give us an aggregate multibillion-dollar potential. Eplontersen first with a prevalence of 300-500,000 patients in two indications, hATTR with polyneuropathy and cardiomyopathy. Our first phase III data readout for that is in 2022, and this is the product that will change the standard of care for patients with TTR amyloidosis. An estimated peak sales here is in the multibillion-dollar category. Next, we go to olezarsen with two indications for familial chylomicronemia syndrome and severe hypertriglyceridemia. This accesses over 3 million patients.
Our first data readout will be in 2023, and this is where we have our first-mover advantage. We will be first in class for both indications for patients with elevated triglycerides. Our estimated peak sales here are over $1 billion. For donidalorsen, we have about 20,000 patients in the U.S. and EU. We got great phase II data. Ken's gonna review actually that with you a little bit later, but we have a best-in-class prophylactic treatment for hereditary angioedema. We expect the data readout of that phase III to be in 2024. Again, this is gonna be a very high-value, high-margin opportunity for Ionis. With that overview, I would like to now go into more of a deeper review that this excellent team has prepared around eplontersen. And then this will be followed by olezarsen and donidalorsen.
Starting off with eplontersen, the team has had a lot of achievements in 2021. They have been working through obviously the clinical trial enrollment, and I am pleased to say that we completed our enrollment in NEURO-TTRansform, and the data readout for that, as I said, is expected in mid-2022. We also formed the first global brand team, and that brand strategy has been delivered to the organization as well as we launched our first medical affairs team. The team has been out in the field helping with market development and clinical trial enrollment. As we think about realizing the potential of eplontersen, we think about it in three ways. The first one really goes back to the center, which is the patient. This is a very debilitating disease. Patients are progressing.
It's systemic, and as Sam said, it is fatal. We are seeing that these patients are quite underserved in the marketplace. They're underserved in a variety of ways. It is multidisciplinary. They're not actually at the right centers to get diagnosed. We believe with the advent of new diagnostic tools and treatments that we will be able to enhance patient success here. Second, we expect to rapidly penetrate and expand the ATTR market. First of all, we have a very complementary partnership that is emerging with AstraZeneca. We bring industry-leading expertise in amyloidosis. We've been in this marketplace. We know the KOLs for the last 10 years, and AstraZeneca brings global scale and cardiovascular leadership. This is a great complementary combination for us to penetrate the ATTR market with eplontersen and unlock a multibillion-dollar opportunity.
Our robust clinical program that Sam just reviewed addresses the unmet needs in the marketplace, and it's moving where the puck is and giving physicians the ability to have the data and the evidence to treat eplontersen in a broad range of patients. Let's start with the patient. I think every great product launch needs to know their patient as well as they can. Here we've gotten a very intense patient journey that has allowed us to gather some really great insights about what these patients need and what they're suffering from. As I already said, this is a systemic disease. It is progressive, it's debilitating, and it is fatal. The systemic nature of the disease presents in multiple different disciplines. Some present at the neurologist, some at the cardiologist, some at hand surgeons.
We really see that their journey is actually, you know, quite erratic, to get the right diagnosis. We do think that with the advent of new diagnostic tools and with treatment options, this is gonna improve. We see an overall population of 40,000 with hereditary ATTR, with symptoms of polyneuropathy, which we will first launch in, and then this will be followed by the larger wild-type ATTR cardiomyopathy, which we will enter as well. Again, a systemic disease that we will be able to help patients with from beginning to end. I might have painted a bit of a bleak picture about the diagnosis rates and what these patients are suffering from. I just wanna say there's hope, and I'm confident that this is changing.
When we first did our projections based on external market research and validating our assumptions, what you see is we had a projection of what's on the orange line over here of how the diagnosis rates in the market for ATTR would improve. The actual data right now shows that the diagnosis rates has grown three times faster than what we predicted, accelerating now the market expansion. This has been fueled by just easier diagnostic tools such as PYP scintigraphy, right versus a cardiac MRI. PYP scintigraphy is much more affordable and much more readily available to physicians. Also, the launch of new treatments, as we know, increases HCP awareness and the education on what's available to help treat these patients, leading to improved patient outcomes, is also fueling the market expansion.
You know, how do we see this partnership with AZ unfolding, and why do we think that this is the best quality collaboration for eplontersen? Well, first of all, as I've already said, we've got about a decade of experience in amyloidosis and rare disease. We know these patients, right? We know what they need to kinda go from beginning to end to help get their treatment and support them on their access journey as well. As we've been in the marketplace, we've seen that the pool of treaters are really much more in the centers of excellence, and we have great expertise there, and we will bring that in our partnership with AstraZeneca.
AstraZeneca, where they will actually play a really big role, is their cardiovascular leadership and their heart failure franchise, which actually calls on the specialty cardiology group quite a bit. Again, as we move in the systemic disease from hATTR to wild-type ATTR, this will be really beneficial, their global scale as well as their leadership in heart failure. The third prong of our strategy is the most robust clinical program that you're gonna see for patients in ATTR. This is actually really important and a big differentiator for us. We have multiple studies that are designed to fully inform patient and physician choice. Starting off with NEURO-TTRansform multicenter open-label study, as I said, completed enrollment this year, and data is expected in mid-2022.
CARDIO-TTRansform, it's a bold study. It is the one that's out there to say where the puck is going, and it is looking at a large set of patients. It's the largest cardiomyopathy study in 750 patients and expected to generate data with and without standard of care tafamidis. In addition to our phase IIIs, we continually know that we need to inform physicians and patients with additional data to help them make really good choices, and we have ongoing profile-enhancing studies that will inform and add to our data evidence package. NEURO-TTRansform, quickly, I think I already touched upon this, but here is the study design. Again, fully enrolled. The highlight of this in July 2021, and data is expected mid-2022. We expect to file the NDA next year.
The three unmet needs that are still in the marketplace around cardiomyopathy as we've been going out and really trying to understand from physicians what is the data and the evidence that they're gonna need to help increase this pool of patients who are being treated. What we're hearing from physicians is really that more than half of the patients who are already on treatment are still experiencing heart failure symptoms. They are progressing, so there is a need for additional treatment. What they still don't know is how to actually treat some of these patients. If you are progressing, do I start then on a silencer? Do I add them on to the stabilizer that they're on? There's just really lack of data in combination use and again, more than 40% of ATTR patients have systemic symptoms.
The treatment guidelines are just really young. They're naive, right? As treatment guidelines, they require data and evidence to help progress that further. The data from our phase III program really help all three aspects as we go forward. CARDIO-TTRansform, again, a very bold study. 750 patients looking to really understand how patients who are naive to treatment, who are also on background standard of care and tafamidis, and compare the active treatment to the stabilizers, will be available to physicians to make the choice in the broadest range of patients. I'd also say that we still hear that there's just, again, as we increase the pool of treaters, just more need to understand how not just the products work, but how the disease is progressing.
Some of our studies on understanding the impact on cardiac structure and function will also be really informative. Again, a great totality of data and evidence to help physicians make the choice in the broadest range of ATTR patients. Our market research validates our TPP. We've gone out and done qualitative studies, quantitative studies, to really understand the needs of patients, providers, and payers and what is the target product profile that will be the most compelling for them. We see from patients that they're eager for a therapy, they understand the seriousness of their disease, and they wanna improve the symptoms that improve their quality of life, but also want to see the stopping of the progression of the disease. They're willing to do anything that they can to activate that path.
Providers, we talked to 130 physicians out there. They're really excited about the second-generation silencers. Again, they need the data from us to anticipate how they're going to see the use of eplontersen in this very evolving dynamic treatment paradigm. You know, patients who are naive to therapy, do I start them on eplontersen? If they are not naive to therapy, what is the data that supports combination use? We will be able to deliver that. For payers, we did some research here to really test kind of the hypothesis, are they going to actually support combination use in the marketplace? Well, we know that if you're just starting on eplontersen, there is a really clear pathway for eplontersen to be used from a payer perspective and an affordability perspective with payers. The combination use is also very supported.
They view these patients as sick patients and they believe that if there is clinical justification and data and evidence behind that, they will be covered through a prior authorization process. All in all, across all three key stakeholders in the marketplace, we are validating our winning product profile that can unlock a multibillion-dollar opportunity. From an efficacy perspective, we expect to see TTR reductions that improve both PN and CM symptoms. We expect to see improved morbidity and mortality over standard of care, plus tafamidis therapy regimens. We expect to see data in naive patients. This totality of evidence will really be a winning profile in the marketplace. The safety, well-tolerated, and we see increased potency with well-characterized LICA platform. Then, lastly, the administration, which is also really important here.
We did some additional work to understand what's most important to these physicians, particularly as they get out of the centers of excellence and into the community. A patient-friendly auto-injector with at-home administration is really a highly preferred by HCPs. We get that question on dosing. We've tested this out. They're pretty agnostic to monthly versus quarterly dosing. What's really important to them is the at-home administration. Particularly since COVID, as you can see in the quotes by a TTR expert, the follow-ups have been online for many patients. I don't have the time to worry about an injection during their appointment. A really great feature for us as we go into the marketplace. Where do we predict this market to grow to?
