I'd like to welcome everybody out today to Ionis' Innovation Day. I'd like to welcome everybody who's joined us in the room here in New York City, and those who are joining us on the webcast. Today, you're gonna learn a lot about Ionis' innovative medicines and our plans to deliver those medicines directly to patients. Ionis is in the business of discovering, developing, and delivering innovative medicines to patients. As part of that, it's a risky business, so we will be making forward-looking statements. And if you'd like to learn more about those risks that we'll be talking about today, you can go to our website, download our SEC filings, and take a look there to learn more.
At Ionis, we know that sick people depend on us, and this knowledge drives everything that we do in our work to help patients with the opportunity to have a better life. Building off of that foundation, we strive to be good corporate citizens. We work to empower our employees to support our communities and to support sustainable planet. If you'd like to learn more about Ionis's commitment to corporate responsibility, I encourage you to go to our website and download our latest corporate responsibility report. Today, you're gonna be hearing from a number of leaders from across the company, from senior management to leaders in research, clinical development, and on the commercial functions. I'm not gonna introduce everybody today here right now, but we're very excited that you're gonna have a chance to hear from them, and they'll be introduced ahead of their sections.
You'll also get to hear today from two renowned physicians, Dr. Henry Ginsberg, Professor of Medicine at Columbia University, and a key thought leader in the treatment for patients with familial chylomicronemia syndrome, or FCS, and severe hypertriglyceridemia, or SHTG. You'll also get to hear from Dr. Raffi Tachdjian, Associate Professor at UCLA, and a thought leader in treatment of patients with hereditary angioedema. This is our agenda for today. In the morning session, we'll focus mostly on our late stage commercial medicines, talking a little bit about our plans to deliver these drugs directly to patients. And we'll also be talking more about our technology and the innovations we're making in our technology pipeline to make those programs even better.
In the afternoon, we'll talk more about the next wave of wholly-owned medicines that we're working on, and also, Beth Hougen, our CFO, will talk about our clear path to unlocking next-level value. We'll have two Q&A sessions during the day, one towards the end of the morning session for 30 minutes, and one at the end of the afternoon session for 30 minutes. Our CEO, Brett Monia, will introduce us, with some discussion about our strategy and our accomplishments to date, and then we'll wrap up the day with concluding remarks. And with that, I'd like to turn the program over to our CEO, Dr. Brett Monia.
Good morning. Thank you, Wade. It's great to see so many, so many familiar faces in person here live today in New York, and also great to have so many people dialing in remotely through our webcast. We really are excited. We've been excited for the last several months to provide you with an update on the tremendous progress we've been making over the last really couple of years, several months. Progress that we believe at Ionis is poised, positioned to drive substantial value for all stakeholders, patients, our shareholders, everybody that's associated with the Ionis family. So at Ionis, we truly have a rich, rich history, a heritage that we are incredibly, incredibly proud of.
And what we're most proud of is the fact that Ionis led the way in the creation of a new modality to treat and tackle devastating, debilitating diseases, diseases that were not approachable with existing platforms at the time. A history that we're proud of because it's poised to help so many patients in the future. It started with antisense, right? Many years ago, and for decades, it was antisense with RNA. RNA is our target. Today, RNA is a very exciting, hot topic today, but it was a very novel idea back in the day. And today, this sector that we really led the way in creating has helped thousands and thousands of patients already around the globe, benefited many patients.
But what's really exciting is it's positioned right now, poised on the cusp of helping millions of patients around the globe. And Ionis, Ionis is leading the way in doing this, and you, and you'll see that, see that today. We did this by focusing on all of the key aspects that needed to be focused on, nailed down, understood, and validated to create a new platform for drug discovery, including establishing a world-leading medicinal chemistry platform for oligonucleotide drugs, right? To give these drugs their drug-like properties such that they can be effective and safe. We also led the way in establishing leading industry-leading manufacturing capabilities. Capabilities to ensure that we can provide our treatments for clinical trials at scale, commercially, and at a pro- and at acceptable costs.
We also dug deep into understanding how these drugs behave in animals and in humans, understanding how they're distributed, what cell types they get into, how they get into those cells, what cell types they don't get into. And that really led the way in identifying where we can apply this technology for drug discovery. Organs such as the liver and now the CNS for neurological diseases. We led the way in understanding, validating multiple mechanisms of action, such as, for example, RNAi, the RNAi mechanism of action, which typically is used to block the production of a toxic protein for gain-of-function diseases. We also led the way in applying the technology to utilize splicing mechanisms, to modulate splicing, such that we can, for example, upregulate the production of a toxic protein in loss-of-function genetic diseases.
We led the way in discovering and developing first-in-class medicines. We showed the way, regulatory paths, clinical paths, and so on, getting drugs approved. This was the vision for Ionis from the onset, from the outset. Right from the beginning, it was the vision to create a new way to discover drugs, to treat diseases that were intractable using other modalities, a new sector in the biotech industry. It was this vision that drew me to Ionis many, many years ago. It was a long time ago. I came to Ionis because I was excited about this vision, and I was excited about the people, and I knew that if anyone was going to make this successful, it would be the people at Ionis.
I started as a bench scientist in the beginning of the company, on the bench with my colleagues, addressing all the things that I just covered. How do these things get into cells? How do we make them? What's their mechanisms of action? Splicing, I was heavily involved in splicing in the early days. Fast forward to, I don't know, about four years ago, four or five years ago, as I was approaching my new role as CEO of Ionis, I, of course, was part of and recognized all the greatness in the Fabric of the organization of Ionis, right? Dedication, perseverance, unwillingness to fail to deliver medicines for patients that were in desperate need for new treatments. And of course, as CEO, that was a top priority for me, to maintain that, in fact, embrace it and strengthen it.
But we needed to do more. We needed to do more to bring Ionis to the next level, to drive substantially greater value for patients, for shareholders, for all stakeholders. And I identified two, two key objectives that we needed to pursue and, and be successful at to drive that value. You know, when you create something great, like, a new way to discover drugs and apply treatments for patients, a new sector in the biotech industry, it's inevitable that others will follow, right? Follow in your footsteps. Competition will emerge. When we first started Ionis, which was Isis in the early days, for those that remember, there was a handful of other companies, working on trying to make oligonucleotides work through an antisense mechanism of action, for example. Most of those companies quit or failed. We persevered. Today, there are...
I can't count how many. Everybody seems to be in the oligonucleotide space because it has such tremendous potential. I mean, we started with antisense, as I mentioned before, now it's expanded many years later to RNAi, even to DNA editing. These are all oligonucleotide-based platforms, and again, I, I believe we showed the way. So when number one- but competition emerges when you do something great, and therefore, when I was approaching my role as the CEO, I said, "There's, there's one or two things-- There's two things we need to do, and the first thing is we need to invest much more significantly into technology. To expand and diversify our technological capabilities, to not, not maintain, but to extend our leadership position in the field we created, oligonucleotide therapeutics." That was the first thing.
The second thing we needed to do was we needed to deliver our treatments to patients directly. Commercialization. I mean, after all, who knows our platform better than Ionis? Our people. Or who knows our platform. Who knows our drugs, the drugs that our leaders, our scientific leadership, and people conceived and identified and discovered. Who knows them better than Ionis employees? And nobody moves with a sense of urgency as Ionis. We can no longer rely on others to deliver our treatments to patients directly. We have to do it ourselves. And of course, all of this would drive tremendous greater value for not only patients, but to all stakeholders, including our shareholders. So that was my vision when I was approaching my new role as CEO, approaching 2020. So that was the vision.
We would continue to maintain and strengthen our everything that we've always done great at Ionis. Innovation, and innovation across all aspects of the company, but also but in particular, scientific innovation and innovation in clinical development, while also, of course, strengthening our financial stability, our strength, and always maintaining our financial responsibility along the way. But adding to that would be to expand and diversify our technological capabilities for drug discovery, to extend our leadership position in oligonucleotide therapeutics. That was a number one priority, and the second priority was to deliver our medicines to patients ourselves directly. Patients like, on the left, Mark Irwin. I know Mark. I've known him for many years. Mark suffers with hereditary TTR amyloidosis. He has polyneuropathy and cardiomyopathy, so he's a mixed phenotype.
Hardly a few weeks go by in which Mark does not reach out to me, and this is the truth. Mark does not reach out to me and tell me how grateful he is to be on a drug like eplontersen, a drug that he's been on for several years. And he's always telling me how well he's doing. He's gaining strength in ways that, you know, he just never expected that he would be able to achieve. And he also often tells me how much he wishes his dad... This is a hereditary disease. His dad had a treatment, had access to a drug like eplontersen. His dad succumbed to the disease eventually, because there were no treatments for eplontersen. Or Nicole. Nicole, who suffers with FCS and waiting for a drug like olezarsen. Or Kira.
Kira was one of the first patients to receive Spinraza following its accelerated approval after our landmark phase III study, Nurture, in which we proved that Spinraza was providing tremendous benefit to patients with SMA. We ran that study. We conceived Spinraza. We developed Spinraza. Kira today is living a normal, healthy life. She received Spinraza just less than two weeks after the approval, and today she's living a healthy life, and she had a form of SMA that was a fatal disease within the first two years of life, prior to Spinraza. Sydney. Sydney, with HAE, waiting for better prophylactic options to manage her disease, like donidalorsen. Dr. Dennis Leahy, a cardiologist, ironically, suffering with Lp(a)-driven cardiovascular disease, a disease that afflicts millions and millions of people globally. Globally with this disease, and there are little to no treatment options available for it. Dr.
Leahy undergoes several times a month, he undergoes a procedure called apheresis to just filter out his Lp(a) to the best he can to help manage his disease. It's a highly invasive procedure. It's not very effective. It doesn't last long. Dr. Leahy is looking, waiting for a treatment like pelacarsen. And then there's Grayson. Grayson, patiently awaiting for someone to come forward with a blockbuster treatment or block- a breakthrough treatment for his Angelman syndrome. Somebody like Ionis. Ionis led the way in conceiving and discovering and bringing forward treatments for every one of these diseases today. And this is just the tip of the iceberg. There is so much more, and you're going to hear about it today. When I refer to million- we're on the cusp of helping millions and millions of people globally, this is what I'm talking about.
This is what Ionis is doing, and we're leading the way. And as I mentioned, you're gonna hear about that today. And by doing this, we're going to provide great value for patients, for shareholders, for all stakeholders. And this is what we're laser-focused on. And I'm pleased to say that today, after the investments we've made over the last several years, we're there. We have expanded and extended our capabilities in drug discovery by extending our technology in many ways, and you're going to hear about that from Eric Swayze today. We have an outstanding clinical organization that knows how to take our medicines through clinical development, through proof of concept, and to the finish line. And today, we have all the pieces in place to deliver our medicines directly to patients ourselves, and you'll hear about that today.
We have a world-class research and development organization that that conceived and discovered four treatments today that are truly transformational, that are on the market today, two of which are real breakthroughs. Real breakthroughs for neurological diseases. Spinraza, as I just mentioned, and then this year, our approval of Qalsody for SOD1 ALS, a real breakthrough for the ALS community. And we're expanding our ability to tackle other diseases, not just in tissues that have been approachable in the past, but new organs and new tissues. We have one of the richest late-stage pipelines in the industry. We have nine phase III programs in development across 11 disease indications, mostly coming from our leading cardiology franchise and our neurology franchise. And we're ready to go. We're ready to launch.
We're ready to bring our medicines directly to patients with our near-term commercial launches, eplontersen, olezarsen, and donidalorsen, and more, that's gonna come after that. We indeed have a really outstanding research organization. Our research organization today, with the investments we've made to extend and expand our, our capabilities in drug discovery, are optimizing potency, optimizing durability to extend dosing intervals, less frequent dosing for both systemic applications and local applications as well. And today, we are mechanistic agnostic for oligonucleotides, right? ASO mechanisms, many different ASO mechanisms, RNAi, and now even DNA editing. Why? These, these mechanisms, these, these platforms have more in common than they do have differences. These are oligonucleotide-based approaches, genetic medicine approaches, and nobody has the breadth of capabilities that Ionis researchers do in optimizing and delivering on these types of mechanisms over and over again. So that's what we're doing.
We're mechanistic, agnostic. May the best drug win for patients. We're optimizing targeted delivery, right? Opening up new tissues, new cell types through targeted delivery strategies such as cardiac muscle for heart failure and skeletal muscle for neuromuscular diseases. And we're even now further extending our leadership in CNS diseases by overcoming and traversing the blood-brain barrier to be able to apply our drugs for CNS diseases by an intravenous route of delivery or a subcutaneous route of delivery. And you're going to hear about all this today from Eric, Eric Swayze. And all this lays the groundwork for expanded and sustained pipeline delivery of transformational medicines for, for today, tomorrow, for many years to come, from our established franchises as well as from new therapeutic areas. I'm also pleased to report that after 3.5 years or so, we're ready to launch our own products.
We're ready to deliver our treatments directly to patients. We have all of the functional areas that need to be in place at this point to deliver our medicines directly to patients. And this organization that is now being formed and is largely formed at Ionis, is outstanding. There is so much enthusiasm to come to Ionis. I mean, look at our pipeline for people that, for people that have careers in, in, in these areas. It's an outstanding organization to match the excellence across other areas of Ionis, including clinical research and development and other areas. And you're going to hear about that today from Onaiza Cadoret-Manier. These are our near-term commercial launch opportunities. Eplontersen for being developed for two disease indications, a rare disease indication for ATTR polyneuropathy.
We reported really remarkable phase III data, full data set this year in that in our phase III trial for eplontersen in this patient population. This treatment is now under review, both in by the FDA and in Health Canada, and we're expecting a decision for approvability by December of this year. Then our CARDIO-TTRansform study, the second indication. We have fully enrolled our CARDIO-TTRansform study for a much broader patient population with TTR cardiomyopathy. This is a landmark study, folks. More than 1,400 patients in this study. A study of this size has never been done before, not even close. This is with our co-commercialization partnership with AstraZeneca. And then we're approaching our first independent commercial launches.
Olezarsen, for diseases related to severely elevated triglycerides, both a rare genetic disease, FCS, monogenic, genetic, monogenic disease, FCS, as well as a polygenic form, severely elevated hypertriglyceridemia, a much larger patient population. You're going to hear a lot about olezarsen and FCS and SHTG today. And then donidalorsen as a potential best-in-class treatment for hereditary angioedema, for prophylactic treatment for hereditary angioedema. And we're very much looking forward to the phase III results in the first half of next year, and you're going to hear about our progress for HAE. And if that wasn't exciting enough, today, for the first time, we're going to share with you the next wave. At least a glimpse into the next wave of our wholly owned Ionis medicines that we're planning to bring to patients directly, with a deep dive into our leading neurology franchise.
That'll be covered by Holly Kordasiewicz as well as, Rachel Carnes. So look forward to that. We truly have one of the most remarkable late-stage pipelines in the industry, phase III pipelines. It's broad, it's deep. It is, we're tackling all kinds of disease indications where the unmet need is very high. Nine treatments, nine medicines in phase III development today for eleven disease indications, and this pipeline grew substantially this year, and this week. Today, this week, we announced for the first time, our ninth drug to enter the pipeline, a medicine from our wholly owned neurology franchise, zilganersen, for Alexander disease. And you're going to hear about it, about this program, later today from the team.
We have programs for very large disease indications, like pelacarsen for Lp(a)-driven cardiovascular disease, olezarsen and eplontersen, and also for severe rare disease indications such as for FCS, HAE, IgA nephropathy, ATTR polyneuropathy, and more. Diverse in the diseases we're tackling. But one thing that these diseases, that these medicines have in common throughout, is that they're positioned to tackle diseases where the unmet medical need is substantial, that the unmet need is great. Patients are waiting. There's very few treatment options available, and for most of these, we're in position to be first to patients, first to market. It's truly a remarkable phase III pipeline, and a pipeline that we expect to continue to grow. Every year around this time, we sit down, the team, the leadership team sit down and asks the question: "Okay, next year's coming....
What are we going to do to drive value? Drive value for our patients, drive value for our shareholders. What are our key strategic objectives going to be for the upcoming year? We did that last year, and the objectives we set for 2023 were particularly aggressive, particularly challenging. I'm happy to report, very pleased to report, and proud to report, that we're well on our way to achieving everything we set out to achieve and to deliver everything we said we were going to deliver for Ionis in the beginning of the year. We've had many positive clinical data events, readouts this year, with positive, full data set for our phase III program for eplontersen for ATTR polyneuropathy. Just last week, we reported highly positive phase III data for olezarsen in FCS and more. Several important enrollment achievements, really important enrollment achievements.
Completion of the phase III enrollment for enrollment of the phase III OASIS study for donidalorsen in HAE, and then completion of enrollment for eplontersen, our phase III study, CARDIO-TTRansform. Again, a landmark study for TTR cardiomyopathy, more than 1,400 patients. As I mentioned earlier, we also initiated and expanded our phase III pipeline, initiated new phase III studies. Zilganersen, as I mentioned, but also our HBV program and our IgA nephropathy program. We've had several really important regulatory actions, again, progressing us forward, that we set out to achieve this year, including the approval of Qalsody for SOD1 ALS, a treatment that was conceived and discovered at Ionis, a real breakthrough, not just for SOD1 ALS patients, but a real breakthrough for the ALS community.
Eplontersen's acceptance in filing acceptance in the United States by the FDA and also now in Health Canada and other regulatory achievements as well, including orphan drug a couple of orphan drug designation outcomes. We're not finished. We have a lot more to do by the end of this year and a lot that we're looking forward to through next year. An incredible agenda ahead of us, set up with really strategic milestones that we're looking forward to achieve. Such as more phase II mid-stage pipeline of clinical readouts that we're very much looking forward to, including three treatments, three programs that, if positive, have the potential to go to phase III development to further expand our phase III pipeline.
phase II studies that can go to phase III, including our drug IONIS-FB-LRx for geographic atrophy, ION582 for Angelman syndrome, and ION541 for sporadic ALS. Important phase III clinical data events, including olezarsen, the full dataset for olezarsen for FCS and the phase III results for donidalorsen in hereditary angioedema in the first half of next year. Several important regulatory actions coming up, including by the end of this year, the expected decision on the approvability of eplontersen for ATTR polyneuropathy. Discussions with regulators are going very smoothly, and we're very much looking forward to that. Next year, the potential approval of olezarsen for FCS in the second half of the year, assuming priority review and much more. Then, of course, our new product launches. Assuming approval for eplontersen and ATTR polyneuropathy, we're going to launch.
We're ready to go and ready to launch just a few weeks after approval. Olezarsen for FCS, if approved next year through priority review in the second half of the year, and the potential for Qalsody to launch in additional markets for SOD1 ALS outside of the non-US. So it really is, we really are set up for a really exciting list of milestones that are coming up for Ionis that we believe is going to drive substantial value for everybody. So let me leave you with these four take-home messages before handing it over to the next speaker. Of which there are four take-homes here. The first is that Ionis has prioritized our wholly owned and established our wholly owned pipeline, and we expect this pipeline to expand well into the future.
It's a top priority. We have everything in place today that needs to be in place at this stage to launch our own medicines, to deliver our own treatments to patients directly. Thirdly, the investments we've made over the last few years to expand and diversify our technological capabilities to extend, substantially extend our leadership position in oligonucleotide therapeutics is on track, and we're leading the way. Finally, we have a financial position that's strong, enabling us to make all the investments we need to make to be successful. Now, before handing it over to the next speaker, I'd like to tell you a brief story, and I'll promise to be brief.
I don't know, nine, 20, 2018 , 2019 or so, I was approaching my new role at Ionis as CEO, thinking about all the strategic imperatives I just took you through. What are the key objectives to drive value for the company? And it was obvious, I'm sure it was obvious to all of you, we needed somebody, I needed somebody to build a commercial organization, to set strategy, to execute on that strategy. Somebody with a lot of experience to, in, in this, doing this and successfully.... And I pursued Onaiza Cadoret. I knew Onaiza from the past, from years past. We knew each other. We interacted on several occasions. And I pursued her, and I asked her: Can you do this? I would-- You're a perfect fit.
Onaiza was, not surprisingly, very excited to do that. She would often cite, like, what a great platform, what a great technology, what a pipeline. I mean, who wouldn't want to bring medicines like this to patients to commercialize a pipeline like this? What great people at Ionis. They're smart, they're dedicated, they persevere. Of course, this is exciting, but over the period of months, she would often ask me the same question at the end of our meetings. The same four questions, actually, which were: Are you really going to do this? Is the board behind it? Are the employees behind it, and are you behind it? And every single time, I concluded the meeting with simple answers. Yes, yes, yes, and most of all, yes. Right. So there I was, January 15, 2020.
I was in San Francisco at the J.P. Morgan Healthcare Conference. I see Jess here. Jess introduced me. Representing Ionis for the first time as CEO, and presenting on the corporate update, corporate overview, what my vision was for Ionis. And folks, I laid out the same thing I just said to you, I just reviewed for you today, our key strategic goals and priorities. I said it at that time, you can look it up. We're going to invest and extend our leadership position in technology, and we're going to build our commercial capabilities and deliver our treatments directly to patients, bring our medicines directly to patients.
And, there was Onaiza in the front row, and, when I stepped down and finished, she came up to me and she says, "Okay, you're on the record now, so let's do this. I'm all in and, sign me up. I couldn't be more excited about it." So Onaiza was my first hire as CEO, and, she's been working on this, ever since she started in January 2020, and here she is, Onaiza Cadoret.
Thank you, Brett. That was fantastic discussion, and most of it's actually really accurate. Great to see all of you. I'll add a little bit that's a little different than what he said, but I definitely interrogated Brett quite a deal on the strategy for the company. It's a transformational vision, right? And very different than where the company had been in the last 30 years. So his commitment was just relentless. And I have to say, since I've been here for the last 3.5 years, his commitment is steadfast. And there is one thing I know about Brett: when he commits to getting something done, he gets it done. So a bit more around the commitment. First of all, it's been a great collaboration with the people at Ionis. They are ready.
They want to do this. They've been really great partners, and there is change that comes along with the commitment, and I have been very pleased with the level of change we're making. The one thing that did surprise me, from the story that Brett said was the pace. He's a pace setter. The pace at which we have gone has been incredible. I really didn't think we'd be here in 3.5 years in this measured manner, to be launch-ready for this organization for three programs, five indications in the next three years. It's pretty remarkable. I have to say, we have a great team in place to be able to, to deliver on this transformational vision that has been set out. So, I have been on a journey.
I've been in life sciences for about 30 years, and I actually started off my career right here across the street at Pfizer, about 25 years ago. Where it was in the prime, I would say, of bringing small molecules as a modality into the marketplace, conquering kind of cardiovascular and CNS diseases. But I've had the privilege to work across very many modalities. So it was really only fitting that I went over to peptides next, and I was at Amylin, where we discovered GLP-1. And as we know now, GLP-1 is right square in the heyday of where it is right now. And actually, Amylin was the first to bring a GLP-1 to market, which is Byetta, for diabetes. And then I had the fortune of actually going to the birthplace of biotechnology.
I worked for Genentech for many years, and that was prosecuting monoclonal antibodies to get to undruggable targets, right? Proteins. Very, very different. So it's really only fitting that I am just here at Ionis, which is kind of the next modality that's just on the cusp of entering its prime. Just on the cusp, right? The RNA platform is really prosecuting rare diseases, as Brett just went through, diseases that are intractable, have not had the opportunity to have even a single treatment for these patients. And then we're also in our prime and on the cusp of getting to large, broad, prevalent diseases, where the standard of care just isn't sufficient enough for patients anymore. So we're really at the cusp of entering this wonderful new modality and in a new era as well. It's exciting.
So the first thing we did when we came in was said: Okay, well, we want to go commercial. Great vision. What's our strategy, and how do we actually take this, this pipeline that we have that's coming forward and really focus on the things that are really going to make a difference, where Ionis can be very successful in terms of, of reaching all the patients in these indications that really deserve it, in that disease area. So as a result, we came in and looked at their late-stage portfolio, and we said, "Wow, these actually look very exciting. Here are the things that we think we can do really well." And we chose cardiovascular and neurology as our two areas of focus. I would say there are two pillars.
There are two pillars here, and we did that with also thoughtfulness as to not what was available just in the late-stage portfolio, but also what's coming behind it. So we did a really big review of the portfolio strategy. We prioritized the things that we were going to bring to commercialization as Ionis on our own, and really thought about the cadence within which this could come, so we could actually build our commercial capabilities alongside of that and really deliver and execute well. So through that exercise, we took that to the board, got it approved, and we started building.
I'm pleased to say, and you'll see some of the core capabilities that we've established are really thinking about how we are going to be innovative in our approach, do the right sizing of our capabilities that are gated to good, as we call it, asset stage milestones, and then really have the ability to scale as we need. As a result of that plan, well, I can't do it by myself, so I have a team. We have been able to really recruit a lot of exceptional and experienced talent. Much of which I'm gonna actually go through today with you is the work of really a great team in Carlsbad and actually in our Boston office as well. I have a couple of members here I would like to introduce you to as well. First of all, Rachel Carnes.
Rachel has been the Head of Global Product Strategy for about a year now. She came from Celgene and has really launched some really fantastic products in oncology over there, Abraxane being one of her major accolades. But Rachel is going to be responsible and has been responsible for our early and mid-stage portfolio. So she's thinking about the next wave of medicines that will be coming, and you'll hear from her a little bit later. About, I guess, 48 hours into the role, we have our new Chief Commercial Officer, Jonathan Birchall. Jonathan has just joined us as well. And Jonathan will be leading our late-stage portfolio, primarily the three eplontersen and a co-co with with AstraZeneca, olezarsen, and donidalorsen, and preparing those capabilities and markets for launch as well.
Jonathan is a classic leader, been in sales and marketing throughout his whole career. Started off at Sanofi, so has a lot of global experience, but spent about another dozen years here at Genentech and has also launched really a lot of products in rare disease type of launches, Kadcyla, for HER2 breast cancer, and then broad-scale types of launches, such as Lantus, for diabetes as well. So he brings a good core set of capabilities. As you can see, these other leaders, who are not here today, are functional leaders that have been in place for the last, I would say, two years or one years, depending on their role. We've got the Head of Medical Affairs, Shai Bichner, Chris, who heads up market insights and portfolio.
And then, very importantly, what you see in the next row is really the heads of each of the brands. We've got a Vice President of Marketing for olezarsen, one for donidalorsen, and eplontersen, and for neurology. So everybody is really in place and structured and focused in their therapeutic areas. We also have the functional leaders who are building the capabilities that are necessary. I call it the machinery that's necessary to launch the strategy and the products. And that includes patient services, commercial operations, omni-channel, and obviously U.S. market access and reimbursement for our payer strategy as well. So as I said, there's a really great team in place, and really, I have the opportunity and the privilege to really present the work, the great work that they're doing. So, this is our launch cadence.
This is probably the best recruiting tool I've had to get the top talent in place. I've been here 30 y ears, I don't think I've ever seen a cadence of launches such as that's coming up in such unmet needs, as Brett said. And this is coming again, we've got eplontersen, followed by olezarsen, then followed by donidalorsen. So that's three programs, five indication launches in the next three years. That's exciting. It's exciting because we get a pipeline that's as large as what you get in big pharma, but we get it in a small, nimble, agile company such as Ionis, so you can actually create the right blueprint of what you need to get done to launch these products well. Very exciting times.
We'll talk about each one of these as we get through the day. So, hold on to that. And let me tell you a little bit about our innovative model to bring these products to market and to our customers. So, you know what the great thing is? We've got a lot of talent. They've come from large pharma, they've come from small biotech, they've done rare diseases, they've done broad-scale launches. And one of the great things about this team is we all look back in our careers and say, "If I could, I wish I would have." And guess what? Over here, you get to do that.
We are building the blueprint from all the learnings that we've had through so many different launches we've been through, to make sure that not only are we capturing those learnings and making sure that we're doing this differently this time around, but also we're looking to the future. The future looks different in our marketplace, particularly since COVID. We're really thinking about how we're going to deliver this wonderful set of products through an excellent customer experience along the way. At the center of it all is really focusing on the people living with the disease. We must.... But we also know in order to get to the patient, we actually have to really delight a lot of different care providers and treatment influencers along the way.
We know that our healthcare providers are really kind of centric to be able to, to get the right decision made and also given the right care along the way. We do work in genetic diseases, so our influencers are really broader than I would say most others. As rare diseases, we hit treatment centers of excellence. We need to work with geneticists, and then our market influencers, obviously wide from payers also to advocacy groups as well. What you see here to the right are table stakes. These are table stakes in terms of everything we need to get done to be able to be ready to launch. Every company does that. Because if you don't do that, you're not going to make it. To the left is what we're doing in addition to table stakes.
This is really thinking about how are we going to use innovative techniques to create that delightful customer experience along the journey so our patients really get the product. We're doing a lot on data. We're really looking at data and optimizing the insights that we can get from them and integrating very different data sources. Data is great, it's all available, but how you integrate it and how you get the insights is really important. So that includes your traditional claims data, but also looks at integrating EMR data. It also looks at looking at lab data, and this gives us insights into rare disease, particularly where these patients are, because there's a lot of patient finding that goes into it, and also in terms of how do we want to communicate to our customers at the right time, at the right level.
As a result, complementary to that data integration is omni-channel. We are going to be big and digital. We're not going to do it exactly what everybody sees on the street, but omni-channel in a very bright way to be able to, again, reach our customers in these influencers that we have in a very broad manner. We obviously are in rare diseases, so we need a patient hub and patient support services. That is, a big heavy cost sometimes. So we're thinking about what biotech does, is keeping some of those case managers, you would say, outside, but then you kind of lose the integration with your internal team.
So we've got a novel way to bring everybody in here, get the efficiency that we need, but also the integration and the teamwork that it takes to get all of the insights and the products to patients as well. So as you can see, this has been really set up with the blueprint in mind for ensuring that although we have these great products, and we can talk about our products all the time, in order to make it meaningful to the person living with the disease, we actually really have to delight everybody all along the way, from influencers to care providers to get there. So we have three near-term commercial medicines. I'm going to talk about the commercial opportunity for each of them, but I'll leave you maybe with some top lines, as we go into the day.
So for ATTR, we are well poised to be the leader with eplontersen. We have ambition and a goal to be the leader for both polyneuropathy and cardiomyopathy as we launch this. And we believe that our clinical data, the strength of what we have seen today, alongside the complementary capabilities that come with both AstraZeneca and Ionis together, is really magic, and that's what's going to make it happen. For olezarsen, we've seen unprecedented data last week. It was just about a week ago that we were going through the FCS data. This unprecedented data that we've seen in reduction of acute pancreatitis really gives us a good foothold into the marketplace for our first independent launch, and the team is just chomping at the bit and ready to go.
