Ionis Pharmaceuticals, Inc. (IONS) Earnings Call Transcript & Summary

Good morning, and welcome, everyone, to Ionis Pharmaceuticals 2025 Innovation Day. I'm Wade Walke, Head of Investor Relations. And it's great to see so many of you here in the room with us today. We'd also like to welcome those who are joining us today online via our webcast. Every 2 years, we host this meeting in order to give you an update on the progress we're making on our goal to transform the lives of people with unmet -- severe unmet medical needs. And today, we are thrilled to showcase how we are leveraging our technology, our pipeline and our medicines to accelerate growth and to deliver transformative medicines to patients. Before we begin, a brief note that we will be making forward-looking statements today that are based on our current expectations and beliefs. These are often associated with certain risks and uncertainties. And so our actual results may vary. And as our lawyers want me to say and like me to say, please refer to our SEC filings for additional risk factors on our company. For the next few hours, you will get to hear directly from key Ionis leaders across the company who are spearheading the tremendous progress that we've made to date and are helping us to execute on our goals. We're also very pleased today to have with us Dr. Robert Fishberg. Dr. Fishberg is a respected thought leader and treating physician for patients with severely elevated triglycerides. His perspective will provide valuable real-world clinical insights into how these patients are treated. And as you can see from the agenda, we have a packed program for you today, covering topics from our recently launched medicines, our cutting-edge pipeline, our innovative technology, all of this accelerating growth of the company and helping us to deliver transformative medicines to patients. So without further ado, I will introduce the CEO of Ionis, Dr. Brett Monia.

Good morning, everybody. Thank you, Wade. I too want to welcome everybody for joining us today, those in person. It's great to see so many people here live as well as all the folks that are dialed into our webcast. We really are excited, thrilled today to provide you all with a comprehensive overview of the remarkable progress that we're making at Ionis Pharmaceuticals today, and of course, we're -- what the future looks like. It's an incredibly bright future based on all the momentum we've created; it's going to drive accelerating value. We're going to provide you with an update on -- across all key functions of our business, a comprehensive overview of our science and technology advancements, an overview of the remarkable progress we're making across the pipeline with game-changing medicines continuously being delivered on an ongoing basis, our commercial strategy. And where we are in our first independent commercial launches for Ionis in our history and what those -- in our plans for future launches as well as our financial strategy, where we are today and our clear path, and we're going to provide to you also a clear path, a road map to achieving positive cash flow in the near term with growing revenue. So we've accomplished a great deal over the last couple of years. And that has laid out in a very strong foundation for Ionis to drive value, to drive momentum. We are very well positioned based on all of our success lately to drive accelerating growth and value for Ionis for all of our stakeholders, our patients and our shareholders. And that's based on one of the most incredible attractive pipelines in biotech. And we'll take you through that. And of course, that pipeline is based on innovation. That's why we call this Innovation Day. Innovation in our science, innovation in our clinic, clinical development programs, innovation in everything we do. The pipeline, as I said, is delivering and is positioned to continue to deliver on an ongoing basis. And the profiles that our medicines are delivering in the clinic are setting us up for highly successful commercial launches. We're already off to a good start with our first couple of independent launches today, and we're well positioned to a high -- strong trajectory of very successful launches in the future. The profiles are important. Of course, we're also in the business typically of delivering first-to-market medicines, which also helps those launches very successfully -- to be very successful. Today, we are fully integrated commercial stage biotechnology company with our first 2 independent launches in our history. And we've evolved to become a fully integrated technology biotech company to drive value, to drive great value for patients, to drive value for our shareholders, for all stakeholders to control our own destiny, if you will, and not rely on partners to deliver our medicines, our precious medicines to patients who are in need. And that is driving accelerated value, accelerating growth, sustained positive cash flow, which is enabling us to reinvest in the company. It was about 6 years ago, give or take, that we set out on a new course for Ionis, when I moved into the role as Chief Executive Officer at Ionis. Building on the incredible reputation we've always had in leaders in research and early clinical development, I felt that it was time for Ionis to take the final step in our journey to become a leading biotechnology company by moving towards full integration, full commercial integration. And when we did that, we laid out a plan. Of course, we put together a plan. And we focused on and laid out 3 strategic imperatives that we needed to be successful in achieving to ensure great success. The first was to build a pipeline to prioritize and advance our wholly owned pipeline. And number two was to build an experienced and innovative commercial organization to deliver our medicines independently to the market to patients that are in need. And three, was to expand and diversify our technology, our drug discovery capabilities to extend our leadership position in RNA-targeted oligonucleotide therapeutics. And doing all of this while strengthening our financial position. When you lay out a plan, you put out milestones, right? We need to achieve this at this point, and this point in time, and I couldn't be more thrilled to say that we are exactly where we should be at this point. In fact, we've achieved or exceeded all of the key milestones in our journey to be a highly successful fully integrated commercial stage biotechnology company at this time. We've had a remarkable run over the last couple of years across our pipeline, our launches and our science and so on. Over the last 2 years alone, we've had 6 positive Phase III data readouts, enabling 4 approved medicines with more to come next year. Four of those approved medicines are now -- are independently owned by Ionis and independently launched by Ionis today. TRYNGOLZA for familial chylomicronemia syndrome and DAWNZERA as a prophylactic treatment for HAE. We've also invested tirelessly in expanding our pipeline and growing our pipeline and based on the innovative research we do at Ionis with industry-leading first-in-class, best-in-class molecules that are in late-stage development. We've created 10 medicines that are in late-stage development today, setting us up for a steady cadence of Phase III data readouts as we have this year. We're going to replicate that next year and for many, many years to come. We are highly focused that Ionis across our business, right? We need to take care of our precious resources and optimize the usage of those resources, and therefore, we are highly focused in all we do. That includes our drug discovery areas of focus. We are focused on 2 therapeutic areas today, neurology and cardiometabolic diseases. Two areas where there is high unmet medical need. Two areas where our technology and our drug discovery work has proven value for patients, for shareholders and so on. In neurology, We, of course, have proven the value of our technology with breakthrough treatments that were conceived, discovered and developed at Ionis, like SPINRAZA, the first ever FDA-approved medicine for Spinal Muscular Atrophy in QALSODY, the first ever FDA-approved medicine for a genetic form of ALS. The only medicine that has a disease-modifying impact on any course of ALS. And we have a whole pipeline of 11 medicines in neurology behind that and dementia in rare genetic neuro -- pediatric neurological diseases and so on. And it's the same for cardiometabolic -- in our cardiometabolic pipeline. We have a leading pipeline that's anchored by olezarsen for severe hypertriglyceridemia, a breakthrough treatment for people with super-high levels of triglycerides that are at risk for pancreatitis and pancreatic failure, a program that we expect to be FDA approved next year and launched independently by Ionis next year. And other medicines in our cardiometabolic pipeline including pelacarsen for (Lp(a))-driven cardiovascular disease and eplontersen for ATTR cardiomyopathy, both on track. Cardiovascular outcome trials that are both on track to read out next year. So obviously, we're delivering an amazing pipeline for both severe, rare and highly prevalent diseases across these 2 therapeutic areas. I mentioned that our Phase III programs -- our Phase III pipeline is positioned to continue to deliver a steady cadence of Phase III readouts as we did this year. We're going to replicate that next year and for years to come. What's most important, of course, is getting these medicines to the market, to patients. And we are on a steady cadence to deliver FDA approvals and launches on a continuous basis. We began our journey to commercial full integration with WAINUA, the medicine that we created at Ionis for TTR amyloidosis. And today, WAINUA is approved for ATTR polyneuropathy, and we're looking forward to cardiomyopathy Phase III data next year. That first step where WAINUA was planned to involve a co-development, more importantly, co-commercialization relationship with a trusted partner to help us build our commercial capabilities as we prepare for our first independent launches, right? That was the plan. We partnered with a trusted partner, AstraZeneca, we've been working with for many years, and WAINUA is doing very well on the market today for the neuropathy indication. We're looking forward to the cardiomyopathy data next year. And that has set us up very well for our first 2 independent commercial launches as planned, TRYNGOLZA for FCS and DAWNZERA as a prophylactic for HAE. And those launches are off to good starts. Next year, we're looking for 3 -- we're looking to 3 more FDA-approved medicines and commercial launches, 2 from our wholly owned pipeline, olezarsen for severe hypertriglyceridemia and zilganersen for a rare pediatric disease called Alexander disease. And thirdly, bepirovirsen from our partner pipeline for chronic HBV and the beat goes on. In 2027, we're expecting 3 more FDA-approved medicines and commercial launches, including pelacarsen, which I already mentioned, for (Lp(a))-driven cardiovascular disease, eplontersen for ATTR cardiomyopathy and sefaxersen, a complement targeted medicine for the treatment of IgA nephropathy and more coming after that, including our Angelman's program with these numbers, these really impressive numbers indicate is that Ionis will have launched 4 independent programs to the market by the end of next year. And by the end of 2027, our partner pipeline will have launched 4 medicines by the end of 2027, really remarkable numbers. We couldn't be more pleased with the FDA approval of TRYNGOLZA for familial chylomicronemia syndrome, the first and only FDA-approved medicine for this severe rare genetic disease. This disease, of course, is associated with severely elevated super high levels of triglycerides. These patients suffer from all kinds of problems because of those triglycerides most -- the biggest risk, of course, is a potentially fatal attack of the pancreas, acute pancreatitis. There's around 3,000 people with FCS in the United States today, and our Phase III program delivered a compelling Phase III -- compelling data from our Phase III program, showed substantial reductions in triglycerides, substantial reductions in outcome, acute pancreatitis with good safety and favorable safety and tolerability with the convenience of once-monthly self-administration. Not surprisingly based on the unmet need and the excellent execution by our commercial team to launch us off to a very strong start. Patient feedback has been very positive as has been HCP feedback. We're going to hear some of that later this morning. And then what's coming, of course, is even bigger for TRYNGOLZA. We're going to refer -- I'll refer to this now as olezarsen until it gets approved, and we'll call it TRYNGOLZA. Olezarsen is positioned to target a highly prevalent disease, severe hypertriglyceridemia, sHTG, more than 3 million people in the United States suffer from severe hypertriglyceridemia defined as triglycerides 500 and above with over 1 million that are we call high-risk patients, patients that are high risk for acute pancreatitis. We announced groundbreaking results in September for olezarsen in severe hypertriglyceridemia, highly statistically significant reductions of triglycerides on top of standard of care, 72% mean placebo-adjusted reductions in triglycerides on top of standard of care, never been shown before in this patient population in our core Phase III study and 85% reduction in acute pancreatitis, a first, another first for Ionis demonstrating the clinical benefit of lowering triglycerides in sHTG. We are marking -- we are working around the clock to deliver olezarsen for this blockbuster opportunity to this patient population around the clock. We're going to take advantage of our first-mover advantage by doing so. And we're looking forward to getting the sNDA filed by the end of the year with an anticipated launch in the second half of next year, assuming FDA approval. We're also looking forward to presenting the full data at the American Heart Association Scientific Sessions in November in the clinical trial late-breaking session, a highly prestigious session at the AHA. We're honored to have been selected for this very important presentation. We're also very pleased with the on-time approval this year of DAWNZERA as a prophylactic treatment for hereditary angioedema, the first and only RNA-targeted medicine for the prophylactic treatment of hereditary angioedema. A mechanism of action that is resonating extremely well in the physician community. There's about 7,000 people with hereditary angioedema in the United States today. And we recognize the fact, of course, that there are prophylactic treatments out there today to prevent HAE attacks in this genetic -- severe genetic disease population. But what we also know is that patients are very unsatisfied with their current treatments. And HCPs that manage these patients are recognizing that based on the emergence of medicines like DAWNZERA. DAWNZERA has a profile to address the unmet needs of patients. Patients are looking for better efficacy, fewer attacks, better tolerability, and better convenience. And DAWNZERA is positioned to check every -- all 3 of those boxes. Remarkable efficacy, great tolerability and the convenience of every 4-week or every 8-week subcutaneous cell administration using a simple autoinjector. So we're pleased with the approval. The launch is underway. We're in the early innings with DAWNZERA, but we're very encouraged by the feedback we're getting from the community and how the launch is going so far. And Kyle Jenne will provide you with an update on the TRYNGOLZA FCS launch, and the DAWNZERA HAE launch later this morning. September was a heck of a month with the Phase III data that we announced, the groundbreaking results we announced for severe hypertriglyceridemia. And we're also incredibly proud of the Phase III data that we announced for zilganersen, a game-changing disease-modifying medicine for a rare pediatric disease called Alexander disease. This disease is a genetic disease. It's a rare severe neurodegenerative leukodystrophy that is usually diagnosed in the first couple of years of life and is almost always fatal. There are no treatments of the disease-modifying treatments available for Alexander disease. So obviously, these results are unprecedented. And obviously, we have first mover advantage here, what's more importantly is we have a medicine that's going to change the course of Alexander disease for the families, the mothers, the fathers, that manage these poor children. We're looking forward to presenting the full data or at least I shouldn't say the full data, some of the data at the CNS meeting later this week. I think it's Friday or Saturday of this week. And then the full data at medical meetings next year with publications planned. We're also working around the clock to submit our NDA as quickly as possible and to launch next year. And this is, again, with sHTG for olezarsen, this represents a second independent launch for Ionis next year. Our independent neurology pipeline is growing and delivering. And it's a high priority for Ionis. Right behind zilganersen is another potential game-changing medicine, ION582, a promising investigational medicine for Angelman syndrome, a rare neurodevelopmental genetic disease that afflicts more than 100,000 people in major geographies. We think we have a medicine that can change the course of this disease in ION582. We presented last year at multiple Angelman conferences, some really encouraging data, positive results from our Phase I/II study called HALOS, which we demonstrated consistent and meaningful benefits on clinical measures of the course of the disease across essentially all measures of disease progression. But I'm also -- what we are also very pleased about is that all the patients essentially in that Phase I/II study rolled over into a long-term extension. And now as we reviewed the data at 6, 9, 12, 18 months, the drug seems to continue to perform well. Supporting the profile of this drug as a disease-modifying treatment for Angelman syndrome and our decision to move into Phase III development. Holly Kordasiewicz will present you some of that data from that long-term extension later this morning. Next steps are to -- well, first of all, we're pleased that we initiated Phase III development enrollment in June of this year, the REVEAL study. We want to complete enrollment next year and then have data in 2027. The Ionis wholly owned pipeline has delivered groundbreaking results over the last couple of years, as I just took you through and is positioned to continue the delivery of meaningful value-creating events going forward including next year from our cardiometabolic pipeline, we're looking forward to the approval of olezarsen for severe hypertriglyceridemia and our first independent launch in a prevalent disease. We're also looking forward to starting Phase II development for ION775 from our cardiometabolic pipeline. This is Ionis' first-ever siRNA discovered using Ionis know-how, Ionis chemistry, Ionis engineering. That drug is now in Phase I development, and we're positioning 775 as a follow-on to olezarsen. It's hard to beat the efficacy of olezarsen. The bar is incredibly high. What we're focused on for 775 is to allow us to dose semi-price a year or less treatment. And Sam Tsimikas will take you through some of the Phase I clinical data we're sharing with -- we've seen for ION775. And then in neurology, of course, is the approval of zilganersen next year. And the launch of zilganersen, our first independent commercial launch in neurology, the Angelman program completed enrollment, as I mentioned. We're also looking forward to several -- or at least 2 key mid-stage pipeline readouts, prion and our alpha-synuclein program in multiple system atrophy, which if any of those -- either of those are positive, they'll advance into Phase III development. And we're also looking forward to initiating a brand-new clinical study from our wholly owned neurology pipeline in Dravet syndrome. And again, Holly will take you through our rationale for moving into this disease and our plans. And folks, that's only our wholly owned pipeline what I've been taking you through. Layered on top of this is an amazing, a remarkable phase -- late-stage Phase III pipeline from our partnered pipeline. Next year, we're expecting 4 Phase III readouts from our partner pipeline, the first half of next year, bepirovirsen for chronic HBV, pelacarsen for (Lp(a))-driven cardiovascular disease, highly prevalent diseases, millions of people with high unmet need. And then in the second half of next year, eplontersen for ATTR cardiomyopathy and sefaxersen, a complement targeted medicine for IgA nephropathy. These programs are incredibly important for patients. These programs are incredibly important for all stakeholders in Ionis and that the economics to Ionis is really, really attractive, allowing us, if successful, to continue to invest in our research, our pipeline and our independent commercial launches. And Beth will provide you with an update on why this pipeline is so helpful as we work towards financial sales efficiency and positive cash flow. So I've taken you through now in our journey to be a leading commercial stage fully integrated biotechnology company by focusing on a high level on how we're prioritizing the wholly owned pipeline and how we're independently bringing our medicines to the market ourselves. And you'll hear more about that later. We're also making great progress in expanding and diversifying our drug discovery capabilities. I'm so proud of the work we're doing in research today. I just want to touch very briefly on the progress we're making here before I close. We're focused on 3 areas to expand and diversify our science, drug discovery capabilities, new platforms enhancing our ability to target new tissues and cell types, targeted delivery. And then thirdly, expanding our therapeutic opportunities based on the science that we create. We're making great progress in expanding our capabilities on new platform technologies, including, as I mentioned, first Ionis engineered siRNAs are now in the clinic for indications where -- or opportunities where we think an siRNA might have advantages over an antisense approach. New chemistries such as NMA chemistry, which are supporting annual dosing for CNS diseases administered intrathecally. And new approaches that are allowing us to overcome the blood-brain barrier, so further extend our leadership in CNS diseases by administering our drug subcutaneously or intravenously. We're making great progress here. First candidates are coming. Holly is going to give you an update on all this great progress. We're also making great progress in gene editing as well. Targeted delivery to open up new tissues, new cell types to tackle new diseases. We're focused on cardiac myocytes and skeletal muscle to strengthen our leadership in cardiometabolic diseases and in neurology moving into neuromuscular diseases. We have candidates coming for neuromuscular diseases, we're expecting our first clinical start for a cardiac myocyte target with a partner with an Ionis program coming right behind that for heart failure indications. And we're making great progress in the blood-brain barrier as well as I already mentioned. And all of this is strengthening our ability to tackle more diseases in related areas, in neurology, neuromuscular diseases and in cardiometabolic diseases targeting the cardiac myocytes directly, not just relying on risk factors to derive from the liver and tackling indications like heart failure. We're also making great progress in opening up new potential therapeutic areas. We're looking forward to our development candidate to be approved for a pulmonary indication by the end of this year as well. So to close, I'd like to leave you -- close my introduction, I'd like to leave you with a few take-home messages. First, we've had an incredible run over the last couple of years, creating a very strong foundation for Ionis to launch off from to drive accelerating value. We are in accelerating value creation today. We've just begun. We've just scratched the surface. There's so much more coming based on how our pipeline is continuing to deliver based on the value we're creating from our independent commercial launches and based on the value from our independent pipeline. And this is going to provide substantial and sustained value creation for years to come based on, and I showed you what's coming, a steady cadence of transformational medicines to reach the market for serious diseases for many years to come. So thank you, and I'd like to now hand it over -- the stage over to Dr. Sam Tsimikas, Senior Vice President of Cardiometabolic Drug Development at Ionis.