Well, we know that today we expect the end of the year that the total ATTR market would land around $2.5 billion. As I've said, with improved diagnosis, with new treatments, and the increase in awareness and education and our new approaches to patient finding, we expect this market to grow and reach $10 billion globally. In summary, I hope you can see that, we are on our way to realizing the full potential of eplontersen. We have the potential to drive improved patient outcomes. This is a large, underserved and growing market. We are ready to play with data and clinical evidence to serve the broadest ATTR market, and we are positioned to reach this not just in the U.S., but in global markets with our partnership with AstraZeneca.
All right, now moving on to our second product in cardiovascular, olezarsen. One of the things I wanna make sure I start with is think about the timing and think about the scale that we will be building in terms of commercial capabilities, for Ionis. We will do that first with eplontersen. As we are building our commercial capabilities and getting into the marketplace, we will also be getting experience in cardiovascular. This is a really nice transition into going forward with olezarsen with both of our indications alone, and we will be ready to commercialize that as they come forward. Let's take a look at the potential for olezarsen. What is going on in this marketplace and what is our approach for treating severely elevated triglycerides? Well, first of all, there's a high unmet need.
The standard of care is just ineffective for patients with severely elevated triglycerides. I'll share some of that data with you, but we really need something much more powerful in terms of efficacy for these patients. We have the potential to be a category leader here. We have the first-mover advantage. We have a powerful triglyceride-lowering product profile, and we have had many discussions with the FDA, so we see a very clear regulatory path with a validated biomarker endpoint. This is a large market, 3 million patients in the U.S., and we know that this is going to be the product with the two indications that will achieve the blockbuster market potential. Blockbusters don't come on their own. They come with a lot of work. Here we've got a really head start with genetics on our side.
APOC3 is a genetically validated target and an independent cardiovascular risk factor. As Sam explained earlier, we're looking at this for two indications. The first with familial chylomicronemia syndrome and then in SHTG with TGs greater than 500. As you can see that we have different levels of cutoffs in the marketplace for TG levels over 500. The cardiovascular event risk is really just those patients that are over 500. As soon as you start getting to the 880 to the 1,000 level, we see that physicians then look at this as a risk for acute pancreatitis for these patients. We really have two emerging segments in this broad indication as we go forward. As I said, the peak sales are expected to be well over $1 billion.
We've got a lot of treatments that are out there already for TG lowering, right? There's still a high unmet need. The reason is that the standard of care is just ineffective at lowering TG levels. We only have about a third of the patients that MDs report are on fibrates. This has generally been effective at lowering TG levels. They get about a 20%-30% decrease in TGs. For the omega-3s, we see more patients on treatment, about two-thirds. Like fibrates, they're also relatively ineffective at lowering the TGs. About a 30% decrease that's been seen in their clinical trials. As we think about the future, there are a lot of different players that we expect will be in the marketplace.
For a positioning, I really want you to kind of hone in on this Venn diagram. We see a large patient population with multiple risk factors. We call it the mixed dyslipidemia patient pool. They have high LDLs and VLDLs and high triglycerides. We know that we will have some use in the comorbid risk factor patient. You can see that by the slice on the orange on the Venn diagram. We also have a very ownable space in severe hypertriglyceridemia in the raspberry, and that is where these patients are predominantly really suffering from triglycerides alone.
We know that over 50% of the patients have just that single independent risk factor, and this is where our powerful TG lowering will really differentiate olezarsen versus other classes. Here's a data slide to really demonstrate for you that there's room for a more efficacious agent versus standard of care. This is the data for VASCEPA. They studied patients with over 500 triglycerides. Their mean baseline levels of triglycerides were at 680 mg/dl, and they showed through their studies just a 33% reduction in TG levels. As you know from our phase II results and what Sam just reviewed, we actually saw a 60% reduction triglycerides. This was in our phase II study and, you know, we looked at a 50 mg dose here. Our...
We met the primary endpoint, obviously, and really saw great favorable safety and tolerability profile. What's really important on this to note is that as we go into our phase III studies, we will be studying both the 50 mg dose, which is a very, very efficacious dose, well over standard of care, but we also are studying an 80 mg monthly dose, and we expect that to actually even show us greater reduction in triglycerides. A very powerful profile that is expected and that is being studied in a very broad development program designed to support the approval in the large SHTG market. We first start off with FCS with the BALANCE study. This is up to 60 patients, and we expect data for that in 2023. We also initiated the CORE study.
This is the large study with up to 450 patients. Again, enrollment is underway here. This is for the large severe hypertriglyceridemia, greater than 500 group, and data for that trial is expected in 2024. We also expect to start a study in early 2022, the ESSENCE study. As you may well know, this is to fulfill the requirement by the FDA to achieve the 1,500 patient exposure that is required in these large indications as well, so a broad development program. We always do market research to better understand, you know, how our product profile will meet the unmet needs in the marketplace. We did here as well for olezarsen. We studied our profile with over 40 HCPs.
They treat a lot of cardiovascular patients, and they immediately saw that this is a really winning profile. Triglycerides in acute pancreatitis and cardiovascular events is understood. We don't have to do tons of market development. They naturally saw where this could be used. Over 50% of their patients have only elevated triglycerides, no other cardiovascular risk factor. Again, as I said on that Venn diagram, a very ownable space for olezarsen, and they understand that a large unmet need still exists. We also did a very robust patient journey with 600+ patients. We got a better understanding that the underlying medical need and the willingness to take a new medication to address their TGs is there. Then lastly, as we always do, we talk to payers.
We actually talk to 10 very diversified set of payers here. They viewed the target product profile very favorably here, suggesting potential for broad access. We have a winning TPP here for the treatment of severely elevated triglycerides that's emerging. We expect to see greater than 60% reduction in TGs in our phase IIIs, building upon the data that we got in our phase IIs. It's safe, it's well-tolerated, increased potency that's well-characterized on our LICA platform, and a once monthly dosing with an auto-injector. As you enter large markets, it's really important, as you all know, that, you know, with greater than 3 million patients in the U.S., we're not gonna access everybody right away. What was really encouraging from the market research that I shared with you there is an immediate early adopter population.
We're gonna see a nice launch curve on this. They saw the opportunity for that greater than 50% of patients who really have elevated TGs and really have no effective treatments at their disposal. We expect that about a third of the population will be early adopters. We will then move into an expanded patient opportunity. About half of our patients reside there. This will come with, you know, additional promotion, education, and awareness and obviously, the data evidence package that we bring to payer. We expect that about 20% of the patients and physicians will require some more work on market development to really understand that TGs are a strong surrogate marker for cardiovascular risk. That's how we see the market expanding over time.
In summary, I hope you've seen that we have a lot of excitement and potential for olezarsen for delivering a very new approach for treating severely elevated triglycerides. High unmet need, one product, two potential indications, first-mover advantage, blockbuster market opportunity, positioned to be a category leader. Our third product is donidalorsen, and I'm gonna give you all a break from hearing from me and invite up Dr. Ken Newman, who has been a great partner as a development partner in planning out the phase III designs. He's gonna review the exciting phase II data for you. Ken.
Thank you, Onaiza. Good morning, everyone. It's my pleasure to be able to talk to you about donidalorsen, which has the potential to be a best-in-class HAE prophylactic treatment. Specifically, I'm going to show you the phase II results. Hereditary angioedema, or HAE, is a rare genetic disease which is characterized by unpredictable attacks of mucosal edema and swelling. Typically, these attacks can occur in extremities such as an arm or a leg, but also in the intestinal tract, the face, and most dangerously in the throat. In the throat, various of these attacks occur that can be fatal. Therefore, there is significant anxiety which is due to the unpredictable nature of this disease, and there is a significant physical and emotional burden on these patients and their families. There are over 20,000 patients in the U.S. and the EU that have this disease.
On the right, you can see an overview of the HAE disease pathway. There is a dysregulation of the C1 inhibitor, which results in abnormal prekallikrein-bradykinin pathway. Prekallikrein is a zymogen which is metabolized, activated to kallikrein, which in turn activates high molecular weight kininogen to produce bradykinin, which is the primary mediator of the increased vascular permeability which causes edema. Donidalorsen decreases the production of prekallikrein in the liver and therefore prevents the ability of bradykinin production in the plasma. This is an overview of the phase II study design. The inclusion criteria is that these were HAE type one or two patients, and these were adults. They were over 18 years old. There was a screening period that lasted up to eight weeks, during which the patients had to have a minimum of two HAE attacks.
After this time, they were randomized in a 2:1 ratio to donidalorsen or placebo. Study drug was given four times, four weeks apart with a primary endpoint at week 17. At that point, they had the option to enter into a post-treatment follow-up period or to roll over into an open-label extension. During this open-label extension, patients had the option to move into an every eight-week dosing. The primary outcome variable was the time normalized number of HAE attacks. The results of this study were extremely impressive and supported the potential for donidalorsen to be a best-in-class HAE prophylactic therapy. Specifically, there was a 90% reduction in monthly HAE attacks as compared to placebo. Starting with the second dose, there was a 97% reduction in the rate of HAE attacks and 92% of patients were attack-free versus zero on placebo.
As I'll go over in some detail, there was a dramatic, rapid, and sustained reduction in HAE attacks. There was a very favorable safety and tolerability profile in this study, and an open label extension study is progressing well. This is the baseline characteristics of these patients, and pretty typical for an HAE study in adults. These are generally young, healthy patients. Their age was less than 40. Two-thirds of these patients were women. All but one patient in each group were type one patients. There was one type two patient in each group. The age of onset was 10- 16 years old. Most importantly, the number of HAE attacks that they suffered in the previous 12 months was 23- 25 attacks, meaning they were averaging two attacks per month in the year prior to entering into the study.