They also have a great line of sight into where they're looking for the next larger scale-up launch for severe hypertriglyceridemia. For donidalorsen, we've seen our phase IIs. We're going to review that again. We have a potential best-in-class profile. We are really on track for getting that data in the first half of 2024. And this is a very attractive market for us, very concentrated set of prescribers. And we're again very excited to launch donidalorsen and preparing for our next wave of Ionis medicines, which Richard will talk to you about later. So key takeaways from the morning. We've got a great team. They are in place. We are commercial ready. We have a very unique way to think about bringing our commercialization process into medicines and directly to patients.
This team is prepared for multiple upcoming launches. So, I hope that, I hope that you're feeling as ready and excited as we are, and we'll talk about, again, each of these medicines as we go forward for the rest of the morning. So I'd like to now invite Sam Tsimikas, who's going to walk you through our eplontersen program. Sam?
Good morning, everybody. Thank you, Onaiza, and thank you for joining us today. Let me just first start out by saying that, as a practicing cardiologist who's seen many kinds of cardiovascular disease, I'm very, very proud to be part of the team that's going to give patients a drug for a very morbid and deadly disease, which is transthyretin amyloidosis. Transthyretin amyloidosis is also called ATTR, and it's caused by a production of transthyretin from the liver that misfolds, aggregates, and causes deposition of the transthyretin in multiple tissues and organs, which is the cause of the disease. Eplontersen is designed to inhibit the production of that protein and treat the root cause of the disease.
We have been waiting as cardiologists and also neurologists for a long time, to have a way to treat this disorder, and I think we're finally at the cusp of offering these patients some important therapies. Now, there are two versions of this disease. There's a hereditary version and there's a wild type version. The major manifestations of polyneuropathy and cardiomyopathy, and this is why we are targeting those two indications with eplontersen. So I'm going to review for you in the next 15 minutes, our polyneuropathy program and our cardiomyopathy program. I hope at the end of my 15 minutes, that you feel as excited as we are for what a great advance this should be for our patients. Now, if you look at the slide, on the bottom, on the right side, let me give you a sense of what these patients feel and function like.
So if you look at the bottom, they have peripheral neuropathy, okay? And that's manifested in motor, sensory, and autonomic dysfunction. So what does that mean? That means they have numbness, tingling, and pain in their legs, and they develop imbalance. So they initially need to have a cane or, you know, a walker, and eventually end up in a wheelchair. Okay? The next manifestation that's major is cardiovascular manifestation. What is this? The transthyretin accumulates between the muscle fibers of the heart, and the heart actually enlarges. It gets very thick and gets very boggy. This creates arrhythmias, it creates heart failure, and it creates ultimately, it leads to death. In the past, and even until recently, the treatment for this has been liver and lung transplantation as the only viable approach.
Obviously, we're going to have-- going to be able to, overcome that and provide better therapies. Now, the other part of this is that, in my practice in interventional cardiology, I perform many biopsies, cardiac biopsies, in these patients to diagnose them with cardiomyopathy. Luckily, we no longer have to do that. We have non-invasive ways to, to detect, amyloidosis in the heart and with non-invasive testing, and that has allowed us to diagnose these patients much, much earlier versus when they come in in extremis and heart failure in the hospital. So this is why you can see here that the prevalence of the disease is going up very rapidly, because we actually can find the patients way before they're at their very end stage of the disease. The other part of this disease that's very important to understand, is these patients develop cachexia.
This is the same kind of cachexia that you see in patients that are undergoing chemotherapy. Why is that? Because there are GI manifestations of the disease. It affects both the parasympathetic and the sympathetic nervous system, and these patients get alternating bouts of constipation and diarrhea, and eventually, they can't eat. They start losing weight, and they start losing weight and ultimately succumb from that as a kind of end-stage manifestation of this disease. I'm going to show you how we're going to be able to treat all these manifestations that you see here. Now, if you look in the middle of the slide, you see the prevalence is about 500,000 patients, okay? That seems to be growing as we're able to diagnose these patients.
As I mentioned, there are two versions of the disease, so it's important to understand this. So the major version is the wild type TTR. The transthyretin here has no mutations on it, but it misfolds, and it occurs mostly in older patients, and their main manifestation is cardiovascular. The other version of the disease, when there are multiple mutations in the transthyretin gene or protein, gene, and ultimately the protein, so then this folds. Those patients tend to have neuropathy, and you see on the bottom there, that about 40,000 patients are estimated to have neuropathy, but these patients can also have cardiac involvement, so we call that a mixed phenotype. So what you-- so the bottom line is, there's a lot of patients with the wild type TTR, and there's a lot of patients with hereditary or variant TTR.
Our drug does not discriminate against each one of those. It treats the same problem in those patients, therefore, we can use it for both indications. Now, we have a very robust development program to address these two major clinical manifestations. The first program on the top right is our NEURO-TTRansform study. This is for ATTR hereditary version of the polyneuropathy. Now, I'm very pleased to tell you, and you probably have seen this already, that last week we published the main findings from this study in the Journal of the American Medical Association. So you can look at that and see all the details from that. It met its three co-primary endpoints and four of its secondary endpoints, highly consistent and highly statistically significant results. As you know, the NDA has been accepted.
We look forward to having approval in a couple of months and bringing this drug to patients very soon after that. The second indication is ATTR cardiomyopathy, which is a much larger indication. We think we have the best study design in the field, and I'll go over that in more detail. It's going to allow us to get very rich data set to analyze all the different varieties of amyloidosis that the patients are coming in with. That study has fully enrolled as of July, and it can read out as early as the first half of 2023. Now, along with this, we have several other, profile enhancing studies and lifecycle management studies. We have open label extensions for both, and we have imaging studies that I will review for you in a bit of detail.
Then we have plans for additional lifecycle management studies going forward. So let me now review for you our polyneuropathy program and show you a summary of the data that we just published. This study is called Neuro-TRANSFORM, and this has the hereditary version of TTR, and its polyneuropathy is the main manifestation. Okay, now it's unethical or felt to be unethical to do a placebo trial because these patients have such a poor prognosis. So the design is a little bit unusual from the perspective of what you typically see with placebo-controlled trials. So what you see here is 144 patients were treated with 45 mg of eplontersen monthly. The control group is from NEURO-TTR, which is a prior study, and this is a historical control that you see has 60 patients. So that's going to be our comparator group.
There's another group in between there, inotersen, 24 patients, that the regulators asked us to have a contemporary cohort treated with inotersen. This is to basically just have some qualitative data. This is not going to be into any of our analyses that I'm going to show you. These patients were treated for 35 weeks and then switched over to eplontersen after that. Now, the study design has or had an interim analysis at week 35. The full analysis was at week 66. We also had a pre-specified end of treatment analysis that you see there at week 85. There are three co-primary endpoints, and I'll go over those for you on the next slide with a little more detail. So the first co-primary endpoint is TTR concentration. Why do we want to know that? Because this directly tells us how the drug is working, okay?
We're going to look at this as a percentage change from baseline. I just want to make the point here that we measured the levels right before the next dose. So this is a conservative measure of the actual effect of the drug. The other two co-primary endpoints are based on evidence of nerve fiber involvement and then how the patient feels and functions. So the first one of those is called the Neuropathy Impairment Score, or NIS, NIS+ 7, and this measures objectively how much TTR is getting accumulated into the nerves. And you can do that in the motor neurons, the sensory neurons, and the autonomic neurons. And you see some of the tests on the right, how that is done, okay? So this is an objective measure of TTR accumulation.
So we're going to measure that and see if it gets better. The other part of this is the Norfolk Quality of Life Questionnaire. This allows us, the patient, to tell us how they're feeling and how they're functioning. All of these are highly validated for this field, and so they're widely accepted as proper endpoints. These are the baseline characteristics. A lot of stuff here. Bottom line is there were some minor differences in the groups, but essentially very well balanced. I just want to point out a couple of things. Because this is a hereditary version of the disease, the patients are showing up about 20 years earlier than the cardiomyopathy patients. So notice here, their age is in the mid-fifties, okay? So they're starting from birth with this disease, and it's finally accumulating when they're 50 years old and causing them symptoms.
On the bottom, notice here that about 70%, 60%, 70% were actually previously treated with stabilizers. On the right side, you can see the stages of the disease. There's one particular version of the disease called the V30M that was predominant in these patients. On the bottom right, you see the actual scores of the NIS+7 and Norfolk. The higher the number, the worse the patient is doing. So keep that in mind when I show you the data as a percentage change from baseline. This is the first co-primary endpoint. We're looking at the mean percentage change in the TTR level in the plasma, in the historical placebo group, in orange, and then in the purple color, are our eplontersen data. Notice a couple of things.
Placebo group data is declining, and this is not a fluke of variability. This is a sign that the patient's actually getting worse because they're getting more cachexia. On the eplontersen arm, what you see here is that there's a massive decline or rapid decline, I should say, in the TTR level. That actually goes down by about, or sorry, about—by about 13 weeks. And then the level is sustained and stays all the way down to week 85. Notice that the error bars are very small here, which means that there's very little variability between doses of the level. And so, this is a very robust finding that should now translate to other clinically relevant measurements. And what are those? So NIS+7 . So remember I said, if the level go, the number goes up, the patients are doing worse.
So in this case, this is a neuropathy score. So this is the objective measurement. That means there's more accumulation of TTR in the nerve fibers. Now, look at this interesting part of this disease. Every single week, the curve, the orange curve in the placebo is going up. That means that relatives of these patients are watching them degrade week by week by week. So by that 35-week time point we measure, you see already a rapid progression of these patients in their neuropathy score. And then the curve, even the slope of that curve, goes up even faster from 35 to 6six weeks. So in one year, you're seeing a rapid accumulation of more TTR in the nerve fibers that's manifested in the test that we're doing. Now, on the bottom, you see here, we completely halted the disease from using eplontersen.
There's absolutely no change. In fact, by week 85, you see here that the actual levels are, declining, the numbers are declining, means that the patient's, nerve test is actually improving. And so we don't have data beyond this, but presumably, as we're going to treat these patients for a lifetime, these curves should continue to separate. Now, the quality of life, life data looks even better. As you see here, that not only do we have a halting of progression, but from quality of life, the data is actually improving. The patients are feeling better before their objective findings on the neuropathy scores are changing. This is a great sign that tells us that not only, you know, these are all aligned, but the patient is actually telling us they're feeling better than their scores are.
So, a large number of patients that you see on the top left actually had a significant improvement. Importantly, for both NIS+7 and this score, all of the subgroups that were pre-specified and all of the, domains of the Norfolk and the NIS+7 went in the same direction. So very robust findings. Now, one important aspect of the disease I mentioned is cachexia. I want to make one point here on the top right as a secondary endpoint, the, the modified BMI score. BMI is a combination of height and weight. The modification here is that we add albumin to this measurement, and so if your body stops making albumin, that means you're nutritionally deficient. So you're losing weight and your liver stops making proteins, so that number becomes negative. And you see here on the purple curve, completely flat.
That means the nutritional status of the patients is maintained when it entered into the study. Okay, what about safety and tolerability? Bottom line is, there were no serious adverse events in this study. There was no imbalance of ocular events. I know there's been some talk about this. Let me explain this real briefly. When we did the placebo group, the patients had to be the physicians and the patients had to be blinded on their vitamin A levels, right? Otherwise, we would know who was on the drug and who wasn't. So there was no way for the patients or the physicians, I should say, to check a box that says the vitamin A level is low. However, in the current study, we did not blind the study, right?
It was open label, so they could get a report that says vitamin A level is low. Now, anytime you inhibit transthyretin, the vitamin A level is going to go down because that's its function. We supplement vitamin A in these patients as a way to mitigate that. So what this basically was, was there was a checkbox for the vitamin A, that basically said there was an ocular event, but it wasn't a clinical event, it was just a lab test. If you take that lab test out of the equation here, you see that the events are fairly balanced. There was also no other imbalances of any other things that we worry about, that you see here that are listed on this slide. There were three deaths. These were all related to disease progression and not related to drug.
So what is the bottom line here? The bottom line, I think, is that we have a very potent therapy to reduce TTR levels. We have objective evidence of nerve function improvement, and we have quality of life that goes along with that. We have a favorable safety and tolerability profile, and we are now ready to have approval for this drug and launch it as we go forward. Okay, now let me transition over very briefly to cardiomyopathy. I'm not going to have any data to show you, but I'm going to show you the trial design and explain to you why we think this is a fantastic design. Now, we're going to be able to take our neuropathy data and have it read through into our cardiomyopathy. Why is that?
Because we're using the exact same dose, so we're going to know about how much TTR reduction we're going to get. Okay, also, we have the safety profile and tolerability data that we can read through into what we're going to see in the cardiomyopathy program. So we expect the drug to be safe and tolerable and to have a fantastic TTR reduction. So this is the design of this study. It's about twice as large as other studies that have been done in this field. It's global, it's randomized, it's going to have 45 mg of eplontersen versus placebo. It can go as long as 140 weeks, but we have the optionality to bring that back based on various criteria. It has hard endpoints, cardiovascular death, and cardiovascular events.
It's going to have a lot of patients on tafamidis, a lot of patients off tafamidis, and we're going to have the largest number of hereditary patients with cardiac involvement in this study. So we expect to be able to have a positive trial at the end and have a very rich database to be able to analyze all of these other things that are important to you and to the patients and to the physicians, to show that the drug works in various clinical scenarios. Now, built into this study, we have two sub-studies that are going to tell us how well the drug is working in the heart itself, above and beyond the clinical outcomes. Okay? We have an MRI sub-study that's 128 patients. We have serial imaging. Why do we use MRI? MRI can pick up the fluid between the TTR fibrils.
Think of the heart as a swollen ankle, right? The MRI will image that in fluid. As you remove the TTR, the fluid is going to decrease. We can image that and tell us we're actually having a removal of the TTR from the myocardium. So this is going to tell us how well we deplete the TTR, because that's what we expect to have the benefit from this drug, ultimately. We also have a complementary study using nuclear scintigraphy, and that does the very same thing. It. The nuclear isotope called pyrophosphate accumulates in the myocardium and binds to the fibrils, so when we image that, we can tell how much TTR is there. So let me show you some very exciting data using this technique that just got published in the Europe- or presented at the European Society of Cardiology.
This is 6 patients from the Neuro-TRANSFORM study. Remember, this is open label, so we know all these patients are on eplontersen. This is an investigator-initiated study. We had nothing to do with it. The investigators did it themselves. Notice here that when you have a high score on the, on the left, there's a lot of accumulation in the heart relative to the lung. Okay? And an average of 144 days, notice here that there's a significant reduction in the accumulation of the pyrophosphate label in the myocardium. So what this tells us is that we're already depleting the amyloid using this imaging technique, and we can demonstrate it in only six patients. We're going to have 150 patients in our cohort, and we're going to have 1,438 patients in our study.
So this makes us feel very good that the drug is already working, and we can have an idea of how it's going to be working. So to summarize then, we have a fantastic drug.... We have two programs that address the most relevant parts of this disease, and we are ready to go forward with a fantastic program to get these drugs to our patients that need them. So thank you. I'm going to hand now the podium back to Onaiza, who's going to tell us how we're going to achieve that last part.
All right. Thanks, Sam. Happy to. So it's great to have actually Sam on board. His depth of clinical acumen that he brings as a cardiologist is fantastic for our program. The other thing to know about Sam, he's actually still a practicing physician at UCSD, and with that, I think he brings in a very real-world perspective of what is the type of data that will be really compelling that physicians need, as well as what patients really need to be able to treat them really fully. So it's fantastic to have him lead our eplontersen development program. So we are ready to bring eplontersen to patients. We're a short, I would say less than three months away from a PDUFA for polyneuropathy, December 22nd. And we are entering this market with a growth mindset.
Growth, because as you will see, and, and Sam went through it, the prevalence is high, both in polyneuropathy, mixed phenotype, and cardiomyopathy, but not all of these patients have been found, and not all of these patients have been treated. So we have a lot of headroom over here. As Sam also explained to you, this is a systemic disease. That means it manifests in different parts of your body. That means the pain is going to show up differently, and our patients are going to present in a variety of different physician settings. They're going to show up at the neurologist, the cardiologist, the GI, the hand surgeon, carpal tunnel.
That means we have to use some of the techniques I described just earlier about really integrated data and insights to know where these patients are, where they may show up next, and where they may be stuck in the system and misdiagnosed as well. With the excellent data that we have in polyneuropathy, really great on all three co-primary endpoints, TTR, neuropathy, impairment, and quality of life, we believe eplontersen will be the preferred treatment in this space. We are confident that the global partnership we have with AstraZeneca is really the right thing to do here. It complements Ionis in a very meaningful way. We know ATTR. We've been in this market for more than a decade. We know the investigators, we know the KOLs, we know where the treatment patterns are going.
We are also very adept at rare disease, and as this sits in AstraZeneca's global cardiovascular business unit for the commercialization, we believe that both of those items are really necessary to really fully, fully realize the potential of eplontersen and treating this disease. So I'll point you to one number here, which is the 20%. Currently, less than 20% of ATTR patients are treated. So we've got, as I said, a lot of work to do. Our goal is to become the preferred choice for patients who are new to silencer treatment. And, as a result of the clinical profile that Sam just shared and our self-administered auto-injector profile, we will be the preferred choice in this marketplace. Let's deeply take a look at the clinical profile.
What are the things that we're actually testing in market right now, as we're preparing and waiting for our label and the discussions going on, that's really resonating well with the physician community? First of all, our targeted knockdown of TTR. The knockdown with very consistent and tight, sustained suppression on a month-to-month basis. If you remember, the curve was like this and just flat. As Sam said, this is a disease, when you look to the placebo line, it gets worse. Patients are progressively getting worse. So the ability to halt the progression of the disease, as many of our KOLs when they saw the data, was very exciting. It's like we really didn't think that could actually materialize. You've halted the progression for these patients. And then with our Norfolk Quality of Life, we actually saw improvement.
We saw improvement in a substantial number of patients on their quality of life, measured through Norfolk QoL, and we've seen that sustained over 85 weeks as well. So the duration of the data is really strong. In cardiomyopathy, again, largest clinical trial in cardiomyopathy. Many of our KOLs are calling it a potential landmark trial over here. Why is that important? Well, there are 300,000-500,000 estimated hereditary and wild-type cardiomyopathy patients, right? If you think about it, they range in a variety of different ways. It's heterogeneous. They're not all going to be the same. And we will have the clinical data to be able to bring to physicians how best to treat these patients.
Be it that they're mild in their severity, to be it that they're severe in their severity, anyhow, Class 1, 2, and 3, it's going to be really important to have some subsets of population data. Second, I would say, what does it mean to treat a hereditary patient versus a wild type? And what types of things can I expect in their treatment journey? And very importantly, in the United States particularly, how do you see a benefit, a cardiovascular risk reduction benefit on top of tafamidis, which is a lot of stabilizers are used here, and what do you-- what can I expect to see for patients who are naive to any treatment?... This is going to be very compelling.
This, alongside our significant commercial reach, the global partnership, the patient support these rare disease patients need, and being a very high touch organization in their journey, along with our administration profile, really sets us up for success. So we're ready to execute. We have everything in place. Both the Ionis team and AstraZeneca team is ready to go, and we have a shared strategy to bring eplontersen to patients around the globe. We're filing in the US. We filed in the US, but we're also filing in Europe and Canada and other global markets. With AstraZeneca scale, we're actually going to be first in filing in regions such as China as well as Japan, and really get into this very large $10 billion market opportunity worldwide.
We have a one customer team approach that's designed to drive some rapid adoption, and broad uptake. Many of the teams that you see here are complementary between the two teams. Our field medical team has been in market for the last two years, really, creating the disease awareness and the signs and symptoms that one should see around the manifestation of polyneuropathy, for example, that can be very new to different types of physicians. Our patient education manager team is hired and trained. This is what Ionis is actually leading, and they're going to be very complementary to the sales team that, that AZ has already hired and trained, and as of last week, they were actually in field and talking about, again, the disease and signs and symptoms. So this team is ready to go.
We're waiting on our last few weeks from a label discussion and getting things prepared in advance at risk for what these materials are going to look like in anticipation of the label. We launched recently a I think a very compelling disease awareness campaign. As you can see, it talks about seeing the patterns, very clever play on ATTR, and it's a showstopper. It was launched at the ESC meeting at the Congress, and it really grabs an attention on the patterns, but really gets you to think about the consequences. The consequences of not accelerating the diagnosis of this disease, and what does that mean if you have a delayed diagnosis or a misdiagnosis for patients.
We are very excited that we have a publication that was just published in JAMA, and that will be available at the time of launch for the sales reps as well, to bring to their physicians. Of course, in every rare disease, patient and caregiver support is extremely important. We're assisting the patients through their journey, including genetic testing. Our patient education manager team is going to be there, post the prescription decision to actually help them all the way through their journey. And our self-administration program, we're going to just train the patients so they're really confident on their first try to do this. Given that this is so different and unique in our profile, we did extensive market research to understand what the needs of the patients and the healthcare professionals are around the self-administration.
As I'll share with you now, two-thirds of the patients indicated that going into an HCP office for their administration is actually difficult in the sense they can't do it on their own. They often need to be accompanied by a caregiver. And given that right now, much of the treatment is in centers of excellence, they're not really close by. So they have a long drive, and this actually adds a lot of financial burden for them, because sometimes they have to come in the night before, stay in a hotel to be able to just see their physician and get an administration. We also talked to HCPs, and about two-thirds of them said that this is actually a negative impact on the lives of people living with ATTR. And why is that?
That is because it doesn't give the freedom and the independence, really, to take care of their own disease, and it does impact their quality of life in a negative way. So we really do believe this is going to be a preferred option for HCPs and for patients, and it's a much more important factor than dosing frequency. So what are the next steps to bring eplontersen to this market? Well, first of all, got a lot of completes on this slide, which is exciting, right? The Neuro-TRANSFORM data was presented at AAN. We saw the positive 85 durability of the data, as well as the recent JAMA publication.
So what we're really waiting for is December 22nd, and the road to December 22nd as our PDUFA, and really getting into just, you know, finalizing the label and getting into discussions with the FDA on that. Alongside of that, we're preparing our regulatory submissions, as I said, EMA, Health Canada and others, that AstraZeneca will be leading in global markets. And more importantly, just at the turn of the calendar year, this team is ready to go for the PN launch in the United States as well. And then, for CARDIO-TTRansform, that Sam reviewed with you, waiting for the readout as early as the first half of 2025. So as Brett opened this morning, we have been very inspired by Mark.
He has come to our team meeting as the brand teams have been getting ready to really give us a day in the life of a patient with polyneuropathy, and how meaningful it has been for him to be in the clinical trials for eplontersen. He's been courageous, actually, and been on this journey for many years because it is hereditary. He did see his father die from this, and he was courageous enough to go get a genetic test and really know what was coming in the future, and was really activating himself to find the right clinical trial to get into so he could get the treatment he needed.
And out there right now, he is doing really well on eplontersen, which is great to see, but he's also a real patient advocate in getting others to go out and get their genetic tests done and really be courageous enough to kind of enter into a treatment pattern as well. Very, very inspiring for us. And so I'd like to now invite Brett up to introduce our next speaker. Thanks, Brett.
Thank you, Onaiza. Thank you, Sam. So now we're gonna move into the next segment of our morning. The next near-term commercial launch opportunity for Ionis, our first potential independent launch for Ionis olezarsen. And the diseases that olezarsen is set to treat, diseases related to severely elevated triglycerides. We're honored to have one of the key opinion leaders in the cardiometabolic space, Dr. Henry Ginsberg, from Columbia University, Professor of Columbia at Columbia University. He's an endocrinologist, a leading physician, a leading investigator who evaluates potential new treatments for diseases related to cardiometabolic diseases and in particular, diseases related to lipoprotein abnormalities, lipid, high lipids and so on. Dr.
Ginsberg will cover for us today the unmet medical need in patients suffering with high, high triglycerides and the changing medical landscape. Following Dr. Ginsberg, Sam Tsimikas will take us through the olezarsen clinical development program, and in particular, the top-line data that we reported last week for FCS. And then Onaiza will come up again and present to you our, our strategy to deliver olezarsen to patients in need. So no further delay, Dr. Ginsberg.
Good morning. I'm here to present an overview of FCS and SHTG. As you heard, I'm an endocrinologist who became a... I call myself an ex-endocrinologist. Now I'm a lipidologist. But I've been in this field for half a century and have seen the many patients with this disorder that I'm going to talk about today. And so, severe hypertriglyceridemia and familial chylomicronemia syndrome, unmet needs and current treatments. These are my disclosures. So I deal, without getting in too much into the weeds, with things called lipoproteins, and there are probably some MD PhDs in the program who know as much as I do about this, and there are some with MBAs who know very little about lipoproteins. So here's what I tell my patients: think of tiny little golf balls. They're actually submicroscopic.
You need electron microscopy to see them, and we have them circulating in our bloodstream because we move triglyceride, fat, and cholesterol, a waxy, like, fatty substance, through our bloodstream. Now, think of oil and vinegar. Those two substances would phase out in the blood, which is salt water, plus cells and proteins. And so to allow the movement of triglyceride and cholesterol through the bloodstream, mother nature gave us lipoproteins, where this little droplet of oily substance is covered with something called phospholipid. You don't have to remember that, but that's the coating to the golf ball. And then it gets a little more complicated, and I'll get back to that because I have to talk about ApoC3. But on this slide, what you see are the ApoB lipoproteins. So you don't see HDL here, which you all know about to varying degrees.
What you see in the lower left of the screen are the chylomicrons, and they are the largest and lightest and the most triglyceride-rich golf balls. They're made, as I'll show you, in the intestine when you eat fat, and the upper panel shows very low-density lipoproteins, which are also triglyceride-rich spheres coming out of the liver, the chylomicrons coming out of the intestine. ApoC3 is a small protein that is found on chylomicrons, on very low-density lipoproteins, and on the golf balls I didn't show you on the last slide, HDL, because they don't really play a role in what we're talking about today. ApoC3 plays a key role in determining serum chylomicrons, VLDL, and triglyceride levels.
And that's because ApoC3 inhibits the activity of the most important part of this discussion, which is lipoprotein lipase, an enzyme that we make in our fat cells and in our muscle cells, including heart muscle cells, and that enzyme gets out into the capillary beds, the smallest blood vessels we have, and sits there waiting for a chylomicrons or a VLDL to come along to take out their triglyceride. ApoC3 also inhibits the uptake of particles that we call triglyceride-rich lipoproteins, and more specifically, remnants. And I'll show you what I mean by that in a moment. So it has two roles, both of them not helpful in terms of what your plasma triglyceride levels will be, because one is, one role is to inhibit the enzyme that moves triglyceride out of the bloodstream.
The other is inhibiting a process that removes the whole golf ball out of the bloodstream. This is a schematic of that. On the right side of the screen, you see a little squiggly tube, and that's your small intestine. You've eaten some fat, and in the intestine, the fat, the triglyceride, is broken down to its components, called fatty acids and glycerol. They're taken up by the wall of the intestine, put back together, and what emerges from the intestine is the chylomicrons. These are just balls of triglyceride. It's an oil droplet with that phospholipid coating and some proteins on them, and that chylomicrons gets to the bloodstream. Now, if you look down at the bottom, it's pretty complex. Essentially, you're in that little capillary bed, and there's lipoprotein lipase, a little golden circle with LPL there. That's the key enzyme.
It sticks onto a chylomicrons, and it's going to chew up that triglyceride and send out its components the way the enzymes in the gut did, but now it's in, not in the gut, it's in all over the body, particularly the adipose tissue and muscle beds. And those fatty acids are gonna be taken up by those tissues, either stored for energy in adipose tissue or used for energy in skeletal muscle or cardiac muscle. And what emerges from that is something we call the chylomicrons remnant, which is taken up by the liver. So it's a two-step process to move from the intestine to the liver. If you look back to the bottom of the slide, surrounding that chylomicrons and surrounding the LPL are a number of acronyms, and there's ApoC3, there's ApoC2, ANGPTL3, 4, 8, ApoA5. Some of them are activating lipoprotein lipase.
Some of them, like ApoC3, are inhibiting lipoprotein lipase. Okay? And, that is where all the complexity of the system comes from. But simplify it, if lipase is working, you move from a chylomicrons to a chylomicrons remnant, which goes into the liver. Simple. What happens if you have no lipoprotein lipase? Okay. Well, you never get from the chylomicrons to the chylomicrons remnants, and they accumulate in the plasma. And as I said, they are the largest of the lipoproteins, but they're still very small, but they accumulate in very large amounts. And you can actually, in patients that I see who have FCS or SHTG, when they come in with triglycerides, that should be... If you're very healthy triglyceride-wise, your triglyceride might be 100 mg per deciliter.
If you're not so healthy, for whatever reasons, you might have a triglyceride of 200 mg/dL . These individuals have triglycerides of 2,000, 3,000, 5,000, 10,000 mg/dL , and as I draw their blood, it's coming out looking like cream of tomato soup. And if I just let the tube lie on its side, I get the oil and vinegar effect. But this is a light, the chylomicrons are phasing out. Just because they're so light, they float up to the top of the tube or the side of the tube above the blood. So that's what we see clinically. There are many other sequelae that we'll talk about, the worst, of course, being pancreatitis. So in the absence of LPL, none of those activators or inhibitors can do anything.
On the other hand, we have more than just LPL total loss of function. We have the severe hypertriglyceridemia, and I'll get back to that. But here is a way to look at this as a pyramid of triglyceride levels, starting from 150, which experts decided about 25 years ago, would be the upper limit of normal. People from 150 to 500 have a simple hypertriglyceridemia. They're mostly individuals with what we call metabolic syndrome, with diabetes. They have multiple risk factors for cardiovascular disease, which are added to by hypertriglyceridemia, and they are very common in the populations. I'll show you, probably 20% or 25% of the population falls in that range.
Above that, we have those with severe hypertriglyceridemia, two flavors, the lesser severe of 500-880 mg/dL , the more severe, greater than 880 mg/dL , and they smear into the FCS, the familial chylomicronemia syndromes. So if we look across those panels toward the right, you can see the differences. The most common group of hypertriglyceridemia, their major risk is cardiovascular disease. Although some of them, under certain circumstances, can explode their triglycerides up to the thousands and actually get pancreatitis. But as you move higher, then the pancreatitis story becomes more and more prevalent, more and more likely, and more and more difficult to prevent all the way to the FCS patients. Along the way, there's... We're all genetic. Sometimes we're 100% genetic for something, like FCS patients.
Sometimes we're 50%, 60%-70%, and you can see that, that brings in the environment. Alcohol intake raises triglycerides. You're overweight, your triglycerides will be higher. Diabetes, particularly poorly controlled diabetes, your triglycerides will be higher. Dietary-wise, and that gets more complicated, but certainly saturated fats and refined sugars both raise triglycerides and certain medications, that I'll get back to them briefly. So here's the overview of the prevalence of these disorders. FCS one to two per million individuals. I now have, in my practice, six individuals with FCS, okay? That's a lot for one physician in the United States, because there are a lot of us. In some countries in Europe, with small populations and few lipidologists, they may have 20 or 30, but this is a very rare disorder. Okay.