Well, good morning, everybody. Thank you, Brett. Well, it wasn't that amazing presentation. Hard to keep track of all of that. Thank you so much, Brett. And I'm very happy to be here with you today. I've had the privilege of running the cardiovascular franchise for the last 11 years. And I can say that this is the most exciting time since I started. In that last 11 years, I think we've laid the foundation for where we are today and what I'm going to show you today, which is that we are, I think, arguably a leader in the cardiovascular arena as far as the industry goes. And I hope to be able to convince you of that when we go through our portfolio and some of the drugs that we have developed over the last 10 years. So let me go and start out and give you some of the tenets of how we got here over the last decade or so. We really based our portfolio on 4 tenets. One is that we want to target major cardiovascular diseases, which are the leading cause of mortality in the world. We are very well positioned to have a steady cadence of drugs, late stage, mid-stage and early stage to achieve those goals. We have led the field in triglyceride-mediated disorders. We've started with FCS. We understood that. We developed a drug for it, and we finally approved those drugs. And now we will continue that legacy of remaining the leader over the next decade for triglyceride-driven diseases. And finally, I'll show you some evidence that we continue to innovate our cardiovascular franchise portfolio. We'll go beyond the lipid disorders; we're going into the myocardium and we expect to be very well positioned in the industry in the near term and also over the next 5 to 10 years with many of these indications. Now you know about TRYNGOLZA. This is Ionis' first independent commercial medicine. We were very pleased with the FDA approval for FCS. That was about a decade of work to get to that stage, and we finally achieved it. However, we're not resting on our laurels for this indication. About 5 years ago, we set a program in motion to have -- expand this indication into severe hypertriglyceridemia, which is a highly prevalent disorder with at least 3 million people in the U.S. and tens of millions of people globally with elevated triglycerides. And as you heard from the top line data, which I will review for you briefly when we get to the next section, we were very pleased with our top line core data that demonstrates the ability for us to go beyond a rare indication to a broad indication and have the ability to manage that as an Ionis-owned medicine. Now the cardiovascular franchise right now consists of 7 assets, 2 are wholly owned, 3 are partnered and 2 are preclinical that are coming to the clinic shortly. Let me take you through this on the right side. We're going to talk a lot about olezarsen today and the expansion into severe hypertriglyceridemia that has just finished its Phase III trials and is ready for a regulatory submissions. As Brett mentioned, we are now expanding our expertise in triglyceride disorders with ION775. This drug represents the very first and most advanced liver-targeted siRNA that Ionis has developed. And I'll be pleased to show you in a little bit data from our Phase I trial on this drug. We will use this to develop additional capabilities for expanded duration of dosing in severe hypertriglyceridemia and other triglyceride disorders depending on the ultimate profile of that drug. Now for partner medicines, Brett already mentioned these, but I want to highlight a couple of things, eplontersen is undergoing a Phase III outcomes trial for TTR amyloidosis. That trial is being run by Ionis with our partners at AZ, but we are doing all the heavy lifting for earning that trial. Along with our olezarsen experience, we have now run 2 very large Phase III outcome trials, and we plan on leveraging this capability to be able to run any outcome trial in cardiovascular disease that we choose to in the future. Pelacarsen will be reading out in the first half of next year. This is also our drug that we developed many years ago, that's licensed to Novartis as you all know. This will be a first of its kind medicine, if approved, or a highly, highly prevalent disorder, which is elevated Lp(a). And we look forward to the results of that trial. That drug is a couple of years or more ahead of anybody else. So if the trial is positive, we anticipate this to be a historic trial as far as trials go in the Annals of Medicine. I also want to point out to you 2 assets here that have code names that have undisclosed targets, but we are going beyond the lipid disorders and TTR amyloidosis into the myocardium. We will be leveraging our technologies to deliver drugs to the myocardium or myocardial diseases and our plan is to be both first and best-in-class with these 2 compounds that you see on this list. Okay. So to set the stage for what I will talk about later, I'd like to invite Dr. Robert Fishberg to the stage to go over the unmet needs and the treatment landscape for severe hypertriglyceridemia. Dr. Fishberg, is an eminent cardiologist and lipidologists. He has run a very large referral practice in all lipid disorders. He's particularly interested in triglycerides, and he has had experience running clinical trials on all the lipid disorders, including with statins, PCSK9 inhibitors, CETP inhibitors, (Lp(a))-lower drugs and triglyceride disorders, and I think he's going to give you a flavor of what these patients suffer from and what the clinical need is. And we look forward to your presentation.

You've answered this way. Great. Well, thank you for having me here today. It's a pleasure with such an esteemed group. And I'm a cardiologist in New Jersey. I work in Atlantic Health, Overlook Hospital, Morristown Hospital, you may be familiar with them. And I've been in practice since 1989. I've done over 30 years of clinical research on all different areas of cardiovascular disease, particularly with lipids. And I want to share my expertise with you and see if I could elucidate what we found, particularly in the area of triglycerides. This has been, again, an area which we had very little success. We're very good at lowering LDL. We're working this LPA drugs with triglycerides something that we've had very poor successful over the years. These are my disclosures. So looking at the FCS significant patient burden unmet needs. And it's usually -- this is usually a genetic disorder, familial chylomicronemia syndrome is easily -- it's caused a loss of LPL, which is one of the key enzymes in the body and it's usually 5 genes that causes. And often, you need to have 2 genes to cause the syndrome. But actually, in many patients, you may be 1 gene and you may diagnose it by a clinical syndrome. And it's usually -- triglyceride levels are usually over 880 over -- often over 1,000, and it's usually 10 to 100x greater than normal. Normally, when you eat -- soon after eating your triglycerides level go down, these patients maintain very high levels of triglycerides, and it causes acute potentially fatal pancreatitis, debilitating chronic syndromes. And again, these patients are sometimes hard to diagnose, they have -- often will have brain fog, they'll have the Lipemia Retinalis, [indiscernible] have enlarged liver and spleen. And again, acute pancreatitis associated with severe abdominal pain, nausea, and vomiting. They'll have eruptive xanthomas. Often, this -- it looks like a rash, we think this might be a drug reaction. But when you see this is a very specific finding for this disease. And again, I've seen this in a number of patients who triglycerides are routinely over 1,000. High disease burden, meaning a long-term complication, increased psychological stress reduced quality of life. I'll go into that a little more when I show some patients. But again, if you can imagine, if you suffer from severe abdominal pain, recurrent pancreatitis, you're worried any time you have any abdominal pain, you worried this could be your next trip to the hospital and it's these patients live in fear of recurrent pancreatitis. And we think there's between 1 to 13 people per million with FCS. Again, depending if the diagnosis purely on genetic terms or clinical terms, that's why there's a variation in the number. But I think this is probably a very underdiagnosed disease. Most physicians don't do genetic testing. And again, these patients are often misdiagnosed when they come to the hospital, even with the acute pancreatitis. Now this is a pivotal study, and this is the balance trial, and this is looking at the initiation of olezarsen 80 milligrams, 6 and 12 months. And again, it shows significant triglyceride reduction at 6 months compared to placebo in FCS patients and further reduced for 12 months. And what's remarkable is this is the first trial that actually showed reduction of pancreatitis. Now we have other drugs that reduce triglycerides, but no drug has ever shown reduction of pancreatitis. Again, the -- we recommend [indiscernible] or typically over 880 to reduce triglycerides to prevent pancreatitis. But it turns out all the other medications we have, none of them actually have ever been shown to prevent pancreatitis. So again, this is a breakthrough medication, the first time we actually see reduction in pancreatitis and 84% reduction in all hospitalization. And again, substantial reduction in days spent in hospital compared to placebo and had a very safety and tolerable profile was excellent. Again, you can't imagine what it's like for these patients to suffer acute pancreatitis and just the physical and the psychological [indiscernible] on them and their families. Now when you suspect it, there's actually 2 ways of doing genetic and clinical confirmation. Clinical confirmation is with a couple of scores that the North American FCS score and the Moulin scores, but either one will clinically diagnose it. And genetic -- again, very few physicians actually do genetic testing. But when you do it, it's remarkable what you find. And again, in my clinical experience, I've diagnosed patients with clinical and with genetic confirmation with this diagnosis. So that's why there's a variability in the numbers. I think it's probably more common than originally thought if you look combined genetic and the clinical confirmation. Again, looking at the scores, its high triglycerides, no secondary factors. Again, you want to eliminate patients who -- any alcohol use. Pregnancy, I had a patient recently in the hospital, her triglycerides went to 3,000, she did develop acute pancreatitis. So pregnancy is one of the things that caused increase in triglycerides. Honestly abdominal pain, and again, they don't have Familial Combined Hyperlipidemia. And the key thing with these patients is they don't respond to gestalt methods. So even though we may try Fibrates, Niacin, fish oil, none of these really have much of an effect or statins. And they -- Again, the onset of symptoms important, many of these patients have had symptoms since there were young adults, even teenagers with recurrent pancreatitis. So a score over 10, 10 or higher FCS is likely. And we -- in my clinical practice, again, I'm in a large hospital system with 300 locations, 6 hospitals, 16,000 physicians over 400 advanced practice specialists and about 1 million covered lives. And I was actually had a database of everyone in the system who had triglycerides over 500, so I was actually able to recruit or look at patients in the entire health care system. That's one of the reasons I was able to recruit a number of patients who are candidates for this medication. So let me go through 2 case studies. And I have actually 9 patients on the medication, all confirmed either genetically or clinically some with both. So case #1 his triglycerides were over 1,200. And this patients had 20 events, so really his whole life, he suffered from acute pancreatitis. He developed diabetes. And one of the things about having pancreatitis that actually could destroy their pancreas and actually could cause diabetes and had very little response to gemfibrozil fibrate or Vascepa, which is omega-3, his genetics, he was homozygous. That means they had 2 genes for one of the causes of FCS LMF1, and also had APOA5. So actually 3 genes associated with the syndrome. And interesting, TRYNGOLZA reduced his triglyceride to 381 and had no further episodes of pancreatitis. Again, this is only in the first few months is a relatively new drug. So remarkably, his triglycerides reduced from 1,200. And he's had higher levels than that down to 381, which seems greater than I had expected from the clinical trials. Case 2 was another patient and his triglycerides were 1,400. I think he's had triglycerides as high as 3,000 recurrent pancreatitis. He's actually had 9 episodes. He also developed diabetes and had minimal response to fibrate, Vascepa. His Moulin Score was 13 and his triglycerides went from over 1,400 down to 232 with no pancreatitis. And his -- again, his response to this when he saw his numbers that he was astonished. Again, this is someone who suffered from recurrent pancreatitis, recurrent abdominal pain, he would often be riding in pain, going the hospital, prolonged hospitalizations. And when I spoke to him about this, it was really life-changing that he can actually go about his life and hopefully not worry about every stomachache, could this be another episode. Again, pancreatis can be a fatal event. So he's just happy to go on with his life. And hopefully, by taking TRYNGOLZA, he won't have further episode. Again, all these patients have to be on diet, exercise the usual things we do. And we -- again, they have to be on -- often on a very low fat diet. But again, even with all that, with the medicine we have available, low-fat diet, these patients still will have triglycerides hovering around 1,000. So look -- let's look at severe hypertriglyceridemia disease overview. So these are patients who have triglycerides over 500. There's actually a very common -- in the U.S. population, this occurs 1% to 2% of the time. And actually, I looked at our system at Atlantic Health and I had 1 million patients, I saw like about 500,000 were tested for triglycerides. And about -- at least in this population, again, it's a -- just going through the medical records, we had about a few thousand patients who had high triglycerides over 500. Again, I didn't go through everyone want to see what the other disease is, but it is at least in Atlantic Health, this was a relatively high, similar to what is predicted by enhanced data. And this is these patients who have triglycerides over 500, typically over 880 are at increased risk acute pancreatitis. And actually, some of them -- and this group also be at risk for atherosclerotic cardiovascular disease. Again, as a clinical cardiologist, I'm very concerned about reducing their risk for heart attacks and strokes. So these patients in this group, not only are at risk for pancreatitis, are at risk for ASCVD. As you may know, we could reduce LDL that patient still have residual risk. So anything we could do to reduce residual risk be it reducing LP(a), reduce the triglycerides. We're trying to find avenues to that care. And this is multifactorial combination triglyceride variants, lifestyle obesity, high-risk morbidities, including type 2 diabetes, metabolic syndrome and MASH. MASH, if you don't know, is Metabolic Associated liver disease. It's usually associated with Steatohepatitis associated with fatty liver. And this is a very common problem, again, something that we're trying to address in many patients, reduce the risk of fatty liver, which could lead to cirrhosis. So these patients are at risk for that, too. And again, if you look at the treatments we have available fibrates, omega-3s, none of which are that successful that reduce triglyceride -- typically very high triglycerides, these drugs appear to be potentially less effective. And this is prevalence is about 3 million in the U.S. population, again, associated with stroke, heart disease, again, pancreatitis, diabetes, abdominal pain, obesity and MASH. So what are the guidelines for clinical treatment of high triglycerides. Again, these patients, if triglycerides over 500, we recommend reducing triglycerides. But what we have currently is just not very effective. Even though the guidelines that says consider using omega-3s, using fibrates, these drugs reduce fibrates about 20%, 30%. Omega-3s may have some benefit above and beyond the triglyceride lowering. But again, it doesn't reduce triglycerides very effectively, typically if their triglycerides are high. statins, as a clinical cardiologist, I have many -- most of my patients on statins, but they only reduce triglycerides 10% to 20%. And none of these drugs affect pancreatitis. Niacin is very attractive because it does raise HDL, lower triglycerides might lower Lp(a), but the studies have not been shown to be effective. So we actually -- we've basically stopped using Niacin for most of the patients. It's not very well tolerated. GLP-1s, well, every one of my patients now in New Jersey want to be a GLP-1 injection. That goes without saying. But guidelines say not to use in a patient with a history of pancreatitis. And again, it really only has minimal triglyceride reduction in patients with type 2 diabetes and high triglycerides. Thank you so much.