This is a graph of the number of HAE attacks versus the number of weeks after randomization. What you can see is that even in the first two weeks, which you see here as zero to two , there was a greater than 50% reduction in the number of HAE attacks. From two weeks moving forward, there was almost a complete resolution of these attacks, with the attack rates approaching zero. Statistically at the bottom, this is the primary outcome variable. The number of attacks in the placebo group was 2.21 per month, which was reduced with donidalorsen to 0.23 attacks a month, which was a 90% reduction with a P value of less than 0.001. This is attacks for individual patients. It's what we refer to as the birds on a wire plot.
What you can see is on the placebo group, which is up on top, that these attacks continued throughout the course of the study. Whereas in the donidalorsen-treated patients, which is on the bottom, there was total resolution of attacks in all but one patient. Furthermore, there was a very favorable safety and tolerability profile in this study. The number of adverse events was actually lower in the donidalorsen group than in the placebo-treated group. That there was 71% of patients on donidalorsen who had an adverse event, compared to 83% on placebo. Any possibly drug-related adverse event was about 29% with donidalorsen versus 67% on placebo. The specific adverse events are on the right side of the screen. These are the only adverse events that occurred in greater than one patient.
The only adverse events were headache and nausea, which are actually less common in the donidalorsen-treated patients than in the placebo-treated patients. Due to the success of this phase II study, we have now entered into phase III in the OASIS-HAE study, and this is an overview of the design. It's a randomized, double-blind, placebo-controlled study on monthly and bimonthly subcutaneous injections of donidalorsen or placebo in up to 84 patients aged 12 and above with HAE Type 1 and 2. Following the screening period where patients have to show that they have attacks, the patients are randomized to one of four groups, which is donidalorsen 80 mg given every four weeks or matching placebo or 80 mg given every eight weeks or matching placebo.
The study continues for 24 weeks, at the end of which time patients are given the option of going into an open label extension study, during which time donidalorsen will be continued at 80 mg every four weeks or every eight weeks. Patients can also go into a post-treatment follow-up period. The primary outcome variable is exactly the same as in phase II, which is the time-normalized number of HAE attacks from weeks 1- 25. In conclusion, donidalorsen has the potential to be a best-in-class prophylactic therapy for patients with HAE. Patients with HAE, like Haley here, really wanna be symptom-free, and we were able to accomplish this in phase II, meaning that 92% of the patients were in fact attack-free. In addition, the study demonstrated that there was a favorable safety and tolerability profile. We have the potential moving forward with bi-monthly dosing.
Also of note is the injection itself is a very low volume with an extra fine needle in order to reduce any pain and discomfort with the injection, and we do have a plan for an auto-injector. With that, I'd like to turn it back to Onaiza.
Thank you, Ken. Wow, that's exciting. What an exciting profile and great phase II results that Ken just shared with us. I'll just say, Haley is the inspiration here. We have many more patients such as Haley that are waiting for a better and more effective treatment. Let me tell you about the HAE market. It's a very, very attractive market for Ionis. Why? It's established. We don't have to do a lot of market development. The patients are well-defined. The prescribers are known. We know where to go with our best-in-class product. The market is also growing. The physicians are getting, and the patients are getting much more confident about using prophylaxis treatment. You know, as we've seen a lot of acute treatments are moving to the adoption of prophylaxis.
We see this growing multifold in the coming years. The last reason I would say it's very attractive, it's rare disease. It's kind of where our core capabilities are. This is where Ionis was founded. We have 5,000+ diagnosed patients in the U.S. Very, very accessible for us. Ken talked about the phase II data, the market. You know, Ken's one of those physicians that sat through every single market research with us, so he actually knows this well. Some of the things I'm gonna be saying is, might be repetitive, but I just want you to make sure you get it, that there is still unmet medical need in this marketplace. Patients still experience breakthrough attacks with the current market products. The prophylactic therapies actually require frequent administration.
Some are daily, some are weekly, some are bi-weekly. As we know in this particular category, because the patients are very commercial patients, if you think about it, they're younger, that if they're not compliant, this will negatively affect their efficacy, right? They're looking for just, to reduce their anxiety. They're looking to regain their freedom from the disease and really improve their quality of life. There continues to be a need for a prophylactic treatment offering HAE patients greater efficacy, safety, tolerability, and ease of use. Donidalorsen represents a compelling opportunity in its product profile. It addresses the unmet need with these breakthrough attacks that patients are still experiencing. It addresses the dosing by offering a once-monthly dosing.
Again, this is an area where the efficacy is really amplified if you're staying on drug, and it has a really favorable safety profile. It's a very good fit for Ionis. It's a very valuable rare disease market for us, again, in combination, a very compelling opportunity. The phase II results Ken just reviewed with you support a potential best-in-class in our profile. We see the words that are really resonating with physicians out there is its rapid onset and its sustained reductions in HAE attacks. That is key. That, along with a favorable safety profile and an OLE that is suggesting some patients can actually get to bi-monthly dosing is supporting why we believe this is best in class.
The data Ken just reviewed with you in our phase II suggests that we have a mean reduction in monthly HAE attacks of 90%, mean reduction of 97% from weeks 5-17 versus placebo. This is actually really important because the onset is pretty fast. That means after one dose, these patients can get to 92% attack-free rates, which is very, very compelling. We did market research. We talked to HCPs to ensure as our phase II data was reading out that they see this as an advance in treating HAE, and they do. We had a very, very positive response to donidalorsen. All of the physicians saw this as a meaningful advance. The word cloud here represents what we heard in the market research for them.
Let me amplify a couple of things for you over here. They said it's top of their list, and they're gonna offer it to patients. They said that this is very appealing because it gives me everything I'm looking for in terms of the efficacy, the fast onset, and the dosing. Then when we asked them what was really differentiating for them, all of them said the dosing interval was, but very importantly, the efficacy elements of onset of action and the zero attack rates were very high up there as differentiating features for donidalorsen. From a patient perspective, this is actually really an area where physicians and patients jointly make their decisions for their therapy. It is a very duality that is going on here. Very interested to hear, see how patients felt about this profile.
It was again blinded, and we heard that, you know, virtually all were interested in trying donidalorsen. 71% said definitively, and about 20 were possibly. They said they'd be interested because it does everything I want. It reduces the severity, it reduces and increases the duration. That's actually very appealing to them. Again, it gives them that freedom and the quality of life improvements that are really important to them. I love the last quote. It said, "I'd be extremely interested if it was available tomorrow. I'd go ask my doctor about it to switch. It wouldn't take much." I hope you understand then from the research as well as the phase II data that we have a very strong product profile that we will bring to bear.
We know that strong product profile isn't sufficient. This market, by the time we are in market, we will have a lot and the majority of the patients already on prophylactic treatment. It will be a switch market for us. As a result, in addition to the strong product profile, we will need to really amp up our patient engagement and our advocacy to support this community, which we're already very much beginning. Here, the switch also requires some you know very important things for physicians as well as to patients as you're changing insurance. Our access, our patient support hub, and reimbursement services will really need to be top-notch to deliver on the switch and drive donidalorsen's success. This is a very efficient and targeted market approach for us here. We have a concentrated prescriber base.
This is primarily prescribed by allergists, immunologists, and about 500 allergists actually treat about 50% of the HAE patients. As a result, we'll have a very targeted sales force. We've done some benchmarking work to understand what the other players in the place are doing. We're looking at about 50-80 customer-facing FTEs. Then, again, as I said, this is gonna be shared decision-making, so our direct-to-patient engagement here will be really important, really educating them and making sure that they're supported as they make the decision for the switch. We will have some good high-touch patient services to take them through their access journey and the digital tools. Again, given this is a very commercial population, we'll be really adaptive to the digital tools for continued engagement and adherence on product.
In summary, I'd like to say that donidalorsen is just a really exciting product potential for us. It will help us reimagine the treatment of hereditary angioedema for these patients. This is about, in one dose, I can feel that I'm in control of my disease. It is excellent phase II data, very attractive product profile, and potential for best in class across all dimensions and a high-value, high-margin opportunity for Ionis. I've walked you through the three near-term product opportunities. I'm gonna bring it back to our commercial vision that I reviewed with you in the beginning of the presentation. I hope you have now seen that we are maximizing the value of our innovation again by focusing on the patient and the success and therefore creating value for shareholders.
We will have our focus on our two core franchises in cardiovascular and neurology, and we will add in compelling products from our specialty franchise as the clinical data unfolds, and we see that there are attractive commercial markets that support those launches. We are building out our commercial capabilities. I gave you a viewpoint of how that's gonna happen across these three product launches, and Beth will again review with you how well-capitalized we are, and we have the financial wherewithal to bring all of this together. In addition to thinking about the capabilities that we build, I think it's really important and we started to design what is the commercial operating model at Ionis gonna look like? What are the design principles that we think are really important and compelling for us to differentiate?
At the core of it is patient centricity and world-class talent. If you don't think about the patient first and you don't hire the best talent team to build together, well, you know, that's not gonna help you even as great as that product may be. You gotta bring that to market together. The other elements of our design principles that are very important for us is the interconnectivity of commercial with research development. We think that's really important as we're transforming the organization to a fully integrated pharmaceutical company over here.