It's monogenic, associated with deficient LPL activity and complete loss. These patients are homozygous for loss-of-function mutations, and you see the genes there. And the most common one leading to FCS would be lipoprotein lipase itself, and then there are those activators of lipase's activity that if they're absent, the lipase won't work. TG levels, as I said, can go into the 5,000-10,000 mg/dL range, but mostly in the 2,000-4,000 mg/dL range. Quality of life is very markedly reduced. Beyond the risk for pancreatitis or the events with pancreatitis that they have, there are debilitating symptoms. There's often abdominal pain that's not quite pancreatitis, and it's a little bit poorly characterized. There's... Many of them have a fog associated, maybe with thickening of their blood because all those chylomicrons are circulating.
Clearly, FCS is unmet medical need. There are no approved treatments. They, they're refractory to any of the treatments that we can use off-label, such as, fibrates or, or omega-3 fatty acids. And the standard of care is to become an ascetic, essentially, in your lifestyle. I have a couple of patients who have BMIs of 18, if you know what that means. That's, that's in the low, low normal to almost abnormal range, but that's where they keep themselves. They eat almost no fat. And if you look at labels, like many people do today, take a look at the labels of how many grams of fat are in some of the products you eat. Pick up a little, a little, portion of Häagen-Dazs ice cream and look at how many grams of fat are in there.
15-20 grams of fat is hard to reach, and our patients actually need to go lower than that, five to 10 grams of fat, excuse me. No oil is good for them. All fat is bad for them. What about SHTG? Well, here we have a broader population of about one million individuals who run triglycerides over 880 and another two million between 500 and 880, and this is a complicated disease. Polygenic, that's the term we all use today for everything that's wrong with us, and 99.9% of the time, polygenic disorder, and it's also lifestyle impacting on polygenic risk. There is a risk for acute, potentially fatal pancreatitis, as there was in FCS. There's also a risk depending on other factors for ASCVD.
This is a double bad disease to have associated with chronic daily symptoms, as it is in FCS, and again, depending where they fall on this broader spectrum of TGs, and it leads to poor quality of life. And the care of these patients is not as intractable as it is for FCS, but it's very difficult, okay? And they have to work hard at the diet. Fibrates and fish oils may be beneficial, but they may not get to the point where they totally that they're totally healthy in their sense of daily living, or they're totally outside the risk for pancreatitis. And there are situations, particularly in women, getting anything that raises estrogen, whether it's oral contraception or whether it's pregnancy itself, that can push them way up into the pancreatitis stage of the disease.
So this is another way of looking at this. This is from a Danish population of 100,000 individuals. Looks at the distribution of triglycerides, and as I've said, when you get above 500 to probably 880 or above, you're in this polygenic range. Many genes involved, some of the same genes, but they would not have a full loss of function. The environment's much more important, and the HTG, SHTG group can smear over, can move over into the same levels of, of TG and the same risk of pancreatitis, depending on the polygenes, depending on their lifestyle, and the monogenics are there all the time. So what does olezarsen do in this situation?
Well, here's the patient who has no lipoprotein lipase, and this was, to us in the field, I don't know what it was to people at Ionis, but to us in the field, this was unexpected. You didn't have lipoprotein lipase, we wouldn't expect knocking down an inhibitor of lipoprotein lipase to have any efficacy at all, and yet it did. And that's because of that second pathway that's affected by C3, and that's uptake by the liver. It's not been definitively shown in people... but the TGs are falling in people with FCS when they're given olezarsen. There's not much else that could be doing this, except uptake of chylomicrons that have been maybe remodeled somehow in the blood without LPL around and being taken up by the liver. In the SHTG population, olezarsen is gonna hit both of the problems.
Remember, they have lipase, but it's somewhat reduced for a number of reasons: polygenic reasons, environmental and dietary reasons, and knocking down C3 is gonna allow that lipase to work better. Knocking down C3 will allow the remnants to get into the liver better. So here it's clear it's a double benefit in these patients with SHTG. Importantly, when you look at the risk for pancreatitis, logically, the higher your TG, the greater the risk, and this is another Danish study where they took people in the mid-eighties. They have an incredible, epic kind of medical record system there for everybody. They looked at the TG at point zero and followed them for 15-20 years, and if wherever you started, the higher you started, the greater your chance of having pancreatitis later in your life.
Here's a way to look at the more likely group to have pancreatitis, those with SHTG and FCS, with ranges of triglyceride, in this case, 750 up to over 2,000, and greater and greater risk for pancreatitis. These are some of the most important data that I'll show you, and that is here. We see that compared to people who have pancreatitis due to gallstones or alcohol, two much more common causes of pancreatitis, people with pancreatitis due to hypertriglyceridemia do much worse, the green bars. That's because they're mostly SHTG, who also have diabetes and hypertension and cardiovascular disease. But even the FCS patients do worse. Not exactly clear why. Maybe the people with gallstone pancreatitis have the surgery, and it takes care of that problem, and the alcohol pancreatitis stop drinking while they're in the hospital, but those are the data.
Also, importantly, once a patient has an episode of pancreatitis, their risk of having a second and a third and a fourth is markedly increased. So we've got to keep them from having the first event. So lastly, the unmet need here. I mentioned fibrates and omega-three fatty acids. They worked to lower TGs between the two of them, maybe 30%-40% in people with not FCS, but all of the types of hypertriglyceridemia. But mostly modest reductions, and they don't get to the point where they can't blow up at a, in some environmental way and get pancreatitis. The statins, they have very modest effect on TG levels, and so they really don't play a role in this population. GLP-1 receptor agonist, the rage these days.
What happens if you lose 20% of your body weight and your TG was 2000? While you're losing weight on those drugs, it'll probably fall. They haven't shown any of those data for a population like this. They haven't studied people who have SHTG or FCS and obesity, but it's not going to be enough, and not going to normalize their TGs in most cases. So the takeaways, FCS and SHTG, both defined by very high TG levels in the top 1% of the population at most, but they have genetic and mechanistic differences. FCS, monogenic mutations, homozygous, complete absence of LPL, and but they do have that clearance in the liver that allows this drug to work. SHTG, polygenic mutations, a bad environment on top of that, reduced LPL activity and reduced TRL clearance by the liver. Both can be improved with olezarsen.
Both patient populations at high risk for pancreatitis. The current treatment options do not provide adequate benefit, certainly for FCS patients and also for many SHTG patients. Thank you. Sam.
Dr. Ginsberg, it's really an honor to have Dr. Ginsberg here because he calls himself a triglyceride nerd. So after today, if you have unanswered questions, go to Starbucks, get two large coffees, and go visit him, and he, he'd be glad to talk to you for hours about triglycerides. All right, so with that, I'm going to actually review for you our olezarsen data. And so for those of you that have children, you know that you absolutely, positively cannot choose favorites. And so I feel the same way about olezarsen and eplontersen. Really in the same realm in my franchise for treating patients with unmet needs. Now, as a quick aside, I think a lot of you probably don't know this, but Ionis right now is number three with having cardiovascular drugs in development, okay, in the industry, okay?
My goal and my hope is by the end of the decade, we'll be number one. We'll see if we can pull that off, but we're conceiving a lot more children in this area, and so stay tuned because there's gonna be a lot of important things coming across, as the decade goes on. Now, let me just briefly summarize how we think olezarsen will work. Dr. Ginsberg very eloquently showed you the mechanisms, and so two natural questions you might have: Well, if the problem with FCS is just having too much dietary fat, why don't you just prevent the gut from absorbing it? Or why don't you just give back a lipoprotein lipase and deal with it that way? And the answer is, both of those have been tried and failed.
So we have to outsmart Mother Nature here, and the way we're going to do that is by inhibiting ApoC3, because ApoC3 is a key regulator of the clearance of chylomicrons and other triglyceride-rich lipoproteins. Now, I want to emphasize that the mechanism is going to be different in FCS and SHTG. In FCS, we're missing lipoprotein lipase, so we're dependent entirely on the clearance of these very large particles. ApoC3, you can think of it as an invisibility cloak, okay? Going back to Harry Potter. It coats these particles and hides them from the receptors, so they just circulate forever, essentially. Okay? What we're doing with olezarsen is we're pulling those ApoC3 particles off the surface, and all of a sudden, they're recognized by the receptors and clear. So you don't need to have lipoprotein lipase for FCS to get a benefit.
In SHTG, you do have lipoprotein lipase activity, so you can bring both mechanisms into the clearance of these particles, and theoretically, it actually be even a more effective approach by doing that. So now why do we think ApoC3 outside of the pathophysiology, do we have evidence that actually that will work? And the answer is yes. This is a natural history study that was published in 2008 and really led the way to develop an ApoC3 antagonist. So what did Mother Nature do for us here? There are patients in the Pennsylvania Amish community that are missing ApoC3. And so what do they look like? They have very low triglyceride levels and actually have a low rate of cardiovascular disease.
So if you look at this slide here, and you look at the dashed line, these are non-carriers of a loss-of-function mutation in ApoC3, so they're 50% of the function. Notice their triglyceride levels start at 60, probably like most of you here or a lot of you here, and now they were given a fat load. So a big milkshake, and then you measure their triglycerides, which is mostly chylomicrons, over the next six hours. And you see here that the levels peak at about four hours, and it's coming down. If this was an FCS patients, the levels would start at 2,500 and skyrocket to about 5,000. So what happens now if you're missing ApoC3? You notice the levels now start at about 35, okay? And then when they eat the fat, the levels are suppressed, so the delta between those curves increases.
This is what we're going to replicate with olezarsen, okay? Except we're going to set a much higher triglyceride levels because we want to treat patients with disease, not the so-called normal triglyceride levels. So that's going to be the basis for why we think, olezarsen is actually going to work in both of these, indications. Now, let me give you an overview of the programs, and then I'll go over the data. So for FCS, I'm going to go over the BALANCE study, which is a pivotal trial. Then, I just want to summarize for you that we have a phase IIb study ongoing, which is an SHTG population that's going to be a supporting safety database study for the NDA submission. So the NDA is going to go in with the BALANCE, and it's going to go in with this phase IIb.
We're going to have data very soon on the phase IIb, so stay tuned for that. Everything's on track for appropriate regulatory filings and launch preparations, as you'll hear from Onaiza when she comes up. Our much larger program is SHTG. So the FCS is one to two in a million. The SHTG in the U.S. alone is about three to four million, okay? So orders of magnitude more patients. And we have two pivotal trials in this indication. We have CORE and CORE2. Okay, the regulators expect us to have two trials in this indication because it's more common, and it's not outcome-based, it's based on triglyceride lowering, which is accepted as a regulatory filing, and therefore we need to have two trials. That's why you see CORE and CORE2.
They're in patients with triglycerides over 500, and then both of these are pivotal registration trials, and you see the numbers of patients in each one. They're fairly large, 540 and 390. Now, we need to have a supportive database for this besides those patients, so we have another 1,300 patients in the FCS trial, which is going to be patients with triglycerides over 200, and that those three trials will form the basis for NDA submission. These trials are going very well. They're recruiting rapidly. The data is expected in about a year from now or early 2025, and we should have an NDA in 2025 based on the findings. Okay, so let me show you the BALANCE. You I suspect a lot of you saw this in the webcast.
This is a rare population. These are genetically defined FCS patients, so they had to have a known mutation that we know is associated with a lack of lipoprotein lipase activity. It's randomized, double-blind, because placebo-controlled. Our initial going in approach was to have only one dose, the 80 mg dose, but in discussions with the regulators, they wanted a lower dose. And this is why you're seeing here two doses, a 50 mg and 80 mg every four weeks, along with a placebo group. So this is a 2 -to-1 randomization. The primary outcome is a % change in fasting triglycerides at six months, and we have two secondary endpoints that you see here, which are changes in fasting triglycerides at 12 months and a reduction of pancreatitis events. And we have a series of other secondary endpoints that are not on this slide.
So this is a patient disposition. The patients tolerated this drug fairly well. There were over 90% of patients completed the study. There were two voluntary withdrawals, and there was one patient in the placebo group, where the investigator wanted to stop the drug. So essentially, there were only three patients that had any significant withdrawal from the study. Now, very importantly, and this is an index of how the patients like being on the drug, every single patient that finished the study went into the open-label extension. So that should tell you both that there's a significant need for this kind of drug and that the patients are liking it and tolerating it and are willing to now go on open-label extension. This is the baseline characteristics. Again, this is a genetic disorder, so people are born with this problem, right?
So they have the issue for a long time. A lot of them have problems in childhood with pancreatitis, teenagers, but in this study, they're adults. We chose adult patients. You notice they're in their low, low 40s for their age. A couple of important things on this slide. Notice on the bottom here, the body weight is normal, normal or low. Okay? Like a lot of you in the audience, okay, their BMIs at 24. This is very typical of FCS, okay? These patients don't have the typical metabolic parameters that SHTG patients have, so they're a genetic disorder. On the top right, notice about 70% have already had a pancreatitis episode, at least one. Sometimes these patients have 10, 20, 30 episodes, and the mortality, as Dr. Ginsberg mentioned, can be fairly high. Sometimes it's even higher than acute MI.
Also in this particular study, about 40% of these patients were treated with volanesorsen. And this is at least one year prior, not recently treated. So they are pretty much washed out of volanesorsen. So this is a key finding for the target. Notice here a couple of things that are very important. We're going to be looking at the mean % change in ApoC3 levels over the time course of the study. Notice in the placebo group, the levels are fairly flat, and then they start to rise at six months and 12 months. So this is an index of dietary intake. It's extremely difficult to have five, 10, 20 grams of fat a day.
When you see the ApoC3 levels going up, that tells us the patients are not able to keep their low-fat diet, and the ApoC3 is accumulating on triglycerides. It's extremely important when you do these studies, to do placebo correction, because everything the patient eats goes into the bloodstream. Then if you measure that as a biomarker, you have to know how much input there is, and it's extremely hard to control that in a day-to-day, on these patients. If you notice, there's a dose-dependent reduction in ApoC3 levels, reaching 74% at six months, with the 80 mg dose and 66% with the 50 mg dose. The data actually continued to improve over time, with a 77% reduction in the 50 and an 81% reduction in the 80 d oses.
Now, these are the key findings from the study. Now, this is top-line data. We have not closed our database yet, so we're not sharing everything that we can share. We will do that at the next major cardiovascular meeting. A couple of things I want to point out. We had a highly statistically significant reduction in triglycerides, and you see the P value there. We barely missed our triglyceride lowering with the lower dose. We understand the reason for that. We'll share that with you later, but it apparently had to do with the variability at that specific time point. On the bottom, shows the most important and really unprecedented findings for the study. Dr. Ginsberg has been waiting 50 years to see this, and I'm glad to say Ionis finally delivered to you and your patients a way to inhibit pancreatitis. This is unprecedented.
Nobody's ever done this before in the 50 years in the field. So what you see here with both doses, we had a massive reduction in pancreatitis. We had 11 events in the placebo group in seven patients. We had zero events in the 80 mg dose, and we had one event only in the 50 mg dose. Despite the fact that you see there, we missed our primary endpoint for the 50 mg dose. This tells you that over time, when you look at the time average reductions, they're actually very significant, and we'll be able to provide more data for this for you in the future. In terms of safety and tolerability, what you're seeing here is that the GalNAc drugs are safe and tolerable as a class. We're not seeing some of the issues we've seen in the past.
Most of these issues are balanced. What's important in this study, which tells us the drug is working outside of the endpoint, is there was actually an imbalance of treatment-emergent adverse events in the placebo group with higher numbers, and most of these were related to GI side effects. So these patients are feeling ill. They have a lot of GI side effects, so they actually tended to be more in the placebo group. So sorry, let me just go back a second and make a couple other points. The rest of the points here in terms of other significant adverse events were fairly low. There was one death in the 50 mg dose. This was unrelated to the study drug.
So, in summary, I think what you can see is, extremely good data on ApoC3, statistically reduction on triglycerides with the 80 mg dose that we were going in with. We have a tremendous effect on pancreatitis, and the drug looks like it's going to be very tolerable. So with the supporting data from the other trial, we're on track to complete, at the end of this year. We have an expanded access program to capture, these patients, that are coming off the trial. Our regulatory findings should be on track and launch preparations are now underway. So now I want to invite my tag team partner, Onaiza, to come back and tell us how she's going to, get this drug to patients. Oh, I'm sorry, I finished too soon.
I had a little brain disconnect there. Yes. Let me give you some... Sorry about that. Let me give you some details on the core program. I apologize. So I mentioned briefly the data on this. So we have the two trials, as I mentioned, complementary. They have very similar trial design, okay, as the balance study. So we're going to be able to read through some, but not completely, because it's a different population, as I mentioned. We have a 50 mg dose, we have an 80 mg dose, we have a placebo. We have the primary endpoint here is going to be triglyceride lowering from baseline to six months. You do not need hard endpoints for this indication, at least in the U.S.
Anything over 500, if you lower triglycerides, that's good enough for regulatory submission if your drug is safe. We're going to be able to take these two, two studies and look at them individually and also combine them. Okay, so we'll have 930 patients to be able to get great data on a variety of different things. About 25% of these patients are coming with a history of pancreatitis. So we're going to have really, really good power to not just look at triglyceride lowering, but also the pancreatitis effect of these drugs. So, this, these two are the pivotal trials. The supportive study is called FCS. This is going to be much larger. It's going to be in patients with triglycerides over 200.
It's going to have very similar design, and you can see here, and this is going to be extremely fast. We built into it several important imaging studies, including MRI of the liver, and we've shown recently that volanesorsen reduces liver steatosis. We also have built into it a CT CT angiography study to look at plaque burden. Those are kind of like profile enhancers. They're not part of the main safety parameters that we need for the CORE and CORE2. So the data for this is expected in late 2024, early 2025. So bottom line, I think, is that we have a great drug. We have beautiful data, particularly on pancreatitis in the BALANCE study.
We have a great program, I think, for then to take this drug and expand it to a very, very broad population. We have now preparations for going forward to patients. Thank you very much. Now, Onaiza?
I'm glad you did that part. Wonderful. So it's been really a pleasure to hear from Dr. Ginsberg. He's taught me a lot, and I hope you appreciated his teachings of triglyceride biology and the different mechanisms that are at play in both the FCS population and the severe hypertriglyceridemia population as well. So, we are with olezarsen, as you know, as Sam just went through the clinical trial program, addressing two distinct populations, two distinct indications. The first one in FCS is really about treating the significant risk these patients have for acute and potentially fatal pancreatitis, and this comes from really them having no and zero lipoprotein lipase activity, as Dr. Ginsberg just went through. We are going to enter this market with a first-mover advantage.
We will be the first to bring a treatment, where there hasn't existed a treatment for these FCS patients. It's a real honor to be able to do that, for many of the patients that have been waiting for many, many years for a treatment option. We are then also have a line of sight into severe hypertriglyceridemia. Here, the job is different. We're addressing a very large population of about three million patients. And one of the things I really liked about this is when we went to the end of phase II, studies and discussions with the FDA, they were very clear about, "Please do the right study here.
Do the right study for all patients over 500 in SHTG." There was a thought process that we had that we might actually look at 880 and above or, you know, other guideline indicators and above. They were like: No, these are all severely hypertriglyceridemia patients. Do the right study, and the biomarker that's really important here is triglyceride reduction. So we have a clear regulatory path. It's important to know. The other thing that's actually very, I think, unique, at least from my experience in different launches in this area, is the treatment guidelines are already set. Usually, you're looking for the data that comes out that's very robust, and you go back to the guideline committees, and you have the guidelines updated as a result of that. Here, the risks are known.
The risks are known because these patients are at risk for acute pancreatitis, and as Dr. Ginsberg said, because of the remnants floating around, also for ASCVD. Both the ACC guidelines, the endocrine guidelines, and other guidelines really reflect this treatment. The only challenge here is that the treatment guidelines are there, but there are no great options for these physicians to get them down to the levels of goal of triglyceride reduction that is needed. So this together really represents a fantastic blockbuster opportunity for olezarsen across both of these indications. Starting with FCS, you've heard a lot. It's rare, it's severe, it's debilitating. Let me just spend a couple of moments on the debilitating piece, because I think it's really important to get. We heard a lot from both Sam and from Dr. Ginsberg about the physical and the physical symptoms that these patients have.
You know, the severe nausea, vomiting, and abdominal pain. It is absolutely true. But in addition to that, they really carry a lot of emotional symptoms as well. There's cognition abilities that are really difficult. And you can imagine when you have to be on a strict diet, as they have to do each and every day, which is like a handful of maybe fat intake of five almonds, one to two tablespoons of olive oil, it is really hard to have a really normal social life. They can't actually go out and and engage, and enter restaurants and kind of eat at will. And it really does impact some of their emotional well-being as well, impacts their relationships and their ability, in terms of productivity, in showing up work, because they're usually have some of those physical symptoms that are debilitating as well.
We're very, very honored and excited to bring a treatment option with the results of the BALANCE data, potentially getting that approved in rapid fashion for a patient population that's had no effective treatments to date. Our market research that we did with HCPs, patients, and payers really leads to a couple of things about olezarsen that's very exciting. First of all, patients don't even need to measure their triglyceride levels. They know when their body is in danger. They say, "My body tells me, and there is very little I can do about it." Patients are at fear for having an AP attack, and they are very, very motivated to take action. Very pleasingly surprising, the payers of this area actually understand the disease and then they know there's nothing there.
We tested our target product profile, which we expected would show significant results in terms of trends in improving acute pancreatitis, but we actually got a hard outcome and a statistically significant outcomes data for them was supposed to be a home run. I'm very excited to know that we don't believe that this is going to be a real problem from an access perspective, and payers are gonna really recognize the value proposition of our product easily. So FCS patients are at increased risk for acute pancreatitis, as we've seen. In fact, two-thirds of FCS patients have experienced an AP event in their lifetime, and as a result of having an event, they're 10x more likely to have a recurrent attack.
You could imagine, if you know that, that you're always living in fear and anxiety, that you wind up in that ICU again with another attack. And then the attacks that they do have are 2x more deadly because they're more likely to result in death versus other acute pancreatitis causes. So what are we doing to get ready? Well, this is a rare disease, one to two per million patients. And we have looked at some of the registries for FCS patients, and they're smaller, actually lighter than where we would expect the prevalence to be in the United States. So we're doing a lot of work through that data integration tools that I said, to identify FCS patients, to figure out where they are in the system. And that's been a core activity of our launch readiness plan over here.
We also have field medical that have been out in talking to lipidologists, but also, endocrinologists and, cardiologists to really kind of prepare the market from an understanding of disease and symptoms. And then with the data that we have from the balance, we can actually now start engaging with payers to let them know that this product is coming. Post-approval, we'll do all the usual things of sales and marketing execution. Here, given the rare disease nature of this, the access, the distribution, the specialty pharmacy are really key things that we need to just really nail down, and we will, and the patient services are going to be really important. So this is that circle of our customer model. We're entering it in. You just saw it for eplontersen. We have a very similar philosophy for the olezarsen team. It's a one customer team.
One key thing that's different here is that the sales account management team will be the Ionis sales account management team because this will be our first independent launch. Then alongside of that, we have all the additional field-facing, customer-facing resources to create a very delightful customer experience on their journey. Moving to SHTG, this is also a severe disease. It's just much more prevalent and still has a significant unmet need. It is common. As I said, there are about three million patients in the United States, and it is severe. These patients are also, as Dr. Ginsberg went through, at risk for fatal pancreatitis.
And when I had a conversation with him last evening, he said, he goes, "Well, we actually see many more of these, you know, in the ICU for acute pancreatitis with SHTG." And that's just because there's so many more, right? Absolute number of them as well. This has a high disease burden. These patients, I often get the question, it's like it's a silent, TGs are silent, right? It's a silent biomarker. Like, are they gonna go and do something about this? Well, in fact, it actually is silent. It has patients who suffer from lots of physical symptoms, abdominal pain, pain, and reduced quality of life as well. So this is not gonna be as silent as, let's say, LDL was. And these patients are also very underserved by current treatment options.
You're looking at fibrates, niacin, and fish oils really as available. It's really important to know, and, I'm sure, and Sam highlighted this, but our studies in CORE and CORE2 are designed to show the benefit of olezarsen on top of those treatments that are already available to them. So really do think this is gonna be a significant change in the treatment paradigm for severe hypertriglyceridemia. As you can imagine, with three million patients, we have to think about, you know, how do we target these patients? We're not expecting we're gonna get all three million patients on olezarsen, but in order to understand where we're gonna go and where we're gonna get the adoption, we did some really great work to understand where the highest degree of unmet need is.
As you can see, that the higher risk of greater than 880, which is a nice demarcation line in the treatment guidelines, is where the higher risk SHTG patients are. Not to say that the SHTG patients on greater than 500 are not at risk either. They just present differently, and some of their risks are different around the ASCVD that they carry as well. So we're gonna actually robustly target both parts of this population, and what we're not going to focus on is the hypertriglyceridemia patients that are in the 150 to 500 patients. That is not where our strategy, nor our indication, nor our clinical trials are designed to.... I've mentioned the guidelines a few times. It's really important to see how they put this into the guidelines.
For patients, they do do that demarcation line of 880, and therefore high risk SHTG. They recommend that you, you know, do your weight loss and diet, diabetes, but you initiate treatment with fibrates to reduce triglycerides. And we expect if we have an olezarsen on the market, those are the types of things you will see in the guidelines as well. And then they also have recommendations for patients who are at the 500-880 mark, where they're also recommending the weight loss, but also statin therapy to reduce CV risk and initiate treatment with omega fatty acids and fibrates as well. So great to know that the guidelines already exist. I think with the advent of the data we have for olezarsen, we expect that this to be really mainstream and updated as a result of our data.
So as usual, we do a lot of market research here. It's a large market, so we really went deep. We talked to 200 HCPs, 600+ patients and 20 payers that cover about 100 million+ lives, most of the United States. Payers view the target product profile very favorably, suggesting potential for broad access in more in that high premium kind of cardiovascular prevalent disease range. For the HCPs, they understand the association between TGs and the risk, the risk of acute pancreatitis and ASCVD. And very many physicians really told us, "I get the guidelines, this is great, but I really don't have any effective treatment options here." From a patient perspective, they're motivated. They're motivated to take on a new medication, one that really works and is effective for them, and they understand the underlying medical need.
These patients also live with some of the emotional symptoms that we have. The physical areas are well known, but as a result of an anticipated attack, as a result of an anticipated admission into the hospital, they live with increased stress. It impacts their quality of life from a sleep perspective and their ability to work. And these in the cloud are some of the cloud-words that really came out that keeps them really socially isolated. And because the disease isn't taken as seriously, they feel that they really don't have a good support system around them as well to really help them through this journey.
As we're preparing to address this market with SHTG, we can see to the right is the cutoff in the United States for the patients who are greater than 880 mg/dL . That's about one million patients. And then to the left, the 500-880 comprises actually 2.5 million patients. Now, one of the things I really want to leave you with here is this is not a static demarcation line, and we have a little dotted line around these patients. And the reason is the way triglycerides are measured is at fasting. And all our measures, when you go into the doctor, you go in fasting, you get your blood drawn.
But we know that as soon as we eat during a day, the fasting, actually changes because you have postprandial fluctuations that happen through the day, which accompanies your meals. And these levels change during a day. So you can easily be in that kind of, you know, intersection right there of being in the 500 range, and all of a sudden you're up into that 880 range during the day. And once patients are in the higher risk segment, they are often unable to reduce their TGs and remain a higher risk patient. So our plan really is to do the education that's needed with the physicians to understand this postprandial level that is fluctuating as well and really address both segments in parallel, parallel for rapid adoption. We also needed to understand who the treaters are, because this is actually wide.
But instead of going, well, we've got lipidologists and cardiologists and endocrinologists, we really wanted to think about the behavioral segmentation here. Like, what want to make you actually treat SHTG over here? The behavioral segmentation comes out like this. We have a very nice portion of physicians who are, we call aggressive treaters, and we call them aggressive because they understand the two underlying risks of this biology, and they are ready to treat all patients over 500. They will certainly be a priority in our launch focus as well.
And then we have the actives, and the actives are also going to be a priority because they get the TGs, but they're really more on the line, "I want to treat the patients who are really high risk at over 880." So we're going to actually, you know, focus on both of these segments as we launch, and we always know when we get to launch phases over time, the actives become aggressive and this changes. But right now, this is how the market is playing out, and this will consist of, again, lipidologists, cardiologists, and endocrinologists, and we're really looking for cardiologists here that have that preventative mindset. So, our launch is designed already. We're launching in FCS first. Here, our goal is to establish Ionis's first commercial presence in the marketplace.
We're going to cultivate advocates for olezarsen, and this gives us an opportunity to deploy and optimize our commercial capabilities ahead of the broader SHTG launch. For the launch in SHTG, our priority launch phases that I just went through will be our focus. We're going to leverage existing treatment practices of priority treaters and quickly establish olezarsen as preferred treatment. And then over time, we will extend our physician engagement and really get to more broadly reach more than the patients with SHTG. So Sam went through our baseline data. It is complete. It's exciting, unprecedented data as we saw. And as he also explained, we're just waiting for the completion of the phase IIb study, which is just to give us the additional patient exposure for the full filing of FCS.
We expect the regulatory filing to be very early in 2024, just in the turn of the year. Then with that filing, we also believe we have a very strong potential for priority review here. Huge unmet need, great unprecedented data, and we are planning for that. And that is the way we're planning for a launch, expected for FCS at the end of 2024. In parallel, we're waiting for the completion of our severe hypertriglyceridemia program, and the readout is going to be in late 2024 or early 2025. And then we expect that to be an sNDA and get that ready for an olezarsen launch in mid to late 2026. So I conclude and leave you with a patient, patient that, Brett actually opened with Nicole.
Hearing from FCS patients again here, I think the thing that I am left most, most with is the kind of social isolation these patients really live with. And same for SHTG, just kind of the emotional cloud. I hope that remains with you in terms of what they really face on a day-to-day basis. With our robust ApoC3 reduction, significant triglyceride reductions, and substantial reductions in acute pancreatitis in the balanced phase III study, we are ready for our FCS filing and launch ready in late 2024. And then olezarsen, we expect, will be the first of many medicines that you should expect to launch from our fully owned pipeline. So with that, I'd like to actually invite Wade Walke, Head of Investor Relations, up.
Thank you, Onaiza. A little bit behind schedule, so I'm going to ask everybody if they could come back here, and we'll restart again at the bottom of the hour. For those that are on the East Coast, that's 10:30 A.M. All right, see you in a bit.
I've always had trouble with my weight.
Now with Wegovy, I've seen real change. I've lost weight, and I'm keeping it off.
Wegovy helped reduce my appetite. Who I'm meant to be, Wegovy.