Thank you, Rob. That was an excellent overview. And I think what you can see from that presentation, particularly those 2 cases is that really TRYNGOLZA offers hope to these patients. They're suffering all their lives with a potentially life-threatening problem with no effective therapy. And I think we've come to the point now where we can offer these patients something effective to be able to manage their disease effectively. So I'd like to now drill down and give you some granularity on olezarsen and some of the recent results that we reported and go through a little bit of the detail as best as we can reveal today. So first of all, I think we can easily justify calling these groundbreaking results. And the reason for that is that there were 2 important findings of the 2 core studies, the 2 pivotal trials for the sHTG population. The first was that we had highly statistically significant and clinically relevant reductions in triglycerides. To get a 72% placebo-corrected reduction in triglycerides is really outstanding. And if you put the numbers in context, you started at 1,000, you're now down to about 250, which is very similar to what Dr. Fishberg has shown for some of his patients with FCS. So reducing a number is great, but that's not what matters to the patient, right? The numbers are excellent. They like to look at them. But what matters to them is do they feel better? Do they do better. And this is the first time in the Annals of Medicine that a reduction in pancreatitis was shown with a drug for this patient population. This, along with a favorable safety and tolerability profile. And so briefly to take you through the mechanism and then to review the data in a little more detail, why is olezarsen effective in this patient population. The reason it's effective is because apoC-III is the bad guy. When patients make a lot of apoC-III, it does 2 things to raise plasma triglycerides and the complications you get from that, which are pancreatitis and cardiovascular disease. First, it prevents the metabolism of these particles. So think of these particles as ice cubes and they melt. They melt with lipoprotein lipase, apoC-III inhibits that. The second thing that apoC-III does is it prevents their clearance. So they now they accumulate. The numbers go up in the circulation and all that leads to high triglycerides and the complications that you saw. Olezarsen inhibits the production of apoC-III. So what it basically does is it resets the metabolism of triglycerides. It allows now these particles to get metabolized faster and to clear faster. So it's a very elegant mechanism to be able to treat hypertriglyceridemia. Now our Phase III program for the expanded indication consists of these 3 studies. We have the 2 pivotal CORE trials, which are identically designed to be able to show a reduction in triglyceride levels as a primary endpoint. And then we have the supporting study called ESSENCE that was recently just published in the New England Journal of Medicine. The 2 pivotal trials are required for this indication to get a triglyceride lowering indication. So that's why there are 2 trials here. They are in patients with triglycerides over 500. There are over 1,000 participants in those 2 studies combined, and this represents the largest program of its kind for this indication. The ESSENCE trial is a supporting safety study. It was in about 1,500 patients. That was in a population with lower triglycerides greater than 150, and that just wrapped up and was published in the New England Journal of Medicine, as I mentioned. So the combination of these studies is over 2,500 patients, and this study was run at Ionis with our partners, the TIMI Group. So let me now take you through the results, the top line results from the CORE studies. And first, the trial design. So patients were screened to have triglyceride levels over 500. They went through a diet and medication adherence program for about 12 weeks, and they were randomized to placebo, olezarsen 50 milligrams and olezarsen 80 milligrams. We used the primary endpoint at 6 months, but the treatment duration was actually 12 months. At 12 months, we then had additional prespecified secondary endpoints, and the key one is acute pancreatitis events. The acute pancreatitis events were defined in the combined 2 groups of olezarsen and in both studies combined. So in a way, it's a pooled analysis of all of the data from both studies. There were additional endpoints that we'll reveal later in future meetings. But today, I'm going to focus on the triglyceride reduction and the pancreatitis events. Now who are these patients? Dr. Fishberg has showed you who his FCS patients are, who are patients with sHTG. And you see here some important characteristics. First, they're relatively young. They're in mid-50s, and a lot of them have diabetes, which goes along with the syndrome. Importantly, over the last 10 years, between 13% and 22% had a history of pancreatitis in the last 10 years. So that's a fairly large number of pancreatitis events in a highly prevalent population of approximately 3 million people in the U.S. Now let's look at their triglyceride levels. Notice the median levels are about 800, which is fairly high. So normal is 150 or less. So this is over 5x above normal triglyceride levels. The mean triglyceride levels are about 1,100. And so there's a difference between the mean and the median here because many patients with sHTG have very high triglycerides in the thousands, even as high as FCS patients. Now they're treated according to standard of care. But clearly, the standard of care is insufficient here. Note here that if you look on the bottom box here, the patients are on statins, they are on Fibrates, they are on Omega-3 fatty acids, they are on Ezetimibe and some of them are on PCSK9 inhibitors, and they still have triglyceride levels of 800. So what does this tell us? It tells us a couple of things. One is these patients have a polygenic etiology for their disorder. They have multiple disorders of triglyceride genes. There are about 15 triglyceride genes and have variations in those that are not functioning normally. So they have a predisposition, a genetic predisposition for high triglycerides, but it's not like FCS where they have complete loss of function of these genes, they have partial loss of function. So they're genetically predisposed to have triglycerides and on top of it, they have comorbidities like diabetes, obesity and advanced age. So you put all that together, you do the best you can, and they're still coming in with very high triglyceride levels. So this speaks to the unmet need. These patients need a therapy to lower their triglycerides more. And this is why we developed olezarsen to be able to specifically address this unmet need that's currently being unmet. Okay. So this is now the primary endpoint of the studies. And if you look on the top is the CORE study and on the bottom of the table is the CORE 2 study. And let me focus first on the top. Note here that the olezarsen 50 milligram group in the orange bar had a 63% reduction from baseline in the triglyceride levels. The 80 milligram dose had a 73% reduction from baseline, so 1% reduction. So when you do the placebo correction here, you have 63% and 72% reduction in triglyceride levels. The absolute values, as I mentioned here, go from about 800 to close to 200, which is a massive reduction in triglycerides. When clinicians look at these numbers, they cannot believe how much lowering they get because what they know is Fibrates and omega-3 fatty acids, which give you about a 20%, 30% reduction of triglycerides. So this is 2 orders or 3 orders of magnitude more triglyceride lowering than what's been documented. The CORE study, even though had identical inclusion criteria, had very similar findings in terms of the olezarsen groups as 1% reduction from baseline. You see there 63% and 68% for reasons that are still not fully clear yet, the placebo group had an accentuated reduction in the triglyceride reduction. So the placebo-corrected data are still very robust and highly statistically significant, but are slightly lower than the CORE study. The CORE study was the largest of the 2 studies, by the way, and it was the first one to be initiated. Now along with this tremendous triglyceride reduction, we had an 85% reduction in pancreatitis events in the 2 studies combined. We've used lots of adjectives to define this, but let me put this in context. When we do cardiovascular outcome trials, we're very happy to get 12%, 15%, 20% reduction in relative risk when we do these trials, okay? And we consider a 20% relative risk reduction excellent for cardiovascular outcomes trials. Well, here, we're getting 85% reduction in the first trial of its kind to do that. So this really can be put into the category of a landmark finding as far as clinical trials go to be able to achieve near cure for these patients. Importantly, this reduction was only in 1 year. And so think about that, putting a patient on a medication and in 1 year having this massive benefit. So we are very happy with this result. I think clinicians like Dr. Fishberg and others, patients will be very happy with this, and we anticipate the patients will continue to benefit as they stay on these drugs for a long time. Now what about the safety and tolerability? Overall, it was favorable. I notice here that any adverse events were fairly equally matched across the 6 groups that you see here. Serious adverse events were also fairly well matched, but notice here that the serious AEs were more common numerically in the placebo group. And we had noted this previously in the Balance trial. And we think some of this is because the patients are having abdominal pain and other events that are showing up in the placebo group as serious adverse events that seem to be the cause for these higher -- slightly numerically higher numbers. Now drugs that are RNA-based can cause injection site reactions. This was the most common AE that we noted with olezarsen in about 15% of patients. These were mild. They weren't really an issue for the patients. They did not require any discontinuation. And so we don't think this is going to be a major issue going forward for this. Okay. What are the next steps for this program? First of all, we're very pleased to announce that the CORE studies were accepted to be on the very first late-breaking clinical trial presentation at the American Heart Association, November 8. More data will be shown from these studies with more details. Next, we're working extremely hard to have an on-time submission for an sNDA by the end of this year. Everything is online to do that to expand indication into the sHTG. And then in 2026, we anticipate additional filings in other geographies. And most importantly, for our patients and the physicians taking care of them, we anticipate an on-time launch in the second half of next year for expanded indication for olezarsen. Okay. So now let me transition to some of the other key aspects of the cardiovascular franchise that will continue to bring value to Ionis, to our shareholders and especially to our patients, which is our primary reason for why we are developing many of these drugs. Now I mentioned TRYNGOLZA for FCS. You know about this. I run over olezarsen. Let me now give you some early interim analysis of ION775, which we are extremely excited about because it represents our advancement into new technologies, and we've unleashed our medicinal chemistry to be able to now create value beyond antisense oligonucleotides. This represents the very first siRNA that will be in the clinic from Ionis, and it targets apoC-III and we have designed this to prolong the duration of treatment. And I will show you for the first time here today, some data from our interim analysis with ION775. Now coming right shortly after that, we have 2 myocardial targeting drugs whose targets are undisclosed. One is partnered; one is wholly owned. This is going to leverage our other technology, which is using cardiac muscle targeting. So we can deliver these drugs to cardiac muscle and treat myocardial diseases. And we plan to have both of these drugs be both first-in-class and best-in-class as we progress them to clinical development. Okay. Let me review now apoC-III siRNA, ION775. And as I mentioned, this is the most advanced of several siRNA compounds that we're developing for other indications. This is going to focus obviously on elevated triglycerides. And depending on the profile, obviously, the first indication will be severe hypertriglyceridemia, but we'll see if there's potential indications in that field. Our goal is to increase durability, as I mentioned, and we just are underway close to finishing our Phase I study in a single ascending dose in patients with moderate hypertriglyceridemia. So let me focus on this now and show you some new data. This is a Phase I study. Patients are healthy volunteers, but otherwise have elevated triglyceride levels. In this study, they had triglyceride levels of 150 to 500. So this is in the moderate range. They were randomized to get placebo. And here, I'm going to show you 2 doses of ION775, 100 milligrams and 300 milligrams. This is a small study. So keep that in mind. The primary interim analysis here is going to be at 6 months with a single injection. But however, we're following the patients for 12 months, and then we'll have a safety follow-up after that. So this is really a 1-year study, and I'm going to show you the interim data for these 2 doses at 6 months. Now the patient's baseline triglyceride levels here are about 220 milligrams per deciliter, which is in the range of the ESSENCE trial that was recently just published. So these are the key findings of the study. On the left is the apoC-III levels and on the right is the change in the fasting triglyceride levels. The black line is placebo. The orange line is 100 milligram and the purple line is 300 milligrams. On the Y-axis is the percent change. And on the X-axis is the follow-up. So single dose happens day 1, and then we go up to 180 days and what you see here on the left is a dramatic reduction in apoC-III with both doses that nadir to about 95% to 96% at day 15. And then you see a very slow decline as you follow the patients out to 6 months. And so by 6 months with a single dose, we still have a 74% and 82% reduction in apoC-III levels. So how does that translate to triglycerides? If you notice on the right, you get a concomitant very dramatic reduction in triglycerides of 80% to 81% day 15. And then the slope of that curve is actually flatter so that by day 180 or 6 months, there's a 68% reduction. Now keep in mind that these patients started at 220 and the absolute values on the right side are about 50 milligrams per deciliter for triglycerides, which is also one of the lowest triglyceride levels you can achieve, unlike lowering LDL and LP(a) that you can get to 0, you cannot get triglyceride to 0 because you need it for energy. So usually, you can get to about 40 to 50 milligrams per deciliter. So the reason I mentioned this is it's possible that these results are underestimated. And if we started at 1,000, we could still get very low and have a more potent reduction. So we will know that as we go into Phase II, we will be able to recruit patients with much higher triglyceride levels and see what the effect is. Now keep this in mind, it's going to be very hard to beat olezarsen. When we have a 63% to 72% reduction in triglycerides and 85% reduction in pancreatitis, it's hard to beat that. However, we are looking at this as we want to be leaders in the field for the next decade, not for the next couple of years. And so this may represent life cycle management for our franchise for triglycerides to be able to maintain that leadership position and be able to be best-in-class as we go through the next decade. Now in addition to what I showed you here, with the very durable reductions and sustained reductions, this drug did have a favorable safety and tolerability profile, and we are on track to initiate Phase II in 2026. Okay. What are the rest of the key events in late 2025 and '26? Let me take you through this. We have a lot of stuff going on in the cardiovascular franchise. Besides ION775 and TRYNGOLZA and olezarsen, I want to point out a couple of things. If you look on the yellow box on the bottom, the pelacarsen trial with Lp(a) HORIZON is expected to read out in the first half of next year. We are very proud to have partnered this with Novartis, who has been a tremendous partner in managing this trial, exceedingly well. And it will be the first of its kind just has the Lp(a) hypothesis that lowering Lp(a) will lead to cardiovascular risk reduction. If that trial reads out positive as we anticipate, it should be a historic trial. And it's -- as I mentioned earlier, it's way ahead of the field and pelacarsen should have a long run, and there's so much unmet demand for treating patients with high Lp(a). 1 in 5 people have elevated levels. And so you can imagine what this will create if this trial is positive, the amount of excitement that we can further reduce residual risk that Dr. Fishberg mentioned with that medicine. Now we're also very proud to be close to completing the CARDIO-TTRansform trial with our drug, eplontersen. That's going to complete in the second half of 2026. As you know, eplontersen is already approved for the polyneuropathy version of TTR amyloidosis. We are -- I think we -- I think it can be argued strongly that we are running the best trial in the field. It's certainly the largest. It's 1,400 patients, almost twice as large as any other trial to date. It will have a very rich data set beyond its primary endpoint to look at subgroups. And we also have an excellent partner with AZ. I want to reemphasize that the olezarsen program and the eplontersen program are completely run at Ionis. We now have experience in 2 very complicated large outcome trials, and we will leverage this experience as we have our future assets like ION775 and other assets in that lipid field and also the myocardial targeting agents. We have a slew of regulatory events coming up besides the sNDA submission for olezarsen. And I just want to highlight those briefly. We're very focused on getting eplontersen approved. And the goal is to have both U.S. and EU submissions in 2026 for the sNDA for cardiomyopathy mediated by TTR amyloidosis. Same for pelacarsen, assuming positive readouts, Novartis plans to have a U.S. submission for pelacarsen. And finally, the most exciting part for us because its wholly owned, is that we anticipate a second half of the year launch of olezarsen for sHTG. So that's the summary. I hope I've convinced you that we are -- we have reached to be a leader in the cardiovascular arena among all global companies. We have many things going on besides TRYNGOLZA. Next year is going to be transformative for us for the 2 Phase III readouts. And I invite you to be on our journey for the next few years as I think it will be a very exciting one, and we're very interested to see how these drugs bring benefit to our patients. So thank you very much. And I'd like to now hand the podium over to Kyle Jenne. Kyle is our Chief Global Product Strategy Officer, and he's going to continue the conversation going forward. Thank you, Kyle.