That insight, as early as we can get it into our research and development from a commercial perspective and market perspective, will be really beneficial for our future product portfolio. We are, as you know, focusing on U.S. execution, but we do believe and are acting with a very global mindset in developing global strategy. This will benefit the whole globe. As we are early and thinking about what is needed for endpoints, we're thinking about not just payers in the U.S., but we're also thinking about HTAs in Europe and embedding that thought process into the organization for our development designs. At the center of it is carrying forward the thread of innovation from the research and the development organization into the commercial organization and ensuring that we're taking a very agile approach to our growth.
In summary, I'd like to conclude with that, we have a great opportunity in the near term ahead of us. We have multiple launches with significant peak sales potential, first beginning with eplontersen in hereditary ATTR polyneuropathy, followed by olezarsen in FCS, and the larger opportunity for eplontersen ATTR cardiomyopathy, followed by donidalorsen in HAE, and then olezarsen in severe hypertriglyceridemia. Thank you very much, and I am gonna now invite up our EVP of Research, Eric Swayze, to really pivot our conversations to the early part of the organization and talk about our technology and antisense.
Thanks, Onaiza. I do wanna change gears a little bit and move from commercial and talk about one of my favorite topics in the world, which is antisense technology. In doing that, I wanna cover two key spaces. The first is Ionis technology today, and then I wanna move and talk about some new key advancements in the technology that we are very hopeful will contribute to new drugs in our pipeline in the not-too-distant future. Ionis technology today has delivered our current pipeline of medicines. We've heard about some of these from Sam and Ken. They're performing well in the clinic and part of the composition of these medicines is some key chemical technology that's unique to Ionis.
This technology is working well in these medicines, and importantly, we think that this technology is very important for continuing to add value in tomorrow's antisense medicines. Shown here is two elements of the key technologies that we use. One is MOE, and the other is cEt, which we also call Gen 2 and Gen 2.5. MOE, shown on the cartoon on the left, gives great potency due to high binding affinity and stability, and it also gives high stability in biological systems like animals and human beings, which gives a long duration. This is made possible by the unique properties of the MOE side chain, which is highlighted in the cartoon with the little pink part.
This side chain gives rigidity to the molecule, which was result from its high binding affinity, and it also can block interactions with the phosphate backbone, which is shown in the orange part of the cartoon, interactions with proteins like nucleases, which are responsible for degrading the antisense drug. This is responsible for the increased stability. cEt, shown in the cartoon on the right, further increases potency by really rigidifying the structure. It actually rigidifies it as a bicyclic structure, so it can't move. This further increases binding affinity over MOE, giving greater increases in potency. Importantly, key features of the cEt side chain kind of mimic the conformation of MOE with regard to blocking the ability of things like nucleases to interact with the phosphate.
The result is that cEt actually has more stability than MOE, maintains the extended dosing interval, and also maintains the great therapeutic index we observe with MOE. These are key chemicals that we use today and continue to use. Another key component of our technology today is LICA technology, and specifically liver LICA. You've heard about this in the drugs from donidalorsen and also eplontersen, and basically all of our late stage lipid pipeline. This technology has really been transformational for our drugs which target the liver. It consists of a trivalent GalNAc cluster of carbohydrates, which is evident in the upper left-hand part of the cartoon. What this does is it delivers a cargo, in this case an oligonucleotide, to the hepatocyte directly, and it does this via a receptor that's expressed exclusively on the surface of hepatocytes.
It's called the asialoglycoprotein receptor. What happens is the carbohydrate cluster binds selectively to that receptor. It's then taken up into the hepatocyte. The carbohydrate cluster is actually rapidly metabolized, and that leaves the ASO in the cell where we want it, and it's free to go do its business of engaging its target. This increases potency 20- 30 fold in human beings, and it does this by increasing the fraction of drug that's delivered to the hepatocyte. This allows an extended dosing interval, which can then match the drug half-life, gets us under 100 mg per month, as you heard, earlier today about some of the drugs that are in our pipeline, which is amenable to low volume monthly administration via an easy-to-use auto-injector. Importantly, the reduced dose and frequency dramatically improves therapeutic index and safety profile of these drugs.
This performance is exemplified on this slide. Shown on the left is donidalorsen, which is a MOE LICA medicine. The key thing to take away from this is the nice duration of response. If you look at the blue line at the bottom, that's our clinical dose of donidalorsen of 80 mg, and this is phase I data from a multi-administration study. You can see the dosage points in the little red arrows at the bottom. It's given monthly. We have maximal target reduction at the end of dosing on day 85, week 12 of about 92%. We then stop dosing, and you can see the recovery is quite slow, meaning the target stays suppressed for some period of time.
If you look at the purple arrow, that's week 20, which is eight weeks post the cessation of dosing, and you see that the target has only recovered to about 88% decline, 80% reduction. This clearly supports the every two-month dosing regimen that Ken talked about in our phase III trial and highlights the durability of this medicine that could be used monthly or every other month. On the right is ION449 or AZD8233, which is a GalNAc LICA medicine that Sam talked about, which we hope will be a best-in-class drug for LDL cholesterol lowering. We hope it will be best in class because of its great efficacy, and you can see that from this multi-administration study, where at the highest dose, we got over 90% suppression of PCSK9.
That's better than other PCSK9-lowering medicines have done to date, and we're hopeful that'll translate into a best-in-class LDL-lowering medicine as well. We also have used optimized designs in our CNS programs that have given really nice dose-responsive and efficacious and durable suppression in humans. This example is from our MAPT program, which is targeting the RNA that makes up the protein tau. This protein is implicated in the pathogenesis of Alzheimer's disease, and this drug is currently in a phase II program for Alzheimer's disease. In the graph is a nice dose-dependent suppression of tau protein as measured in the CSF of patients with the lowest dose in the yellow line and the highest dose in the purple line.
We got over 50% suppression in the CSF, and as we've discussed previously, we think that CSF underpredicts the tissue levels where we really need to engage tau and lower tau to make a difference in Alzheimer's disease. What I really want you to hone in on in this graph is the blue line and the blue arrows where we've given the dose quarterly. The patients only got two doses of drug, once at initial dose and then once at three months. You can see the blue line continues to decline well past the last dose. Up to 16 weeks post-dosing, we're still reducing the target, which means the drug is there, and it's still working.
Furthermore, if you then extend out the graph and look at the point that's labeled D one P two on the far right side of the graph, that's the first visit in the open label extension. This highlights the duration of effect of this drug, and these visits were six months or longer after the last dose. This definitely supports extended dosing frequency for our CNS ASO medicines, six months, perhaps longer. I'd now like to switch to some key advancements in the technology and highlight a couple programs that we're particularly enthusiastic about moving into our drug discovery programs as soon as we possibly can. This is by no means all that we're doing in research.
It's just two things that are good examples of the technology that we're trying to bring forward and that we can share with you today. First is our bicyclic peptide LICA, and then I'd like to talk a little bit about a new backbone chemistry. First, LICA is a platform that we're very committed to at Ionis. We're investing quite broadly in LICA platform. LICA stands for Ligand Conjugated Antisense. What it means is there's a ligand that you conjugate chemically to an antisense drug, and the ligand takes the antisense drug to where you want it to go. We've shown this works for multiple ligands.
We can put lots of different chemicals on antisense drugs, carbohydrates such as the liver LICA, peptides such as what we've described previously for our GLP-1 LICA, which I won't talk about today, antibodies and Fab fragments, and the newest member of the family is bicyclic peptides. These ligands in turn direct the antisense drug where we want it to go, and we've exploited multiple tissues, liver, pancreas, and muscle, which I'll talk about today, looking at lots of other LICAs. Today I want to focus in on the transferrin system, which has been shown to target drugs to muscle and heart, and hopefully someday we'll get it to cross the blood-brain barrier, which other transferrin systems have been shown to do. Transferrin receptor LICAs. How does this work?
Exemplified in the cartoon on the left, you have some ligand which will engage the transferrin receptor in the blood system. That then transits the vascular endothelium and then engages probably another transferrin receptor molecule on the surface of its muscle cell, allows the drug to enter the cell where it's metabolized, and then the drug's there to do its business. This was initially reported by Sugo et al., where they did a really nice work conjugating an siRNA to a fragment antigen-binding fragment or Fab, which is a part of an antibody that binds transferrin receptor 1. This, as evidenced from the graph, gave nice target reduction in both muscle, and this is calf muscle highlighted, as well as heart, demonstrating that the transferrin system can deliver a cargo into the muscle.
We were particularly interested in this paper, as were lots of others in the field. What we did at Ionis was validate it with Ionis technology and an Ionis-developed Fab ASO. We identified a Fab, conjugated it to an oligo, and then compared the unconjugated oligo to the Fab oligo in a dose-response study, which is shown in the graph. What we saw was about an eight-fold increase in potency with the Fab conjugation. This is based on the weight of the oligo dosed. That's the difference between the dotted line, which is the unconjugated oligo, and the solid line, which is the Fab ASO. That was nice, but there's a problem with antibody ligands, is they're very big, and they increase the total dose of the drug administered. I've used this table to try and highlight that.