Wegovy is the number one prescribed once-weekly weight management medicine for adults with obesity or some with excess weight. People taking Wegovy lost an average of 35 pounds. Some lost over 46 pounds.
Wegovy shouldn't be used with other semaglutide containing or GLP- ... Well, Belinda used to get me when it, you know, just years ago.
I'm on donidalorsen. It's a privilege to have one of our key opinion leaders, a key opinion leader. As well as, in addition to covering the unmet medical need in HAE, Dr. Tachdjian will also review for us the treatment landscape for this disease. Following Dr. Tachdjian will be Ken Newman. Ken Newman leads our donidalorsen phase III development program for HAE. Then after Ken, we'll bring Onaiza back up to talk about how we plan to deliver donidalorsen to patients in need. So, Dr. Tachdjian, it's all yours.
Morning, everyone. Thanks for the opportunity to speak to you on hereditary angioedema. I'll give you a quick comparison with allergic angioedema. The word angioedema, as you know, is swelling, and if you have a penicillin allergy, or you got stung by a bee that you're sensitized to, you have an allergic reaction, and that swelling usually would be taking course over 24 hours. Whereas with hereditary angioedema, you'll see that that kind of picture is a little different. I'll be talking about how unpredictable, debilitating, and potentially life-threatening, and in some instances, deadly, this condition can be. These are my disclosures for speaking as well as research on our area. Oops. We'll dive right in. This is obviously a rare and potentially life-threatening condition. It is genetic, hereditary in the sense, it's autosomal dominant.
So each patient that is identified has a 50/50 chance of passing that on to their next progeny. It's hallmarked by painful, but most importantly, unpredictable attacks of swelling. Like I mentioned at the outset, if you have peanut anaphylaxis today, you could say, "I'm not gonna eat anything at this hotel," et cetera, and we can predict that you're not gonna have a swelling attack. The HAE patient opens their eyes and is not sure if it's gonna be a smooth day, or if they're gonna miss their daughter's graduation, their significant other's job promotion party, their birthday. And so at the crux of this condition is C1 esterase, which is a protein that's either deficient or dysfunctional in these patients, and that drives the majority of HAE. What does that look like?
So on the right side of your slide, you'll see attacks that can occur at any part of the body. Obviously, the laryngeal ones can be life-threatening, and there have been deaths reported on the way to the emergency room or blamed on something they ate and so on and so forth. The stomach or abdominal attacks can mimic anything under the sun. So these patients typically get appendectomy done, open laparotomy, laparoscopy, et cetera. Unnecessary procedures. And the rest of the body, when it's your hand, your feet, you might think, "Oh, well, suck it up." But what if that's your flight attendant, your surgeon, or my hairstylist?
So as I mentioned, C1 esterase inhibitor is at the center of this condition, and you'll see in the gray bar in the middle of the right diagram that it's there to block the progress after prekallikrein, which is the zymogen or the precursor of kallikrein, can then facilitate the release of bradykinin from high molecular weight kininogen. Bradykinin is responsible then for loosening up or opening up the blood vessels on the venous side of the body to then release fluid, extravasate. That's what causes the swelling. Against a hard surface, such as the back of your hand, cheekbone, that swelling will be more prominent than, say, in the intestinal area, where you've got a lot of room to expand. What does that look like when I get called to the emergency room? Here's a young lady, panel.
By the time she gets to the emergency room, our first concern, she's drooling. Meaning, she's not able to swallow something as simple as her saliva. And what follows there is not being able to pass the airway, and so the airway can be compromised. Fortunately, she's caught in time, plus or minus intubation, and you could see the resolution start to happen. Now, this patient could look like an allergic angioedema patient to the untrained triage nurse, for instance, in the emergency room. But there's no hives, so no urticaria associated with HAE, and there's no itching, so no pruritus associated with HAE attacks. And so this patient can be given all the antihistamines you want, corticosteroids, even epinephrine does not really help this condition because you remember from the diagram I showed you earlier, there's nothing about histamine, IgE, et cetera, that hints to allergic.
This is purely an immunologic complement-based condition. As far as HAE, this is a condition that occurs in one in approximately 50,000 patients or individuals across the world, and I've seen pretty much every race and ethnicity represented. Remember, it's 50/50 for gender because it's autosomal dominant. It tends to affect women a little more than it does men due to hormonal differences. But when you calculate that sum, there should be over 20,000 patients across the U.S. and Europe combined. In the middle panel, you'll see, again, focus back on the basis of this condition. So Type 1 patients comprise about 85% of the pool, and those are the folks who have not enough C1 esterase inhibitor. And I call it not enough wheels on your car, so it's not gonna run well. One wheel's missing.
Type 2 looks like it's got four wheels, should run like a car, but they're actually triangular wheels, right? So that's not gonna be a smooth ride. So it's dysfunctional C1 inhibitor. So the number is fine, and this got diagnosed or classified later in the last 30 years. Lastly, extremely rare and less than 1% of this total population, is the HAE with normal C1 inhibitor, which we formerly used to call Type 3, and these patients have genetic mutations and extremely rare, like I said, so the focus is more on type one and type two. Now, age of onset. It's great that we can describe the condition, but are we missing it?
So as someone who did pediatrics, this was not on my radar, simply because it's only been about 13, 14 years that we've got the novel era of therapeutics, and we were stuck with mainly anabolic androgens in the past and archaic forms of treatment. But 50% of patients will experience their attack, their first attack, under the age of 10. And in that last bullet point, you'll see that there are a good amount of individuals that will have their first attack in infancy, in the first year of life. And it could be something as daunting as scrotal swelling or labial swelling that warrants a $1 million-dollar workup from urology, nephrology, and so on.
Now, that's for just detecting someone who may or may not have a family history, because remember, it's hereditary and you may have a patient above you and a patient below you as family members. Now, 25% of individuals are de novo mutations, so that means there's no parental or great-grandparental history. So that makes the challenge of diagnosing these patients even greater. You can see on the right that patients will experience a number of years meandering through the system, the healthcare system, seeing multiple specialists until they get to the immunologist who knows what to draw. Because think about it, if you're in the emergency room, you don't have time to follow through. You just stabilize the patient. But then we always ask the emergency room physicians to at least refer them for the workup.
That might take a week or so to come back. What is that workup? Essentially, what I mentioned, the tires on the car. Check the C1 esterase inhibitor level. Check the function. Oftentimes, we check complement four, which also gets run down in the immune system. Less commonly, because it's cost prohibitive and access-wise, might be difficult to attain, genetic testing is available. For instance, I have a young female patient who's now in her teens, but we diagnosed her right at birth using cord blood, matched her mutation to her dad's. Her older brother was fine, so the dad essentially got a 50/50, one child without, one child with HAE.
The problem is for the normal C1 inhibitor, that third portion that I told you, the less than 1%, their labs look essentially the same as most people here who do not have HAE, and so there's no approved diagnostic testing for that category of patients. Now, when the attacks hit, the patients in a recent study from the Hereditary Angioedema Association, and this is a big organization, patient organization that is amazing in how it works. And my clinic is actually the referral center for Southern California for patients that are identified through that venue. So this is a recent study that's just gotten into the publication. You'll see that patients were responding as saying the majority of them have gone to the emergency room, so 87% utilization there. Over two-thirds have been hospitalized.
A good amount of folks have been in the ICU, with or without intubation. Then 16% have had unnecessary and inappropriate abdominal surgery, simply when laboratory testing could have been done at that time or earlier. When you look at a quote of a patient saying, "I've been intubated three times, and the very first time they had to resuscitate me because they had trouble getting the tube down, and I stayed in the ICU for three days." I actually have a female patient whose husband is a hunter, and this gentleman practices on a deer every time he...
I'm not a pro hunting guy, no, don't judge me, but he sits there and does his little surgical exercise every time he brings down a deer because he's had to assist with his wife when she shut down her airway in the past. So it's that extreme of a condition. Mind you, these guys diagnosed their HAE before we had novel medications, but to tell you that we've come a long way and still have a long ways to go is an understatement. On the right, you'll see that attacks may last up to five days. Remember back to the peanut, the honeybee, penicillin allergy that I told you, that angioedema lasting 24 hours? Here, the uptick of angioedema in hereditary angioedema or HAE could be up to two days, so you can still continue swelling.
The downtrend can take up to three days, and there's nothing you can do at that point to accelerate resorption of that fluid. It's through the lymphatics. And so a typical HAE attack could put you out for five days, so you're out of the pocket as far as being present, having presenteeism in society. Moving forward to the treatment landscape, it's divided into two portions. I will start with the right side, acute therapies. So every patient, according to the guidelines, the HAE guidelines, are stipulated to have two on-demand therapies, available to them, or two doses, I should say. And on the left, you'll see that the move is more and more towards we should try to control the condition rather than this disease controlling the patient, and that's through prophylactic therapy to prevent attacks.
If there are breakthrough attacks, to really dampen them so that the severity is reduced. Approved prophylactic therapies to date include daily, twice-weekly, bi-weekly, and for a few select patients, maybe up to every four weeks dosing. Why do I mention that? I showed you a lot about the burden of disease, but there's also a burden of treatment that's a real thing there, where patients might get fatigue from twice a week, infusions, injections, and so on. From that patient-reported survey of over 500 participants, 57% reported that they've used a prophylactic medication in the past 12 months. A little over a third said that they had more than two attacks per month, which, in the majority of HAE specialists will say that's severe HAE phenotype.
13% reported they had good control of their disease with less than or equal to one attack per year. So I hope you take these key takeaways, mainly the sense of urgency in the HAE community to help these patients who have this unpredictable disease that's making an impact, not just in their lives, but really in, in their community. So their teacher is affected, the coach, et cetera, young kids with their siblings. And then on average, it takes multiple years for patients to be diagnosed. And remember that 25% of them don't have a family history.
So when they show up to that emergency room or whichever portion of the medical world they, that they present to, there isn't that extra hint of like, "Oh, yeah, family-based condition that you may, you may realize or you may find out on my labs." And then, despite approved prophylactic therapies on the market today, less than 15% of these patients are reporting good control of their disease, which tells us that there's still an unmet need, and patients are looking for better treatments to reduce the disease burden, as I mentioned, and the treatment burden. And so at this point, I'd like to invite Dr. Ken Newman from Ionis to take us into the next phase.
Good morning, everyone. Thank you, Dr. Tachdjian, for your really insightful comments about what it's like to actually treat patients with hereditary angioedema. It's actually a reminder of the first patient that I ever saw with HAE. I was a fellow at Johns Hopkins some decades ago, and a young woman was admitted into the intensive care unit with massive laryngeal swelling. With major effort, we were able to intubate her, put an endotracheal tube into her airway, save her life. It was a great reminder that this is a fatal disease. In fact, in the days before effective therapy, excuse me, 30% of patients would actually die of asphyxiation due to their disease. There was no effective therapy for acute angioedema attacks until 2008. The only thing we could do was supportive care.
It's always a reminder that this disease continues to have high morbidity, anxiety, depression, and sadly, occasionally, still mortality. The importance of the kinin kallikrein system was pointed out by Dr. Tachdjian . What Ionis scientists did was they produced antisense oligonucleotides to every step in the pathway in order to determine which of these were the most important proteins to be able to reduce, therefore determining which was the most effective therapeutic target. They determined that prekallikrein was the best target for a therapeutic intervention. So prekallikrein is metabolized to activate the kallikrein. Kallikrein cleaves bradykinin from high molecular weight kininogen, therefore producing the characteristic submucosal and subepithelial swelling that characterizes hereditary angioedema. So we're going to walk through why donidalorsen is such a compelling HAE prophylactic therapy, potentially.
It can be dosed every month or every other month, and in a patient-friendly auto-injector, meaning the auto-injector has a low volume and has an ultrafine needle. We're going to walk through the striking phase II data at a high level, which was so unique that it was accepted for publication in the New England Journal of Medicine. We're then going to show you some new open-label extension data from the phase II trial, and then we're going to walk through the phase III program, which is the OASIS study. OASIS stands for Oligonucleotide Antisense in Symptoms of HAE. This is a phase III, phase III study, which is fully enrolled, but which we expect data in the first half of next year. Then we're going to talk about the open label extension study called OASIS Plus.
This study actually has two parts, one of which is an open label extension, another part is a unique switch protocol, which we will talk about. This is an overview of the phase II study with donidalorsen. This was a randomized, double-blind, placebo-controlled study of monthly subcutaneous injections of donidalorsen or a placebo. So what you can see is patients entered into a screening period of up to eight weeks, during which time they needed to have at least two attacks. After they had their second attack, they were then randomized in a 2-to-1 ratio to either donidalorsen or a placebo, given every four weeks, so that the primary endpoint was at week 17, which is 16 weeks after the first dose. At that point, they could either enter into a post-treatment period or roll over into an open label extension.
There were 20 patients that participated in this study. 17 of them, or 85%, rolled over into the open-label extension. The data was remarkable and compelling. It showed a rapid and sustained improvement in HAE attacks. Specifically, starting from the first dose, there was a 90% reduction in the rate of HAE attacks. We know with anti-C1 esterase inhibitors that it often will take two doses in order to get maximum efficacy. So we predefined a key secondary endpoint being the efficacy starting from the second dose. From that dose, there was a 97% reduction in the rate of HAE attacks. In fact, every patient but one was completely attack-free. That's 92% of the patients on active drug versus no one, none of the patients on placebo. Importantly, this was associated with a statistically and clinically significant improvement in their quality of life.
At the same time, there was a favorable safety and tolerability profile. Specifically, the adverse events were actually lower in the active group than they were in the placebo group, and there was no safety signal of any type. Following the completion of the phase II double-blind study, patients could enter into the open label extension study, and this is the design of that study. There was a fixed dosing period, during which time patients received donidalorsen 80 mg every four weeks for four doses, after which the dose could be varied depending on how the patient was doing. The patient could continue on 80 mg every four weeks, or if they were doing really well, the dose could be extended to 80 mg every eight weeks.
If for some reason the patient was still having attacks or was symptomatic, the dose could be increased up to 100 mg every four weeks. We now have two-year data from this. I will only show you a little bit of that data. The rest of this data will be presented at upcoming congresses. For the first time, I am showing you this striking data, and this graph basically says it all. What you can see on the Y-axis here is the HAE monthly attack rate, and on the X-axis, you see time in the study. So starting on the left, you can see the time in the double-blind study, and then after the dashed line, you can see year one and year two in the open label extension. And you can see the rate of attacks go down dramatically.
In fact, it's reduced 96% over two years. The rate of attacks is 0.06 attacks per month. It's remarkable. If you remember what I said on the prior slide, with 97% reduction, starting with the second dose, what we see now is that that is sustained and durable over two years of the study. As Dr. Tachdjian mentioned, the goal of therapy is to improve quality of life for these patients. This is the quality of life data. This is for year one. Year two data will be, has been submitted and accepted for presentation at an upcoming congress very shortly. So this is the angioedema, specific quality of life questionnaire. The minimum clinically important change is four points. I'm sorry, six points.
And what we found in this study is we had a change of four times that much, as an improvement of 24 points. So what you can see on the right is what's called a radar plot, which I think it looks really cool. So on the top is the total score for the angioedema quality of life questionnaire. And on the side, you see the subscales, nutrition, fear, shame, functioning, fatigue, and mood. And there was dramatic improvement in every one of these endpoints. This is remarkable, especially for such a small study, to see these sort of effects. Turning to the safety data, what we found is that the drug was well tolerated. Specifically, there's been no serious adverse events.
There've been no treatment emergent adverse events that avoided discontinuation, and the only TEAE that's occurred in more than one patient was injection site reactions or discolorations, which have occurred in two patients. There have been no changes in any laboratory parameter, no changes in ECGs. So with this data being so striking, we urgently moved to a phase III study. This is a fully powered, well-designed study of donidalorsen in hereditary angioedema. This is a global, randomized, double-blind, placebo-controlled trial of monthly and bimonthly doses of donidalorsen in patients aged 12 and up. This study is fully enrolled. There are 91 patients that have enrolled in this trial. The design is what you see on the bottom.
Patients enter into a screening period, during which time they need to show at least two attacks, after which they are randomized to either donidalorsen 80 mg every four weeks, donidalorsen 80 mg every eight weeks, or matching placebo. At the completion of the trial, which is 24 weeks, they can continue into a post-treatment period, which is an additional 13 weeks, or they go into an open-label extension. The primary outcome, as in all studies of this type, are time-normalized number of HAE attacks. The open-label extension trial has been termed OASIS Plus. This is a continuation of dosing for patients in the OASIS trial. I can say that more than 90% of the patients in OASIS have been rolling over into OASIS Plus.
The study patients will continue getting the dose that they received in the prior study, so they'll receive 80 mg every four weeks or 80 mg every eight weeks. The primary outcome is safety. So it's the incidence of treatment-emergent adverse events, but the key secondaries are, of course, efficacy and durability of effect. This is a totally unique part of the study, and it is almost like two studies in one. This is what we term a switch study, and what it basically says is that we're taking patients that were on treatment with other HAE prophylactic therapies, whether it's lanadelumab, berotralstat, whatever, and then they are switched to donidalorsen 80 mg every four weeks for at least one year. And the reason for doing this are multiple. First of all, we want to be able to show comparable efficacy.
It's a way of being able to say, "What is the efficacy of what you were on previously, and what's the efficacy while you're on donidalorsen?" In that way, we can measure patient satisfaction. We can say, "How well are you satisfied with the medication that you were on?" Versus, "How satisfied are you with donidalorsen?" And we can ask them their preference. The Coke versus Pepsi question: Do you prefer donidalorsen, or do you prefer what you were on previously? And finally, it gives physicians guidance on how to switch medications. Right now, there is no data out there on how physicians should switch from one prophylactic therapy to another. So we're gonna fill that gap. So the takeaway message is we have a really compelling and robust story. We have great data to date. We have a phase III program which is fully enrolled.
We are planning on taking all of this data, of both the phase II and the phase III program, and using it to file an NDA, in the middle of next year. If we are fortunate enough to get approval from, from the FDA, it will then be our responsibility to bring this medication as a therapeutic option to patients, and for that, I turn it over to Onaiza.
Thank you. So donidalorsen, the last of our three near-term opportunities and much more to come in the next wave. I hope that you were struck by some of the patient illustrations of what it means to actually live with this disease. What really struck me was the patient that Ken treated when he was a postdoc at Johns Hopkins. I can't imagine what it would feel like if you're really getting this shortness of breath while your larynx is actually swelling up, and you only have just that much time to get yourself to the hospital. And I cannot imagine what that feels like as that constriction in your airways continues to happen on that journey. So the whole thing about this area is prophylactic treatment to prevent that. And I have to say that the market dynamics ...
I'm thankful actually to all the prophylactic treatments that have done a really nice job of moving patients out of acute treatments into prophylactic treatments. As a result, we have a very well-defined population. Yet there continues to be significant unmet need. The increasing rate of prophylactic treatment is actually very high, and it's growing. In the United States, we're at about 70%. We expect to be at 70% by the time donidalorsen enters the marketplace. This is not the case, actually, in Europe, which is still another sad state for these patients. And I'm encouraged to see that it is increasing, but we're not there yet. The other thing to note about this patient population is they're really searching for the efficacious product that are gonna prevent the attacks alongside the convenience that they need for their lifestyle. Dr.
Tachdjian actually told us how young these patients are. They're like, average attack at the age of 18. They're on the go. They need something really that's accompaniment to them, not refrigerated and not obviously going into a, a physician's office to do that. So we've seen patients switch both ways to find both of those things together. And then, lastly, the launch plans for this is, it's simple. We actually really know where the physicians are who treat these patients in the United States. They're very concentrated, and about a quarter of the allergists and immunologists only treat, HAE, so easy for us in a very efficient commercial model to get to them. So Sydney is your typical, you know, younger population for HAE. We have about 20,000 patients in, from a prevalence perspective in Europe and United States.
About 6,600 of them are in the US. We believe with our very strong profile that we've seen in the phase IIs, where the product is designed to reduce the source of the problem, which is the production of prekallikrein. Our studies have actually shown some really great data you saw from Ken, where you see a rapid, that's in one to two doses, a rapid reduction of HAE attacks. Rapid is actually really important here if you're going on a prophylaxis treatment, right? And then, as he just revealed with the two-year data, we see that sustained reduction over two years. It's pretty compelling. So we really feel like we're in a very, very strong position to deliver a compelling HAE prophylaxis product to the marketplace. Now, the question I get asked sometimes, "Is there... Well, there are already these prophylactic agents.
Is there an unmet need?" Dr. Tachdjian also revealed to you a study that was done by the HAE, actually just got published online, and it was a study of about 500 patients, right? We did similar market research. Ours is much smaller, but the nice thing to know, it's really corroborated, and on average, half of the patients that are on prophylactic treatment still experience about over three attacks in an 18-month period. They're still in that need. There are obviously approved treatments that require more frequent administration as a standard of care. I'm very excited about our once monthly self-administration here. Then it's important to know, again, these patients are really looking for something on the go. They want freedom from their HAE, and importantly, just improve their quality of life.
So here's the data that we did, that was a smaller subsection. We ran a market research study to understand, well, are patients still having attacks? About half of the patients in the U.S. have had three or more attacks in the past 18 months. If you look at that chart to the right, you see that only 22% of the patients said they did not have any attacks in the past 18 months. If you look again, deeper in kind of the raspberry portion of this, you see that 25% of the patients having six or more attacks in a period of 18 months, pretty substantial. In Europe, the situation is even more dire. We have about 70% of the patients have three or more attacks in the past 18 months.
The other question we really wanted to know, are these patients willing to switch? We see that about 80% of these patients have actually switched treatments, and we've seen the switching driven by wanting more efficacy. They want fewer attacks, they want more predictability, and as I said, they're really looking for that improved convenience. Getting deeper on the reasons for switching, what are the top drivers for switching? We really see at 72% it's equal. Like I said, it's, I want fewer attacks and I want more convenience. Then, of course, some of the other things that are really important to them, you know, side effects, safety, having it be available and lower out-of-pocket costs for the medications also become a choice in their factor as well. I cite some of the quotes here.
I think they're really telling as to what's going on for these patients. Clearly, efficacy, "My prior medication didn't work properly. I would have breakthrough attacks," a good reason for switching. And the other one is just that the self-administration they've had, but the injection actually really hurt. "I had to do it myself, and so I switched and had to be stored in the fridge, and that just was very complicated." So when we no doubt bring the donidalorsen blinded profile to patients, they have a very strong interest in saying, "I'd like that product." Almost 98% were moderately or very enthusiastic about Dani. And going from dosing from once every two weeks, which is where standard of care is right now, to once every four weeks, is gonna be a really nice step change for them.
And then, as Ken said, we might have the possibility of even seeing this every eight weeks as well. And we asked them about, again, their switch and said, "If it was available tomorrow, I'd go ask my doctor about it." And as Dr. Tachdjian said, this is really a shared decision-making process between, between the physician and the patient, and we can see that coming through. Healthcare professionals view the profile, again, in a very blinded fashion with our target product profile as a meaningful advance in treating HAE. What do they like about donidalorsen? Well, it was favorable across all dimensions, which is reduced attack frequency, attack severity, and very importantly, what they look at is the attack-free rate.
They also like the onset of action because getting a prophylactic on board, particularly in a switch situation and having them be controlled and have no breakthrough attack, is really important. As I said earlier, donidalorsen reaches kind of this max clinical efficacy in one to two doses. As a result, they're very excited about the once monthly dosing. They said, "Oh, God, I, my patients are finally gonna be compliant." So the feedback on the expected TPP is, has been, has been very positive, by healthcare professionals. As I said, we know where these physicians are, we know who treats them. It's very concentrated. Actually, about 1,000 allergists and immunologists manage about 70% of HAE patients in the United States. So we really feel like we can get to all of them with a field team.
When I say field team, not just salespeople, but all the other customer-facing teams that you need to get to, including your patient education managers, your field reimbursement managers, and all the support that these patients need. We believe we can get there in less than 100 customer-facing team size. And of course, here, high-touch patient service is going to be really important, and the direct-to-patient engagement activities are being planned. And we're gonna be building from all of the high-touch patient engagement activities we're gonna be launching for FCS, and then six months later is our timeline to get them ready for donidalorsen. So it leverages really, really well. So what are the next steps for donidalorsen? Well, you know, pleased to say we've got a lot of things that are complete on this list.
As Ken just said, we just finished our two-year OLE data, and that will be presented in the second half of this year, before end of year. We expect the phase III OASIS HAE data readout in the first half of 2024. We also are very excited in the commercial setting, to get the switch study data readout as well, and that's gonna be mid-2024. That's gonna be very important for physicians to understand how to make a switch in this marketplace, and that lines us up for a filing in the second half of 2024 for HAE and expecting a second half mid-2025 launch. So I leave you with a very dynamic marketplace for donidalorsen. Lots of things going on in terms of unmet need and switching and continued rate of attacks for these patients.
Our product profile will really deliver very well against that unmet need. Quality of life and switch studies that we have in the dataset are going to be really informative for physicians to actually really make the right choices for their patients, and then we will support the patients in terms of what's most important: access, patient support hub, and patient engagement. All right. So to wrap up the morning of our near-term commercial opportunities, I just take you back to what we covered. In summary, we are poised and ready to launch eplontersen, olezarsen, and donidalorsen. Eplontersen PN, right around the corner in just a few months at the turn of the calendar year. For ATTR continues to be a very underserved and growing population.
Prepare to launch both indications for FCS on the heels of the unprecedented data and preparing for SHTG, and just as I covered right now, the continued unmet need in HAE and a great best-in-class potential profile coming up as the phase threes read out. We are ready, starting first with the co-commercialization and then followed by our independent launches for olezarsen and donidalorsen. All right. So with that, the morning is concluded. I'm going to invite Wade Walke to come back here and lead the Q&A session. Wade?
Okay, so I'm going to invite the speakers from the morning session so far to come up here and join us on stage. And as we get to this Q&A session, we're going to have about 30 minutes, and so we'll probably have a lot of people want to ask questions. I'm going to ask the people to limit their questions to two questions. If we have time, we'll come back around again, but initially, let's just have two questions per person. And if you would, for the people on the webcast, please, when, before you ask your question, state your name and also your affiliation. Okay? So we'll kick it off, Jennifer.
Hey, good morning. Debjit from Guggenheim. So question for Dr. Ginsberg. In your practice and in a history of treating, SHTG patients, if you were to segment patients between above 500 and above 880, what would be the rate of pancreatitis events in those patients versus those over 1500 or 2000?
Well, it's not a simple question to answer because these patients move. Certainly there is some divergence in the phenotype related to genetic background and the environment. And so we have some patients who are SHTG, who have genetically much more complicated than the FCS, but almost as much of a loss of LPL as FCS. And we have those who have a much more complicated polygenic and environmental. So I'd say 500-1,500, that group will have less of a, of a chance of having less risk of having pancreatitis than someone 1,500-2,500 who's not FCS. Obviously, that's... And because to get up there, they're more likely to have just this, a much more severe genetic background than those who are lower.
But again, the patients I've seen most often are women who were never diagnosed as having even hypertriglyceridemia, who start on oral contraception or become pregnant or are having fertility treatments, and on those estrogenic approaches, have TGs that go to 2000 and get pancreatitis. And so it's, it's very difficult to put a nail on the box, but if somebody shows up with a 2000, regardless of what their genetics are, they're more likely to have, over the lifetime, more severe disease. That's, that's, I think, obvious. I hope that's an answer. I'm not sure exactly if that's what you were looking for.
How would you think the treatment patterns?
So if any-
Repeat it.
Yes, so what the treatment patterns for those two groups. It's so we do genetics, and obviously 99.99% of the time, they come back as some mixture of polygenic. Maybe some of them are the big genes for FCS, but they're heterozygous. Others are just variants. Those people would get fibrate, omega-3 fatty acids, diet, whereas the FCS would get diet, but probably not the other two. And then we watch them, and we see where they go. And so there are many of them who will drop below 1,000, or if they're below 1,000, drop below 500. But if they come. And many there are those who won't.
So I think in that group, it's trial by error in terms of what drugs they will need. But there are, again, several million of them in the population, so there'll be a lot of people who won't... won't succeed at the existing treatments.
Thank you, Dr. Ginsberg, again. I don't know if my mic is on or not, but, I'd like just to just add to that. I must be having mic problems today. Something Sam touched on in his presentation. It's important to remember that the patients in our CORE and CORE2 studies are on top of the standard of care. So these patients are in the above 500. Many of them are above 1,000 or 2,000, and that's in our study already. That's on top of fibrates, fish oils, what have you. Isn't that right, Sam?
Yep. Mm-hmm, and if I could add one color, a little bit of color to your question on pancreatitis. We, because we're doing these SHTG studies in the Maccabi trial, in patients who are in their 40s, about 25% have already had pancreatitis. Just to give you a sense of the lifetime risk of SHTG, versus, you know, the, the control group I study. So, you know, it's, it's a sizable proportion of these SHTG patients who get pancreatitis, and the higher the value of the triglyceride, the more, the more the risk.
One of the things I would add, just to make sure, is that when we talk to physicians about how are they going to treat this, it really comes down to treating the risk, right? They're really not necessarily thinking about, "I gotta treat the disease." It's the risk and the prevention mindset, and hence we get these, these treaters that are very aggressive and very active, as I said, in terms of our behavioral segmentation.
Okay, let's go, have Yanan, then Kostas and Ellie.
Thanks for taking our question. Yanan Xu, Wells Fargo. I have a question for Dr. Ginsberg on what... Just to follow up on the prior question, what proportion of your patients are those that have above 500, despite having been on standard care? And what proportion are above 880? I also have another question on pricing. Dr. Ginsberg, could you comment on what kind of price will payers be willing to pay for the severe HTG population? We understand FCS is obviously a very orphan disease, but just trying to understand, you think payers' level of acceptance of pricing point.
So I'll take the first one. I don't think I can give you an answer of 500 versus 800. Those people move back and forth. You know, the day-to-day variability of triglyceride on a percentage basis can be 25%, depending what you eat in the previous day. It's a very dynamic situation. And so these people, they're not 500-799 or 800-879 for all their lives. They move back and forth. And so I don't, you know. Again, the higher they are, the more likely there's a stronger genetic background, less likely that I'll be able to get them below 500 and permanently, just on the standard therapies.
I can't. So I, I have a handful of those patients, and, when they, when they get a TG that's better and they, and they're further away from the pancreatitis, they don't show up for a while. That's the big problem, is we, we see in a lot of diseases where there's no symptom every day, but then they come back in again with pancreatitis. As far as payers go, I'm sorry, you're touching on a, a sore point. I just would point out that I've had patients who've been in the hospital for six months in an ICU, on dialysis, intubated with pancreatitis, and when they get out, I have trouble getting a fibrate or an omega-3 fatty acid from the payers.
I have to fight with them on the telephone, convincing them that patient will cost them another $1 million if they don't let me treat them. I'll probably have the same battle.