Thank you, Sam, and good morning, everyone. I am tasked with the very high bar of building a commercial organization that is to the standard in which our research and development organizations have been for the last 36 years at Ionis. It's a really exciting time as we talk about the launch of TRYNGOLZA in FCS. And then I'll also bring you up to speed on to our preparations for our sHTG. Preparations in order to get ready for that launch in the second half of 2026. So as Sam just took you through, there's a lot happening in the cardiometabolic space. Our commercial portfolio today, it will start with TRYNGOLZA and FCS. It will expand into olezarsen and sHTG the second half of next year. And then we will continue to build on that with ION775 and the next wave of cardiometabolic disease programs that come behind that. So this really is an exciting time. We're building a foundation and a capability from a commercial infrastructure standpoint to be able to support the launches today and building towards the future and what's to come. Talking a little bit more in detail about FCS first, and then I'll speak to sHTG later in the presentation. To begin with, as we know, this is a severe, rare and potentially fatal disease. This affects up to about 3,000 patients in the United States. It is genetically confirmed. And as Dr. Fishberg mentioned, not only can you diagnose this through a genetic test, but you can also diagnose FCS through clinical confirmation using 1 of the 2 scoring tools that are available today. The majority of these patients are still not diagnosed or not treated for the disease. It's a tremendous opportunity for Ionis to lead the way here. This is the medicine that we have launched in TRYNGOLZA is the first to market. We are the ones that have been able to set the stage for disease education, for patient finding, for pricing and for the standard that the product represents as well. So what does TRYNGOLZA represent? It's the first and only approved FDA treatment in FCS today. We have very, very strong and robust efficacy and safety data behind this program. It's very well appreciated by physicians and patients that are on drug today. And what we see with TRYNGOLZA are significant and sustained reductions in triglyceride levels. We also see substantial reductions in acute pancreatitis events. And as we also heard earlier, there is a reduction in hospitalization visits as well -- excuse me, hospitalization stays, length of stay as well as ER visits with patients that are on TRYNGOLZA. So it's a very strong product profile that's resonating well with HCPs, with patients and with payers. As we represented at the end of Q2 at earnings, we generated $19 million in revenue in Q2. That was a 3x increase over Q1. And we also provided full year 2025 guidance to be $75 million to $80 million this year. The commercial execution, as I mentioned, is really key here. What we are seeing in this market that it's really hard, right? We're up to 3,000 patients. We've got to make sure that HCPs understand what high triglycerides mean, why they should be treating these patients. They understand the need to get these patients to goal, either below 880 or below 500. And what we've seen based on the presentation of TRYNGOLZA to the HCPs and to patients is that HCPs are motivated to use TRYNGOLZA. We're seeing strong patient uptake -- we're seeing a very broad group of prescribers. So we're seeing a cardiologist, endocrinologists and lipidologists, all prescribing TRYNGOLZA today. And the feedback, as I mentioned, has been very positive in terms of the triglyceride-lowering effects and the control of their triglycerides that patients are experiencing. Today, we are reaching about 3,000 of the highest treaters of sHTG with our current field force. That is our face-to-face interaction. What we're able to do beyond that based on the capabilities that we've created within our marketing and our omnichannel capabilities is to go much broader than that with our physician and patient education. We're reaching over 30,000 HCPs right now with our omnichannel and our nonpersonal campaign. So we're able to educate on what high triglycerides are, we're able to educate on specifically how to diagnose and identify and find FCS patients. And that obviously is being very effective in terms of our ability to, number one, diagnose and then get patients on to TRYNGOLZA today. The split that we're seeing with our commercial and government payers is 60% commercial and 40% government. So that is representative of a patient population that have high triglycerides. And what we do know is that the majority of these patients are also paying $0 out of pocket for their prescription medication. So it's very affordable and a very positive route to patients getting on drug. I want to highlight our Ionis Every Step program. This is our patient support program. This is a capability that we developed with WAINUA as we led the [ cocoa ] area of patient services with AstraZeneca. This is a capability in which we have Ionis nurses that are employees of Ionis that are working directly with patients to interact based on where they're at in their journey. So we start from the very beginning with disease education. We move into product education, we provide different resources and different support mechanisms in order to allow patients to be able to get on and stay on drug long term. It also supports financial assistance programs. And what we've seen is, number one, patients -- the majority of patients opt into this service. They see value in this program, and we're able to collect a lot of feedback directly from patients in terms of how they're doing on treatment today, what their experiences have been and also how we can help provide even more support for these patients as they go through their experience of living day-to-day with familial chylomicronemia syndrome. This program, not only for WAINUA and TRYNGOLZA, but I'll also talk about it with DAWNZERA as well. It's really a critical core capability, something that we focused on it's something that's differentiating the way that we are commercializing our medicines at Ionis. So what are we doing today? Patient finding is critical. I just touched on that. So identification of patients is number one. We're reaching greater than 3,000 HCPs today face-to-face with our customer-facing team. We're going well beyond that as I represented with our omnichannel and our marketing capabilities to do even broader awareness and broader education. The second thing that we're doing is really focusing on that reach, right? How are we communicating about the disease? How are we talking about severe high triglycerides? How are we getting HCPs to want to assess and understand that there is now a treatment available. And if they do diagnose this disease that they're able to actually move forward with treating these patients. So we are increasing diagnosis rates, and we're also increasing the ability for HCPs to prescribe and treat these patients. The payer dynamics are very strong. We are seeing both clinical and genetic confirmation being accepted by the payers. That's really important, right? TRYNGOLZA has a broad label that includes both clinical and genetic confirmation of the disease. And so we want to make sure that payer access represents that as well. And we're seeing that through the policies that are being put in place today. Now I want to move beyond FCS and talk about olezarsen and sHTG, our first potential blockbuster wholly owned medicine at Ionis. This is really an exciting program. You just heard some of the details from Sam and Dr. Fishberg talked about the disease and the complexity of treating these patients. But there's a significant unmet need here in the marketplace for a medicine like olezarsen and sHTG. What we know is that patients are currently trying to treat these patients with other triglyceride-lowering agents their suboptimal therapies. And unfortunately, they're not able to get these patients down below 500 and get these patients out of harm's way for acute pancreatitis. And so we are working right now to educate the market on what sHTG is, where the gaps are and also the need to treat aggressively when you do see these patients. Acute pancreatitis is the major risk factor here that we know that patients have severe abdominal pain. They often have brain fog. They're not feeling well on a day-to-day basis because of their elevated triglycerides. But the main challenge that they have and the biggest risk that we see is with acute pancreatitis. Now there's a fivefold higher risk of acute pancreatitis with sHTG versus patients with normal triglyceride levels. There's up to an 8% mortality associated with sHTG driven acute pancreatitis. And there's approximately $100,000 in annual cost for health care resulting from sHTG pancreatitis with hospitalization. So this is a very high-risk patient population. There's a need to treat aggressively and quickly and they're high cost associated with not treating these patients. So I'll start with the quote here because it's very important because KOLs and HCPs really understand that high triglycerides are bad. They need to get these patients down. They've had suboptimal treatments today in order to do that. But just a quote here from one of our KOLs, a treatment that meaningfully lowers triglycerides and reduces acute pancreatitis risk, something we've never seen before, would be a game changer". what we represent or what olezarsen represents in this patient population is the ability to be a game changer. So what we see are highly statistically significant reductions in triglycerides up to 72% on top of standard of care. So these patients are already on fibrates and omega-3s and other treatments, and they're still not getting low enough and there's the ability to get an incremental 72% reduction by adding olezarsen to these patients' treatment. The first and only significant reductions in acute pancreatitis, 85% reductions in acute pancreatitis, a very meaningful. The first product ever to demonstrate olezarsen, reducing triglycerides, reduces the risk of acute pancreatitis. It's a very strong and a strong message and a strong need in the market. Favorable safety and tolerability and also the ability to self-administer with an autoinjector. This is something that we have for WAINUA today. We know that it resonates very well in the market. We also have the same autoinjector with DAWNZERA but it's a simple to use, self-administered autoinjector that these patients find very well tolerated and do very well with. In terms of our go-to-market strategy, where do we want to start? There are approximately 3 million patients with sHTG in the United States today. Within that population, there are about 1 million patients with high-risk sHTG. These are patients that have triglyceride levels of over 880 or patients that have 0triglycerides over 500 with a history of acute pancreatitis and/or other comorbidities, such as type 2 diabetes or ASCVD. That will be our beachhead. This will be the area where we will spend the majority of our time with HCPs that are treating these patients to bring olezarsen to these patients as quickly as possible, where there's the highest need to treat, there's immediate sense of urgency and HCPs already recognize and understand the value of needing to add a therapy like olezarsen to this patient group. I already mentioned this, but what we continue to hear from HCPs is that they're really challenged by the therapies that are available today. They're suboptimal in terms of their triglyceride lowering, they're trying to do what they can with omega-3s and fibrates. And unfortunately, they just can't get these patients down low enough today. So they're aggressively treating these patients to begin with. They understand the thresholds and the risk associated with acute pancreatitis and they know that they need to get these patients down below 500 or get them as low as they possibly can. And they know that what they've got today is just suboptimal as I represented. So what can we do from a field force standpoint and from a commercialization standpoint to help move this marketplace along quickly. Number one, we can reach more HCPs. So our plan is to go out to approximately 20,000 of the highest treaters of sHTG with a face-to-face customer team. We can do that with a couple of hundred representatives. And we believe that, that education will allow us to identify these patients that are appropriate for therapy we'll be able to educate around high triglycerides and we'll be able to educate around the risk of acute pancreatitis and the need to treat. The other thing that's optimal here is our omnichannel and our marketing capabilities. So it's we're able to optimize and maximize our reach in a very efficient and cost-effective way by doing different nonpersonal promotion tactics and being very targeted in the way in which we deliver our marketing messages and the way that we communicate around the disease and educate the marketplace. And then the final thing is around the payer dynamics. So what we're working on today is to make sure that payers are aware that patients remain above 500. They remain -- patients remain at risk of acute pancreatitis and we're able to work with payers right now with TRYNGOLZA approved in FCS to make sure the policies are in place for our FCS indication, but payers are also beginning to understand that there are follow-on potential indications here, and they're starting to ask about covering a broader patient population of up to 3 million in the United States. So our biggest step right now is around pricing and access. We recently got the CORE and CORE2 data, as Sam communicated in his presentation. What we will do is we will put that body of evidence together with the profile that we know olezarsen represents, we will go out and we will do testing with HCPs and with payers to come up with the optimal pricing for olezarsen and sHTG. What we want to make sure of is that we maximize value for the medication based on what the profile represents and the patient population that we are addressing, and what we also want to be cautious of is not pricing at a point where payers end up putting restrictions and limitations and hurdles in place that create negative experiences for HCPs or patients in order to get on olezarsen. So we're working through that right now. I anticipate that taking several months we'll announce the final pricing upon approval as we've done with our other programs. But it's really a key focus of the work that is ongoing right now to make sure that we maximize the value of olezarsen in the sHTG marketplace. So this is our potential blockbuster. This is a wholly owned medicine. It's positioned to change the sHTG treatment paradigm. We've got a tremendous opportunity with this medicine. We are first to market. We're leading the way in every aspect from disease education to working with these HCPs to understand and diagnose and find FCS patients today. And we've got a tremendous opportunity to expand that indication upon approval in the second half of next year in bringing this patient -- bringing this therapy to millions of patients in the United States. So with that, let me open it up for Q&A and invite my colleagues up for a discussion.