On the top, you have the molecular weight of ASO, and say you want to deliver 3 mg per kg of the oligo to an animal or a patient. If you scale it up to a clinical theoretical dose, you'd be about 200 mg. If you then look at what would happen if you conjugate a Fab to the ASO, well, the Fab has a much higher molecular weight. It's larger. The molecular weight is over 55,000. That would be a theoretical clinical dose of over 2 g of total drug. Whereas if you did it with a monoclonal antibody or mAb, you'd have over 6 g of total drug. We're interested in making smaller ligands. Smaller ligands like Centyrins, which we're working on with our collaboration with Arrow. That does better. The theoretical clinical dose would be under 600 mg.
Still, the mass of the total of the delivery vehicle still makes up more than the mass of the oligo. I'd like to talk today about some of our Bicycle work. Bicycles are small cyclic peptides, which make up a small fraction of the mass of a total drug. In this case, you'd be under 300 mg clinical dose, adding just a small bit to the total dose of the drug. This could be the difference between sub-Q administration, IV administration, monthly versus weekly. We think the Bicycle has the potential to be the best-in-class transferrin targeting ligand for these reasons. What are Bicycles? Bicycles are peptides that are then constrained with a chemical modification scaffold. This is shown in the cartoon at the top. The little three-pronged dot is a scaffold.
It reacts with cysteine groups on the linear peptide and kind of snaps it together into this bicyclic constrained structure represented by the cartoon with two loops. These have been shown by our collaborators at Bicycle Therapeutics who developed this technology to form biologically relevant 3D structures as shown in the upper right. It can form hairpins, helices, loops, all sorts of structures that bind and interact with proteins, which is what we're trying to do with the LICA program. Bicycles are developed using phage display technology, which means you can get a huge diversity of bicycles. Once you get them, they're like small molecules. They're little cyclic peptides. They can be optimized using traditional medicinal chemistry techniques and refined even using structural biology. In fact, that's what our colleagues at Bicycle have done.
Shown in the lower right is an actual crystal structure of human transferrin receptor 1 bound to one of our Bicycle leads, shown in red. You can see it sits in a nice little cleft and interacts with the transferrin receptor. We're using this structure to refine and modify the Bicycles, as I speak. Because we've been able to do medicinal chemistry on these, we have a whole family of Bicycles that bind human transferrin, and that's just exemplified by some of the curves on the left which show binding of the Bicycle peptides to human transferrin and a table at the bottom that shows we have a range of different binding affinities. Importantly, the bicyclic peptides do not compete with human transferrin.
This is shown by the crystal structure on the right where we docked the human transferrin in at the known binding site. This is the big gray and white blob is human transferrin. You can see that the bicycle binds at a distinct site, same site as was on the previous slide up near the apical domain. Not competing with human transferrin is important for both activity as well as safety reasons, and these don't compete. Do they work in vivo? The answer is yes, as shown in this slide. We focus on the left side, the left graph. What we've done, again, just like we did previously for the Fab, we would take an unconjugated oligo in the dotted lines and a Fab conjugated oligo, which is shown in the black solid lines with the squares.
In the graph on the left, you can't actually see the Fab conjugated oligo line, and that's because it's underneath the two bicyclic conjugated peptides. This suggests that the bicyles have identical potency on a molecule per molecule basis as to the Fab, right? They work very well, just as well as a Fab. If you have one molecule of Fab conjugate oligo and one molecule of bicyclic, both are delivered to the muscle equally well. Remember I said that the Fabs have higher molecular weight. If you take that into account, look at the graph on the right. What you see is that now I'm plotting based on total dose of drug as opposed to the mg/ kg ASO delivered, the total amount of drug that you'd have to inject into the animal.
Bicycles, as shown by the pink and blue lines, still give great increased potency relative to the unconjugated oligo. The Fab, now because it's heavier, shifts actually the wrong direction. It's now less potent based on total mass of drug. For these reasons, we think. This is one of the reasons we're very enthused about the bicycle technology. Gives great potency. We wanted to ask the question, do they also work with siRNAs? Gratifyingly, they do. As shown in this experiment where we conjugated a Fab, a siRNA conjugate shown with the gray bars, and we compared it to a bicycle siRNA conjugate shown with orange bars. Both SIs were given at 3.5 mg/kg SI dose, which corresponds to about 15 mg/kg for the Fab SI and 4 mg/kg for the bicycle SI.
You can see from the data at the bottom that they reduce target about equally well when dosed at the same mass of siRNA in quadriceps. Importantly, they work in heart for our cardiology programs. The Bicycle actually looks to have a little bit improved selectivity over the Fab, giving less reduction in liver, where we don't want the drug, as compared to muscle, whereas the Fab actually gives more reduction in liver than the muscle. This is early data, but does suggest that Bicycles are useful for both ASOs and for siRNAs. Key points for the Bicycle LICA. They efficiently target oligo drugs to muscle and heart. They're small and low molecular weight, and in this case, smaller is better.
Reduces the total dose required compared to an antibody delivery strategy by 10- 20 fold, which gives us the potential for increased dosing flexibility. We think they're gonna be easy to manufacture. We have to demonstrate that, of course, and hope to translate that to reduce costs of goods, and we know we can optimize them, so we can tune the binding affinities to whatever we want them to be. What are the next steps for the Bicycle-like? Well, first we're gonna optimize the final design. We're very close to doing that. We're gonna implement a manufacturing process and then identify Bicycle-conjugated drug candidates. We're gonna apply this technology broadly to our heart and skeletal muscle programs, determining the optimal modality for each target, whether it be an ASO, a splicing modifier, or an siRNA. We'll identify and develop the best drug.
As I mentioned, we're exploring the potential to use Bicycles to cross the blood-brain barrier. I next wanna talk about a new backbone chemistry called mesylphosphoramidate, or MSPA for short. We've been working on trying to design new backbones. Ever since I joined the company many years ago, it's been an objective. The objectives in trying to find a new backbone to replace phosphorothioate, which is shown in the figure in the upper left of the figure, is first to maintain or improve potency. Next, we'd like to improve duration relative to existing designs, and that's because when we use phosphorothioate DNA in a molecule, we know that's the weak point, that's the metabolic weak point, which is degraded fastest in an animal.
To exemplify this, a splicing oligo with full modification with like full methoxyethyl, those have been shown to have a year-long duration of effect in animals. We'd like to stabilize a DNA-containing oligo to that point so we can have longer duration. We also wanna be able to reduce the nonspecific protein binding of phosphorothioates. This is expected to reduce some side effects, especially pro-inflammatory effects. We have to do all this while maintaining other important attributes, such as gotta keep binding to the target, we have to support our mechanism of action. It's gotta be chemically stable, and we have to be able to manufacture the things. With all these in mind, we've been making hundreds of backbones over the years. And as evidenced by the nice X through the arrow, multiple different backbone chemistries have failed to meet these criteria.
Mesylphosphoramidate appears to meet all of these objectives, and because of this, we consider it kind of a breakthrough in backbone development for an ASO design. Why is it a breakthrough? Well, we have a lot of details in this paper that was recently published, and I give the reference here and encourage people interested to go read the paper, and I just highlight one experiment that we were doing that kind of highlights the key properties of the backbone. What we did in this experiment is shown in the pink boxes where we walked two MSPA linkages throughout the DNA portion of a molecule and asked a couple basic questions about how they performed. First, we saw that they maintained or even increased potency in this instance.
The red line in the graph on the upper left is the phosphorothioate parent oligo, and you can see all the other lines are moved a little bit to the left. We didn't lose potency. Maybe it helped a little bit. The middle graph, what we did was measure protein binding for a model target. The red line is the full phosphorothioate oligo, and you can see what we did is we shifted all of the MSPA lines to the right. This indicates reduced protein binding as we would expect. That translates to reduced immune stimulation. I would just highlight a couple of the baby blue line at the bottom. This is measuring cytokine activation in a human cell assay where we have the MSPA linkage incorporated.
The 3' end of the molecule gives pretty much complete abrogation of the immune stimulation effects of this very immune stimulatory oligo that we chose as a model system. We also wanted to ask, Does MsPA have any benefit in siRNA designs? The answer is, well, maybe, but it certainly works well in siRNA designs. Shown in the cartoon is what I'll call a standard siRNA design, and I just wanna zoom in on where we incorporated some MsPA linkages for this experiment, which was on the 5' and 3' ends of the antisense strand of the siRNA, which is the one that interacts with the target and promotes degradation of the target. If you zoom in on the cartoon, it just highlights some of the key chemical modifications and how we use the MsPA at the 5' end of that.
First, we incorporated vinyl phosphonate, which is kind of a privileged modification that improves potency. This is an Ionis-developed modification that we developed in our work on single-strand RNAi years ago. It's proven to be very important, for example, in the CNS. We also use 2'-fluoro, as is common in the field, and 2'-fluoro at position two is really critical for potency. What we did is we put an MsPA linkage on the 3' side of the 2'-fluoro nucleoside, anticipating that MsPA would stabilize it and prevent degradation there. We think this has multiple benefits, not only for duration, but also for the ability to restrict metabolism of 2'-fluoro nucleosides, which we think have some potential toxicity liabilities and also have been shown to be incorporated into the host DNA and RNA. What we did then was make
Take these compounds and test them to see how well they worked in mice, and that's shown at the bottom in with administration to the CNS, where the pink graphs represent a 3'/5' MSPA-modified compound, and the orange is just the 3' and the red is the standard. They work just as well, maybe a tiny bit better. MSPA increases stability. We next ask, can this improve duration? Our current platform delivers great drug profiles, if you heard, with infrequent dosing and consistent target suppression. I've mentioned MAPT in the liver-like programs and the long duration of splicing oligos. Our hypothesis was, could we substitute MSPA at weak points in the oligo, and could that improve durability? I just note that we use mouse for these experiments, which we know underpredicts human duration by 3x-5x, but it can guide optimization.