Maybe, Onaiza, you could provide a little more precision?
Sure, Sam, be happy to. I think my mic is on, right? So we just actually recently completed a pretty extensive payer and pricing research to understand kind of where payers are gonna land on both indications. Again, with the blinded profiles that we tested for olezarsen in both FCS and in severe hypertriglyceridemia, I'm very pleased to see they see the value proposition of the product. They know it's gonna be really an add to the armamentarium of what physicians really have right now, and they clearly see, you know, the rare disease for FCS. And you could imagine that, you know, we're thinking then the value proposition lines up with other rare disease pricing alongside that corridor.
On the SHTG, where we get pegged mostly is on the premium price cardiovascular agents that are there for more prevalent conditions. I can certainly point you to a few analogs, inclisiran happens to be one of them, and then, and some others that have come close to that. I would take a look at that, and that's where it's being pegged as well.
Great. Thanks for the answers. I have my second and last question for Dr. Tsimikas. Thanks for the very helpful reference about the unmet need, which is apparently consistent with what the company's own research show. I was wondering, could you speak to patients who have access to Takhzyro ? Is that level of unmet need still exist in that population? And also, could you compare olezarsen with the Factor XII inhibitor antibody, as well as the YTE-engineered, like, half-life extended Takhzyro , so to speak? Thank you very much.
Sure. I'll start with Takhzyro, which is currently approved. That is, in the trenches, it starts off at every two weeks, and if someone has no attacks for six weeks, six months, then they can go on to every four weeks as shared decision-making between the patient and the physician. That said, I'm not going to comment on how easy it is to go back if they start having more attacks. Okay. And the other two that you've alluded to, getting Factor XII activation at the top of the cascade, as well as the YTE engineered extension of the monoclonal. Those are in clinical trial still. How that pans out remains on the outcomes that are published, essentially.
On the need-wise, all of those, all three, including the Ionis product, will at least increase the interval and so decrease the burden of treatment for the patients.
Can you hear me?
Yes.
Hello, thanks, for the very helpful presentations. Kostas Biliouris here from, BMO Capital Markets. A couple of questions, one for Sam, the other one for the HA expert. Some on, ATTR cardiomyopathy. We recently saw that, patisiran benefit on top of tafamidis was not, significant. Given the robust clinical trial design of eplontersen, I'm wondering, in case you see a significant effect of eplontersen on top of tafamidis, do you think this would be representative of, all the silencers, or there is any reason to believe that this effect could be specific only to eplontersen and not representative of, the silencers? Thank you.
Yeah, that's a great question. You know, I, it's going to be hard to compare because the trial designs are a little bit different from BridgeBio and the Alnylam trial. There are some differences. Even though they all have hard endpoints, we're focusing on cardiovascular mortality as part of our key part of that endpoint, besides all the heart failure hospitalizations. So, you know, if the trial designs give you different data, then it's going to be hard to say if it's, you know, a broad effect of just the target or the drug. So I think I can't commit to one way or the other. I think we have the best design as, as you have seen.
We're going to have, you know, multiple hundreds of patients on and off tafamidis, so we'll be able to answer that question fairly definitively, I think, based on our trial design. Hopefully, that will help answer your question once we get the readout.
I'd like to just add to that. You know, my simple way I think about it is that you need two things to demonstrate, you know, best-in-class efficacy and a profile that patients really, really prefer and physicians prefer. One is you need a great drug. And we believe we have a great drug in eplontersen, and we believe the silencer class will end, at the end of the day, win out on efficacy. The second thing you need is you need to be able to prove it. You need a trial design in which you actually have the data that actually supports the conclusion that your drug works well on top of a silencer, which in the United States, we all know tafamidis is a standard of care, or your drug works really well, alone and maybe better than a stabilizer.
So we believe in silencers, we believe in eplontersen, but we also need to—we believe in our trial design, which is as important as having a great drug. Then you had a follow-up question?
Great. Yeah, before we go to the Sam, you mentioned, Ionis is the first cardiovascular company. Maybe you can give us the other two on top of, Ionis.
Sure. I think it's BMS and AZ.
Perfect. Thank you. And then for HAE, you mentioned the importance of, the unpredictability of, of the attacks. So I'm wondering, in the phase III trial, what would be most important endpoint for you, the reduction of the attacks on average or the percentage of people with zero attacks? And obviously both are great here, but because we have larger, sample size in phase III, these numbers may be a little different. Thank you.
Yeah, I can. Yeah, I think it's, it's a combination. Clearly, the primary endpoint is the reduction of HAE attacks. But you're right, what patients with HAE want is they want to have a normal life. They don't want to have to wake up and worry, am I going to have an attack today? And for that, the attack-free rate becomes critically important. And that's why I was so pleased that in the phase II trial, we had 92% of patients, every patient but one, that was attack-free. So I think it's the totality of the data which is most important. Having said that, it's clearly the point what our primary endpoint is.
Hey, guys, thanks so much for taking the question. Eliana Merle, UBS. Just, you know, on the question of combinations and ATTR, maybe just from a clinical perspective as well as a commercial perspective in terms of what is meaningful on top of tafamidis, I guess, how are you thinking about what would be a clinically meaningful benefit of the combination versus tafamidis alone? And then from a commercial perspective and some of maybe your early work discussing this with the payers, is there any expectation of potential step edits or demonstration of, say, progression on tafamidis before, say, a switch or, you know, going on to a branded combination? Thanks.
Sure.
I can take the first one. I think if you look at heart failure trials in general, which is basically what it is, we have the field in cardiology has really focused on hard endpoints. We want to see cardiovascular mortality, and we want to see heart failure hospitalizations. That's what physicians are expecting to see from a drug that will impact their patient's prognosis. And we have designed the study to do that. If you look at the tafamidis data, note that, in the ATTRACT trial, the placebo group had 45, 44% mortality rate, and the treatment group had 30%. Okay? So that means 30% of people on tafamidis are dying. So we think we can now take that 30% and get it further down. So we hope that we've designed our trial in the right way.
We have cardiovascular mortality, we have heart failure hospitalizations, and we have very serious arrhythmias. These are the kind that bring patients to the hospital. They get cardioversions, they get defibrillators, and those are the sort of arrhythmias that we can count as clinically meaningful. Those three things, I think, will be the key for what we'll be looking for in the cardiology.
Yeah. You know, it's a really great question on what payers are going to think and how they're going to treat it. It's one of the first questions we had as we went into the trial design. So, the way to think about this is they actually recognize what a serious debilitating and terminal disease this is, right? So at the end of the day, they say if a physician is going to attest that you need both mechanisms on board to keep the patient in control, we will approve both mechanisms. So they do view these as different classes. As a result of the different class designation of a stabilizer and silencer, there is a new kind of thought process of step-edit treatment in that way.
We also think that our design will have both subgroup data, right? Naive to tafamidis as well as on top of tafamidis, and it's a clinically meaningful kind of improvement that we are expecting to show on top of tafamidis, as Sam just described. So that also becomes really relevant in the payer conversations, to show a cardiovascular risk reduction on top of that that's clinically meaningful, will be really important in the value proposition of the product.
Great, thanks. Just a quick follow-up. I guess, is there a scenario where HELIOS-B would be positive, but you still would take the analysis after the first half of 2025, such as if you wanted more powering on the combination? I guess, how should we kind of think about that decision matrix?
Well, everything is on the table. We are monitoring... We're mostly laser focused on our study, of course, how the study is going, and it's going very well. We have a laser focus on blinded event rates, which are going well, as planned. And we'll continue to monitor that and make sure the study is properly powered. If there's something that emerges externally, the competitive landscape or elsewhere, that teaches us something new that might cause us to make a decision to end early, we'll certainly have that option. Or to your point, we may say, "Okay, we got a drug. Now we want to really round out this profile.
We really want to bring it to the finish line or, or to a later point to make sure we have the most robust, dataset possible." As Onaiza always tells me, "This isn't a sprint, okay? This is a, a race to get the best possible data in a market that is enormous and untapped." Go ahead.
Yaron Werber from TD Cowen. So I thought maybe just a quick follow-up, maybe Brett, to you. On CARDIO-TTRansform , when you're thinking about what we just learned from the last panel, are you thinking that patients who are on tafamidis, what's going to be the profile? Are they sort of patients who are recently been diagnosed and been put on tafamidis, and now they're getting enrolled into the study? Or they're typically patients who've been on tafamidis, maybe they're not doing that great, and as a result, they're getting enrolled in the study. And then, secondly, would you announce if you've done an interim analysis, or would you do one and either announce it if it's positive or continue to study? And I have a follow-up.
Thanks, Yaron. I will actually ask Sam to take the first one. I can address the second part.
Yeah. So, you know, we're one of the things that we've designed in this trial that's unique is we did not limit the amount of tafamidis use at baseline. And we think that is the best approach because we didn't want to interrupt the standard of care wherever it was in that geography. So in the U.S., for example, there's a lot of patients on tafamidis versus some other countries. And so we're going to be analyzing, you know, how long they've been on it and how many patients, you know, drop in or, or take tafamidis afterwards. But the bottom line is everybody that's sort of in the trial that's on tafamidis has been on it for a while. We're not-- we didn't screen for patients that are, like, failing on it. If you were on it for any reason, you can get into the trial.
So we'll be able to look at that granularity at the end of the trial and be able to understand that much better.
I think we've also shared that it's been very interesting following the demographics in the CARDIO-TTRansform study. We're not seeing a lot of drop-ins, a very, very low percentage of patients that are actually coming on to tafamidis that weren't on tafamidis stably coming into the study. We don't prevent that from happening, but we're seeing almost none of it. As far as interim analysis, we're not planning an interim analysis in CARDIO-TTRansform , but we have several options to read the study out early. That's different, right? There's no statistical penalty for reading the study out early. And if we decide to end the study early because we think we have all the data with all the powering we need for a successful study, we'll certainly make that.
... and, make that an announcement.
study early means, but before the 36, before everybody's on 36 months? Or is it you want to have at least 14— Well, you already have 1,400 patients.
That's right.
Yeah, we have all the patients, so the longest duration of the study is going to be 140 weeks, which is about 32 months. But we can pull that back, you know, to early 2025 if we want to.
So we would have patients that would have. We already have patients, obviously, in the open label expansion that have completed and so on. So it would be a snapshot in time at that point, in the study. Does that answer your question?
Patients in the O-OLE are able to continue to get those?
Yes.
Yes.
I'm way past my two questions. I'll count the second one as a second topic. The OASIS study is a question about HAE. You're going to have data in the first half and mid next year from the eight weeks and also from the switch study. Can you file for a label for both of those, too? One label for monthly, Q two months, and switch.
Yes, that's it. That is the intention to file for every four-week dosing, and if the data is supportive, to also file for 8-week dosing.
It's just important to note that we actually don't need the switch study for filing, but it's really important for commercialization and also obviously for physicians' direction of use, so.
Hi, Gary Nachman at Raymond James. So I have a broader question about the transition to becoming a commercial company. So when you talk about the omni-channel approach versus having a targeted sales force, and when you think about, you know, the unmet need in improving diagnosis rates, maybe give us a better sense of how much headroom there is in some of these markets, whether it's ATTR or FCS or SHTG or HAE. And, you know, what you think is reasonable, with the approach that you have in order to get to the kinds of targets maybe that people are thinking about. And I guess specifically with ATTR, just because there's going to be multiple competitors in that market, how you see that sort of coexistence, given that it is so untapped at this point.
Yeah, it's... I, as you're asking that question, Gary, my mind is kind of racing back to all of the other products I've worked on in terms of where we tend to peak out. So I think if you have really good data tools, as I said, great diagnostic tools, right? And Sam spoke to this in ATTR, with scintigraphy actually being really much more available now. And as the diagnosis and treatment rate extends out of the centers of excellence into the community, you start seeing the treatment rate going up. So those are kind of the fundamentals to really think about. I do not see treatment rates really going up beyond 80% versus virtually in any category I've worked in.
I think the only place I've seen it is in HER2, which Jonathan's worked on HER2, where it was such a specific diagnosis, such a deadly disease, we're in the nineties, and even they couldn't get to 100%. So you're never going to get to 100. 80 is really optimally great, but what it takes is really thinking through what I said, is just doing your data analysis, getting the reps to go where they need to go, but also, very importantly, the diagnostic tools, the disease awareness, and all the other things, you know, that multiple, when there are multiple companies, actually, all boats are rising at that point in time. And I think that's what it's going to take for ATTR.
That is why we're so excited about having such a, you know, large-scale partner such as AZ on board alongside with us to really capture the market opportunity for eplontersen.
Okay. And then just a follow-up for Dr. Tachdjian. Specifically on HAE, I think someone put up the number, less than 15% or so of patients are effectively treated or are satisfied with the current treatment regimen. Is that more to do with the effectiveness of the treatments or because of the administration and maybe a lack of compliance in getting where they need to be, and how you think donidalorsen will help address that? Thank you.
Sure. One thing I always emphasize with the patient is I, I'm not a patient, so I got to best empathize and feel what it, what it's like to have HAE. And HAE is particular because the minute you put a tourniquet on someone to get the blood draw, for instance, for a clinical trial, already their hand is just a big sponge and turning blue compared to an average person. So to correct that pathophysiology, to me, already innately renders them normal-ish. So quality of life contains that factor of, that innate sense of just wellness that some of these meds can attain. And so I don't think it's so much the efficacy that that survey reflects, but more the burden of treatment.
Because you look at some of these, it's daily versus, I mean, the first drug that got approved in this era, 14 years ago now, was something that reduced the attack rate by 52%. And that was the whole, you know, the screaming, the new era is coming on in 22 patients that finished the study, but it's IV, C1 inhibitor, given twice a week. That's a
... That's a tall order now. Back then, it was great. It was a wow moment. So now, especially when the Q8 weeks approval should occur, presumptively, I mean, that changes the paradigm at that point. To have six injections a year with efficacy that goes with it, and obviously safety. So that's the huge eighty-some percent unmet need for me.
I apologize. We're running low on time, so Jess, and then Myles will be our last question for this session, and then we'll have to get back on to our presentation schedule. Go ahead, Jess.
Great. Thanks. Jess Fye, J.P. Morgan. You flashed up the treatment guidelines for the SHTG population for 500+ and 880+. What's your expectation for olezarsen's inclusion in those guidelines, and what's the path to get it added there?
Yeah. So I mean, you know, I based on kind of what I've seen, Jess, is that once you have a robust data set and you have a novel mechanism, as we do right now, you're really then taking it to the advisory committee of the medical guidelines and really reviewing the robust data set that you have. And it's really up to them and their decision whether they're gonna wanna include it or not. But what I've seen is that, you know, particularly in areas such as in SHTG, we haven't really had, you know, tons of innovation in here. We've had omega-three fatty acids, and they were added in one of them. And in right fashion or so we expect the same for olezarsen to bring that in.
Our medical affairs groups will be working on that with the clin dev group, and hopefully, you know, they'll see the robustness of the data and make the right decision.
Uh.
Hey, I'm Myles Minter from William Blair. I'll keep it to one. Just on the scintigraphy sub-study, curious as to whether you're enrolling patients in that sub-study that are taking tafamidis as well. Only reason why I say that is there's some emerging data coming out that tafamidis alone can actually reduce Perugini grades, and there was some talk at the icon that they might want to use that as a biomarker for potential efficacy, should these studies be positive. And so I'm wondering whether or not you'll actually have enough patients in that study to show that, or whether enrolling patients on tafamidis might actually confound the potential findings there, 'cause you're already reducing amyloid burden in the heart in those patients.
Sure, sure. I can take the question. So we're stratifying the entry or was already stratified by tafamidis use. So we anticipate any subsequent analysis is gonna be equal distribution of tafamidis use. We're not restricting tafamidis use in the scintigraphy. We'd like to have equal numbers, let's say, of on and off tafamidis in the scintigraphy study. We're way overpowered. As you saw, six patients gives you a difference. So we think we're gonna have great data with or without tafamidis and scintigraphy, and we'll be able to see if it's one, the other, both or neither in terms of the final analysis.
We're good? Okay. That's all the time we have for Q&A today. For this session, anyway. We'll have another one in the afternoon. And let the speakers go back to their seats, and we have one more presentation before lunch break, and I'll have Brett introduce our next speaker.
This is working? Okay. So we have one more... As Wade said, we have one more presentation before completing the morning session before lunch. We've covered a lot already. We've really focused on Ionis's the building of our commercial organization, our preparations to launch and, and the status of our pre and near-term launch opportunities, which we're very excited about. Now for something a little different. We're gonna really move into the advancements we're making in research.
Again, consistent with what I laid out in my introduction, one of our key strategic imperatives is to invest heavily in advance and expand and diversify our technological capabilities to extend our leadership position in oligonucleotide therapeutics, and Eric Swayze will lead us in this. Eric Swayze is Executive Vice President of Research at Ionis. He started at Ionis a long time ago as well. He came in as a medicinal chemist, and then soon progressed to run medicinal chemistry and really established our medicinal chemistry organization today. Today he's now Head of Research. With no further delay, Eric, it's all yours.
Thanks, Brett. Get the mic on now? Hopefully. So, to finish off the morning session, I wanna talk about technology, oligonucleotide technology, and specifically three key things that we're bringing forward, which we hope will lay the foundation for advancing our future medicines that we're bringing in to development, the new molecules we're making. So as many of you know, Ionis has a history of technology advances, and this has resulted in what we're pretty proud of as a pretty rich pipeline and some medicines that are on the market, that have really some of which have been transformational and some of the molecules you've heard about earlier today. So to do this, we had to first invent what we consider is a best-in-class chemistry that we use as the basis for all of our drugs.
For medicines like Qalsody and Spinraza, we optimized delivery to the CNS via local administration. We've also pioneered a variety of mechanisms to modulate gene expression, and this includes both downregulation, for example, silencing a toxic gene like we talked about with some of the medicines this morning. Qalsody, for example, downregulates SOD1, turns off the expression of SOD1 protein, which is responsible for causing SOD1 ALS. We've also been able to upregulate genes to replace function. Spinraza does this by modulating gene expression such that it creates a functional protein where there was none in spinal muscular atrophy, and that medicine has really transformed the care of SMA. We've also developed targeted delivery strategies, specifically to the liver, and those have made some of the medicines that we've talked about today, such as eplontersen, olezarsen, and donidalorsen possible.
But I'm not gonna talk about those technologies today. We're gonna talk about some new technologies that we're bringing forward, which we think will make a difference in future medicines. Ionis has a really fantastic research organization. I've been privileged to be part of it for almost 30 years, and I don't think people really know and appreciate this, but about 50% of the research organization's total effort is dedicated to enhancing and improving our technology in one way or another. That includes making new things, testing new things, investigating the mechanistic basis for how these things work, applying them to drug discovery problems, and ultimately trying to make new medicines for these drugs. Lots of technology research.
Some of it's very broad, but when we get close to advancing something into preclinical development, i.e., making a new molecule, we're gonna put in people, we focus that, and we focus our technology research on achieving three key objectives, which we think will add value to our areas of work and the patients that we're trying to serve. The first is enhancing the profile of new therapies, and the idea here is quite simple, is to make our new molecules that are in our pipeline even better than the ones that we have now. The next is to expand opportunities in existing franchises, and here we're looking to add new opportunities for our cardiovascular franchise and our neurology franchise. The last bit is opening up therapeutic opportunities in new spaces and trying to find new areas where we can develop drugs.
Here I'll highlight a couple of opportunities that we think are hopefully upcoming in pulmonary and renal. This focus has led to really three things that I wanna cover today that we think are really potentially important advances for Ionis and will be the key for some of the next molecules. The highlight here is the bright pink slide. If you're gonna remember one slide, remember this bright pink, red raspberry slide. It's hard to miss. The idea is, these are the key things that we're gonna be bringing forward. The first is MsPA backbone, and we think this is a potential breakthrough. I'll describe that in a little bit. The next is Ionis's siRNA technology, and here, this really just adds an additional mechanism and chemical class that we can use to make drugs.
Key for us is that for each new program we bring forward, we'll evaluate multiple different approaches, including siRNA, to find the best molecule for the job. Then we'll close with targeted delivery, where we're really focusing our delivery efforts on bicycle peptides in collaboration with our colleagues at Bicycle Therapeutics to target the heart and skeletal muscle, and hopefully potentially enable the future delivery of neurology drugs across the blood-brain barrier. So first up is the MsPA backbone. This increases duration of effect and improves therapeutic index. This is why we think it's such a big deal, and we think it's going to be broadly useful in all of the new drugs that we bring forward, both in existing therapies and also in new areas. So what the heck is MsPA? What is a backbone, and why do we need a new one?
Why do we need to improve it? So I'll, I'll start with the cartoon labeled... Well, not labeled. I'll start with the cartoon shown here, labeled phosphorothioate. So this represents a backbone, and it's actually a dimer. The cartoon just really represents a three-dimensional shape that an oligonucleotide has that interacts with biological systems. I'm a chemist, so I draw structures. The dimer, there's 10 of these in a drug like Qalsody, which is a 20-mer, and actually, Qalsody has five of these dimers that make up the DNA portion of the region of, of, of the backbone. And the backbone part is really this part around the phosphorus or the P in the middle. The stuff around the P, that's the backbone. One of the modifications that we've made very early on in oligonucleotide medicinal chemistry is to change an oxygen for a sulfur.
So the sulfur is the red S next to the P. This does us several things for us. One, it improves stability over DNA. You can't make a drug without it being stable in a biological system. Phosphorothioate helps, but it's not quite good enough. It is still the limiting part; it's still metabolized at that linkage, and it limits stability, which limits duration of effect. The other thing phosphorothioate does that's very nice is it imparts a basic level of protein binding, and that allows the drugs to actually distribute into tissues and stay there, where we need the drugs to behave to do their job.
There's a two-edged sword there because that protein binding is not precisely specific, and it can bind to the surface of tissues and cells, but it can also bind to things like immune sensors, things we don't want it to bind to, and that can give us some side effects. So we've kind of had this love-hate relationship with phosphorothioate for a long time. In fact, I started Ionis, Isis then, in March 1994, and my first reaction was trying to make one of these XYZ things to replace the phosphorothioate backbone and find a substitute.... So my reaction worked.
We made the molecule, but the backbone failed, as did hundreds of other backbones that we've explored at Ionis to try and find something that works better than phosphorothioate and achieves the goals that we have set up here to work well, improve duration, and reduce side effects. Nothing worked until we started working with MsPA, and that's why we're kind of so fired up about this particular backbone, is we think it can do something that nothing else has been able to do before. So once we started playing with MsPA, one of the first key objectives we set out to ask was, well, does it maintain potency? The next key objective was, well, can it really modulate protein binding like we want it to and demonstrate some improved properties? So some of the experiments we do are described here, and I'll first orient you with a little cartoon.
So the cartoons are representing the oligonucleotide, and it's a series of little balls that are strung together with little loops. So each ball represents a monomer in an oligonucleotide. This one is actually 16 units long, and the color of the balls tells you what type of base chemical it is. In this instance, the backbone that I discussed earlier is represented by the open circles, which is a DNA, and the little linkage between it, the mustardy color, is phosphorothioate, and then the MsPA is the little purple color. So the kind of experiment we did, is we take an oligonucleotide, and we walk MsPA modifications throughout the molecule. And then we ask, well, what does that do to the properties of the oligomer? And those are represented by the pink line. So first, potency or activity.
If you look at the graph on the left, that shows you that MsPA maintains potency relative to the parent. The pink lines are all to the left of the blue line. The blue line is the dose response to the parent oligo. A leftward shift means we're improving potency, so at least we definitely are not hurting it, and it looks like there's a slight improvement in potency for these types of MsPA molecules. That's good. The next graph on the right shows you that MsPA can also reduce protein binding. Here, the pink lines are shifted to the right. That shows reduced affinity for this model protein relative to the blue line. So that's two things we wanted it to do. Well, how does that translate? Does this reduce protein binding, do anything of value for us? So the answer is yes, it does.
Shown here is data from an oligonucleotide that is a model system. We know it's a pro-inflammatory oligo, and we know that because if you dose this oligonucleotide to an animal, what you can see is enlarged in spleen, shown in the blue box, cytokine induction, which measures inflammatory stimuli. We then did the same type of experiment with this particular molecule by walking MsPA linkages through the DNA portion of the molecule, and that's shown by the little pink boxes highlighted with the MsPA oligos. And what happens? So if we do that, now highlighted in the pinkish box, we can see that the MsPA substitution, just three of them, at various points in the DNA, reduces immune stimulation, presumably by reducing binding to the TLR9-driven pro-inflammatory sequence that's causing this immune stimulation. It's evidenced by lowered spleen weight.
They're essentially normal, the same as vehicle and lowered cytokine induction. So that's nice. That's a model system. Does it have a beneficial effect in a real system? And so to test that, we took a very real system that was also unfortunately a very real problem for us. And some of you in the audience will remember our ENaC program, where we had a molecule that was well-tolerated in humans and it was showing nice early evidence of activity in humans, but had a problem in a chronic tox program. And the problem it had was due to inflammation in the lung of non-human primates. And so we wanted to ask, could MsPA help us fix this type of problem by putting MsPA in the molecule in much the same design as we used before?
And so here the design in the little pink boxes shows that we have MsPA in each end of the DNA portion. We wanted to ask three questions: Does it have similar activity to the parent drug? So that's shown here. Again, the blue line is the parent oligonucleotide. The pink line is the MsPA drug. Yes, it has the same activity. Next, and the big question is, does it help some of our inflammation problems? We saw complement activation in the monkey lung. Does MsPA reduce that? And so here we did a study where we dosed the compound. It did tox dose, a fairly high dose for 13 weeks. So you can see the parent oligo is increased. The blue bar is induction of complement in the monkey lung. The little pink dots are the MsPA oligo. Absolutely no activation of complement.
So it has addressed and solved our problem. In this experiment, we also included an siRNA for fun, which is somewhere in between the parent oligo and the MsPA oligo in terms of complement action. The last thing is, well, did we reduce inflammation? This is just an example. Of course, we looked at this histopathologically, but we also looked at it with IP-10, which is a cytokine. Again, the parent oligo in blue shows an induction of cytokines. The MsPA is normal, like saline, and the siRNA is somewhere in between. So this suggests that MsPA, when used in the right design, can help us make molecules that target the lung with local administration and do it safely. And so suggest that we can advance MsPA in pulmonary indications.
We next ask a very similar question for a renal-targeted drug, and this is a molecule that has a reasonably decent profile, but not quite good enough for us, and we ask the same type of question. Here we put MsPAs at just one end of the DNA portion of the oligo. Ask very similar series of questions. Does it work as well as the parent? Yes, it does. Again, the pink line is the same as the blue line, suggesting the MsPA will have the same activity as the parent oligo. Next, we asked: how is it tolerated? And again, we did an NHP study at a toxicological dose level and asked, "What does it look like?" And so the parent oligo, we see some induction in kidney injury markers. These are commonly used to assess the potential for kidney injury.
Both are increased with the parent oligo, MsPA takes it back down, no increase, it looks like vehicle. We then also, of course, looked histopathologically in the kidney, and we looked for signs of inflammation, and shown in the little chart, shows that the MsPA has reduced the inflammation that's observed by a histopathologist in all the measures we looked at, including at the injection site. This also suggests to us that we can use MsPA for some kidney in-indications, and kind of starts to lay the foundation of where we're starting to look for some new places to take to make potential drugs for patients with the new chemistries. The next question we wanted to ask with MsPA regards stability and duration of effect.
So because we substituted the most metabolically labile point of the molecule, the DNA phosphorothioate, with something that we know is more stable, MsPA, it's not recognized by nucleases like phosphorothioate is. We asked, "Well, if we substitute MsPA at these weak points, can we improve stability? And this should improve duration, can we improve duration of effect?" And the answer is yes, it works. And this is shown in this experiment here. So we did this in both mouse and non-human primate, a series of experiments. Just focus on the left graph. This is an experiment where we give a single dose of an oligo, an MsPA oligo, or a benchmark siRNA. Those are represented by the curves in blue, pink, and green. So the parent oligo, if you just look at the blue curve, the target goes down.
It's Factor XII , we can measure it in the plasma, so it's a, a nice one for this experiment, and you can see then over time it recovers, and so at about six to seven weeks, it's recovered back to the baseline. If we make an MsPA substituted variant of this compound, again, using a design like we had for the renal oligonucleotide, just some MsPAs, as evidenced by the pink box in the five' end of the DNA portion, you can see a pretty dramatic improvement in duration. The MsPA oligo reduces the Factor XII target and then recovers much more slowly, such that when the blue line is back to baseline, the pink one is still suppressed. And it's kind of on top of the green line.
The green line is what I'll call an industry standard siRNA, and those are typically dosed quarterly in clinical trials right now, suggesting that the MsPA oligo has the potential to achieve quarterly dosing in the liver. We also then looked at this in primate. So on the right side is the same experiment with the same target in NHP. The blue oligo represents the parent, goes down, returns to baseline, and the MsPA oligo is clearly prolonged. A little bit better than the siRNA in the experiment, again, suggesting that the MsPA has the potential to get us to quarterly dosing for liver drugs. We also wanted to look in the central nervous system, and this is key for us because, as you'll hear right after lunch, we are very invested in neurology and have a large suite of neurology drugs.
Because our neurology drugs are given locally to the CNS, extending duration here is a big deal, a very big deal for us, and so we wanted to see if the benefits we saw in the liver could translate into the central nervous system. So we did a similar set of experiments. We put some MsPAs in the DNA portion of an oligo, represented by the pink boxes in the little cartoons, and then looked at the duration for both the parent oligo, which is currently a quarterly dose drug that's in clinical trials, and an MsPA variant of this oligo. And what you can see from the graph on the left is that the ASO reduces its target. Again, just a single dose into a mouse, and it recovers over time and returns back to baseline between 16 and 24 weeks post-dosing.
So that's a nice, healthy duration. MsPA does much better. The MsPA oligo is still going down at 16 weeks and then returns back, but even at 32 weeks, it's not yet back to baseline. So we're very enthused about this data, suggesting that MsPA can get us perhaps greater than semi-annual dosing in the clinic with this type of modification. And the increased duration is due to stability, and that's shown on the graph on the right, where we measure half-life. We've measured the drug at each of these time points. More drug in the pink line, it has a lower slope, that means it stays put longer than the orange line, which has a shorter half-life. And so we think this is due to stabilization of the molecule. More drug increases duration of effect.
So MsPA backbone, key points: It maintains and sometimes increases potency, reduces nonspecific protein binding, and increases stability over PS backbone. This has the potential to reduce dosing frequency. Targets are greater than quarterly or quarterly in the liver, and hopefully greater than semiannually in the CNS. Reduce side effects, and this combined allows us to expand into new therapeutic opportunities in new tissues, for example, the lung and the kidney. The next steps here are to evaluate these medicines in human clinical studies, and as I mentioned, we're broadly using it across the platform for many of our clinical studies, or for many of our candidate identification programs. Next up is Ionis' siRNA technology. Here our objective is to expand the technology base with an additional mechanism and chemical class. At Ionis, we have a fairly long history.