So while our speakers are coming up to the stage here to take their seats, I would like to remind everybody that we do have people on the webcast who can't see us. So if you'd like to ask a question, please raise your hand and we will get a microphone to you. [Operator Instructions]. Let's start over here, Gena.

Okay. Gena Wang from Barclays. First, I wanted to thank you with a great update. So I do have two sets of questions. One is there for Dr. Fishberg, so you did mention that regarding the sHTG and you did mention that you have U.S. prevalence is over 3 million. So maybe how many patients under our care is sHTG and once olezarsen's approval, what percentage of patients you will switch over to olezarsen? And I have a one question for the companies, and I think you present super impressive next-gen data 775. So I do wanted to ask when we look at the 100-milligram, 300-milligram at the 6 months, we did not see a dose response. They basically around 68%. So now the question is, what is your goal for your drug profile? How do you balance the dosing frequency versus the triglyceride lowerly?

Sure. Dr. Fishberg, would you...

Sorry, what was the question for me again? Is it just a...

Sorry. So my question is what percent -- like how many patients, sHTG patient under your care? And how would you use olezarsen once olezarsen is approved?

That's an excellent question. I think this is -- right now, I'm addressing my FCS patients, which, again, I'm looking -- I look through the whole health care system to find the patients with the highest triglycerides, and again, a lot of PCPs have referred those patients to me to -- for treatment. I think in the clinical practice, again, this is very common. It's about 1% to 2% of the patients have triglycerides over 500. Certainly, all these patients I'm seeing, I want to make sure they restrict their alcohols restricted, their diet and exercise, make sure that those things are addressed first. And then here you look for other comorbidities. Obviously, if they have coronary disease or they're diabetics, you want that treated you want to make sure they're in a statin that they have atherosclerotic disease. But then that leaves you a large number of patients who do have high triglyceride, who could be at risk of pancreatitis or other commodities. And I think the ones I think that I would focus on first are the ones who have triglycerides consistently over 880 or over 500 with comorbidities, certainly, if they have a history of pancreatitis, those are the ones I'd want to target first with this agent or they have had multiple comorbidities such as diabetes, atherosclerotic disease, and they have residual risk. Again, that's the one I would like -- I would target. So I think there is a large number of patients in clinical practice that I see that would be a candidate for this drug. Again, I have thousands of patients and my colleagues in New Jersey often defer to me for the best treatment. So I do think there's a -- once it gets approved for the high triglyceride group, certainly the ones at highest risk, the ones we want to target first. And I think it's important to increase awareness among my colleagues and also among the patients. I think a lot of times, patients are ones who seek out therapies. Again, these are very intelligent patients, and they're looking for treatment. They know they're at risk, they've had diabetes or other comorbidities. I think patients themselves will be seeking out physicians who are experienced with agents like this. And so far from my experience, I've been very pleased with the safety -- with the profile. I've had really no complaints with patients. Again, I've only had 9 patients, none of them have had any side effects, and it seems to be very easy to administer. So, so far, my initial clinical experience have been very satisfactory. And I think there will be a large number of patients. Again, the agents we have now fibrates, omega-3s, although they're approve -- they're recommended retreated, none of them are very effective, none of them reduce pancreatitis and reduce triglycerides is minimal. So again, we -- we're as clinicians, we'll look for something to address these patients.

Thanks, Dr. Fishberg. Switching gears to 775. So Gena, Sam didn't show all the Phase I data. We actually started at 10 milligrams, I think, 50 milligrams. So we have a dose response there. It looks like we're maxing out. We're beginning to max out at 100 milligrams single dose, 300 milligrams is probably -- we've maxed out apoC-III reductions and triglyceride lowering in this patient population. We'll continue to explore doses in our Phase II sHTG study to really optimize that dose for Phase III development. But again, I want to emphasize that I don't know if anybody can beat the high bar, the efficacy that we've seen for a olezarsen in sHTG. So what we're really focused on is whether we can allow patients to self-administer twice a year, maybe once a year with a long-acting apoC-III inhibitor. And we'll see how that plays out. But right now, the data certainly supports that level of dose -- in frequency of dosing.

Let's give the microphone to Yanan here and then Jason.

Great. Yanan Zhu, Wells Fargo. Dr. Fishberg, maybe a quick follow-up. How many -- you mentioned you might manage thousands of patients. Do you have a rough sense of how many patients would be put on TRYNGOLZA for sHTG? That will be super helpful. For the company, two questions on the siRNA for apoC-III, any thinking about the differentiation from the current siRNA in development other than maybe more extended dosing interval in terms of potency, efficacy, do you have any sense or target profile that you can share? And lastly, on the cardiac program, can you talk about the more [indiscernible] that you utilize to achieve cardiac delivery? Is that something we have seen from others? Or is this a normal mechanism? Any details would be appreciated.

So the first part of the question was how many patients, I think, would be a candidate for this? Well, again, in my system, just doing a brief screen of all the patients in the system, I saw about 2,000, 3,000 patients in Atlantic Health who had triglycerides over 500 that could be a candidate. And that may be a underestimate because again, not every patient had that triglyceride measured. But I do think that the number of 1% or 2% might be realistic. Again, not all those 1% would be a candidate for this. I do think, at least in New Jersey, I do see a few thousand patients that would be candidates for this. So I think that again, we have to wait so it's out clinically to be useful. But I think that every cardiologist, every lipidologist, endocrinologists have patients like this that would be a candidate for it. It's not going to be millions of patients necessarily. But I think it leads to New Jersey, I do see, in my area, a few thousand patients that would be a candidate for this right off the bat. The other question was...

I think that was it. So -- thank you. Let me start, Sam, then you can jump in and fill in anything. So again, I want to emphasize, we don't think beating the efficacy in the overall safety profile with the efficacy we've seen in olezarsen is beatable with any new modality, including maybe 775, it's really all about less frequent dosing for those patients that may prefer twice a year dosing versus monthly dosing. What we really think is important is the number one, what's important, over less frequent dosing is being first to market, Yanan. As Dr. Fishberg has laid out, the unmet need is enormous for really meaningful triglyceride reductions in this field. And we're going to change the field. We're going to change the landscape with olezarsen. That's what our full focused on with 775. For cardiac myocyte targeting, we're -- we have a platform that's targeting transferrin receptor 1 in cardiac myocytes. And we have several approaches and one particular approach is a very low molecular weight peptide, a bicycle peptide that is conjugated to an siRNA actually, in this case, for our first molecule that is opening up the cardiac myocytes. The data in nonimmune primates is just they're remarkable and the level of knockdown that we've achieved. We can't disclose the target yet because it's partnered, but we're expecting that clinical trial to initiate by the end of the year. Would you like to add to that?

Sure. On the question of ION775, we're in the middle of gathering a lot of information and with additional doses, one of the things that we want to look at carefully is this is a profile in terms of kind of atherogenic lipoprotein is different than the rest. So besides the triglyceride lowering for pancreatitis, there's a lot of interest in cardiovascular disease. So we want to look at some of those additional metrics. Apo,B, non-HDL cholesterol. And we'll be able to report those in a future meeting to see if that differentiate from the other drugs. It's a new compound has a long patent life. So we have a lot of options. High triglycerides are associated with not only pancreatitis, but cardiovascular disease and aortic stenosis. So there may be some options for that down the road outside of pancreatitis, that we might consider depending on the profile. And for the myocardium I just want to mention that this is really an untapped frontier in cardiology, right? We have mavacamten, we may have aficamten soon, but we haven't had any new drugs for 50 years. And this field is ripe for disruption, and we hope to be the first to start leading that effort to develop drugs for hypertrophic cardiomyopathy, HFpEF, heart failure. And these two drugs that I mentioned will be the first forays into that for us.

Jason?

Jason Gerberry from Bank of America. Maybe first question for Dr. Fishberg, just -- as it pertains to sHTG, I just kind of wanted to get your perspective on patients who don't have a past history of acute pancreatitis. What do you think the motivations will be to treat how motivated do you think these patients will be to get treatment with the TRYNGOLZA based on the clinical data that you've seen? And then for the company, a somewhat related question, is it a priority or a plan to develop either QOL quality of life and/or some sort of patient-reported symptom composite of some of these chronic symptoms outside of pancreatitis to help elucidate the benefit of the drug? It seems like an area for Phase IV data generation. Just kind of curious your thoughts there or if there are just challenges to developing a validated scale there. And then lastly, just for 775, the regulatory path as you guys think about that, would that be a head-to-head against olezarsen?

Well, I'll address the first question. So if a patient hasn't had pancreatitis their fearful of pancreatic -- getting pancreatitis. So I think that these patients who have progressed or lower 500 persistently, they made them aware of the risk and they're -- again they're desperate not to have episodic. No one wants that pancreatitis. So I think they do have high motivations to do again. We do emphasize diet, exercise, but again -- and the ACC we do recommend if your triglycerides over 500, we do recommend treatment to lower down, although the ACC and AHA are first to admit that none of the approved therapies are very effective, and none of them have ever reduced the risk of pancreatitis. I think that as a cardiologist and a lipidologist, we're really focused on if we can't get it down with other means, we are looking for ways. So I think patients will have high motivation for this. And I do think that patients are looking for treatment, they're looking for options. And again, there's residual risk patients who have high triglycerides are at risk for atherosclerotic disease besides pancreatitis, and they're looking for ways to reduce their risk.

Sam, we're collecting data now as exploratory endpoints on quality of life, hospitalizations, patient reported outcomes now from the CORE and CORE2 studies, isn't that right?

That's right. Yes. So we are doing exactly what you're suggesting. We actually have a dedicated group of health economics and outcomes research at Ionis, and they're basically on all of these programs. So you're going to see a lot of data coming out from the Balance study because we've been able to analyze all of that. And so that's going to start percolating out. And we have a lot of positive feedback from patient reported outcomes already in Balance, and we anticipate we'll have very similar findings when we analyze the sHTG data for the CORE studies.

And for 775, Jason, I think we'll be okay if we get the study started as quickly as we plan to do a placebo-controlled Phase II study for 775. However, whether we -- it's ethical to be able to do a placebo-controlled trial in Phase III, depends on how quickly olezarsen taken up globally and whether there's any patient that are not on ethically not on olezarsen today. That's to be determined. We have to work out our Phase III plans. But we're not necessarily against doing a comparative study versus olezarsen 775. That's to be determined.

Take a question over here. Debjit, did you have your hand up? Sorry, I can't see very well.

This is for Sam. Debjit from Guggenheim. Sam, there is an MRI sub-study part of the CORE1, 2. Do you need that data for the supplemental NDA? And should we expect that data at AHA or at some time point next year?

Yes. So it's a CT angiography substudy. No, we do not need that for an sNDA. That's more of a mechanistic study to help us understand the atherosclerosis angle which is really a secondary issue for olezarsen right now. We're really focused on the pancreatitis risk. And so that is not a regulatory endpoint, but it's going to give us some insights into deciding whether we want to pursue kind of a broader indication later we are working on doing the analysis for that, and I'm not sure exactly when it will come out, but it's probably going to be next year.

Jay Olson, Oppenheimer. Maybe a commercial question for Kyle. Now that the GLP-1s have opened up the direct-to-patient channel and Amgen has announced that they're going to use that for Repatha also. Is that something you would consider for olezarsen for sHTG? Could that be a natural extension of your Ionis Every Step program?

Yes. Thanks, Jay. Great question. I think the programs that are going direct to patients are really going to be targeted towards uninsured or patients that don't have coverage today. And it's also going to be for medications that are at a price point in which patients can probably cover on a monthly basis. So those are two things that we would need to assess and figure out based on our pricing and where we land. Could patients even afford to do that through a direct-to-patient type of a program. But we'll look at all pathways. The Ionis Every Step program is really -- it's a comprehensive program. It is very unique in terms of how we've mapped the patient journey and the way that we interact with these patients and provide support. And we also get such great feedback from patients in terms of how they're doing on treatment and things that we want to make sure that we continue to build out that program. So we'll look at every option available to make sure we continue to evolve the program.