Here's the results of that experiment. If you look at the left panel, this is also published in the paper I referenced. The ASO is shown in the blue lines, standard reference oligonucleotide, which reduces the target dramatically and then recovers over time. If we put four MsPA linkages at the 5' end of the DNA portion of the molecule that's in the pink line, and the pink line sees a clearly extended duration, indicating that we have in fact enhanced duration. We included a reference standard siRNA in this experiment too, and it appears that the MsPA matches the duration of the siRNA.
We also looked at the ability of MsPAs and siRNAs to increase duration of those compounds we have [plotted with] the same standard siRNA on the graph on the right, and the pink MsPA line looks a little bit better. Perhaps we can extend duration. We clearly have shown that we can extend duration, and it also goes with MsPA and perhaps siRNAs. MsPA backbone, key points. It increases stability over both PO and PS. This increases duration of effect, maintains potency in multiple mechanisms, both the ASO mechanism and siRNA mechanism, and it reduces some nonspecific protein binding, which we think will allow us a new tool to tinker with the design of the molecule to maximize therapeutic index. What are the next steps for the MsPA backbone? First, optimize designs and strategies to use in multiple mechanisms and in tissues.
This includes ASOs, splice modulation, siRNAs, et cetera, and multiple tissues. We're looking at it in our muscle LICA programs, liver LICA programs. Every place we can practice antisense, we're employing this backbone. We're working on getting our manufacturing process implemented and developing MSPA-modified drug candidates that have the optimal performance. This backbone is in all of our candidate selection exercises that are ongoing right now. In summary, Ionis technology advancements are key points. The technologies have delivered our pipeline of medicines that we're using today, and they're performing very well in the clinic. We have new technology advancements that we're continuously working on to improve our platform. This includes the Bicycle LICA, broad LICA strategies I didn't have time to cover today, and the new MSPA backbone, which we really think represents a potential breakthrough.
This chemical technology is unique to Ionis, and we feel will continue to add value in tomorrow's antisense medicines with all ligand mechanisms across all franchise areas in new targets with unmet need and also for lifecycle management for existing programs. With that, I'd like to turn it over to Beth to talk about our financial growth.
Great. Thanks, Eric. A lot of exciting things going on at Ionis today. Over the last couple of hours, you've heard my colleagues talk about all of the various elements of our business that together drive substantial value for our shareholders and, frankly, for our patients, importantly for our patients. I hope through the last couple of hours in these conversations that you've gained a keen appreciation of, you know, where we see the bright 2022 and the, frankly, the bright future beyond 2022 for Ionis. It's my privilege today to talk to you about how all of that fits into context from a financial perspective. Today at Ionis, we're in a wonderful position. It's an opportunity for us to move into a new chapter for the company.
It's a chapter in which we are focused on delivering an abundance of new medicines to the market, and we're gonna do that by building off of the renowned research and development excellence and adding commercial excellence. Today we have a validated platform. We have a rich product pipeline. We have a commitment to innovation that is deeply embedded across our organization, and we have a team of employees who are highly dedicated and come to work every day because they know sick people depend on us. All of that is supported by our strong financial strength and, frankly, an attractive financial profile. Today, we're well-capitalized with $2 billion in cash. We have multiple sources of revenue with diverse margin profiles that provide us with substantial cash flows.
We have numerous opportunities for revenue growth as we advance our partnered programs, enter into new partnerships, and most importantly, as we bring new products to market. This puts us in a very enviable position to be able to invest in our commercial capabilities and to advance our pipeline and our technology. Financial strength has been an enduring quality for Ionis for many years, and it's that financial strength that has put us in a position to be able to invest deeply in all aspects of our business. Because of that financial strength, we're sitting here at a time when we need to increase our expenses, and we have the financial resources to be able to underwrite those investments and to be able to build and invest in strengthening our commercial foundation.
We can do that by building off of the capabilities that we acquired from the merger of Akcea. To be able to advance our pipeline, today we're in five phase III studies, very broad phase III programs for our, eplontersen, olezarsen, and donidalorsen. While a substantial portion of our R&D expenses are focused on our late-stage programs, meaningful investments are underway right now in our earlier stage pipeline, as well as in advancing our technology. All of that puts us in a wonderful position to be able to grow revenues well into the future. This slide, I think, does a really nice job of depicting how we see our revenue growing over the coming years. Today, we have a very substantial and sustainable base of commercial revenue with SPINRAZA as the cornerstone. We also have substantial and sustained base of R&D revenues.
Both of these things we anticipate growing, and as early as 2023, we anticipate growing our commercial revenues as we bring eplontersen, olezarsen, and donidalorsen to the market. We also have additional phase III products that we expect will come to the market, in the next several years. Then building off of that and continuing to grow a substantial base of revenue is our mid-stage pipeline. There's lots of opportunity for continued waves of revenue growth year-over-year. We've got three near-term opportunities with an aggregate multibillion-dollar potential. That's a huge agenda and a huge opportunity, and I want to talk about each one of these opportunities for just a moment. Eplontersen is a multibillion-dollar opportunity, and we believe that our recent collaboration with AstraZeneca will help us fully realize the potential of this exciting opportunity.
The substantial and very significant upfront payment and development and approval milestones, I think, strengthens our balance sheet and gives us the ability to further invest across the business. The cost-sharing provisions are very important to Ionis as they enable us to scale our commercial capabilities, not only for eplontersen's initial launches and successive launches, but also for olezarsen and donidalorsen. Because it's a multibillion-dollar opportunity, the substantial royalties that we can earn that go up to the mid-20% range have tremendous value to Ionis. Building off of that are the potential to earn substantial sales milestones up to $3 billion. All of this is important as we think about building on eplontersen for olezarsen and donidalorsen.
Olezarsen is a blockbuster opportunity, and as Onaiza explained, it has the potential to be a category leader with first-mover advantage. That means that it could substantially drive our top-line growth. It's also got the added benefit of really the advantage of all the build that we're doing with eplontersen, we'll be able to apply to olezarsen, and that gives us tremendous leverage on our P&L. Unlike eplontersen and olezarsen, donidalorsen actually requires a more modest investment, and that's for three important reasons. First, we have a very manageable but very important phase III program designed to really capture the switch market penetration opportunity for that drug.
donidalorsen actually doesn't need really will take advantage of a more targeted commercial organization, and it will certainly benefit from the capabilities that we're building in the commercial organization for eplontersen and olezarsen. All that together means that donidalorsen has a best-in-class profile potential with a high value, high margin, and it could be a very meaningful product for Ionis. That's not everything. We've got a very deep pipeline, as I've said before, and as you've heard today. We have 14 phase II medicines, six phase I medicines. They continue to advance, and those pipelines continue to expand. Those, together with our prolific research and development engine, sets us up to continue the growth in our revenue and in our business well into the future.
Our partnerships also generate substantial revenue and cash for Ionis. Not only do they generate research and development revenue from the substantial upfronts and development and regulatory milestones that we earn, but they also will help us build our commercial revenue. In addition, through sales and through royalties. In addition, we anticipate that this very substantial base of R&D revenue can grow as we add new programs into development. As those programs and our existing programs continue to advance, they generate increasingly more valuable milestone payments and licensing payments to the company that are commensurate with the value that we're creating for Ionis. We anticipate new partnerships with innovative structures that will continue to build that core base of R&D revenue as well.
As I said, I think it's really important to not forget that our partnered programs also build our commercial revenues through substantial royalties and potential for increasing our royalty rates through an effective royalty rate with sales milestones. I hope today you've gotten a sense of the real value that we see today in our pipeline and in our commercial opportunities, but that you also see the very bright future that we have in front of us. I'd also like to stop for a moment and just remind and just think about the fact that when we were first formed, we were formed with the understanding that sick people depended on us. We take that responsibility very seriously. As a result, we take our responsibility to be good corporate citizens very seriously as well.
We're looking forward to sharing our inaugural corporate responsibility report later this month. Today, we are well-capitalized with a substantial and sustainable base of commercial revenues and R&D revenues from our partnerships. We have these significant market opportunities as we anticipate bringing many of our medicines to the market over the next several years, beginning with eplontersen, olezarsen, and donidalorsen that together have multibillion-dollar opportunity. We're gonna build on that momentum through our prolific research engine and world-class research development and the commercial organization that we are building today. And with that, I'll ask Brett Monia to come back up to the stage. Thank you. There you go. Thank you.
Thank you, Beth. Thanks to everyone in our audience for sticking with us through these long presentations today, bringing us near the end of our formal presentation. I'd like to just now wrap things up a little bit with some concluding remarks. We had a rich agenda today, a deep agenda, where we went into great depth into many, many of the most important key aspects of Ionis today, our business strategy, our commercial strategy, our pipeline, and our technology. As you I'm sure recall, when I started up with my opening comments, I highlighted four key questions that we set out to answer in great depth today through our various presentations.