I think this is a bit underappreciated also in technology development in the RNAi or siRNA space. We started this in 2000. We had an extensive program focused on the RNA mechanism, and this effort led to the invention of several key chemistries that are crucial to the success of siRNAs, and we think will be crucial to the success of future siRNAs. One is what I've labeled RNA-free siRNA, and so this uses a modification of the drug with 2'-O-methyl and 2'-fluoro chemistries to eliminate RNA from the molecule. It's very important to make them stable. Another key is the 5'-vinylphosphonate, called MoVP, and that is exceptionally useful for optimal potency and also improving duration, especially in non-hepatic tissues.
And then the other one I highlighted is fluoro HNA, which is a unique modification to Ionis that can substitute for 2' -fluoro. So the siRNA optimization strategy at Ionis is fairly simple. We wanna maximize potency, increase stability, and reduce 2' -fluoro nucleoside content via substitution of other residues. The way we're achieving that is first, we use the Ionis Mo vinylphosphonate for maximal potency. Shown there. We then use a whole array of chemistries throughout the molecule to substitute 2' -fluoro and substitute the ends of the molecule to try and increase stability, to maximize duration. We use backbone-stabilizing modifications such as MsPA and/or phosphothioate at the ends to increase stability and increase duration, and for siRNAs, a LICA is usually required. An example of that optimization strategy is shown here.
Use the same Factor XII system that we used before, and we also compared to what I'll call an industry standard siRNA design. That's shown in the red curve. So again, a single dose experiment-
How to change one, two.
With one dose of the siRNA shown in the red curve, it goes down and then recovers back to baseline at roughly eight to 10 weeks. There's no more target suppression. And just to note, these siRNAs again are generally given quarterly in the clinic, so that's the profile of a quarterly molecule. We then looked what happens if we just put the MoVP on the molecule. So this is only one simple change, and there's a little orange ball there at the end of the molecule that represents we substituted MoVP for a regular 2'-O-methyl nucleoside. And you can see the orange line now has an increased duration. It stays down much longer than the red line, which is returned by 10 weeks. The orange line is still suppressed out to 14 weeks.
We've taken that one step farther, and that's what happens if we substitute out all of the fluoros on one of the strands with fluoro HNA. This, this, example just has two fluoro HNAs in the antisense strand of the molecule, and Mo vinylphosphonate, and further extends the duration of action over the MoVP alone. And I mentioned the industry standard designs are generally dosed quarterly, suggesting that hopefully with this type of design, we can have longer duration of action. And we've then taken this into a follow-on program for a hepatic target with the idea to make an siRNA that would have a longer duration for our, our clinical development and see if we're on the right track. And data from that program is shown here. The red line is a clinical stage siRNA, a surrogate of a clinical stage siRNA.
The surrogate is, we used our GalNAc instead of the GalNAc that's on the molecule. You can see much like the previous data, it goes, target goes down and it recovers to baseline by about eight weeks post-dosing. What we were able to do in our optimization program is through a series of chemical modifications, including the MoVP, is produce some siRNAs that have much better durability than the red line, the one that's currently in the clinic. So we're excited about this, and we have transferred the, translated this into preclinical development and hope to start clinical development with that molecule sometime next year. So for Ionis siRNAs, key takeaways, we think Ionis chemistries are beneficial. The Ionis optimized siRNA has the potential to reduce dose, dosing frequency.
Our target is greater than semiannual in the liver, and it gives us another modality that we can use to make drugs and optimize the profile of the molecule for each target. As I said, the next step is to evaluate these in human clinical trials and internally compete with other mechanisms for all new candidate programs. Okay, last up is targeted delivery and specifically Bicycle conjugates, where we focus our targeted delivery efforts. Many of you may have heard me talk about LICA before. That stands for Ligand Conjugated Antisense, and as I just discussed, we're well beyond antisense, so we're just calling it targeted delivery. We had a reasonably broad program, and as we started to advance things towards development, we focused that program.
We focused that program on bicyclic peptides in collaboration with our colleagues at Bicycle Therapeutics, really because they work so well, and it also benefits our cardiovascular franchises and our neurology franchises by targeting both the skeletal and cardiac muscle and potentially crossing the blood-brain barrier. So what are bicyclic peptides? They're developed by our colleagues at Bicycle Therapeutics, and they basically consist of a short linear peptide, which is then reacts with a scaffold, and the scaffold orients the linear peptide into a constrained structure. And that's very important because then that constrained structure allows these small peptides to bind biologically relevant structures, to form biologically relevant structures, and bind a diverse array of proteins. And these have several favorable properties that we really like. One, they're small. They have high specificity because of this constrained structure. They're chemically synthesized....
They can drug complex protein targets, and they're not immunogenic, which is very important. The target that we are interested in, and have licensed from our colleagues at Bicycle, is bicycles that bind human Transferrin Receptor 1. That's shown in the bottom right-hand figure. That's the purple is human Transferrin Receptor 1 , and the red is a bicycle bound to transferrin receptor. We wanna bind transferrin receptor because it's known that that can transfer cargo into the skeletal muscle and cardiac muscle. Bicycles work, that's shown here. This is an experiment where we made a series of compounds, as shown on the right. One is an ASO, that's the dotted lines. Then we took a Fab, which is a piece of an antibody that was known in the literature to transfer oligonucleotides into the muscle and cause target reduction. We made a positive control.
We made two bicycles, represented by the pink and the blue. What you can see in the figure on the left is that the bicycles work. The potency is shifted to the left, as evidenced by the blue and the pink lines to the left of the dotted line, which is the parent oligo. What you can't see very well is the black line, because it's right underneath the blue and the pink ones. That's the Fab. So on a molecule per molecule basis, it works just as well as the Fab, and that's very important. This potency is calculated based on the mass of the oligo administered, not the mass of the total drug. Well, I just told you the bicycles were small, Fabs are pretty big.
If you calculate this then on the mass of the total drug administered, I've highlighted what happens here on the slide. The dotted line on the left shows you 3.5 mg/kg dose based on oligo total weight. The two dotted lines on the graph on the right show the data when it's plotted based on the total dose of the drug administered. That corresponds to about 4-5 mg/kg of the bicycle ASO, because the bicycle's small, it only has a little bit of weight. Whereas the same point that has 3.5 mg/kg ASO on the left, is really 36 mg/kg of total drug, because the Fab is heavy. So most of that is due to the delivery system, not the actual drug.
Based on the total mass administered, the bicycles are actually much more potent than the Fab oligo and maintain their potency advantage relative to the parent, where the Fab actually gets less potent based on the total drug. We've also shown that bicycles work well with siRNAs, and that's very important to us because the siRNAs have been working well in one of our programs. Shown here is data with a Fab conjugated to an siRNA in gray, compared to a bicycle conjugated to the same siRNA in green. You can see that the 15 mg/ kg total dose, which is equal molar, so the same number of siRNA molecules as the green one, has roughly the same activity, yet it's 15 mg/ kg versus 4 mg/ kg total dose.
We've then taken this into NHP and shown the same thing with both oligos on the top panel in the blue bars and siRNAs in the bottom panel in the green bars. They reduce their target in monkey quadriceps to skeletal muscle, heart, cardiac muscle. And importantly, you can see on the left that the bicycle ASOs bind monkey transferrin receptor, which enables this target reduction. We've also had success in a follow-up in a new drug program with the bicycle chemistry, and shown here are two key bits of data from the program. The first one on the top is a PK study, and the objective here was to demonstrate subcutaneous bioavailability with the bicycles, which we did. The blue shaded area shows subcutaneous dosing of an NHP with a bicycle conjugated siRNA.
The red shaded dosing shows the area under the curve of the IV dosing, and the area under the curve equals the amount that is in the blood circulation over a unit time, or the AUC. And if you see at the quantitation, the AUC for the subcutaneous dosing is, if anything, higher than the IV. This suggests that we have very good subcutaneous bioavailability with the bicycle siRNA, and that's made further clear by the quantification of the drug in the tissue at the end of the experiment. The blue bars, which are sub-Q, are the same height as the red bars in both skeletal and cardiac muscle. We have the same amount of drug accumulated. And then our bottom panel shows the activity of this particular construct. We have nice target reductions, skeletal muscles such as quadriceps and also in the heart, which is the target tissue.
So Bicycle-targeted delivery. Key takeaways for the muscle system. Bicycle conjugates are small, low molecular weight, which simplifies the system, and they deliver both ASOs and siRNAs to skeletal and cardiac muscle. The next steps for this program is to evaluate our preclinical program in IND tox studies and ultimately get them into human trials. And we have multiple targets of interest for both neurology and cardiology indications with using the bicycle strategy. So we wanted to ask what else we can do with the transferrin system, and particularly in neurology. So as you'll hear right after lunch, we have a very broad and growing neurology program, where we aspire to do a lot more than we're already doing.
And while this has been enabled by lots of technology advances, we were thinking about what we could do more and what we could do better for neurology. And we really think the next hurdle is systemic delivery of oligonucleotides to the central nervous system, which of course, involves crossing the blood-brain barrier, which normal oligonucleotides don't do. So we wanted to ask, well, does transferrin receptor, can it mediate transcytosis across the blood-brain barrier and bring a cargo with it? And so we started off to have a blood-brain program. The objectives of this program were to understand the characteristics and that are required for crossing the blood-brain barrier, identify systems that could do this and then simplify it, much as we've done with our bicycle strategy targeting the liver. And so our strategy here was fairly straightforward. Make some surrogates.
There's some in the literature that have shown early success. Use them as positive controls. They all have antibody-based systems. Figure out what makes them tick and how they work, and then identify bicycles that have those characteristics, and ultimately, that cross the blood-brain barrier and modulate their targets. So early evidence that bicycles could cross the blood-brain barrier was shown in this really nice experiment that our colleagues at Bicycle Therapeutics did. And what they did was implant surgically a dialysis probe into the brains of NHPs, such that they could measure the concentration of bicycle in the CNS fluid that surrounds the catheter on the other side of the blood-brain barrier.
So they infused bicycles into the plasma, shown on the top graph, measured the concentration of bicycles in the plasma, and then the blue bars at the bottom show the concentration of bicycle in the CNS interstitial fluid on the other side of the blood-brain barrier, providing very nice evidence that the bicycles can cross the blood-brain barrier and do so by transferrin-mediated transcytosis. So that's nice, but we wanted to ask, well, if they cross the blood-brain barrier, can they move a cargo across? And does that cargo engage in and modify and modulate its, its target? So we first asked with a set of bicycles that we had used for our skeletal muscle system.
This is data shown on the left with the pink bars, and you can see they nicely modulate their target in the skeletal muscle, quadriceps, and in the heart, but they don't do anything in the cortex or the spinal cord. So this particular bicycle design doesn't work to cross the blood-brain barrier. So we played around and fooled with it a little bit, came up with a couple other designs that do cross the blood-brain barrier, and this is shown in the graph on the right. The bicycle designs are shown in the orangish colors, and if you see in the bottom, they reduce their target in cortex, spinal cord, and other regions, such as the brain stem. The gray bar is our positive control, which actually works a little bit better.
So we got a lot more work to do, but we're very encouraged that the bicycles are lowering their target in the CNS. And just to note, the bicycles, bicycles are small, so they're actually... This is the same equimolar, same number of molecules of conjugate dosed, but it's much higher total dose of the antibody-based system, because the antibody-based system is large as opposed to the bicycles. So in conclusion, we've talked about three things that we think can make a big difference for Ionis's technology going forward in the new molecules. The first is the MsPA backbone. This increases stability, which can reduce dosing frequency. It reduces nonspecific protein binding, which improves therapeutic index and enables expansion of new tissues.
We've talked about Ionis's siRNA technology, and shown that Ionis chemistries can increase stability, and this adds a new mechanism for us and a new chemical class, which is really optimal for some targets and applications. We've talked about targeted delivery with bicycles, which gets us into the skeletal and cardiac muscle. We think the small size is a huge advantage as it simplifies the structure. We've shown in early preliminary experiments that we can cross the blood-brain barrier, and this sets up the potential for crossing, for systemic delivery to the CNS when we optimize the system. All of these advances are geared towards improving the ultimate profile of our drugs for Ionis's pipeline, enhancing the profile, expanding opportunities in existing franchises, as I've discussed, and opening up new therapeutic opportunities in new spaces.
I just want to leave you with what I think is really important for our technologies. Ionis is the only RNA-targeted therapeutics company with expertise in multiple modalities, which enables us to make the best drug for a given indication, completely agnostic to the modality. We're just trying to find the best molecule for our patients for new indications. Thank you.
Thanks, Eric. The opportunities are limitless with the research and the progress we're making in this area. So I'm not gonna take any extra time. I know it's been. We've covered a lot this morning, and I don't need to summarize it for you. But it's been an exciting morning, and we're right up against lunch. Let me just give you a quick preview of what's coming after lunch. This is really exciting. We're gonna provide for you an overview of a portion of what we see as our next wave of commercial opportunities, doing a deep dive into our neurology franchise and how we plan to bring those products from our wholly owned neurology pipeline to the market.
Then we're gonna wrap up with the final presentation, which will be our financial strategy to maximize value to all shareholders, to unlock value. That'll be done by Beth Hougen. We will have one more Q&A session towards the end. With that, let's try to get back here by 12:50 P.M., Wade is telling me. We have boxed lunches out there and look forward to seeing you in a few minutes.
All right. All right, there we go. All right. Good afternoon, everybody. Welcome to the afternoon session. It's a privilege to introduce our next speaker, Holly Kordasiewicz. Holly will review for us some really new, exciting programs that you haven't seen before from our leading neurology franchise for oligonucleotide therapeutics.
New, new programs we expect to reach clinical development and some programs that are imminent to reach the development soon. And then as a reminder, following Holly, Rachel Carnes will come up and share with you our go-to-market strategy and our plans for bringing these Ionis neurology assets to the patients. And then we'll wrap up the final presentation with Beth Hougen on our financial strategy before we open it up for the final Q&A of the day. So no further ado, Rachel, I mean, Holly, it's all you.
Wow. Thank you, Brett. All right. Good afternoon.
Two people.
First, in this section, we'll walk through the current status of our neurology program, and then we'll take that deep dive into the next wave of Ionis medicine. At Ionis, we have two areas of focus, where we aim to develop therapeutics for cardiovascular and neurological diseases, as well as key specialty medicines. Here, we're going to focus on neurology. This is an area near and dear to me as a trained neuroscientist with more than 15 years' experience working with Ionis technology. I actually started with Ionis technology in the brain back as a postdoc in academics, and even then, the potential of this platform was clear. I followed it to Ionis, and I've been here ever since developing these medicines.
I'm particularly pleased to be here today with you, sharing with you our next wave of Ionis medicine in neurology, and we'll go through the science behind those today. First off, why neurology? Most importantly, there is a huge need for transformative medicines for patients living with these diseases, and many neurological diseases have genetic underpinnings.... This gives us, drug discoverers at Ionis, obvious targets, targets where we can get to the heart of the disease. If we can get to the heart of the disease, we have a chance at making a real benefit for patients, patients who today have next to nothing to control their disease. The need is clear and the opportunity for transformative medicines is clear, but the historical challenge has been making those molecules that can get to those targets in the brain. This is where Ionis stands apart.
We have over a decade of experience making targeted medicines for the brain. We have multiple times now been able to go to the heart of the disease and provide benefit for patients. We have a path and a plan to do this over and over again. This is our job, and we have a proven track record that we can do it. So twice we've done something that at the time, no one else has done, and that's make a transformative medicine in neurology that's now approved by the FDA. The first is Spinraza, which I'm sure most of you are familiar with. This is our treatment for spinal muscular atrophy, and here, patients, oftentimes children, were fated to die from an inherited motor neuron disease and can now develop and meet normal motor milestones because of Spinraza. The second is Qalsody.
This was approved just earlier this year for the treatment of SOD1 ALS. Here, again, another devastating neurological disease. But because of Qalsody, patients now have an option to control their disease. So both these medicines were discovered at Ionis. Both these medicines, we go to the heart of the disease, and we provide benefit for patients. So we have a proven track record. We can make medicines in neurology. So here is a look at our current neurology pipeline. I have to say, I am so proud of the phenomenal team at Ionis that has built this expansive pipeline and continues to grow this pipeline. We have those two approved medicines in neurology, in Spinraza and Qalsody. We have 12 more medicines currently in clinical development.
These programs were all discovered at Ionis, and they range from rare monogenic diseases all the way to common diseases like Alzheimer's. We also have more than 10 medicines in lead identification or IND-enabling toxicology studies. I'm very pleased to be sharing with you today that 4 of these we plan to advance into the clinic before the end of next year for our wholly owned pipeline. What this means, drugs discovered at Ionis, developed by Ionis, and delivered to patients by Ionis. There is a lot of opportunities to help a lot of people on this slide. This pipeline also exemplifies the prolific nature of our platform, the power of our platform, and the experience that we at Ionis have in making medicines in neurology.
So we've made a number of key advancements over the years on both the technology side as well as clinical development. For the technology, we've optimized deliveries. We get broad distribution throughout the brain. We validated in patients both splicing as well as RNA-lowering approaches, and we've also established the potential for a long duration of action, so dosing intervals of up to six months for an RNA-lowering therapy. That's injections just twice a year for someone with a neurological disease. Now on the clinical development side, our lessons here have been innumerable with all those clinical trials. Some of the main ones are that disease reversal is possible. This was unfathomable when we started in these diseases years ago, but it's possible. Also, that early treatment can provide a robust, transformative benefit. It's possible.
And finally, we are at a really exciting time in neurology drug discovery, and that's because the community as a whole is building the drug development tools. And this is just exploding right now. And what I mean by this is the biomarkers, the natural history studies, the understanding of underlying disease course. And the reason these tools are so powerful is they allow us to ask early in development if we're having an effect on the underlying disease course. And if we are, then we can focus in on those medicines most likely to be transformative for patients and move them fast through development. So it allows us to focus and get on track and stay on track. Now, another thing that our many years of experience making many drugs in the brain has taught us is how to optimize the best oligonucleotide.
This is something that's really undervalued in our field, and it's that not every oligonucleotide is the same. We understand there are similarities, and there absolutely are similarities, but also there are differences. To find those molecules that have the potency, the duration of action, the tolerability for brain delivery, requires screening thousands of molecules, and the know-how and the infrastructure to do it well, to do it right, and to do it fast. This is where we excel. Here's a look at our process that we use for our human lead identification, and we do this for all of our oligos we advance into the clinic. We first start in human in vitro systems, and then we move really quickly in vivo. Once we go in vivo, we're looking for potency, duration of action, and tolerability, and then this is an iterative process.
We continue to optimize those molecules until we find the very best one. So at Ionis, we go to the extremes with rigor to find these molecules, and we have an incredible team with decades of cumulative experience identifying, optimizing, and perfecting these drugs. And we do this for our RNA-lowering drugs, our RNA upregulation drugs, and our RNA splicing drugs, and we can practice all three of those in the brain. So an example of an optimized drug is our MAPT or our tau drug. And so real quick, MAPT is the gene that encodes the protein tau. Tau has been a target in Alzheimer's disease for a long time, so any tau drug, if it were to work, has the potential to treat millions.
So when we started out, we wanted a drug with a long duration of action because we wanted to extend the dosing interval, and that's exactly what we did with our tau molecule. So what I'm showing you here is the preclinical data from our tau drug. And our tau drug is one of the first molecules that was RNA lowering that we took into the brain, and I'm comparing that to SOD1, which was our very first that we took into the brain. So with SOD1 in gray, you see the target goes down after a single injection, and then over time, it comes back to baseline. With tau, it goes down, and it stays down.
There's also a shift, if you look at the bottom graph, in potency, that blue line shifts to the left, so less drug required to do the same thing with the tau drug. This molecule, the details of it, we published earlier this year in Nature Medicine, and this includes the first-in-human study. I'm happy to say that this has translated into the clinic, and I'm going to share that data with you next. This was really gratifying data to see because it did exactly what we had hoped it would do. The target goes down, and it stays down for a really long time. I'll walk you through this. In our first-in-human study with our MAPT drug, when we went into this, we knew from the preclinical work we had a long duration of action compound.
We designed the study to test that. This is a MAD, so multiple ascending dose, where patients in the first 2 cohorts received 4 monthly doses, and those are noted with the black arrows. In the final cohort, we spread out the dosing interval to just quarterly doses, so just 2 doses noted in the blue arrows at those 2 time points. We also included a recovery period. This recovery period ranged anywhere from six months to up to 2 years for an individual patient, and that's because this final time point is the first time point in the long-term extension. All patients were able to roll into long-term extension and get drug. What you see with our target engagement biomarker is during the dosing period, the target goes down, so all those lines are projecting down.
At the lower doses, they begin to recover, and that's the orange and the red. These are the patients with those longer time points, out to up to two years. Now, if you go down to the bottom two lines, those are our higher doses, and the target goes down, and it stays down for the full recovery period. My favorite line on this graph is that blue line, 'cause those patients only received two doses, and their tau is down for over half a year. So this is exactly the kind of first-in-human data that you want to see in a clinical study. But that's not all. It actually gets better in here. This is data that when this study came out, this was the first time this was shown. This is really powerful. What this is, is this is tau PET.
So this is imaging your pharmacodynamic biomarker. So on the previous slide, I showed you the CSF biomarker, the target engagement biomarker there. Here, we're now imaging the target, and this is imaging tau pathology. The reason this is so powerful is because you can image an individual patient over time. So what you're looking at is on the top is a single patient, on the bottom is another patient, and then vertically, those are three individual time points for each one of those patients. So tau pathology or tau burden, normally in disease, just goes up. These patients were selected because they received placebo during the MAD portion. So those first two images at screening in week 25, there's no drug on board because they received placebo during that period. And the tau burden is pretty similar.
So your scale is on the left, where red is more burden, blue is less burden, and so you can see they're similar. If anything, they go up a tiny bit. Now, these patients go on drug for the open label extension, quarterly dosing from week 25 to week 100, and the tau burden goes down. This is incredible. Tau pathology reverses. So this teaches us two things. First, tau pathology reversal is possible. Now, we knew this from the preclinical models, but to see it in a human brain, in an aged brain that's been fighting with Alzheimer's disease, is a first. Also, this is another pharmacodynamic biomarker because tau is our target. But here you're looking at it spatially. And when we quantify this, all regions that had tau pathology are decreased. So we were able to engage our target through all the regions.
So not surprising, based on this first-in-human study data, this is now in a phase two study in patients with early AD, and I'm very much looking forward to a presentation at CTAD later this month that our partners at Biogen will be giving to share more data from this study. All right, so here's a look at our current portfolio by the numbers. We have treated over 15,000 patients with Ionis oligos over a number of different diseases. We have two breakthrough medicines. We have 12 more in clinical development and many more coming along. We have the knowledge, the expertise, and the know-how to make drugs in neurology. So this is where we're at today. So what's next? Where are we going? We're going to be building our wholly owned pipeline of medicines in neurology.
Hopefully, what you guys can tell from this presentation is that we have a very prolific drug discovery process. Historically, what we've done is we've partnered these programs in neurology. Biogen is a key long-term partner of ours. They're responsible for seven of the programs in clinical development. We also have other key partnerships. I'm very happy about the announcement just last week. We've expanded our partnership with Roche to include another Huntington program as well as an Alzheimer's disease program... But what I'm most excited about, and what we're going to be talking about next, is we're building our own wholly owned pipeline. This means drugs developed by Ionis and delivered to patients by Ionis. So there's lots of different places that we could take this, and what we strategically decided to focus on is the high reward, transformative therapies.
What I mean by this is the right targets, the targets that have the potential to be disease-modifying, life-changing therapies in areas of significant need. The right development programs, so areas where we have the tools or we can build the tools to determine if we're affecting the underlying disease course. And then also the right commercial fit, where we can recognize synergies, and so we can get our drugs to patients as efficiently as possible. Now, when Brett laid out his vision to build a wholly owned neurology pipeline, we had the expertise at Ionis to take this to many different disease areas and many different targets. What we needed to do was focus.
So we set up two parallel processes, one, where we evaluated individual targets to see which best fit this vision, and then second, build a commercial strategy to realize the full potential of the vision. In both those elements, Rachel is going to be talking to you in detail about the strategy behind them and the thinking behind them next. What I'm going to share with you now is the output from all that work. And so the output from that work is we've chosen four pillars to focus on. And so we're announcing here for the first time, for our wholly owned pipeline, these are the four pillars we'll be focusing on: rare pediatric neurology, dementia, neuromuscular and peripheral neuropathies, and motor diseases. So these balance considerations across research, development, and commercial, and they represent clear opportunities for Ionis to build and continue to grow our wholly owned pipeline.
Okay, now, we aren't new to any of these areas. Each one of these pillars, which are now listed, listed on the left, we have already clinical experience with Ionis technology in. So these are areas we know and we understand. These are also areas with clear opportunities for growth and to other diseases and other targets. We're going to be focusing in even further on the near term on those top two pillars, and we'll go into those in detail. So the top two pillars are rare pediatric neurology and dementia. So these are the programs that are in those top two pillars that should all be on track to be in the clinic before the end of next year. So zilganersen in our pediatric neurology pillar, is a treatment for severe leukodystrophy. Pivotal study here is already underway. This is our most advanced program.
We then have ION356 for another severe leukodystrophy, Tay-Sachs disease, or PMD. Then finally, ION440, for the treatment of MECP2 duplication syndrome. This is a neurodevelopmental disease. So in all three cases, we're going to the heart of the disease, the genetic cause of the disease. In our dementia pillar, I'm very pleased to be saying we are on track and announcing here that we're on track to start our ION717 program before the end of this year in clinical studies. So here, this is a severe fatal dementia with clear genetic underpinning. So all four of these programs, we're going to talk about in detail next and the science behind them. We also have a genetic dementia target that we're not disclosing yet, but is also on track to be in the clinic before the end of next year.
So first pillar, why rare pediatric neurology? Again, there is a clear need for transformative therapies for these patients. There are many children living with neurological disorders, and many of these are caused by mutations, oftentimes in just a single gene. This gives us those obvious targets, those obvious targets where we can get to the central cause of the disease. Another thing is that young brains have tremendous capacity for growth and repair, and we saw this with Spinraza. If you can solve the problem, especially if it's that genetic cause, these brains can develop and meet milestones that wouldn't have been possible because of their disease. So this is what we're looking for, and this is what we're hoping to do and re-reproduce. So our most advanced program is zilganersen. This is our treatment for Alexander disease. So Alexander disease is a fatal leukodystrophy.
Patients have a myriad of symptoms, including motor, cognitive, speech, and that's just to name a few. It's a devastating disease. Alexander disease is caused by gain-of-function mutations in GFAP. GFAP gene encodes GFAP protein, zilganersen targets GFAP RNA, so on mechanism. At least in preclinical species, we can have a profound effect. We can have effect in preclinical models if we go early in disease, if we go late in disease, and at all the endpoints that those models reproduce. So here's a peek at some of that data. On the left graph, you have body weight. You can see at the beginning of the study, the body weight in the Alexander model in pink is decreased compared to the controls in blue. If you treat with an oligonucleotide, those open pink squares, the body weight improves.
Single injection of oligonucleotide targeting GFAP, there's an improvement in body weight. There's also improvement in motor symptoms on the right, and so lots of support from the preclinical data for this program. And this work is all published in Science Translational Medicine, if you want to see some more of the endpoints in detail. So the next big question for us is, will this preclinical work translate into the clinic? And that's exactly what we're trying to ask with our pivotal study with zilganersen, to see if any of that data can reproduce and lead to a meaningful difference in patients. So this is a global, randomized, double-blind, placebo-controlled study, where here patients will receive either zilganersen or placebo for the first 60 weeks in that randomized period, and then they have the option to go into an open label period where everyone can receive drug.
Now, it's important to note that although Alexander disease is predominantly a pediatric illness affecting children, adults can be affected as well. And so in our study, we're including a large range of ages to capture all those patient populations, because mechanistically, our drug should help in all those different ages. And so that's the question we'll be testing. And the data is planned for this study in 2025. So this is our most advanced program in that pediatric neurology pillar. The next is another severe leukodystrophy. This is Pelizaeus-Merzbacher disease, or PMD. PMD is caused by gain-of-function mutations or duplication in the PLP gene, and our target is PLP RNA. This leukodystrophy affects children, and these patients have very severe cognitive as well as motor symptoms. All these kids will end up in a wheelchair if they ever become ambulatory at all.
So going after that target, we hope to have a benefit for those patients because we're going to that disease-modifying target central to disease. At least in preclinical models, we can have dramatic effects. That's the example here in this graph. This model only lives three weeks. You see that red straight line down? The model succumbs to their disease within just three weeks of birth. If you treat with a single injection of oligonucleotide, now, this is targeting PLP in a disease driven by PLP, that model now lives out to eight months, the late time point. So single injection, you go to three weeks to eight months. This is the kind of preclinical data that you print out and run around the lab showing people. This is really remarkable.
Very happy to say for this program that we've often received orphan designation by the FDA, so we can help, help accelerate this even faster. We have an ongoing natural history study to understand the underlying disease and to look at novel biomarkers. Our third and final program we'll be talking about today in that pediatric neurology pillar is ION440. So ION440 for the treatment of MECP2 duplication syndrome. MECP2 duplication syndrome is caused by duplication or triplications or translocation of the MECP2 gene. Our target is MECP2 RNA. So hopefully you guys are seeing that theme here. So MDS is a severe developmental disease. These children have intellectual delays, speech delays, motor delays, and more than 90% of them will have seizures.
The preclinical models recapitulate some of the phenotype as well, and that data is shared with you on the left. So if you look at a normal brain, and this is looking at EEG activity, and this is a very cool endpoint to be able to look at in a model, because this is the kind of endpoint that translates well to patients because you can also look at EEG activity in a patient. So looking at EEG in the model, on the left you see the activity of a normal brain. In the middle, you have an MDS model brain, and you can see that epileptic activity, brain activity, is increasing. If you treat with an oligonucleotide targeting MECP2, you then have brain activity on the far right, which looks more like the normal brain on the left than the MDS model in the middle.
Now, these effects are just part of what we see. This is published in Nature, as well as the preclinical data for PLP, also published in a Nature publication. So encourage you to check out the more of those endpoints that we've looked at in these model systems. But we're having these very robust effects, compelling effects in the preclinical models with these targets. We also have a natural history study ongoing for this as well, to look at novel biomarkers and understand disease. And in both this and the case of PLP, we're on track to start these clinical studies before the end of next year. So as you can see, we're moving very fast to build that Ionis pipeline up. Now, this is just the tip of the iceberg in pediatric neurology.