Okay. Arsalan here? And then we'll take -- Daniel, we'll take you next, okay?

My name is Arsalan Kamran here from Gary Nachman from Raymond James. Congrats on all the achieving milestones thus far. And my question is, could you elaborate on what we should expect from the upcoming AHA presentation, specifically how robust the data set will be and details that are beyond what's already been shared. And a follow-up for the KOL among the key secondary endpoints in the full CORE and CORE2 data, which do you view as the most important in shaping the clinical in commercial profile for the program?

Sam, do you want to touch on...

For the AHA, we anticipate to present the key primary outcomes of the study that includes the primary and all the secondary endpoints. And remember that it's both studies. So both studies will be presented individually for their primary endpoints. And then we have secondary endpoints, and then we have a pooled analysis of pancreatitis and the rest of the endpoints. And I think Debjit, I must have misunderstood your question. I may have thought you just mentioned ESSENCE, but I think you mentioned CORE. So the MRI is going to be part of that analysis also. So those are the keys. It's a very rich data set. We can't present everything. I suspect we'll have 20, 30 publications from that study to look at all the different parts of that whole story. But the key parts that it's going to be at the AHA are going to be the primary and secondary endpoints.

Those second -- thanks, Sam. So those secondary endpoints will include things like remnant cholesterol, apoC-III reductions. What I think is also very important is the percentage of patients that we're actually getting below 880 and percentage of patients we're getting below 500 and to 150, which is normal triglycerides, which I think will be very compelling. I mean what's compelling to you in the additional data, Dr. Fishberg?

Well, I think the reduction in triglycerides to me is remarkable, first off because, again, that's the major effect. And I think the reduction of the pancreatitis compared to other agents, again, we have these agents approved for reducing triglycerides, but none of them have really [indiscernible] effective, none of them have reduced pancreatitis. So that we a drug that can reduce the instance of pancreatitis is remarkable. And again, I'm used to studies where the reduction in events is 14%, 15% reduction of event of 85% is basically unheard of in cardiovascular studies.

And we will present the details on the AP data from the CORE, CORE2 combined, as Sam said, also the time course for reductions in AP, which is, I think, very impressive when you say.

Daniel?

[ Dan ] from H.C. Wainwright working with [ Ron ] and Mitchell. So one for Dr. Fishberg, you mentioned sort of starting patients on statins first. So what needs to happen for olezarsen to be your first go to? Is this purely a pricing issue? Or is there a safety profile that you need to consider? And then for the company, is there a percentage of your pipeline you expect siRNAs to represent in the future? And how do you decide what you want to target with ASOs versus siRNAs?

So first off, if it's FCS patients, FCS then olezarsen would be the first drug that would use irrespective. These are patients generally who don't have atherosclerosis. So the two FCS patients, this is the first drug, which is approved and those are the ones I would use it first. Again, for the high triglyceride patients, these patients are already on statins and then I'm looking for an additional use, and I think this would be knowing that the other drugs are not affective, they have side effects. I would probably -- again, as we get more familiar with the drug, I would go to the sooner. So I think there will be a process where in the future, we would use this as a very early option for these patients. Some of them might be on omega-3s, but some other reasons, too. But again, if the goal is to reduce triglyceride to reduce pancreatitis, you want to -- I want to prevent disease some happening. It was like look at my situation with atherosclerotic disease, I want to prevent a heart attack, which is a devastating event. The [indiscernible] pancreatitis is as severe event. And for the patient might even be worse event than having a heart attack. So again, these are things you want to prevent and if this could prevent pancreatitis in a high-risk patient, I'm going to go through it pretty quickly.

And on the second question, so when I began -- when I took the helm in 2020 and what we like to say at Ionis unleash the research towns, to explore all oligonucleotide based mechanisms of action, including siRNA, we agreed that we would develop the best drug for the best target that's possible. So we go head to head for every drug discovery effort that we initiate in our research organization using Ionis medicinal chemistry for antisense oligonucleotides and siRNAs using our discovery processes and so forth. It's hard to predict what the future will be with respect to balance. We're going to have a good balance of ASOs and siRNAs in the future. But there's targets that just make complete sense for a single-stranded data cell mechanism of action such as splicing modulator like for spinal muscular atrophy or for Dravet syndrome, right? SIs aren't going to work there or for nuclear retained RNAs like UBE3A for Angelman syndrome, where SIs don't work as well for -- if we ever got into myotonic dystrophy, DMPK, right, which is a nuclear retained RNA clearly works better in the nucleus with single stranded versus double stranded based on the research that we have done. New chemistries that are coming with single-stranded oligonucleotides that are giving us durability that matches siRNAs, like in the CNS, Holly will talk about this later. For new chemistries that we've developed in CNS, it's allowing us to dose once a year. We haven't seen SIs that do better than that. With that said, there are advantages with siRNA on durability in the liver. We see greater duration of action. And if that is important for patients and health care providers, we're going to make it available to them. So I can't predict what the balance will be in the future, but I can tell you that we will utilize the best mechanism for the best target for the best opportunity.

Okay. I think we have time for one more question. I think that's Salveen over there.

Salveen Richter, Goldman Sachs. If I could just ask how -- clinically how you're thinking about glycemic control in this population? And then on the payer front, how that has progressed so far in sHTG and how that might evolve with this medication being entered into the market?

So glycemic control is actually very important. Again, it's somewhat different from triglycerides. Again, a lot of these patients have because the pancreatitis have developed diabetes in FCS and a patient on high triglycerides, they may have diabetes of comorbidity. So I do think controlled getting A1c down below 7 as well as you can is very important. And I think these -- we have these new agents on the market, which are remarkably effective for reducing glucose and have outcome data. So I think again, they're all very complementary. And I can tell you as a cardiologist until a few years ago, I kind of separate my -- I was doing atherosclerosis, I let the endocrinologists deal with diabetes, now as a cardiologist, I deal with everything because everything is mixed together. And my patients have atherosclerosis also have high glucose and diabetes and you have to treat the whole patient. So I think it all kind of fits together. You want to reduce triglycerides and reduce glucose and treat the whole patients. And I think they all kind of work together. You do want to get these patients try using triglycerides want to use another agent to get their A1c and glucose as low as possible.

Yes. And for TRYNGOLZA and FCS today, what we're seeing are payers are reimbursing based on the indication statement. So in adults with FCS as adjunct to diet. And then they can be clinically or genetically confirmed typically with the payers. And as Dr. Fishberg, represented, he's got both of those patients in his practice, and he's got a number of approvals and patients on commercial drug. So we know that the pathways are working effectively. And then as it relates to side effect profiles, et cetera, it's managed, as Dr. Fishberg, just described, as you would with any other treatment or medication, but we've seen no pushback or no concern on the payer side of that dynamic.

I think Kyle, it would be worth to -- for Salveen to address the sHTG plans going forward for what we are expecting from a payer dynamics and pricing.

Yes. So as this population grows, right, we're up to 3,000 patients in FCS today. The payers are looking at the sHTG marketplace as 3 million patients, right? They're going to look at the prevalence in the United States and they're going to build their budget impact models based on the anticipated indication statement and what we believe olezarsen will potentially be approved for based on how the clinical trial was designed. So the payers today are looking at patients that are above 500, and they're looking at patients that are on some sort of triglyceride lowering agent today and still unable to get to goal and they will build their analysis on budget impact based on price, based on the volume of patients that they expect to see in their population and then they will start to build policy around that. So they're not going to look at a history of AP specifically. They're not going to look at patients that are above 880. They're really going to look to the indication statement and what the prevalence is in the United States in order to drive their policy is what we're hearing today. That's why what I've communicated up to this point is kind of the $10,000 to $20,000 a year range is a ballpark of where we're at today. We're going to go back, as I mentioned, and do comprehensive research with HCPs and payers with the profile that we see coming out of CORE and CORE2 in order to see what our opportunity is to maximize price and value without getting to a point where we put a lot of restrictions in place and limit the population that are above 500 on standard of care today from receiving treatment. So that will be our focus and the work that we'll do over the course of the next year or so.

Thank you. We're going to have to end it there. I want to thank our speakers, our Q&A panelists here for taking the time to talk to us. And we're going to take a break, and we're going to restart the program back here at 10:45 Eastern Time. Thank you. [Break]

We want to get restarted here. Welcome, everyone, back to our second session of the morning. We're glad to have you back here, and I'm happy to introduce now Ken Newman, who's our Senior Vice President of Clinical Development, to come up here and talk to us about DAWNZERA program.

Thank you. Good morning, everyone. Thank you for coming back. It's been over 30 years since I first saw a patient with HAE. At that time, there were no effective therapies. Fortunately, effective therapies do exist today. So I couldn't be more delighted to be here to talk about HAE and DAWNZERA. What you see here is a picture of Lauren. Lauren is actually a patient in our Phase III clinical trial. She and her twin sister were both patients in our Phase III clinical trial. They had tried all the available HAE prophylactic therapies. None of them worked. That's why they enrolled in our study. They responded so well that they say being on DAWNZERA has given them their life back. So I'm going to talk about on DAWNZERA today, which we believe is setting a new bar for the prophylactic therapy of HAE. So we can talk about more patients like Lauren. Hereditary angioedema is a rare chronic and genetic disease. It's characterized by acute swelling, which are often turned to HAE attacks. These swellings can be life-threatening and they are unpredictable. They can occur anywhere in the body. They can occur in the hands, the feet, the genitalia, the abdomen, the face, the throat. And as opposed to an allergy attack, these attacks are painful. They're potentially life-threatening and they can last. These attacks without treatment can last 3 to 5 days, even with appropriate treatment. These attacks can last a full day. Think about what it's like if your hand was to swell to the size of a softball, how painful that would be, how debilitating that would be, how embarrassing it would be, how difficult it would be to work. When these people have swelling in their abdomen, it means their intestinal wall is swollen. It's incredibly painful. It's so painful that many of these people have had unnecessary and inappropriate abdominal surgery to treat them and most dangerously have all of the laryngeal attacks, the attacks in the throat. These attacks can cause airway obstruction. By causing airway obstruction these people kind of [ fix it ]. In fact, in the days before there was effective therapy, about 1/3 of these patients would actually die of asphyxia. These symptoms also start early in life. The mean age of onset is 10 with it getting worse during puberty, which means that these patients have to spend most of their lives dealing with this frightening of debilitating disease. The worldwide prevalence of this disease is about 150,000 people, which means there's about 7,000 patients in the United States that have this disease. And it's important to note, even today how long it may take to get diagnosed. It takes an average of 5 years, especially for the 25% of patients that do not have a family history of having HAE. Pictures are worth a thousand words. So this is a patient having a facial HAE attack. In the middle, you can see the grotesque appearance of this patient with massive facial swelling. Here she is in the car going to the emergency room on the right there, she is in the hospital. Fortunately, she received appropriate therapy and responded well, and you can see her upon discharge. Hard to believe it's even the same person. If you look carefully, you can see that she's drooling, which means she can't handle her own secretion, which means she already have throat swell. She was in a life-threatening situation. Fortunately, she did well, but the really good news is that we now understand what the physiology of this disease is and how to prevent it. HAE is caused by a mutation that causes low level of C1 esterase inhibition. C1 is a complement fact. The complement is a normal part of the innate immune system. But without this inhibitor, the system gets revved up like a runaway train. And by the time with this runaway train and causes increased vascular permeability, the specific pathway, which is involved is called the Kallikrein-kinin system. And when this starts going, it starts producing too much bradykinin and bradykinin causes the tissue swelling and edema that we see, that characterizes an HAE attack. So DAWNZERA was targeted specifically to target a unique protein, which is prekallikrein or PKK. In the top of the diagram on the top left, you can see DAWNZERA, which is being targeted to that hepatocytes, targeted to the liver cell. So you can see it binds to a specific receptor on the liver cell. It then becomes endocytosis that's brought into the cell and release where it can then bind with messenger RNA, degrade that messenger RNA and therefore, reduce the amount of protein that's being made. And by reducing the amount of prekallikrein that being made prevent the Kallikrein-Kinin system by going into overdrive and prevent the HAE attacks. So this is a new mechanism of action and we know that it's effective and robust as seen in our clinical program. I want to point out that this program has been validated by the New England Journal of Medicine who have published not just once, but 3x our clinical data, Phase I, Phase II and Phase III have all been seen in the New England Journal, which validates the scientific rigor and clinical importance of this program. And I'll take you through a little bit of that data. DAWNZERA approval was based on the OASIS-HAE and OASIS-Plus open-label extension studies. So on the x-axis here, you see the time within the study. So 0 to 24 weeks within the OASIS-HAE study, which is the double-blind, placebo-controlled study and then a following year in the OASIS-Plus open label extension. On the y-axis, you see the percent reduction in HAE attacks. So what you see in the OASIS-HAE study is that there is a dramatic reduction in terms of the number of attacks seen with both 80 milligrams of DAWNZERA every 4 weeks and 80 milligrams of DAWNZERA every 8 weeks. The 4-week dosing group is robust, compelling and fast. The 8-week dosing group separates nicely from placebo, but not as fast. So that by the end of the study by 24 weeks, the reduction in HAE attacks was very similar to that team with 4 weeks. This is why the recommended starting dose is DAWNZERA, every 4 weeks with the option for patients to go to every 8-week dosing. Importantly, in the open-label extension study, there was a 94% reduction in HAE attacks regardless of whether or not they were on 4 or 8-week dosing. In addition to this reduction in HAE attacks, there was a clinically significant improvement in quality of life in both of these studies as well as high levels of disease control as shown by the angioedema control test or the AECT. In addition, we had an innovative cohort within the OASIS-Plus study. This was the switch study, where we took patients who had been on other prophylactic HAE therapies for a prolonged period of time and rolled them into the study, put them in a 10-week baseline period and then in a prescribed fashion, switch them to DAWNZERA. And what we found in this study is that there was a significant reduction in the rate of attacks as compared to the baseline on their prior prophylactic therapy. So overall, there was a 62% reduction. What this means is for patients who are on lanadelumab previously, there was a 65% reduction in attacks on DAWNZERA as compared to the baseline on lanadelumab. For berotralstat, there was a 73% reduction in attacks as compared to the baseline on berotralstat. And for C1 inhibitor, it's a 41% baseline -- 41% reduction as compared to their baseline. That data was published recently in the Journal of Allergy and Clinical Immunology. There was also associated with an improvement, a clinically significant improvement in their quality of life. In addition, the percentage of patients who were well controlled as shown by the angioedema control test went up. We have a baseline of 67% across all three prior treatments, up to 93% when treated with DAWNZERA. So it's not probably a great surprise that when we survey the patients and ask them which do they prefer, DAWNZERA or their prior agent? 84% said, they preferred DAWNZERA. In addition, DAWNZERA has a favorable safety tolerability profile. We published numerous manuscripts and have numerous abstracts on the safety and tolerability profile. The only -- the adverse event that was -- the most common adverse event that was seen when DAWNZERA as compared to placebo with injection site reactions, which within the OASIS-HAE study were invariably mild or always mild and resolved without treatment. But there's more upcoming. The upcoming American College of Allergy , Asthma and Immunology meeting next month, we'll be presenting even more data. So we'll be talking about the 1-year follow-up of patients within the switch cohort. We're talking about the 4-year analysis of safety from the Phase II open label extension. And I'll tell you a sneak preview, it keeps getting better. So we have a really full and robust data set for DAWNZERA. It meets all 3 pillars that patients want. High efficacy, as shown by a substantial and sustained attack rate reduction, which is durable, showing long-term disease control. Up to four years, we've demonstrated a durability. It's safety and tolerability using a low-volume auto-injector and convenience that has the longest dosing interval every 4 weeks or every 8 weeks and the autoinjector is easy and it can be administered within 10 minutes. So we think this sets a new bar for the treatment of HAE. We look forward to further commercialization of this product, and I look forward personally talking about more patients like Lauren. And with that, I'd like to turn this over to Kyle.