These are questions that we've heard from our investors that were top of mind as we pivoted to becoming a fully integrated leading commercial R&D organization. You heard, I hope, answers to these questions in great depth with high precision during the course of the morning. What I'd like to do now is just touch on at a high level, certainly not going into the depth that you heard from the various presenters today, but touch on the answers to those questions at a high level just to really sum things up. First, what are Ionis' near-term products? What are the products we're gonna prioritize of commercialization ourselves? You heard from Onaiza very specifically, eplontersen for two indications, hereditary ATTR with polyneuropathy and ATTR cardiomyopathy.
Olezarsen, you also heard from Onaiza, for patients with high triglycerides, severely high triglycerides, FCS, severe high triglycerides, and you also heard about donidalorsen, for the prophylaxis of hereditary angioedema. We're committed not just to bring drugs to the market, but we're committed to winning on the market as well. One of the other questions, our second question was, what is our go-to-market strategy, for the drugs that we prioritize, and how do we think we're gonna proceed? I hope you agree with me that Onaiza did a wonderful job of, going in fine detail, in depth, as to what our go-to-market strategy will be and how we expect to win on the market. Eplontersen is a great-looking drug. It has all the advantages of our LICA platform that Eric highlighted today.
We expect a very attractive drug profile for patients that come out of our phase III program. We have a broad phase III program that's designed to address many of the questions and unmet needs that patients and healthcare providers are asking for, including real-world data on the usage of with and without stabilizers in our phase III cardiomyopathy program. We're already well along the way in driving patient awareness and growing the market with improved diagnostic tools and education for our patients and healthcare providers.
Of course, very importantly, we're gonna take full advantage of the excellent collaboration we've now launched with AstraZeneca to combine our expertise in TTR amyloidosis and RNA therapeutics with the global strength of AstraZeneca, especially in the cardiomyopathy market, to reach all patients, as many patients as possible, that are suffering with TTR amyloidosis. Olezarsen market strategy or go-to-market plans were also laid out very nicely today. Olezarsen is the best and first-in-class medicine, and quite simply, that's what we're gonna take advantage of. We're gonna take advantage of our first-mover advantage and achieve category leadership for all indications related to severe, severely elevated triglycerides.
We are gonna provide the data that demonstrates that it's most efficacious and a best-in-class medicine, and we're first, as I said already, and we are planning to change the standard of care for patients suffering from high triglyceride disorders. Then donidalorsen, our objective there to win on the market is to replicate and extend our wonderful phase II data with a successful phase III outcome, and to use that data to communicate to patients and caregivers and drive the switch, if you will. Drive the switch from existing treatments for HAE prophylaxis to donidalorsen. The third question was, how will we extend our technology leadership in a rapidly growing competitive landscape? Why will this matter? Why will it drive continued success for Ionis?
Eric went into quite a bit of detail today on some of the recent advancements we're making in our technology. We are continuing to invest in all aspects of our technology through innovation and through all means really. Our LICA platform continues to grow and expand. You heard a lot about muscle targeting LICAs today and our vast experience with liver LICA as well, and there's more LICAs coming, so stay tuned. You also heard about our medicinal chemistry advancements, like such as mesyl chemistry, backbone replacement, something that the whole field has been trying to do to replace phosphorothioate backbone for decades. We believe we're on the cusp of doing exactly that, and Eric highlighted what the advantages are for a chemistry like mesyl chemistry.
Of course, we continue to invest deeply into genomics, human genomics, to continue to replenish our pipeline with novel, genetically validated targets so that we have a rich future, a sustainable future, for our rich pipeline. Fourthly, Beth highlighted for you in depth our resource capabilities and what our expectations are for revenue growth in the future. We certainly have the resources we need to invest in all aspects of the business to drive significant near- and long-term revenue growth for Ionis. We have all kinds of opportunities, substantial revenue growth opportunities, here at Ionis. We highlighted today for you the near-term commercial opportunities for eplontersen, olezarsen, and donidalorsen. We have a rich mid- and late-stage pipeline, even goes beyond those three drugs for partner drugs as well as non-partner drugs.
We will add additional commercialization opportunities behind eplontersen, olezarsen, and donidalorsen in the future, so stay tuned for that. Of course, we have revenue opportunities from our existing partnerships as well as potentially new partnerships if we choose to do new partnerships. A lot of flexibility here. As I highlighted in the beginning and Beth touched on as well, you know, we have some very important and exciting objectives for Ionis that are gonna lead us to achieving substantial growth in the future to achieve our vision as a top-tier biotech company.
This is involving us leveraging the strong foundation that we've built over many years and to focus now on three strategic imperatives: to build our own pipeline, to commercialize products of our own, to expand and diversify our technology, and to deliver a large number of new products, transformational products to the market in the near future and in a sustainable manner. This, all the progress we're making this year is setting us for a fantastic future and also a very exciting and important 2022. These are some of the areas we're gonna be prioritizing and reporting news out on catalysts, updates on throughout the year next year. We're looking forward to reporting the eplontersen phase III data from
for hereditary polyneuropathy by mid-year and to file for eplontersen marketing authorization next year. We're gonna continue to advance our pipeline, our phase III pipeline, and expand it with through enrollment completions, new phase III study starts, and also phase III study updates along the way. I showed you earlier today our rich mid-stage pipeline of 4-14 drugs now in development in patient studies in individual or distinct patient phase II studies. We're looking forward to reporting a lot of data from those mid-stage programs and to initiate multiple first-in-human studies throughout 2022. Also provide updates on the advancements we're making in technology into our new medicines and updates on the great progress we're making as we prepare to launch eplontersen, olezarsen, and donidalorsen. To conclude, Ionis is well on its way.
2021 has been a pivotal year for the company to reach our vision to become a leading biotech company. We are well positioned for accelerated growth to achieve maximal success for all stakeholders. We have many near-term attractive product opportunities in our pipeline and a big growing and advancing phase III pipeline. We've made tremendous progress already towards becoming a successful, fully integrated research, development, and commercial organization of excellence. We're on track. Our technology advancements are extending our leadership position in this space, and we expect to continue to invest in technology to extend our leadership position. All this is setting us up for a great future, including a very important and successful 2022. With that, thank you again for joining us for today's presentations.
We're now gonna take a pause for a few minutes, so we set up to take some of your questions. Thanks again. Welcome back to the Ionis Investor Day question and answer session. We're glad that you've come back and joined us for this portion of Investor Day. Now, I think I'll look to my panel to open it up for questions from our investors, of course.
The first question is, eplontersen will be the last to enter a competitive market, and it seems that eplontersen's dosing is a disadvantage compared to the competing silencer. How do you expect to overcome these two big disadvantages?
Well, that's a good question, and I think we covered that quite extensively today, the advantages of eplontersen in our distinct and unique capabilities and advantages over other emerging competitors in the space. We don't believe that we're that far behind, quite honestly. In cardiomyopathy space, we actually think that we're there neck and neck with other competitors in the field. Maybe I'll turn it over to Onaiza to talk a little bit about, again, summarize again what she covered in her presentation on-
Yeah.
how we think we're gonna compete in this space.
Sure. Just to reinforce, you know, the efficacy profile is actually really strong, and it is about broad utility in different types of patients for hereditary and wild-type ATTR. Our clinical program is hugely differentiating, and we will give the evidence that is required for it to be used in all different types of patients. We did some extensive research, as I shared with you earlier, on what are the most important benefits that they're looking for, physicians are looking for in the marketplace. Really, the home administration of the eplontersen profile was really highly valued in terms of rank order from efficacy, safety, and then next. Then the dosing advantage was actually agnostic, right? There were lots of physicians who preferred the monthly. Some physicians who preferred the quarterly.
Not a big choice driver, I would say.
How will your commercial build-out in the larger neuro and cardio spaces prepare you well for a more targeted and specialized launch for donidalorsen and HAE?
Sounds like another great question for you, Onaiza.
Yeah, I'd be happy to. So, you know, I think when I laid out the scale of capabilities, it is really important to know there are some foundational capabilities in commercial that really are needed for every single product launch, and we are building that out now. We will continue to build that out for eplontersen, and we'll continue to build that out for olezarsen. What donidalorsen will need is just additional services and additional capabilities because it will be a switch market. We're just gonna add those in terms of what are those amplified capabilities and skill sets that we need to be successful over there. As I said, it's a very targeted market, so from like a sales force synergy perspective, you're looking at a just about, you know, very focused set of prescribers and, you know.
If you can benchmark the other prophylactic treatments, you'll see they're somewhere in the 50-70 range, you know, so very, very approachable for us.
In the presentation, Eric mentioned quite a bit about siRNA. Is Ionis also developing drugs using siRNA and not just ASOs? Is your aim to pick the best one pre-clinically and eliminate the others?
ASOs and siRNA. I think it's important to highlight the fact that single-stranded antisense oligonucleotides are by far the most versatile platform for oligonucleotide therapeutics. We have the ability to, of course, block the production of disease-causing proteins and also replace proteins in loss of function diseases through single-stranded oligonucleotide mechanisms. SPINRAZA is the best example of that, of course. We also have a validated platform for central nervous system diseases, neurodegenerative, neurodevelopmental diseases and so on, with single-stranded oligonucleotides and SIs still have a long way to go to catch up to our CNS platform, and there are other advantages for single-stranded oligonucleotides.