These are some examples of benefits that we've seen in preclinical models over the years in pediatric indications. Even though I'm announcing to you today that this is where we'll be building our Ionis pipeline, Ionis has been in this space for a long time. We have Spinraza, which translated all the way from preclinical models into the clinic, and not many people know Ionis was responsible for the development of Spinraza all the way through pivotal studies. So we have that experience. There's also our Angelman program, targeting UBE3A, currently in a clinical study. The study is being run by Ionis, and we're expecting to see if that translated from this lovely preclinical data into a real, meaningful benefit in patients next year. This track record of benefits across diseases, across disease models is really unheard of, and this is because we have these central targets to disease.
We can go to the heart of the disease, and we have the technology to do it. And so this is, this is our plan. Okay, dementias. This is the final pillar that we'll be talking about today. Dementias affect millions of people. They are very difficult, and it's a significant burden for patients and families living with these diseases. And that's because it affects how someone thinks, feels, reasons, remembers…. And just based on the numbers, I'm sure some of you have dealt and have loved ones who have these diseases. Where we're going to focus on dementias initially is on those with genetic underpinnings. We're focusing on those genetic targets, and we're going to focus on indications that are rightly sized for us while growing into more common indications in the future. So the first indication in this pillar is our prion program.
This is ION717, which targets prion RNA. So prion disease is a fatal dementia, and patients succumb to this disease within a year of onset. Prion disease is caused by either genetic mutations in the prion protein, ingestion of misfolded prion, or endogenous prion misfolding. So in all cases, it's the prion protein misfolding that's causing the disease. So an RNA therapeutic, lowering prion RNA and stopping that protein from being produced, has the potential to treat all forms of prion disease. This includes both pre-symptomatic patients who are gene carriers, as well as symptomatic patients. And our goal is to treat all patients with prion disease. And one of the key questions we had at the onset of this program was: Could you intervene late in disease and still have a benefit? Because this is a rapidly progressing disease.
The answer, at least in preclinical models, is yes. This is a model of prion disease where you take misfolded prion and you inject it into a normal animal's brain. It's not actually a model of prion disease. It is prion disease in an animal. When this prion is in the brain, it spreads that misfolding and toxicity, and you get neuronal damage. On the left, what you're looking at is neurofilament, and in black is that increase in neurofilament that happens in the model after inoculation with prion. And that increase you see in the black corresponds to a decrease in survival on the right. This model succumbs to the disease about 150 days.
Now, if you treat with an oligonucleotide 30 days before the model succumbs to the disease, so at day 120, after the neurofilament has already increased, you can see that increase in all the cohorts up to day 120 on the left graph, looking at neurofilament. Then in blue, you can see a reversal in neurofilament. So presumably, this means a decrease in damage, and then that translates on the right to an increase in survival. So single injection, 30 days before the model succumbs, you can extend survival. So even late in disease, at least in an animal model, we can provide a benefit. So another key question for us was, are we affecting the underlying disease course?
This should be a disease-modifying therapy because we're affecting that central component to disease, which we know from previous studies is required for disease, and that's endogenous prion. And when we look at that, we can do that in these models and look at the pathology. So this is looking at misfolded prion. So in brown, what you're looking at is that misfolded prion depositions throughout the brain. This is a brain section, and at the 120-day baseline, so 120 days after inoculation with misfolded prion, you now have these deposits. With controlled treatment at 150 days, that's the middle panel, those deposits are still there. So baseline, left panel, middle panel is your control treatment. The brown deposits are there.
If at that baseline, you give an injection of oligonucleotide to lower that endogenous prion substrate, you have a reversal in the pathology. So that's on the far right. You can see that brown staining goes away, and that's quantified in the graphs below. So we're reversing pathology. So this is very reminiscent of what I showed you earlier with that tau program. So we saw this preclinically with tau. Now with tau, we've seen this in patients. You can reverse existing pathology. And now here I'm showing you in a prion model that at least in a model, we can reverse pathology. So this is really remarkable. We're getting to those central causes of disease, and the hope is that this will transform into meaningful benefits for patients.
I'm very happy to say that the study is on track to start before the end of this year, and this is ION717, which targets prion RNA in prion disease. The name of that study is going to be PROFILE. Okay. This is our plan. This is where we are. I am confident we are going to deliver on our whole ION pipeline and the full potential of that pipeline. There is so much potential here to make a difference for so many patients. We have two approved therapies already in this space, in neurology for patients with neurological disease. We have 12 more in clinical development, more on the way. We have the expertise, the knowledge, the know-how to do this and to continue to do this and to do it again.
With that, I'm now going to hand it over to Rachel, who's going to share with you how we're now going to deliver these medicines to our patients.
Thank you, Holly. Hopefully, everybody can hear me. Just making sure that my mic's working. Hi, everyone. My name is Rachel Carnes. I'm so happy to be here today, and I'm joining Ionis. This is my year anniversary, actually, after many, many years at a company called Celgene, where I worked in hematology and oncology in increasing areas of responsibility in both the early and also the late pipeline. So I see a lot of similarities, really, between the oncology of maybe 15 years ago versus the neurology of today. And when we think about the oncology of 15 years ago, the advances in terms of biology, understanding the biology and understanding drug development, really led from people having chemotherapy to immunotherapy and personalized medicine. And it's absolutely astounding. It completely changed people's lives in regards to hematology and oncology.
What's really exciting to me is that I can see the same amount of revolution happening in the world of neurology, and Ionis is at the forefront of that revolution, and we are among the leaders that are really bringing neurological treatments to patients who have previously had zero hope. Today, what I hope to be talking to you about is three key things. One is we're gonna be opening the curtain on how we're thinking through the actual strategic thinking about neurology and our neurology pipeline. The second thing, we're gonna talk about the word focus, and how focus is really gonna be helping us to succeed with regard to our neurology pipeline.
Then the third one, we're gonna talk about how we are right-sizing the business to where Ionis is going and how we're proceeding as a company in the near future and in the long term. So how do we think through drug development in general for Ionis? The first thing that we have to think about from a commercial standpoint is it the strategic fit for Ionis? So we do an enormous amount of work, actually, at the beginning of every year, looking at the portfolio, and it's called portfolio prioritization. Actually, with most, if not almost everyone, in the company is thinking through this, and we're making sure that we're aligning our areas of focus to the strategic therapeutic areas that we've chosen as a company. And also, we're balancing the risk and investment.
Secondly, we wanna advance the most attractive opportunities. This success should be a two-way street. So if we are being diligent and really only making sure that we're advancing the technologies that are gonna be life-changing for the patients and the caregivers, we're already halfway there in terms of success. And so, that is, you know, how we approaching the business, as it relates to neurology as well. And the third one is integrating of commercial assessments. So, we are making sure that our commercial personnel are in every single team, every step of the development way. I work in early commercial, and so we're sitting on teams that are from preclinical through phase I, phase II, with Holly and Eric and all of the early commercial...
All of the early development teams, to make sure that we have the end goal in mind. And as we're developing, we're doing endpoints. We're thinking about target product profiles, current, future treatment landscapes, and making sure that we have a really robust product by the time we get to the product being on the market. So I started my career out as a registered nurse, and it was a long, long, long time ago. But and, you know, there's the many, many things that we forget about about our first roles in life. The things that I remember, of course, are my patients.
Everything from the child that was looking up at me, and we're trying to get an IV in the kid before he went to the operating room, and he's not understanding why we're hurting him. Of course, we're trying to help him, but kids don't understand that. All the way to the lady who was at the end of her life, slipping away, and I'm holding her hand because I don't want her to die alone. So these are the things that drove me when I was a registered nurse. And when I came into biotech, the things that really started to become emergent to me is, I don't have to just help one patient at a time.
I can help many patients at a time, and we can help hundreds and tens of thousands as we get treatments into the public domain, as patients can use those treatments for the next 10 years and then forevermore. So this has become my mission, and this is why I work in biotech, and this is why I'm working for Ionis. So I always start with the patients because they're the most important part of why I get up in the morning. And so on the left-hand side, we have patients, a patient, and her name is Leela, and she's got Alexander disease. And there she is with her brother, who has a lovely top hat on.
And Alexander disease, I think Holly was talking about it before, devastating disease causing cognitive delay, speech difficulties, and these patients slip away earlier than they should. On the right-hand side, we have a patient with Alzheimer's disease, and I think we've all been touched by Alzheimer's disease. It's a devastating disease where people have impaired memory, thinking, and eventual loss of independence. One day, you walk through the door, and the person doesn't know you anymore, and that can be devastating. Well, that completely is devastating. So these are the, these are the patients that we wake up and serve every day. The good news is that Ionis is leading the field in advancing important RNA technology medicines for neurologic diseases.
We're creating a broad range of medicines for a large group of people, and one of the key questions that we have and the key things that we have to tackle is: How do we make sure we're harnessing all of this amazing technology and everything that we've been building over the last 30 years, ensuring that they get to the right patients at the right time in an efficient and effective manner? And so when we think about the strategy, and I'm gonna talk about the strategy in just a second, but I'm gonna start where we started, and that is thinking about our vision and purpose. The vision is to make sure that we are working in targeted neurology spaces, realizing the synergies, and making sure that we have a competitive advantage and to, and drive increased value... And the purpose is twofold.
One, we have to be working in first-in-class or best-in-class potential, 'cause this is, where it's at. Like, this is literally how we're going to be able to move forward in a successful way. And then the second one is creating efficiencies and synergies. So if you take nothing away other, else from this presentation, it is the word focus in all its permutations. Focus, efficiency, synergies, making sure that we are, able to move forward in a way that's gonna be right-sized for the growth of Ionis as a company. All right. Holly touched upon before, and Holly and Eric have, really done an amazing job talking through how we are developing our amazing, treatments. And this is, of course, where it starts in terms of Ionis and, and important for how we're gonna move forward successfully. The right targets, the right development.
And now let's go into the right commercial fit, because commercial is, you know, most of the how we actually get the treatments to the patients is through commercial, as well as some other aspects. So neurology is an enormous field, and it's a very heterogeneous field. I talked about the very old, the very young, and everybody in between. So as we were thinking about how we were going to think through the strategy for neurology, we started to apply an enormous amount of rigor and analytics to the space. The first thing we had to really do is to understand how we were gonna group and organize all of the different areas of neurology in order to make sense of the space, and in order to be able to do our analysis and come up with our strategy.
The first area that we thought about is efficient physician specialty target. This is where we focus on the therapeutic areas. Physicians, you know, organize themselves in subspecialties, and it's important for us to understand that, so that we can create an efficient field resource, and then use that efficient field resource. The second area is the treatment setting, and this is important because we are creating, for example, therapies that are gonna be used in an intrathecal way. So we have to make sure that as we are thinking through the treatment setting, that the treatment setting is gonna be able to handle what it is that we do. The third is the disease epidemiology. Ultra rare, common. Completely different ways for us to be thinking about the business. Ultra rare is, can we even find the patients?
Common is, how do we deploy huge amounts of field forces and lots of resources in order to be able to touch all of those millions of patients? And so these are, these are another parameter that we were thinking about. Patient age group. Adults have completely different needs to pediatric patients. Pediatric patients need a lot of different resources to be able to help to get them through their treatments, and this is number four in terms of how we were thinking about the business. And the fifth one, of course, is the treatment objective. When we're thinking about studies of prevention versus studies of treatment, they take a really long time.
There's many, many thousands of patients in the prevention studies, and it takes a lot of resources, versus a treatment study that can take a lot less with a lot fewer patients. So that was the last parameter that we were thinking about in terms of our strategy. So once we took a look at all of these parameters and made sure that we were thinking about them in a strategic way, this is how we came up with the four pillars that Holly had identified earlier in her talk. And these are our two near-term focus pillars, rare pediatric, and we'll talk about zilganersen in there, dementia, we'll talk about prion, and then the future pillars, which are the neuromuscular and peripheral neuropathies, and then also the motor diseases.
So should we be successful in being able to commercialize these treatments, how are we actually going to optimize from a commercial standpoint, getting these treatments out there? There's three key things that we think about. One is lean, second is medical-focused, and the third is digital-minded. Lean. Something's gonna fall apart in the back. Lean. So we're thinking about a single field team per pillar that are focused on the centers of excellence. And this way, we can cluster the patient services and leverage those patient services across medicines. So for example, if patients need help with their intrathecal delivery, that we can do that, and we can do that for several medicines at a time. And then once we've done one launch, then all the other launches become plug and play.
So we can layer the second launch, the third launch, and subsequent launches on top of the same footprint that we have already established. Medical focus. We know that specifically for some of these rare diseases, the disease education, focused on identifying the patients, genetic testing, guidelines, administration, is gonna be paramount to, you know, the success of these treatments. And so we're emphasizing field medical support. I'm really happy to say, Shai, I think Ernesa showed, Shai's picture, earlier on today, has been developing his field medical directives and has an amazing footprint of really talented people who are already visiting, all of our physicians, and especially in neuro. And then digital-minded.
Omni-channel is gonna be really, really important for neurology, you know, almost as important or even more important actually than the development that we're doing in donidalorsen and olezarsen. When you have a rare disease, it's important to be able to reach the people where they are. So the dad that's googling trying to find a treatment for his son at 2:00 A.M. on Google, we need to be able to reach that dad. And we know that maybe even 10 years ago, this wouldn't have been possible. Today, everyone has the possibility in their hands, and it's their cell phones. So today, we can reach those people, where 10 years ago, we may not have been able to do that.
This is gonna really lead to a revolution in the way that we're gonna be able to reach these, these patients with rare disease. It's gonna be great for patients with rare disease. We already are building the infrastructure for that omni-channel offering with donidalorsen and olezarsen. So that should be in place by the time we get to the neurology field. What does that look like? Here is obviously a map of the United States of America, and when we look at the stars, these are the top pediatric leukodystrophy KOL locations, and then the dots are where the kids are, so the pediatric leukodystrophy patient clusters. You can see that in many instances, the stars are actually overlapping with the dots. What does that mean?
It means that when we actually deploy our field forces and our medical directors, that we can do it in a targeted way, and this actually becomes possible for us to be able to launch our near-term treatments for patients, and then the patients can get treated where they live, so close to the centers that they're living in. And again, we can layer on and layer on new treatments as they come to light onto the same footprint. So let's turn our attention to Alexander disease. As Holly said, it's a dreadful, terrible disease for patients, devastating for these patients that are growing up with this disease, with regard to the seizures, the cognitive delays, the impairments. And one number that I was just astounded to hear about was 16.
16 is the average number of caregivers that have to take care of each patient on a daily basis, and these are all the healthcare professionals that are, that are, that are helping these, these children. Devastating disease. And when you think about zilganersen, zilganersen, if it's approved, is set to be the first and only disease-modifying therapy for these patients. So the communities are waiting for zilganersen to come, and, you know, we're, we're really thrilled to be the first and only company that's actually developing a treatment for this disease. So what are the key areas of focus? zilganersen, so Alexander disease is a very rare disease, and the first thing we need to do is increase awareness and recognition of Alexander disease.
So we have our field medical force already out and already asking key questions of KOLs to ensure that we know what the disease entails, and we know how to optimize the treatment once it, once it gets into the hands of the treating physicians. Patient advocacy groups, extremely important for these rare diseases, and we already have stood up a robust patient advocacy group in at Ionis, and we're outreaching for those patient advocacy groups for Alexander disease as we speak, so that we can learn from them, and we can really help us to understand what the patients are going through. And then third is ensuring access to the appropriate patients. So our market access folks are hard at work, making sure that they are understanding exactly what the payers are looking for and the information that the payers need.
We can start building that right now, and we can ensure that by the time we get there, that we have a good package to be able to help the payers easily, support this, treatment, day one, from, from the very first patient. prion disease. Devastating, dreadful disease. The patients present with what looks like dementia. They can, last for 4-six months, basically, you know, going around neurologists and trying to get a proper diagnosis, and the clock is ticking for these patients. They've only got 12 months on diagnosis. And so unfortunately for me, this is very reminiscent of the early days in oncology, where metastatic patients had almost the same amount of time. You've got a small window, in which to actually treat these patients and make a difference.
And so again, Ionis is at the forefront of making treatments that are going to help these patients, and there is no other treatment for these patients at the moment. So the number one thing for prion disease is increase the awareness of the disease. It's important for us, and of course, omni-channel is going to be front and center here as we really spread the word. And of course, as many of you would know, sometimes, you know, just the advent of an actual treatment itself and the understanding that there is a treatment out there, can actually increase awareness and help patients to be getting to the right spot.
We saw with Spinraza, for example, you know, with the, the epidemiology was meant to be 20,000 patients, and now ends up being 60,000+ patients because of now the, the treatment is being identified and the patients are coming forward. And so we're also getting the field medical directors out there. We're supporting an expedited diagnosis. We're trying to understand exactly how neurologists are learning, and neurologists in the field are learning about diseases like prion disease, so that we can expedite and get that message out there. And again, access... Gosh, you get, you get the actual, you get the actual indication, but access goes hand in hand with every indication. Without access, it's, it's almost not worth having an indication.
So we're making sure that we're really spending time understanding what market access needs there are for the prion disease patients, too. So I know that we're extremely excited about our portfolio. We're extremely excited about the future in the midterm and the long term, and I hope I've shown you today that we're growing the neurology franchise over time, at the same time as the growth of the company, so that we can rightsize, and that sets us up for success. We're starting out in rare pediatric. We're going into rare dementia. We've got a future wave of neuromuscular and motor diseases, and then we're going to take our place among leading neurology companies as we're moving into the common neurology diseases in the future. I'm extremely excited about our future.
Our mission is to extend and enhance the lives of patients, and, I'm really, really amazingly happy to have joined Ionis a year ago and to continue with the mission. I'm going to hand it over. Thank you. I'll hand it over to Beth Hougen to take us through the financials.
Thank you, Rachel.
The financial outlook.
Wow, that's a lot to have to follow, right? Good afternoon, everyone. It's great to see so many familiar faces in person. This is our first Investor Day, Innovation Day in probably six years, so it's great to be back in person. We're changing as a company in very many ways across our research organization, our development organization, our commercial organization, and all of these changes are really necessary to drive the substantial value that's inherent in our pipeline, in our innovation, in our medicines. But one of the things that isn't going to change as we continue to evolve as a company, is our long history of commitment to fiscal responsibility.
We're going to retain that commitment to financial responsibility as we continue to advance our technology, as we build these wholly owned medicines into this tremendous pipeline, and as we bring the commercial capabilities to bear to successfully launch those medicines. So that's what I want to talk about with you today. I want to talk about how we're going to take all of those changes and how we're going to unlock substantial value going forward. Ionis is changing in many important ways, and one of the things that I want to do, though, is just look back to the past for just a moment. In the past, we used our powerful and prolific research engine to build pipelines for our partners, and that had some very important benefits for Ionis, and it served us well over the time that we were doing exactly that.
It enabled us to develop our technology and to build a rich pipeline of medicines, transformative medicines that you see in our pipeline today. We were able to use our partners' resources, the funding that they provided to us, to do all the great work that we needed to do. For example, we get tremendous R&D revenues from our partners that funds a lot of the work that we're doing. We also saw significant benefit, and still today see significant benefit from the work that our partners do on behalf of our medicines. For example, Novartis is conducting and fully funding an 8,300-patient cardiovascular outcome study for pelacarsen. Because of that, we don't have to use our capital and our people to do that work. We can use our capital and our people for Ionis's pipeline, our wholly owned medicines.
Our partners also bring to bear their global reach and commercial expertise to bring our medicines to patients. Spinraza is an excellent example of that. While this served us very well and has served us very well for many, many years, it's limited our ability to create more value. Today, we want to use our resources and our expertise, our innovation, to create even more value, to create substantial value from our medicines. We're going to use that, those resources that we have to fund and conduct the development that we're doing right now with our late-stage medicines.
Through all of that, we're going to create what we are calling next level value, because we're going to be able to create with our resources, with our technology, with our wholly owned medicines, and our substantial and exceptional commercial capabilities, we're going to be able to create value beyond what we've been able to create in the past. Ionis' financial strength has been an enduring quality of the company for many years. We have a strong financial foundation today, and we have a very unique financial profile as well, and we're using that to invest in our technology, to invest in our wholly owned pipeline, and to build the commercial capabilities that are necessary to bring these medicines to patients.
We're in a period of necessary investment in order to set us up to unlock that substantial value that I'm talking about and that you've heard all day today... We wanna be able to invest in our three strategic priorities, and I've said it a couple times: our technology, our pipeline, our wholly-owned pipeline, and our commercial capabilities. It's by investing today in these late-stage medicines, eplontersen, olezarsen, and donidalorsen, means that we're gonna be able to bring those medicines to patients, bring them through phase III development and bring those medicines to patients. And as a result, we anticipate being able to move from this period of really necessary investment. It's a period of investment today into an era of significant revenue growth as we bring these medicines to patients.
We can do this again and again and again, as you've heard from Holly and Rachel, as we build our wholly-owned pipeline, starting with our neurology programs, building on neurology and building the rest of our wholly-owned pipeline over time. It's this... It's these, the substantial revenue growth from successes, wave after wave after wave of new products coming to patients successfully, that's going to be able to enable us to generate substantial and sustainable positive cash flow well into the future. Today, we have a very strong financial foundation. We have more than $2 billion worth of cash. We have significant royalty revenues, with Spinraza, the resiliency of Spinraza royalties as the cornerstone, and we have substantial and sustained R&D revenue from multiple sources. Let's talk a little bit more about those investments.
As I mentioned to you, we're investing very significantly right now in our phase III medicines, in donidalorsen, olezarsen, eplontersen, and we need to bring those through phase III development, and we need to be able to get those to patients. While we're investing in that, those development activities, we're also building commercial capabilities. But before we get to that, we're also investing in our next wave of wholly-owned medicines. We're building that wholly-owned pipeline, and that's what you heard from Holly and from Rachel. What that means, though, even with that investment across the pipeline, our R&D expenses are reaching steady state. So let me say that again. This is important.
While we continue to invest in our late-stage pipeline and invest meaningfully in our technology development and in our wholly-owned pipeline in the early and mid-stage pipeline, we are reaching steady state with our R&D expenses. While our R&D expenses are leveling off, you should expect that our commercial expenses are going to increase, and that's really important. That's how we're going to bring these medicines to patients successfully, and that's how we're gonna generate substantial, substantial revenue, substantial cash flow, substantial value. That being said, we're going to be investing in our commercial capabilities responsibly. We're gonna continue our history, our long history, of investing, of, in all of our different areas of the business responsibly.
We're gonna use fiscal responsibility to invest, and importantly, we're going to be investing in our commercial capabilities with the revenue that we see in front of us, so in line with the revenue we see in front of us. By doing so, we'll be able to generate that substantial value that we've been talking about. So let's look at the various different types of revenue that we've got. We're in a very unique position as a company. I don't know of too many other companies, maybe none, that have our financial profile. We have R&D revenue from our partners. This is a substantial source of revenue and cash flow for the company today. It averages about $350 million each year, and it funds, and this is important, it funds a very significant portion of our expenses today.
We also have royalties from our approved products that are on the market and reaching patients today, with Spinraza as the cornerstone. And we also have, in our late-stage pipeline, a number of really important medicines that can also increase our royalties over time. And most importantly, and probably the one we're most excited about today, is the product revenues that we're gonna generate from our wholly-owned medicines, beginning with olezarsen and donidalorsen, and donidalorsen on the horizon, and the wholly-owned pipeline behind that. So let's dive into our R&D revenue from partners. As I said, this has been funding the company for the majority of our past. It's quite substantial. It's probably a revenue source that all of you or most of you know very well.
I venture to guess most of you don't like to model. Yeah, I figured. However, as I said, it's important, and it's important because of the $350 million that we generate each year from this source. It's also important because it has substantial ability to grow, and it's sustainable well into the future. How can it grow? First, the existing partnered medicines, as they advance in development, will generate even larger and more significant milestone payments from our partners as those medicines advance, and we create more value from those medicines. Second, as we bring new medicines under our existing partnerships into development and move them through development, we will also generate substantial value. And third, as we enter into new partnerships, like we recently did with Roche and Novartis.
This is a really important source of revenue, and I want to emphasize again how important it is, because it, it's really a very big piece of how we fund our business today, how we fund our operating expenses today. As we look at royalties, let's just take a quick look at the details behind royalties and why we see they're going to be able to grow. First, we've got very substantial royalties from Spinraza and Qalsody, particularly Spinraza, as the cornerstone, and the resiliency of Spinraza as patients continue to choose Spinraza and continue to stay on Spinraza. We're also three short months away, we believe, from bringing eplontersen to patients. And the very successful negotiations we had with our partner resulted in very attractive economics for Ionis, for this medicine.
In addition to the majority of the phase III development costs that are funded by AstraZeneca, AstraZeneca also pays a very substantial portion of the United States commercial and medical costs, as well as all of those same costs for OUS territories. But importantly, we also negotiated very attractive royalty rates that go up to the mid-20%. That means we can add to our already approved product royalty streams with Spinraza, particularly in Qalsody, with royalties from eplontersen well into the future. And this has a very long-term horizon, just as Spinraza does. It goes well out into the future. And then we have the ability with the economics that we have for eplontersen, to amplify those royalties even more through sales milestones. But that's not all.
Royalties continue to be a really important source for Ionis, because in our late-stage pipeline alone, we have three medicines, each for a different disease, that has the potential to have significant opportunity and, in the marketplace with patients. First is pelacarsen. pelacarsen is our, is our medicine under development with Novartis for Lp(a), for cardiovascular disease as a result of Lp(a). There's about 10 million patients worldwide with this condition. Bepirovirsen is our medicine, partnered with GSK and in development, in late stage development for hepatitis B. There are 300 million patients in the world with hepatitis B. 900,000 of those patients die every single year. And then IONIS-FB-LRx, I hope we get a generic name for that soon, is actually in development right now, in late stage development for two different indications.
The first is IgA nephropathy, and the second is an eye disease called geographic atrophy. What I really want to highlight here is the substantial opportunity for revenues from royalties for these three medicines. Just like Spinraza and Eplontersen, they have long-term horizons. There's a lot of similarities across all of these products, even though they're all for different diseases. Just like with Eplontersen, we have the ability to amplify those royalties with significant sales milestones. Importantly, and something that I find very attractive about royalty revenue is that essentially all of our royalty revenue is 100% profit, drops right to our bottom line, and goes straight into cash flow for Ionis. What does this look like when we just look at our partnered programs?
What does that look like when you, when you look across the years and you put these one on top of the other? Starting first with our two approved products, and then looking out to 2025 and 2026, with potentially five more medicines or indications, and seven or more, 2027 and below and beyond. That's a substantial upward curve in our revenue. And again, it all drops to the bottom line, and virtually all of it drops to the bottom line as profit, and it, it fuels our cash flow.... So now let's turn to product revenue. This is our newest source, or will soon be our new source of revenue. It's, it builds on top of our strong financial foundation. It builds on top of our R&D revenue. It builds on top of our royalty revenue.
It's also the revenue source we at Ionis are extremely excited to add to our financial profile, and you probably heard that or certainly should have heard that today throughout all of these presentations. When we think about product revenues, however, unlike R&D revenue and unlike royalty revenue, we have to also talk about investment, because it's the high-quality efforts of our research, our development, and our commercial organizations that are going to ensure that our product revenues, that our products, as they get to the market, as they get to these patients, are successful and that our product revenues can grow. So we have to be investing. That's really important. But we're going to invest, as I said earlier, we're going to invest with our fiscal responsibility in mind and with the revenue opportunity ahead of us.
So as you think about the really important high-quality work that needs to be done, and I think about olezarsen. Just last week, we saw the importance of the high quality, well-designed, well-executed phase III program for olezarsen in FCS patients with the unprecedented phase III data that we reported last week. And it's with that data in hand that our commercial organization is preparing, actively preparing today to bring olezarsen to these FCS patients who are suffering from a severe and debilitating disease. But we're not done with that. We're taking olezarsen broader. We're conducting a broad phase III program today in severe high triglyceride patients.
Assuming that those studies are positive and that medicine gets to patients, we're going to need to increase our commercial and medical teams and increase our investment in commercial in order to reach that much larger patient population. So you should anticipate that if we have positive phase III data from olezarsen in severe high triglycerides, that our expenses for commercial are going to grow. But they're going to grow with the revenue opportunity in sight, in line with the revenue opportunity we see before us. Unlike olezarsen, however, donidalorsen requires a more modest investment for several reasons.
First, with 20,000 patients in the U.S. and the E.U. with HAE, it's a much smaller, more targeted patient population, and we've designed our phase III program with that patient population in mind, including a switch study, because we know many of these patients are on existing therapy. As Onaiza highlighted, it's also a very targeted, concentrated prescriber base, which means the commercial model is going to be very efficient. We'll be able to target that small number, relatively small number of physicians who treat the vast majority of these patients with a field team of less than 100 people. So a very efficient commercial model.
And then, third, and this is important, donidalorsen is going to build off of the capabilities that we're putting in place today for eplontersen, for olezarsen, and that creates tremendous synergies for us as we bring new medicines to the market. What this all means is that donidalorsen has the potential to be a very high-valued opportunity for Ionis. And then, as you heard from Rachel and from Holly, we have a really exciting next wave of wholly owned medicines in our neurology pipeline. So how are we going to invest to realize the value in those medicines? Everything that gets a green light needs to be first-in-class or best-in-class. We prioritize those programs that build off of our deep know-how and expertise in neurology and utilize our proven track record in neurology with Spinraza and Qalsody.
Importantly, we put considerable weight on the importance of realizing synergies across research, across development, and across commercial. You heard from Rachel that we can do this from a commercial perspective, because by grouping pediatric neurology, just as an example, together, many of those patients are treated by the same physicians in the same centers. So that gives us important commercial synergy. What does this look like when we put them all together and we start stacking them up one on top of the other? It looks like tremendous growth, with olezarsen potentially being our first independent, wholly owned medicine on the market to reach patients with FCS in 2024, and building off of that, up to five medicines in 2025 and 2026, and even more in 2027 and beyond.
Importantly, this is without the royalty medicines, the royalty-generating medicines on top of it. This is just the product revenue potential from our wholly owned medicines. So what does it look like when we put them all together? This is exciting. I love this slide. I really love this slide. Not just because of the financial implications. Obviously, that's something that's gonna, that's gonna resonate with me, but I love it because it reflects the tremendous commitment of everyone at Ionis to bring innovative medicines to patients. That's what's really important about this, and as a result, it's going to drive substantial, substantial value for the company. So as I stand here today, we're not aware of any other company that has a financial profile like us. We're very distinct in this regard.
I'm not aware of anyone with the strong financial foundation and the substantial recurring R&D revenues, plus substantial and long-term and sustainable royalty revenues that can continue to grow. Plus, soon, product revenues, highly valued product revenues, that build on top of the R&D revenue and on top of that royalty revenue. What you just heard and what you just saw is how the power of our technology, the richness of our pipeline, and the potential to successfully bring our medicines to patients, can ultimately translate into substantial and sustainable value creation. Thank you.