Thank you, Ken. I'd tell you, it's great to have a development partner like Ken, when you're on the commercial side of things because products get developed the right way. They give you the right data sets, you end up in the regulatory process, getting a really strong label and it gives you a great opportunity to bring a medicine to potentially thousands of people that could benefit from a new profile and something that's innovative and different, and that's really what DAWNZERA represents. So the launch is really off to an encouraging start. I'll give you a little bit of color here and talk through a little bit about where we're at today. The approval, believe it or not, was on August 21, so we're only a couple of weeks into the launch at this point. Within the first 24 hours, we had already received the first prescription for DAWNZERA. There were HCPs and patients that were waiting for the approval. Number two, we were able to get product in channel within a week. So talking about commercial execution and being able to move things through our supply chain, getting it all the way through to our specialty pharmacy in that period of time, I think, reflects our ability to execute very effectively on the commercial side. And then most importantly is within 10 days, we actually saw a patient receive medication and do their own self-administration using the auto-injector. So the execution around this from the commercial standpoint has gone very smoothly, and I think it just reflects the capability that we've built here. Physician engagement. Our team has gone out and has spent a lot of time with the KOLs and the treating HCPs in HAE prior to launch and then obviously, subsequent talking about the benefits of DAWNZERA and what that represents, and I'll talk through that. But there are a couple of different patient groups that we want to highlight. One is the switch patient, right? The majority of these patients are on a prophylactic treatment today in the United States, so the switch market is a very important market. Another segment of patients are patients that are currently being treated with on-demand therapies only. They're not on a prophylactic today for one reason or another. I'll talk through that. And then we also have the newly diagnosed patients. And regardless of which segment these patients could potentially reside in, DAWNZERA could be a potential treatment option for those patients. I just mentioned a little bit about the market. About 75% of the people in the U.S. with HAE are currently being treated on a long-term prophylactic treatment. There's still opportunity, although a competitive market space, there's an opportunity here for DAWNZERA to be the potential prophylactic of choice for many of these patients based on the profile of the drug. What we also know is that the patients that are on treatments today are switching between these long-term prophylactics already. Over the last several years, when you look at it on a year-over-year basis, on average, about 20% of the patients on a long-term prophylactic are moving between the existing treatments that are available. And they're moving because they are unsatisfied, and I'll mention that here in just a second. And 90% of patients with HAE are interested in trying a new prophylactic therapy. This was from a recently conducted Harris Poll. So although they're being treated, oftentimes, it's either inadequate or it's insufficient in terms of what they're looking for in the product profile that they're being treated with. So the unmet need remains. There's an unmet need around efficacy, tolerability and convenience. Ken just walked you through some of the data and the long-term efficacy going out to 1 year in our open-label extension study. Regardless if you are on a 4-week dose or an 8-week dose, we're seeing a 94% reduction in attack rates. So very strong efficacy. On the tolerability side, what we're seeing is patients today are taking large bolus painful injections and they're not well tolerated or potentially they're on an oral therapy in which they're experiencing side effects like GI disturbance and other things, so there's an opportunity to improve that. And obviously, DAWNZERA represents an improvement in tolerability. And then finally, the dosing frequency. Patients are either on treatment typically every 2 weeks right now or they're on an oral daily therapy. Again, a tremendous opportunity to extend the duration of effect by using DAWNZERA and having a better profile to help these patients. So what does the DAWNZERA profile look like? Number one, the efficacy that I just mentioned, substantial and sustained rates of reduction in attacks with long-term durability -- tolerability, we've got the same patient-friendly auto-injector that we're using for WAINUA and for Tryngolza that we're using with DAWNZERA. It's a very low dose at 0.8 mL, and there's no citric acid, which is often associated with injection site pain. And the third area that patients really struggle with that are living with HAE is around the convenience factor. And what we have designed with DAWNZERA is the longest dosing interval option going out to every 4 weeks or every 8 weeks in terms of being able to treat with the product. No loading dose is required. It takes about 10 seconds to administer, and it can be stored at room temperature for up to 6 weeks, which is actually meaningful to these patients that are trying to live active normal lives to be able to take their medication with them if they're on vacation or traveling for work or doing other things, they don't have to worry about the refrigeration aspect for a period of time. I mentioned the 3 patient segments in the U.S., the most important segment right away is the switch patient population. That's the majority of patients today that are on a long-term prophylactic, greater than 75% in the U.S. So switching and why to switch and how to motivate the patients to switch and obviously, educating physicians on how to do that is something that we're spending a lot of time and a lot of detail around. I mentioned the patients that are on-demand therapy only. These are patients that potentially either were on a prophylactic and aren't anymore or have never been on a prophylactic therapy before. Sometimes it's because of the profile that the current drugs represent. And we believe that with the profile of DAWNZERA, there's the potential to get those patients potentially on to treatment. And obviously, there will be newly diagnosed patients on an annual basis that we want to make sure that the product is positioned appropriately for. In the bottom right-hand corner is the flip to switch on your expectations of HAE prophylactics, just an example of the campaign that we're running to really highlight the fact that you can switch, you can switch effectively and you can switch to a potentially better treatment option for your HAE. So Ken mentioned the prospective switch study that we conducted for DAWNZERA. This is a very important study that was done for a couple of reasons. Number one, we wanted to demonstrate that patients were willing to switch from their current therapy on to DAWNZERA, and they absolutely were and the study enrolled very, very quickly. Number two, we wanted to demonstrate that when patients did make that transition over to DAWNZERA that there was not an increase in attacks. And as Ken shared in his presentation, there was actually an incremental reduction in attacks whenever patients moved over to DAWNZERA. And number three, we wanted to see once they moved over to DAWNZERA, what was their experience and which product did they prefer and 84% of patients preferred DAWNZERA. And the reason for that preference is listed at the bottom, but it's exactly what we've been talking about. It was either because of efficacy, tolerability or convenience. So what you're seeing with DAWNZERA is the totality of a profile that is really well supported and very interesting to patients with HAE, and they respond very [Audio Gap] well [indiscernible]. Back to what I was describing with Tryngolza in FCS today, we have omnichannel and marketing and nonpersonal promotion capabilities within Ionis that are highly differentiated and very innovative. And so we are deploying those tactics and those abilities that we have within the commercial organization towards the HAE marketplace. And we're working very closely on payer access and reimbursement. Obviously, there are other prophylactic treatments that have been in the space for quite some time that have policies in place with the payers, but we want to make sure that DAWNZERA is well covered by the payers, and it's a streamlined process in terms of the experience for HCPs and for patients to be able to move over to DAWNZERA from whatever treatment they're on today. The Ionis Every Step program, I mentioned this with FCS. We designed and really customized this program based on the HAE journey. So it looks different from what it looks like for our Tryngolza program in FCS. But for DAWNZERA, what we've really focused on is, number one, getting patients started in a way that doesn't disrupt their current treatment. So we've done, for example, here, a free trial program that allows patients to get on drug within a couple of days of receiving a prescription. That allows the transition to happen. And as I said, from a switch standpoint, physicians and patients and payers know how to do that safely and effectively because we have the data to support that. And we also have a direct digital companion program that allows patients to actually capture how they're doing on their treatment. And as we're interacting with the patients with our nurse case managers that directly interact with the patients, we're able to have those conversations in a way to understand how patients are doing, how they're feeling, how they -- what they were like prior to coming on DAWNZERA and then how they're performing once on DAWNZERA. So we're doing a lot of things that are very specific and very intentional in terms of helping this patient population get on and manage their disease effectively. So we're transforming the treatment paradigm for HAE. The launch is off to an encouraging start. We're seeing strong interest from HCPs and the treaters as well as the patients that have started on treatment already. The payer engagement is going very well. We're beginning to have those discussions. We'll probably go through the first half of next year in order for us to establish payer policies and make sure that there's really strong coverage here. But we are exactly where we should be in terms of being in a place to have DAWNZERA become potentially the prophylactic treatment of choice in the HAE space. So with that, I'd like to turn the meeting over to Dr. Holly Kordasiewicz. She is our Senior Vice President of Neurology and beginning in January, will become our Chief Development Officer at Ionis. So Holly, over to you.