With that said, when I became the CEO, one of the first things I did was sit down with Eric Swayze and talked about whether or not there could be advantages to using a siRNA approach for drug discovery, as well. The two of us agreed that it made complete sense to focus on the best possible drug and to move drugs forward based on their total profile, their best profile for a given indication. After all, we are here to serve and help patients. Why limit yourself to one particular mechanism of action? That is one of the reasons why Eric and his team have made so much progress and are looking at different types of chemistries to even further advance siRNA as well as ASO technology, to advance the technology forward.
Just to say, I mean, we are the world's experts in oligonucleotide medicinal chemistry and drug discovery, and we think that that is a huge advantage for ASO, siRNA or any other form of genetic medicine that we choose to pursue in the future. Stay tuned.
What happens to severe high triglyceride patients that end up getting pancreatitis? How big of an issue is this, and does lowering TG by 60% help? What AEs do you expect of the higher dose?
Sam.
Yeah. Well, pancreatitis is a very serious condition because once it happens, the patients can't eat, and so they often will get complications, including sepsis, ARDS. The mortality rate is about 6%. It's actually higher than myocardial infarction, so it's a very serious condition. Patients sometimes can't eat for weeks, and it leads to many abdominal complications. It's very important to reduce the triglyceride levels in those patients are mostly related to chylomicrons. We've showed in the volanesorsen program that we can get 78% reduction in triglycerides. Most of those are on chylomicrons, and placebo-corrected was over 90%. We anticipate with the 80 mg dose that we will get the same efficacy. Sixty percent is also very efficacious. That phase II study that we did was designed for cardiovascular indication.
It wasn't designed for a FCS indication. For that reason, we chose a higher dose. We anticipate to be able to replicate the efficacy of volanesorsen, but with the advantage of having essentially a bland side effect profile. We're very excited about olezarsen in that regard, and we think it's going to be an excellent drug for both FCS and SHTG.
Thank you. For donidalorsen phase III, it's a relatively small study, so how long do you think it will take to enroll, and when should we see the phase III data? Will you try to enroll more Type II patients relative to what you had in phase II, and do you think that might impact the results?
That's a great question for our donidalorsen project team leader. Ken?
Okay. Thank you. We anticipate that it'll take us about a year to enroll the phase III study, so we expect to see data in the first half of 2024. With regard to the Type II patients, statistically, 85% of HAE patients are Type I. Only 15% are Type II. They have in the phase II study the exact same response rate. It's the exact same dysfunction of the prekallikrein bradykinin pathway, so we don't think that would make any difference in terms of the effects. We will not actively try to enroll more Type II patients because they should have the exact same response as Type Is.
As we saw in our phase II study.
Exactly.
Right.
A follow-up question to that is, are these patients allowed any rescue treatment if they do get attacks?
Yes, of course. If a patient has an attack, they need to take their acute therapies. It does bring up the challenge of having a placebo-controlled trial, and we do have a safety valve in the study, so if patients are having a lot of attacks, that they can progress into the open label extension. Absolutely, acute therapy is required for these patients for attacks.
Do you anticipate an add-on combo label for TTR considering the structure of your trial?
No, but you should answer.
We expect a very broad label for all ATTR patients. As I said, we have patients who are naive to standard of care as well as on standard of care, and that is the beauty of the trial design. We expect to see those subgroup analyses in a broad label.
Could you provide a financial summation of the magnitude of potential ongoing partnerships R&D funding over the next five years?
Beth.
Sorry.
Sounds like your question.
Sounds like me. Actually, it's really quite substantial. It could be multi-billions of dollars. In our existing partnerships today, we have the potential to earn up to about $10 billion or more in simply upfront fees, license fees, development, and regulatory milestones, and then an incremental $8 billion in sales milestones. That doesn't consider the value of royalties as drugs from our partnered programs partnerships reach the market. It's a very substantial amount of financial leverage that we get from our partnerships. In addition to the revenue opportunities, we also get tremendous P&L leverage because our partners take on the very expensive development and commercialization costs associated with advancing our partnered programs. Overall, we see tremendous financial strength in our partnering model.
It seems you've thought about the pricing of olezarsen. How will it compare to current therapies? Could you talk about your confidence in commercializing olezarsen in severe high triglycerides in the U.S. on your own, given the sheer size of the addressable market?
Okay. Please.
Yeah, we've done some pricing research. I obviously, you know, can't tell you exactly where it is, but I can give you a gauge that it's well above the pricing over standard of care. We believe that we will deliver a really high margin product for Ionis. On the how do we commercialize on our own, I think there are a couple of factors to really look at. It is a large population, so you're absolutely right to think about how do we actually scale this. There are a couple of things that are really specific to this marketplace. First of all, we will be gaining the cardiovascular experience from our launch of eplontersen. We will have solidified kind of that experiential set.
In addition, we do see, and we've all seen a really, you know, nice change in terms of how we use virtual digital tools. This is actually a radical shift since COVID has happened, so we do expect we will have a hybrid model of feet on the street to access our cardiologists. But if we needed to get to GPs and primary care, we can certainly use non-personal promotion. I have to say that with all of the launches that have happened in the last, you know, 18 months during COVID, this is a very adopted behavior by physicians.
We're gonna use a mix of those tools to access and target those physicians and then slowly move down the patient segments with early adopters, broader adopters, and then the later adopters.
Was the AstraZeneca deal for eplontersen very competitive? Some investors commented on the deal being underpriced for Ionis. What is your thought? What are your thoughts?
We were not out selling eplontersen necessarily. I mean, we were planning on some business development transactions this year. As Onaiza highlighted in her presentation, we have a lot of drugs coming to the market in all around the same period of time, and that we were planning to commercialize ourselves. We were thinking about which product made the most sense to partner. As the year evolved, we started answering inbound questions. It wasn't that we were out pushing. It was competitive. We were getting a lot of interest in eplontersen, and a lot of that interest went pretty long into the negotiation process. We have a long-standing relationship with AstraZeneca. They're a great partner. They know our technology. They're a powerhouse in the cardiovascular space, and they're growing their franchise in heart failure.
Made complete sense to this. We believe that the terms of this deal are actually highly attractive, and that's actually the first time I got that question. Everyone else that I've heard during the course of the week since we announced this deal was that this is a really good deal for Ionis. You wanna add to that, Beth?
Oh, absolutely. I would agree. It's, you know, it's valued right now at $3.6 billion, and that's just the upfront payment, and the approval and sales milestones. Additionally, we have the cost-sharing provisions that I think are really, really important. I think the joint commercial and development aspect of this agreement means that we can fully realize the potential value of eplontersen. It also means that we'll be able to use our cost-sharing provisions to build out our commercial capabilities and to scale for eplontersen, but also for olezarsen and donidalorsen. Yeah, I would add the co-commercialization in the U.S. is really ideal for us to work alongside AZ and build our commercial capabilities and scale.
For Lp(a), it looks like patients at the highest risk of having a major adverse cardiac event have levels way above 70 mg. Any risk that Novartis is using a threshold for the primary endpoint that is too low?
Yeah, I'll take that one. I think the premise is wrong of that question. The risk really starts at around 30-50 mg/dl and then increases linearly. You can argue it's actually too high, not too low. It is true, though, that the higher the risk, the higher the level, the higher the risk. You know, in the design of the trial, there had to be some. This is the first trial, so you don't want to be wrong. There have to be some, you know, educational guesses about where you want it to have that threshold. There's nothing magic about 70. It's about 15% of the population at large and probably about 25% of the population with CVD. It's a good number to start.
If the trial is positive, I would see that number actually is going to go down, and probably go towards 50, if there are future trials in this space.
Sam, you want to maybe add to that? I mean, speculate as to whether or not a successful outcome in the 70 mg/dL would then lead to future investigations into lower thresholds?
Yeah, I think it will. In fact, you know, I have probably right now the world's only Lp(a) clinic. I see a lot of patients from all over the world. I can tell you that there's a huge interest in the prevention of MI, not to get treated necessarily after you have an MI, which is obvious. What you're going to see is a very large desire to understand whether we can prevent the first MI, not treat a patient after they have the first one. Stay tuned. I just wrote an editorial how that kind of trial could be done. It's going to come out in JACC in about two or three weeks. If you want to get a little sense of the future of how my primary prevention trial will be designed, you can read about that in a little bit.
It's at Ionis we're always self-promoting ourselves. Sam did a great job. All these guys do, so why not? Okay. I think we have time for one last question. Do we have a question, Roz?
We do. What is the likelihood that CRISPR technology could replace antisense technology?
We don't expect that CRISPR to replace antisense technology in any meaningful way. I mean, you know, antisense, as I opened up with, I think, is such a versatile platform. Different routes of delivery, different mechanisms of action for loss of function diseases as well as gain of toxic function diseases. We could target multiple organ systems. We're opening up new organ systems with new LICAs and so forth and so on that you heard from Eric about today. There's so little data on DNA editing today. Sure, there's been some preliminary data from the clinic that is encouraging, but it's next to no data, really.
When you think about what you need to do to validate a platform and demonstrate that it's effective, reproducibly and safe, I think DNA editing has a long, long way to go. Meanwhile, as we highlighted today, we continue to advance our platform and our technology and our drug discovery capabilities, through all the investments that you heard about today. With that, I think that is our last question. I want to thank everyone who stayed with us through the presentations today and through our question and answer session as well.
I hope you enjoyed our Investor Day presentation today, and I really hope you agree with all of us that Ionis is in a position for tremendous growth in the near term and well into the future, and we're well on our way to achieving our vision as a top-tier biotech company. Thank you very much, and bye for now.