Last Q&A session for the day before Brett gives his concluding remarks. So I'm going to ask, Eric and the speakers from this afternoon to come up here and take the stage for our Q&A session. Again, we're only going to have 30 minutes for Q&A. Oh, yes. I also want to remind people that, before we, before we start taking questions, that there is going to be a national alert that's gonna sound on everybody's phones in about 10 minutes or so. So if you wouldn't mind, just like, even if your phones are silenced, the alert is going to happen. So if you would just, like, turn off your phones for the next little while. That way, the entire room won't erupt with this noise. Oh, iPads too? Oh, could you turn mine off?
Okay, it looks like we've got Debjit. We've got our first. And then if we get Lisa a microphone, Julie. Go ahead, Debjit.
Right. Debjit, a couple of questions. One, on, the business go to your last one. The pipe was really intriguing. Do you think you get insights into, for MAPT function from, the presentation? And number two, when you think about the CNS pipeline, how do you think about the probability of success with these targets compared to say, a never done? Or even within the four pillars, how do you rate pediatric indications versus dementia versus the next treatment on a probability basis?
Maybe I'll take the first one. It'd be great to ask Holly to take the second one. So we don't really have much more to share, except that what's been put out there by our partner, Biogen, for AD. Certainly, they're providing an update on the open label extension from the Tau program, and they seem to be enthusiastic about it. But I really can't go further than that, Debjit, until the actual presentation is given. Holly?
Yeah. So in terms of how we think about the probability of success, it's really not by pillar, but by individual program. An individual program, at least for me, comes down to the target. So are we at a target that's central to the disease? How strong is our understanding of the biology of the target? And that's going to come from both data genetics as well as models. And not just data in the model system, but then the quality of those model systems, because some areas have higher quality model systems than others. And the more data you can generate, the more you can de-risk and understand those targets early on, preclinically in my shop, and then we can use that to decide which ones are going to have the highest probability of success.
And so we can see that the ones that we've selected within our pediatric neurology, we have clear gain of function or duplications or triplications. So genes that are increased cause the genetics and then we lower. And those are supported by preclinical models that are very similar to that disease in patients. And so then they have similar phenotypes, and then we can look at that. So if they check all those boxes to have those things. prion disease is a really interesting one, because here, preclinical models are actually prion disease. And so we can test in them, and we've tested across three different labs, across half a dozen different models, and we get those same results. And so very robust, preclinically, to get the type of disease, and that still has-...
Decades of experience in prion field, people wouldn't know what price is on this, that, that prion is central to the disease. So it's really looking at that individual target, the data that's out there, and the quality of the data, and making our best judgment.
I'd like to just add to that, Debjit. I don't know if this is what you're going to jump in on, Eric, but I forget how many programs we've actually taken into the clinic in neuro. It's a lot. We're, we're 100% successful. I'm sorry. 100% successful in demonstrating robust target engagement for every program we've taken forward. Every program, we've been able to measure target in the CSF or even in the brain, as Holly showed you in our tau program. 100% successful. To expand on that, to your other sort of what you're getting at. I think for Ionis, CNS is where liver is has been for everyone else. Our confidence that we can engage target and tackle diseases in the CNS like others can do, including Ionis in the liver, is really equal today.
And the number of genetic targets that are available for drug discovery, as Holly pointed out, is enormous. So I think for Ionis, liver and CNS are essentially equivalent, but I think that's unique to Ionis. Lisa?
Hi, thanks for taking our questions. Lisa Walter here from RBC Capital Markets on for Luca Issi . I have the first question for Holly and then a follow-up for Eric. For Holly first. On the tau program, I was just wondering your thoughts on whether tau reduction could also help preserve total brain volume in Alzheimer's patients, and whether you think brain volume is a good measure of disease progression or not? Just I think for Leqembi, we have seen some reduction in brain volume with treatment despite improvement in efficacy. So any thoughts on that would be helpful.
Yeah. So we did look at brain volume in the first in human study, and that is published in the Nature Medicine paper that came out earlier this year. We saw reductions in both the placebo as well as the treated groups, and there weren't any dose-dependent effects. So at least in the short-term studies, there wasn't anything that we could see that was meaningful going to tell us how that's going to read out. The main endpoint that's being looked at in the current study now is clinical endpoint, so focusing on clinical endpoints in the phase II study.
Thanks. And then maybe for Eric, just on the pipeline and the chemistry. I was just wondering, did you ever have any thoughts to pursue RNA editing? It just seems like a natural fit for Ionis and the ASO technology. And maybe, just if you could add any color on when you think it's best to use an ASO versus your RNAi platform.
Yeah, sure. First, on RNA editing, we certainly thought about it, and it's a very intriguing and interesting technology, and it's a cool concept. Ultimately, we chose to go with a DNA editing approach. We thought it was more versatile. RNA editing, obviously, you have to keep the drug there for the entire lifetime of the program. You have to continually edit it. And we truthfully, when we looked at the available target space in RNA editing, we thought it was more limiting than what we could do with other modalities. So I think it's very intriguing, interesting technology, but we're not actively in that space right now. And then on the question of when it's best to use which different modalities, I really like our competition approach, for lack of a better term, where we internally compete approaches.
We experimentally answer the question, and we have some ideas about what makes one target more amenable than another target. But they're ideas, and really, I think it's best done experimentally. And so certainly there's some biology approaches where you might want to modulate splicing. That's a different approach. Nuclear retained RNA, for example. There it is.
It's a little early.
Yes. Gee, it's pretty early.
Why did they pick today?
Because it's ours.
Why now?
Why were you speaking?
Reminds me of when I was in grade school, right? The little horns would go off. Okay. Certainly, if you had a nuclear retained RNA where siRNAs don't access as well, an ASO approach would be better. Some transcripts that are super highly expressed in the cytoplasm or siRNA scope might be better targets. I... But the answer is experimentally where we want to be. So that must be a different carrier. I think we're uniquely able to do it.
Thanks. Thanks for taking my question.
Okay. We'll take one question from Yale and then Justin or Julie.
Yale again from Laidlaw. And just two questions to maybe touch on the discussion this morning. The first question is that if, for eplontersen, in the polyneuropathy, what will be the initial focus for targeting, whether that's a new patient or existing patient? And the second question is for the European commercial approach for eplontersen and the donidalorsen and thanks.
Aza? Mm-hmm.
Hi, Yale. So for polyneuropathy, as I said, we have a lot of headroom. There are a lot of new patients and a lot of new patients to be found for silencers. So that's really where the focus will be. Of course, right now, I think the market is experiencing this temporary kind of area of flux, where there's a lot of switching going on. I do expect that's just going to wind its way down, very, very quickly, and then really all of the growth will be, in finding new patients as well.
... For your second question on the OUS approaches for olezarsen and for donidalorsen, as we've said, our initial launches are going to be in the US. So we are focusing our execution on the US. We are setting up the strategy to be ensuring that we're creating value, creating medicines for OUS, and we'll be seeking a partnership of some sorts to be able to bring olezarsen as well as donidalorsen outside of the US, through a partnership or distributorship model.
Is there a timeline for the second question in the U.S.?
It's very data dependent. As the data comes out, the interest grows. So we'll pick the right timing, in terms of making that happen.
Thank you.
Hi, this is Chi Fong for Jason Gerberry from Bank of America. Thanks for taking our questions. So I have two here. So first one on donidalorsen. It looks like you guys have generated some interesting durability data in phase II OLE, and you guys are running OASIS Plus, generating more OLE data in phase III setting. So curious about how important it is to have the durability data in terms of bolstering the competitive profile of your product, and how you decide to weigh it in in terms of, is it gonna come into a publication setting, or do you think that there's a potential opportunity to include it in the label, you know, for commercial purpose? And the second question is on the platform. So looks like you guys have some interesting technology between siRNA, MsPA, and other various technology.
A lot of excitement going on there, and you guys have, previously talked about interest in going to the pulmonary and oral, delivery space, which seems to be fitting in with some of these technologies. So I'm curious, when might we be able to see the first kind of a candidate in for oral dosing or pulmonary target with this newer technology? Thanks.
So maybe I'll start on donidalorsen. So the durability that Ken Newman, the data that he shared, two-year durability with not greater than 97% reduction in attacks is incredibly important. Incredibly important. As, as you heard from Dr. Tachdjian today, what matters most to patients is to control their disease. The efficacy is what matters most. Patients, all patients, almost all patients with HAE are still suffering from potentially fatal attacks despite the medicines that are on the market today. So showing that it wasn't just phase II data after four months, but it was actually long-term durability in which the efficacy was maintained, is incredibly important and importantly, with no emerging safety issues or no emerging tolerability issues with long-term treatment.
So, that will be in very important for Onaiza and her team to drive that message home, assuming approval for donidalorsen reaches the market.
Yeah, and I think there was a part two of your question on whether you think that's going to be label, in the label or not. I almost really doesn't think it matters. So if we get it published, and/or we get it in the label, the promotional guidelines have actually now shifted back from where they were a bit, a while ago, which was substantial evidence, which almost meant like you were trying to get everything in your label to be able to promote from it. We're now back into the mode of consistent with labels. So as long as the data is consistent with your indication statement in the clinical trial sections, we're going to be able to use the data, and reference the publication very readily.
Eric, maybe you could talk a little bit about expectations for some of the technology advancements you've highlighted reaching clinical trials, including pulmonary.
Yep. So I'll start with Bicycle and siRNA. So there we have nominated candidates for preclinical development, and so that's headed for NDA-enabled tox, enabling tox studies. With an siRNA, we have a liver-targeted one that was nominated for candidate development that we hope to get into the clinic next year in the humans. For MsPA, we have two molecules that were nominated for preclinical development in neurology space, and there we think it's important to extend the duration. And one of those we hope to get into human clinical trials next year also. For pulmonary, we're taking a very measured approach. We want to make sure that we've got the right molecules and have the right profile overall.
We have a couple targets that we're highly interested in and are looking for drugs, and we'll update on the timing of when we think that might enter preclinical development at the appropriate time. We're not doing that today. As far as oral goes, I don't think the technologies I talked about today are really gonna make a leap and bound ahead of oral. The problems with oral is getting out of the intestinal system and getting into the vasculature. These really won't address that. And so we're more focused on our local delivery to the lung, local delivery to the CNS, crossing the blood-brain barrier, and our systemic delivery of our drugs at this time right now.
Yanan.
Thanks. Yanan Zhu, Wells Fargo. Have a couple of questions for Holly on neurology programs. For the rare pediatric neurology indications for MECP2 duplication syndrome, this gene has to have a tight window of expression. The lack of it causes Rett syndrome. I'm wondering how the team has thought about mitigating that risk? Or perhaps that risk doesn't exist in a non-developmental setting. And for the other two leukodystrophies-
... indication. I was wondering, because they are both autosomal dominant, is there a risk, or are you adopting an allele-specific knockdown approach? Is there a risk of? If not, is there a risk of knocking down wild type? Thank you.
Yep. So I'll start with MDS. So MDS, you're correct, so that if you have a loss of function that causes Rett syndrome. So here with MECP2 duplication syndrome, we're starting with twice as much or three times as much, and so we're lowering it. The window is actually quite a bit bigger than what you would expect if this was just an endogenously expressed gene. So we're starting with higher levels. And we are, we will be following this and looking at it going forward. Preclinically, we can have a nice benefit by lowering in the duplication model and have that clear window. In patients, we've done a natural history study, so we can identify different phenotypes that we can follow in any MECP2 duplication syndrome versus Rett.
As well as we have a very active biomarker program, identifying viable biomarkers to be able to make sure that we're within that proper window of modulating the pathway. So for GFAP, for Alexander disease, that is very tolerant to lowering. So there we're going for a knockout approach. Not a knockout approach, but a lowering approach from an endogenous level. It is increased at the protein level because there's once it starts aggregating, there's an increased stability, so protein levels actually go up in GFAP in Alexander disease, and so we will be modulating there, but full knockout mice are fine. For PLP1, that is again duplication syndromes in the majority of the patients, so that'll be the patient population we start in. There are gain-of-function conformational mutations; these are much more severe patients that are earlier on.
There, again, there is a window that we need to be working with, that we are conscious of. We're building biomarkers to be able to do that.
Great. Thanks.
Ellie.
Hi, thanks so much. Ellie Merle, UBS. Just for prion disease, can you talk about the design at all of the phase I/2? And since you mentioned you plan to start dosing this year, when should we think about when we could see initial data? And then also, what proof of concept would look like in terms of what would be encouraging, such as, you know, the reversal of PrP deposits? And then I have a follow-up commercial question.
Yeah. So it's primarily going to be it's a first-in-human study, so safety and PK, PE is what we're really looking for. I'm not going to share any more than that at this time, but as we get closer to it, we'll share more details about what the design is going to look like and what that, what that will entail and what the timing will be.
Great. And then commercially, I think you've mentioned that, like, from the last question, that growth from here, once we see a lot of the switches, will come from new diagnoses in polyneuropathy. Can you elaborate a bit on where we are from a diagnosis perspective, both in the U.S. and ex-U.S., in terms of hereditary polyneuropathy?
Yes. So polyneuropathy, hereditary and mixed phenotype, is about a 40,000 patient population, and well under 20% have actually been diagnosed and treated. So lots, lots more to find and get treated with that one person.
Gary.
Hi, Gary Nachman at Raymond James. So I think there's also a follow-up for Holly. So for all the pediatric neuro rare opportunities you talked about, how many of those could you potentially expand into other indications, even if it's on the rare disease side? And then for the dementias, how much proof of concept do you need to go more broadly within the dementia category? How long could that take, potentially?
Yeah, so those are really good, tough questions. So for the rare pediatric neurology diseases, right now, we're focused on those genetic diseases. We, of course, have preclinical experience, experiments ongoing to ask if they can be broader, because, for example, GFAP has been hypothesized that that could be beneficial in ALS and Alzheimer's disease. And so we are doing those preclinical studies to see if there could be some expansion opportunities there. Same thing for prion disease, actually, has been implicated in Alzheimer's disease as well. So again, this is all preclinical stage work, and we are... It is very much on our mind that there could be more opportunities for these therapies beyond. But right now we're going to stay laser focused on the genetic targets where we think we have the highest likelihood of success and opportunity.
And then for expansion into more common diseases and what that preclinical data is going to look like, again, this isn't very satisfying, but it's going to come down to the target in the disease models, because they are not all created equally, they are all different. If we stay on genetic targets, you're going to be more likely to have those, those model systems that are going to be better. But then as you expand out of that, then we'll get into more creative model systems, iPS cell systems, human validation with the genetic data that's out there to go into those more broader indications that are going to be potentially more pathway targets. But that's in the future.
Right. And then just a quick one for Beth. So I know you have that great chart and all the things that are going to be driving a lot of incremental spend. Are you comfortable with all the sources of revenue that you guys have in front of you right now, that you could potentially reach profitability given the, you know, capital requirements that you have to invest in the business? And are there other potential non-dilutive sources of revenue that you could foresee?
So, is this on? Yeah. So what I'll say about that is, and as you could see easily from the chart, that we're, you know, using a very substantial, we have substantial revenue opportunities with our R&D revenue, with our royalty revenues. Those can continue to grow well into the future. As I pointed out, we've got a very well-capitalized balance sheet today. But as CFO, my job is always to make sure that we have the capital that we need to bring these medicines to patients. And so we'll look very carefully at whether or not we need to bring in additional capital as we get closer through the development with these drugs and closer to the market. And if we do decide we do, we'll be very strategic and very opportunistic.
We'll look at ways to raise non-dilutive financing. We have lots of opportunities ahead of us. And we'll be very thoughtful and careful if we have to do that.
Myles?
Yeah, Myles Minter from William Blair again. Just for Beth as well. The guidance that R&D expenditure is approaching a steady state, does that also include all of the efforts for life cycle management of the products that you expect approval for over the next five years? I know you've got next gen Spinraza, but if olezarsen is good, I'm sure there's others coming for you as well as with Donny. So, maybe leveraging some of Eric's new chemistries, does that R&D guidance actually incorporate spend on those potential programs?
It does. It does. And that all of that that you see in front of us is really reflected in our in our R&D spend today. As you think about these very, very large phase III programs starting to trend off and our mid and earlier stage pipeline programs starting to ramp up towards phase III development, we see things starting to shift. But that's what gives us the confidence that our R&D spend is essentially reaching steady state today.
Yeah. And then a quick second one on, the Alexander disease program. Is there any other key secondary endpoints apart from the primary on the 10-meter walk, which is testing gait, right? Any sort of like independent anchor endpoints that we should be looking at to confirm function there?
Yep, there's a number of. Oh, is this not working? It is. Okay. So there's a number of secondary endpoints as well. So we'll be looking at patient-reported outcomes, physician-reported outcomes, a number of aspects, so that we're really looking at the disease in totality. Because it is a disease with a lot of heterogeneity, and so we did settle on that endpoint after a lot of research because it is quantifiable, it is effective in most patients, but we are looking at the totality of the disease and, and hope to have that complete package.
The FDA is obviously going to be, well, hopefully, pretty flexible given the devastating disease it is. But have they pointed you to a specific anchor endpoint in those key secondaries that they'd want you to hit to prove that functional benefit?
Yeah, I actually don't know the answer to that question. I'm sorry.
It's all good.
Hi, Justin Kim from Oppenheimer. You know, it seems like a lot, a number of things have really come together to sort of focus on wholly owned medicines and neurology. I'm just wondering how much of that is sort of driven by the, the delivery and, and expertise there, and to what extent the ability to drive technological innovations in delivering medicines to other organ areas might unlock additional pillars, such as cardiac, kidney, muscle, lung, as mentioned before?
Well, Jason, it starts with a commitment to building what we've created and how we've advanced the technology. With existing chemistries, knowing how to find better molecules, knowing where these drugs distribute, knowing what the most sensitive cell types are in the CNS, and then you couple that with the advancements that Eric has made, or Eric has covered today, has shared with us today, just extends that leadership position even further. So it starts with a commitment to do this, to expand our wholly owned pipeline. And then you layer on top of that all the experience we have. Then I guess the third thing is the fact that there are just so many genetically validated targets to go after. So much low-hanging fruit.
I view the CNS as where the liver was when GalNAc came forward, right? And everybody started going after that low-hanging fruit for hepatic targets. The difference between CNS, as I highlighted before, and liver, is that we're so far ahead. We're well ahead with a big pipeline of 12 medicines in clinical development, two approved products, and as Holly said, four more from our wholly owned pipeline expected to reach clinical development next year. So I think it's all of that that really in combination.
And maybe just a follow-up on the technological innovation front. Is it fair to think about some of the earlier partnerships as reflecting those innovations or maybe not? Just sort of curious in terms of, you know, the recent news with Takeda and focusing there. Additionally, I guess now a renal program, right, also with them through Chinook and maybe some of the neuro programs.
Yeah, you know, I, I think the earlier partnerships reflect the value that we can bring in terms of ability to, to make differentiated molecules that, that add ultimately value to patients, and the partners see that. And so they're certainly looking at our technology and our ability to, to make the best possible molecules when they sign up with us to, to the things that we did. So I, I absolutely think it makes a difference.
There's a very significant amount of inbound interest in our programs. Not to say that, you know, we haven't gone out and looked for certain partners when we felt like this would be better in the hands of a partner than Ionis. But far and away, it's much more incoming interest in the advancements we're making in our technology, advancements we're making in CNS, advancements we're making in kidney, and those sorts of things, and maybe soon in pulmonary. So I think all of that is part of the reason.
Hi, Harshita Polishetty, Barclays, for Gena Wang . I have one for Beth, one for Onaiza, and a quick one for Holly, if I may. Beth, when you're talking about revenue and the three specific pillars, you know, R&D revenue, then the royalty revenue, and then the product revenue, I'm sure we can do the math of like what portion comes from, you know, each of these pillars now. But how do you think about-
... To whatever extent you can quantify, you know, how do we expect these proportions changing maybe in the next three to five years and, you know, in the next, like, 5+ years?
Yeah. I think right now, it's about 50/50 between our royalty revenue and our R&D revenue. Give or take. I expect that that will change over the coming years, and become more heavily weighted to the royalty revenue, as all of those medicines that I highlighted, start to read out phase III, with phase III data and potentially reach patients. And then on top of that, we're going to be adding the product revenues. And I think eventually our product revenues will be our most significant source of revenue, but that's a little bit down the road.
Thank you. One for Onaiza. Onaiza, earlier in the morning, when you were talking about the eplontersen market research, one of the slides covered on the self-administration benefits of eplontersen. But thinking about it, one of the considerations for self-administration would be patient compliance. So how are you thinking about that? And, you know, to preemptively kind of address that patient compliance wouldn't be a concern when eplontersen is on the market.
Yeah. So, you know, I talked a lot about our patient education managers. And, you know, in a rare disease model such as for FCS as well as for polyneuropathy, we really have the ability for these nurse case managers to touch base with these patients on a very, very regular basis. In addition, that will include kind of just, you know, how they're progressing on a disease, nutritional status, and reminder of compliance of their medications, and making sure that, you know, they're confident and comfortable and feeling really good about using it.
Okay. A quick one for Holly. Holly, for prion disease, on the slide for the late stage disease model, there wasn't any information on what kind of disease model it is or what species. Can you shed any color on that?
Yeah, of course. It's the RML is the seed strain of prion, and it's in mice.
Perfect. Thank you.
Yeah.
Take yours and then one more question.
Thanks. Julian, Julian Pino with Stifel. Quick question, going back to FCS and SHTG. So I guess from the presentation, Dr. Ginsberg, you know, FCS, you have an absence in LPL activity, whereas in SHTG, you are getting some LPL activity as well as this TRL clearance. I guess, does it make sense then, mechanistically, that you could potentially get some enhanced benefit in FCS on trigs, given some activity in both these pathways? And then I guess, are there other confounding factors in this patient population that would perhaps take away from any added benefit when compared to FCS? And then also, just on neurology, any update on the Angelman program? Just not many details on that today.
Sam is not miked up, so I'll take a stab at this.
You've got a mic.
Oh, there he goes. Go for it.
Thank you. That's a very important question. So I want to just remind you that we've already looked at a population with normal LPL activity, which is the phase II trial. And remember that one had a 50 milligram dose. We had a 60% reduction in triglycerides. So because of this additional mechanism, one could predict that the SHTG population would respond more to ApoC3 inhibition. The other part of this equation is FCS patients. Their triglyceride levels are highly dependent on what they ate that day before and the week before. I get a lot more variability in triglyceride in an FCS population than you would in SHTG population. So for those two reasons, you could predict that there may be differences in the results.
One thing you have to be careful though, is that all of these studies have slightly different populations. Even there was a difference between approach, our eplontersen study and our current balance study. So just, you have to be careful when you interpret this information about who the patients are, whether they're all genetically confirmed or it's a combination. So some of that also brings into, the equation about what you see.
Then how does that translate to or predict efficacy in SHTG, too? The other part of the question.
Yeah. So for SHTG, well, the FCS patients are completely dependent on liver receptor clearance. For SHTG, you're gonna have that part, plus you're gonna have LPL activity, which might increase as you treat them. So theoretically, they will have both mechanisms, and it could be more efficacious.
As far as Angelman’s, we’re nearing completion of enrollment in the phase one, two study that we’re running, and we expect data in the midyear next year.
Last question?
Last question. I better make it good. It was gonna be maybe just a follow-on biologically is related to clinically for olezarsen. So you're noting that you think for Doni, the peak opportunity is about $500 and above. The market right now is about $2, but obviously it's got some competition in HAE, and you're thinking more than $1 billion for olezarsen, and you're gonna be spending in a gradual way, I presume, based on the initial opportunity. FCS is, I imagine, is gonna be a lot smaller an opportunity relative to SHTG. So does that but inevitably, it sounds like you're gonna have to build some capability that's gonna be overlapping between FCS and SHTG.
... So cash flow, I imagine, is going to be more back-end weighted, depending on success in the second indication. Is that the way we should be thinking about spending? And then secondly, the SHTG opportunity is much bigger patient-wise. I imagine the commercial scale-up is going to have to be a lot bigger. Is that something you can handle internally?
You want to start?
Sure. Sure. So I think it's the way to think about that, Arun, is you always have to be spending on the commercial preparation and your medical affairs activities ahead of, frankly, your phase III data or your launch. So there will be some front-end loaded commercial expenses and medical affairs expenses. A lot of that, frankly, is already built into our SG&A expense line today for FCS. And we've already got medical affairs teams in place. We've got, you know, all of our commercial capabilities that Onaiza highlighted in place today. Then as you get closer to launch, you start to bring on your sales teams, your field teams. And that's usually after you've got your phase III data and after you've already been under review by the regulatory agency.
So you have a much better picture of the risk profile. You have a better sense of the opportunity to get those that drug approved and get it on the market. That's the time that you start to increase your spend to prepare. Do you want to add?
You want to add to that?
Yeah. So, you know, as Beth said, you know, some of the pre-commercial investments you're making it at risk, but they really are gated as well. They're gated on milestones, completion of enrollment, and, you know, kind of how the regulatory discussions are going on along the way. Do we get any feedback on the 120-day safety review, right? So we're looking at all of those and making the right gated investments along the way on the pre-commercial investments. But we need to make those because we have to be really prepared and ready to launch as well. FCS, you are right, will be a much smaller customer-facing field. And then for SHTG, it will be larger, but it will not be at the size of what you expect in a GP sales force by any means.
We're not actually calling on primary care physicians. We're going to be calling on endocrinologists and preventative cardiologists. I gave you a bit of the behavioral segmentation on where these aggressive treaters are. Those are also quantified with the numbers behind it. So we're still working through kind of what that will look like in terms of just total targets, which will then be used to size kind of our sales team accordingly. So it will be larger than FCS, but certainly not at the degree that you would expect for a GP primary care sales force.
And then do remember, for SHTG, we're going to be using, very smartly, the omni-channel and digital capabilities for extended reach for those physicians that we may not be able to get to in person and on the street on our own as well.
Okay. Thanks to our second half speakers for coming up and doing the Q&A session. We'll let them return to their seats, and I'll turn it over to Brett to give us a closing.
So we've been now at this for nearly seven hours, and it's been a really exciting afternoon and morning. So I'm going to be brief. I'm going to be brief, just like to make a few conclusionary statements and then wrap things up. So I think as you heard today, it's very clear that we are laser focused on a clear vision at Ionis to drive substantial value by delivering the transformational medicines to patients, to the market over and over and over again. And this will provide great value not only for patients, but for all stakeholders.
We're focused on expanding and delivering our, on our technology, extending our leadership position in, in technology, and you heard a lot about that today. We have one of the most remarkable late-stage pipelines in the industry, and we're prioritizing our wholly owned pipeline, and that is due, and that is on schedule to continue to grow with potentially first-in-class and best-in-class medicines. We heard today that we have all the capabilities essentially put in place to deliver our medicines, to commercialize our own products, from our wholly owned pipeline, for patients.
We have the financial strength and responsibility to be able to make the investments we need to make, to ensure for our long-term success, focused on delivering a steady and growing cadence of potentially transformational medicines, this year, next year, and for many years to come. I won't spend much time on this. You heard a lot about our near-term launch opportunities, eplontersen, olezarsen, and donidalorsen. Just to remind you, we're very much looking forward to a potential approval for eplontersen in ATTR polyneuropathy by year's end, and we're prepared to launch. The cardiomyopathy phase III trial is fully enrolled and on track. We're very excited about the FCS phase III data that we provided last week, our top-line data, and we're looking to file an NDA in the first half of next year.
You heard a lot about SHTG, a really big opportunity for Ionis. Olezarsen expected to be our first independent commercial launch. And then for donidalorsen, you heard a lot about the unmet need in HAE and our potential best-in-class profile for donidalorsen as a prophylactic treatment for HAE. And we're very much looking forward to the phase III data in the first half of next year. This is a snapshot of our wholly owned pipeline. You saw a version of this from Beth already today, again, eplontersen, olezarsen and donidalorsen are expected to be our first independent commercial launches. And you also got a good look into our next wave of commercial opportunities when we did a deep dive into our neurology wholly-owned neurology franchise.
All of this setting us up for a steady cadence of medicines to reach the market in the near term and well into the future from our wholly-owned pipeline. And then you add on top of this, our partnered programs. Beth said she loves this slide. I love this slide, too. I think everybody at Ionis loves this slide. I mean, it really sets us up for substantial growth. A whole lot of new potential products reaching the market in the near term and in the long term. I mean, we're looking at 6 potential approvals for 8 disease indications, both broad and rare, over the next three years or so, and more to follow after that.
It truly is setting us up for a substantial, substantial, growth opportunity, to provide great value for all stakeholders, all shareholders, and, of course, patients as well, and a steady cadence of new products to reach the market in the future. So to wrap up, I finished my introduction this morning with this slide, which were the key take-home messages, which there are four. I think today we did a, I hope we did a really good job. I'm confident we did a very good job of providing you the evidence that's behind each of these take-home messages. The first is that Ionis has established and prioritizes its wholly owned pipeline, and we're expecting that pipeline to continue to grow.
Second, we have all the capabilities in place to deliver our medicines directly to patients ourselves, and we're looking forward to our first co-commercialization launch in January for eplontersen and ATTR polyneuropathy, and then the following year for olezarsen—or I'm sorry, next year, the second half of next year, potentially for olezarsen in FCS, which will be our first independent commercial launch. You heard a great deal today about the advancements we're making in our technology, unprecedented advancements that are extending our leadership position in oligonucleotide therapeutics as we expand and diversify our capabilities. And we have the financial strength and commitment and responsibility to make all the investments we need to make to ensure great value for all stakeholders as we go forward.
So in conclusion, or to wrap up, I want to start by just thanking the audience here in person. We spent a lot of hours here, as I mentioned before, with all of you. We really appreciate your time, as well as everyone who has been dialed in, remotely, through the webcast. I want to thank our distinguished key opinion leaders, Dr. Henry Ginsberg and Dr. Raffi Tachdjian as well. And I want to thank my colleagues. Great job, team. Really appreciate the effort and the hard work. Their enthusiasm that they shared with you in their presentations today is their enthusiasm all the time. They really are excited about this, and it transcends throughout the Ionis organization.
You know, when Holly mentioned before about seeing data and tearing it off the printer and running around the lab, that's commonplace at Ionis, that when we have data like that. And we see that not only in research, but we also see it in our commercial organization when we do new market research. And people in our Onaiza's team come forward and say: Look at how we're differentiating, look how the preferences are stacking up from physicians and patients for the drug to bring it forward. And Sam did it last week with our FCS phase III data. Of course, he was sequestered because it was highly confidential information, so he was running around a very small group of people until we actually put out the press release.
I think Ken Newman has probably got his track shoes on for the first half of next year for donidalorsen, and when we reveal the HAE Phase III data. So, folks, thank you again very much. We really, really appreciate your time, and we're looking forward to providing you additional updates as we make further progress. Have a great day.