Good morning, everyone. I'm thrilled to share with you today the progress we're making in advancing our neurology programs to bring disease-modifying medicines to patients in need. So at Ionis, we have a proven pipeline of transformative medicines. We have paved the way for RNA therapeutics in neurology, and our track record is clear. We have 3 approved therapies for severe neurological diseases, and we have a path and a plan to do this again and again. And the reason for our success here is because we have the technology to target the central cause of the disease. Our proven RNA therapeutic platform can safely and effectively engage targets in the brain. We have done this for over a decade, and we have built the space -- we have built the field of RNA therapeutics in the CNS. We know this space better than anyone else. And because of this, we're well positioned to deliver a steady cadence of new medicines. These include using our existing established platform as well as new innovations as we continue to push the boundaries of what is possible. So here's a look at our leading neurology pipeline, and I am so proud of the team back at Ionis who has built and continues to grow this really tremendous group of programs. We have 11 medicines in clinical development, 6 of them are wholly owned, 5 of them are partnered and all of them are for the treatment of severe neurological disease. Another common theme is that in all cases, we are going to the heart of the disease, the central cause of the disease, either by targeting the genetic cause in a monogenic disease or stopping the production of a key pathogenic protein. This is how we provide transformative benefits for patients, and this is where our pipeline stands apart. There's a lot of potential to help a lot of people here. But given this enormous potential, to be successful, we need to focus. So we've devised a strategy to systematically bring new medicines into our wholly owned pipeline. And our approach is data-driven and based on key considerations from research, development and commercial. First, we pick the right targets. Those targets that are central to disease, so our programs are built on a strong scientific foundation because we let nature tell us what the targets are. We then make sure we have the right development path. This means we have the tools for data-driven drug development, the natural history studies, the biomarkers, they exist or we build them. We also look for opportunities for early proof of concept. We can decide early in a program what the magnitude of effect is. We can prioritize our late-stage pipeline on those medicines most likely to give that transformative benefit. We also look for the right commercial fit because we're building a commercial organization where we can recognize synergies across medicines. So taking all this together, we focused it on 4 disease areas: pediatric neurology, dementia, motor diseases and neuromuscular diseases. And as you can see here, we have made tremendous progress on executing our strategy. In 2023, when I introduced this to you, we had one program in clinical development in our wholly owned pipeline. That was zilganersen. We were focused on 2 pillars, pediatric neurology and dementias. We now have 6 medicines in clinical development in our wholly owned pipeline across 3 pillars. We recently opened up our motor disease pillar, and this is with ION464 for the treatment of synucleinopathies. This is a really exciting program because this is a first-in-class RNA therapeutic targeting alpha-synuclein for the treatment of synucleinopathies. It's in Phase II testing in patients with Multiple System Atrophy, and we'll have data for you from that next year. Today, what we're going to talk about is our pediatric neurology pillar and the 3 programs highlighted here. And that's because I have new, never before seen data for you -- for these 3 programs. For zilganersen, this is for the treatment of Alexander disease, we have our pivotal data. For ION582 for the treatment of Angelman syndrome, we have our long-term extension data from our HALOS study. And finally, I'm introducing for the first time, ION337 for the treatment of Dravet syndrome, a severe developmental epilepsy. Here, we're going to take a look at the preclinical data that supports the best-in-class profile of this molecule. So why our initial and large focus on pediatric neurology. And that's because 1 in 6 children will be affected with a neurological disease. And many of these have genetic causes, and they give us those central targets where we can make disease-modifying medicines for these children. Young brains also have tremendous capacity for growth and repair. We saw this firsthand with SPINRAZA. If we solve the problem, the children can develop and meet normal milestones that would not have been possible because of their disease. And so this is what we aim to do again and again. And so given the need and given the likelihood for success, this is a major area of focus for us. This is also the area where we're going to have our first independent launch in neurology, and that's with zilganersen. So zilganersen is for the treatment of Alexander disease, and Alexander disease is a severe progressive disease that is almost always fatal. It typically onsets in childhood. It can also onset in adults. It's a disease of the white matter, so it affects almost all brain regions, so it has a complex symptomology. It's caused by mutations in GFAP and the target for zilganersen is GFAP, so right on mechanism. And I am so pleased to say that our pivotal study was positive, and the team is working diligently to file the NDA as fast as possible. So we'll have that filed early next year. And then this will be our first commercial launch in neurology. And Kyle is going to share with you our commercial strategy later this morning. Right now, we're going to go through the pivotal study. So this is a unique trial design and given the patient population, our clinical team had to be innovative. And so what they did here is a controlled, blinded first-in-human and pivotal study, meaning this is an all-in-one Phase I to III. And this is possible because of the strong scientific foundation this program is built on and our understanding of our technology. So what we did is we took a small cohort of individuals to establish safety and pharmacokinetics at a lower dose. We then escalated up to the efficacious dose level and expanded the cohorts. This includes individuals ages 2 to 65 years of age, and it's a controlled study. We also subset the population for our primary analysis. And this is because our primary endpoint was change in the 10-Meter Walk Test at week 61. So we included individuals in the primary analysis that were 5 years of age or older. And if an adult had motor disease for less than 5 years. And this is to ensure that we could enroll a large broad population in our pivotal study, but then also focus our primary endpoint on those individuals able to execute the 10-Meter Walk Test at baseline. And as you'll see in a moment, this worked out extremely well. So here's a look at the demographics for this study. And these are the 54 brave individuals who volunteered for our trial with no notion of how it was going to turn out. So my deepest gratitude to them and their families for their commitment. Let's take a look at how these 54 individuals were separated into cohorts. We first have our low-dose cohort. This is really to establish safety and efficacy -- sorry, safety and pharmacokinetics, and that's in 8 individuals. We then escalate up to our efficacious cohort, and this is in the dash line they're boxed in. This is our pivotal cohort. This is 24 individuals who received 50 milligrams a quarter of zilganersen and 17 individuals with placebo. We then did a primary analysis on a subset of that population based on the criteria I outlined on the previous slide, and that's 17 individuals on the high dose and 13 individuals on the placebo. Now we included a number of secondaries in the study to capture the full constellation of symptoms of Alexander disease. And that secondary analysis was done on the full pivotal data set. So all 24 individuals at 50 milligrams and all 17 individuals with placebo. So as you can see, this is a nice representative broad population of the Alexander community. We were also able to include an instant cohort. This is an open-label cohort to study safety in the youngest individuals with Alexander's. All right. So here it is, the pivotal data. This data is a first for the Alexander community. This is yet another first for Ionis. It is beautiful data, and it's being shown here for the first time. On the graph on the left, you have our 10-Meter Walk Test change over the placebo-controlled portion of the study, so 61 weeks. This is shown as percent baseline that you can see the progression over time. If you look at the orange line, these are the individuals who received placebo, and they decline in their performance over the 61 weeks of the study. Now the pink line are the individuals who received zilganersen, and it's stabilized. We have stabilized their disease. They do not progress. This is the first evidence of disease modification in Alexander disease. And it's not a small effect. If you take a look at the numbers on the right, it's a 33% stabilization that's statistically significant. It is also clinically meaningful. Clinical meaningfulness on the scale is 20%, and that's based on using multiple sclerosis as an analogue. The 10-Meter Walk Test also has good construct validity, meaning it correlates well with other measures in Alexander disease. So in addition to hitting on the primary endpoint, we also, as I mentioned, included another number of secondaries in the study and all key secondaries favored zilganersen. And since this is a disease-modifying treatment, that's what would be expected. So in addition to the robust efficacy, zilganersen also has a nice safety profile, and that's summarized here. Importantly, everything favors zilganersen. So this is great news for the Alexander community. And for Ionis, this is another validation of our platform and our strategy in neurology. So Dr. Amy Waldman of preeminent pediatric neurologist will be sharing additional details from this top line later this week at Child Neurology Society on Thursday. So needless to say, the team is thrilled with this data and working diligently to get the NDA filed as fast as possible. We're planning to have that in early next year. So continuing on through our pediatric neurology pillar now to our second most advanced medicine in that pillar is Angelman syndrome. So Angelman is a severe neurodevelopmental disease where all aspects of neurodevelopment are affected. For example, all individuals have limitations with communication, most only say a few words. You see Jasmine here in the image, she has around her neck, her communication device, and that's what she uses to communicate and express herself. Angelman individuals also have motor dysfunction, many require wheelchairs. They also have cognitive impairment and typically reach the cognitive age of a 2- to 4-year old. Now unlike Alexander disease, this is not a fatal disease. So Angelman individuals will live a normal lifespan. They just require constant care. Angelman is caused by loss of function of UBE3A. ION582 is designed to target UBE3A and upregulate UBE3A. So we're giving back what is lost. So again, right on mechanism. And we've shown in our HALOS study, consistent benefit across neurodevelopmental domain with ION582 treatment. We now have individuals who've been treated for more than 2 years. Everybody has completed 18 months of treatment, and we're going to take a look at that data cut next. But first, I want to highlight that to our HALOS study, we've also added an infant cohort. And this is so important because this is a neurodevelopmental disease. And the belief is that the earlier the intervention, the bigger the benefits will ultimately have for an individual. So very happy to announce that our first patient has been dosed last month. The study is going well, and it's enrolling. We're also enrolling our pivotal REVEAL study. And this is a critically important study because this is our first controlled study with ION582. Here, we're including a broad patient population, children and adults, mutation and deletion carriers, so taking a similar strategy to what we just talked about for Alexander disease. This study is enrolling, and we will complete enrollment next year. All right. Now one of the really wonderful things about working in rare disease and Angelman is a rare disease, but it's actually -- there's quite a large community is working with the communities. And Angelman is no exception. There are incredible patient advocacy organizations like ASF and FAST. And we could not do what we do without their work. And one of the important work that they do is they teach us about the disease from the perspective of a patient and caregiver. And here are some of their recent data, and this is data from a listening session that they held earlier this year in April. And they asked caregivers what symptoms matter most to them? What do they want to see fixed with the therapy? And they were asked to name the top 3 domains. And their response was overwhelmingly communication. And when you listen to these parents, what they want from their loved one is those loved ones to be able to express themselves to tell them what they need, what they want, how they're feeling and so they're looking for that expressive communication. And that's why the primary endpoint in our Phase III REVEAL study is expressive communication because that's what matters most to Angelman families. All right. So let's take a look at expressive communication from our HALOS study, the long-term extension. So this is data that we're sharing for the first time here. And this is expressive communication as quantified by the Bayley-4, which is a physician-administered assessment. We're looking at change over 18 months, and we've included here a natural history comparator. This is an external comparator and that's in black. And you can see from the natural history, it's very stable normally through the course of these 18 months. And so from an endpoint perspective, that's very attractive to have a stable endpoint. If you then take a look at the pink line, you can see an improvement in expressive communication. These patients communicate more. They get better and they get better and that they stay better over time and that effect continues to increase with time and well over what is expected from natural history. So this is exactly what we want to see at this point. We've also quantified expressive communication by other measures, the Vineland, which is a parent-reported measure, the CGI, which is a clinician impression of change, and those tell a similar story that these patients are improving. Now of course, communication is important, but Angelman is a multifactorial disorder where many domains are affected and so we also want to look across domains. Fortunately, the Bayley-4 measures 5 domains that are important in Angelman: receptive communication, expressive communication, fine motor, gross motor and cognition. So what you're looking at here is a responder analysis across those 5 domains on the Bayley. And this responder analysis is more stringent than anything that we've done before. So here, to be considered improved, you have to be above baseline plus 20% of standard deviation. That's a pretty standard number used in neurology to account for placebo effects. So if you look at expressive communication, which is the first column here, this is the data we had seen on the last slide. Here at 6 months, 61% of individuals are improving, 12 months, 64% of individuals and by 18 months, 71% of individuals have improvement on expressive communication. Now if we ask what about any domain on the Bayley, not just expressive communication, but any of those 5 domains and 97% of individuals are showing improvement at 18 months on at least one or more domains. If we then say what about 2 domains or 3 domains, it's 83% of individuals have response on 2 or more domains at 18 months and 71% of individuals on 3 or more domains at 18 months. So this is incredibly encouraging. This provides a suggestion that we're affecting the underlying disease with a disease-modifying therapy. But this is open-label data. So though encouraging, we're very excited for our REVEAL study, which is a controlled study, and that's the study that will complete enrollment next year. Now continuing down through our pediatric pillar to our newest medicine. This is our newest medicine to be entering clinical development and it's ION337. And this is for the treatment of Dravet syndrome, and we're announcing it here for the first time, so I'll tell you a bit about it. So Dravet syndrome is a severe developmental epilepsy. In most individuals, it's caused by loss of function of SCN1A, which encodes the protein Nav1.1, which is important in neuronal signaling. ION-337 is designed to upregulate SCN1A. So again, give back what is lost right on mechanism. And we're doing this with our proprietary NMA technology. So NMA is an Ionis invention that improves the potency of splice modulating oligonucleotides. And this is poised to enter clinical trials at the beginning of next year. We've completed the IND enabling toxicology studies and part of that evaluation was looking at activity of ION337 in non-human primates. And so here is that data from the non-human primates where we quantified SCN1A levels. And to orient you, in all of us, we make the SCN1A RNA. We make productive RNAs that make Nav1.1 protein. We also make nonproductive RNAs that do not make Nav1.1 protein. This is a natural regulation that happens in all of us. It also happens in nonhuman primates. What ION337 is designed to do is it switches that nonproductive RNA to a productive RNA. In this way, you increase the levels of Nav1.1, which is what's needed in Dravet. And so here on the top graph, I've quantified the productive RNA that makes protein. And on the bottom graph is the nonproductive RNA that does not make protein. So the groups here received either vehicle treatment, and that's noted in gray. So normalize that to 100. So this is the baseline levels of SCN1A. And then if you treat with ION337, look at the top graph, this is a productive RNA that increases and it increases to 200%. If you then look at the bottom graph, you see a corresponding decrease in the nonproductive RNA. And that's because we switched the nonproductive RNA to productive. So 95% decrease in nonproductive, 200% increase in productive. Now the really remarkable thing about this graph is how long it lasts. So take a look at the x-axis that 6 months after dosing, we still have complete conversion of nonproductive to productive RNA. What does this mean for Dravet? So in patients with Dravet syndrome, they have a loss of function of Nav1.1, so half the functional levels. So the ideal therapy is to double their levels, and that's exactly what we've done in the non-human primates here. ION337 has also gone through our extensive screening to make sure this is a well-tolerated CNS oligonucleotide using all of our experience and know-how there. So taken together, based on the efficacy and the safety profile of this, we believe we have a best-in-class molecule using our proprietary NMA technology. So this is exciting that this is moving forward, but this is actually not our first NMA oligonucleotide to go into clinical phase testing. Our first NMA oligonucleotide to go into testing is Salanersen. And this is data from a Phase I study that our partners at Biogen released earlier this summer. In Salanersen, modulate splicing of SMN2 for the treatment of spinal muscular atrophy or SMA. In this graph here, you're looking at neurofilament, which is a marker for damage. And the individuals that were enrolled in this study were individuals that had previously had gene therapy but did not fully respond. And so the individuals on the graph had neurofilament still elevated at baseline. If you give them a single dose of Salanersen, neurofilament drops and it stays down for near normal levels per a year after a single dose. This is incredible. This means this could be a yearly dose disease-modifying drug for SMA. This is also beautiful validation of our NMA technology in patients. And so for Salanersen, this is going to start a pivotal study with our partners at Biogen next year, and we'll be starting ION337 with our NMA technology for Dravet syndrome beginning of next year. So it's a very exciting time in our pipeline, and we're having great advances on the clinical side, but we're not stopping there. We're continuing to advance our technology. And Brett shared you with this morning his vision and what that means for neurology is 3 areas of focus. For our intrathecally [indiscernible] 34.03 drugs, we're extending the duration of action. You just saw that for ION337 and Salanersen. We're opening up a new tissue and for neuro, that's neuromuscular, that's skeletal muscle. So we have our first genetic neuromuscular disease clinical candidate going into IND enabling toxicology this year. And then the last thing is opening up the blood brain barrier, the BBB, and this is to enable systemic delivery of our molecules into the brain. And this is what we're going to talk about next. And that's because the blood brain barrier has been the biggest technical challenge for drug development in neurology. And that's because it is a natural barrier designed to keep things out, and that includes medicines and our RNA therapeutics. The way we circumvent this now is we deliver our drugs intrathecally. Now we deliver them directly into the cerebrospinal fluid that bathes the brain in the cord. This is a simple 20-minute outpatient procedure, and we continue to improve the convenience by spreading out the dosing interval. And that's great. But the next frontier is being able to deliver our drugs systemically and getting them into the brain. And the pathway that's most advanced for this is using transferrin or TFR. So transferrin receptors are found in the cells of the blood brain barrier, and they're a natural gatekeeper for iron. Iron binds to them, transports across the cells and delivers iron into the CNS. What we do is we make ligands that selectively bind to transferrin so we can hit your ride on that natural transport system so that TFR also brings into the CNS our oligonucleotides. And we have a multipronged approach to tackle this. The first is using nanobodies or VHH ligands to deliver our oligonucleotides, and we're going to see some data and talk about that in a bit more detail next. But we're also advancing Bicycle technology. And these are small 2 kilodalton ligands that we're using for skeletal muscle and heart. And the potential here is that these ligands are so small that they enable at-home auto-injector SubQ delivery. And so we want to recognize that same potential that we're opening up for skeletal muscle and heart for BBB delivery. And so that's a big area of focus for us to making that a reality. The first program that's going to go into the clinic, though, will be using the VHH, Vect-Horus technology with an Ionis oligonucleotide. And we partnered with Vect-Horus and their VHH nanobodies after extensive research where we looked at all the different modalities out there. We made them, we brought them in-house, we tested them head-to-head so we could understand them in our own [indiscernible] 36.51 hands in our own laboratory. And then we decided on VHH because of its ability and efficiency in bringing cargo across the BBB, the safety profile as well as the potential for SubQ delivery. So we pair our first molecule going to the clinic will be a VHH ligand with Ionis oligonucleotide that has undergone a rigorous screening paradigm for systemic as well as central delivery using our know-how on how to make safe, potent, effective oligonucleotides in both those spaces. So combining that, we have very effective molecules. And here's a look at some of the preclinical data that supports the promise of this technology. And this is data that had the folks in the lab absolutely buzzing when this first came out. So if you take a look at the graph on the top left-hand side and all the graphs are oriented the same way, these non-human primates received either vehicle treatment, and that's in the gray bar or VHH delivered Ionis siRNA, and that's in the colored bars. It was either done through IV delivery in pink or SubQ delivery in orange. And the SubQ delivery here is 1 mg per kg. So you can see in the Frontal Cortex, we have really robust target knockdown and target engagement. If you take a look at the graph below that now, this is the Caudate. This is a deeper brain structure involved in movement. We also have the very similar robust target engagement. Look at Substantia Nigra, Hippocampus, Putamen, all of them have the same robust target engagement with either IV or SubQ delivery. And so this is incredibly encouraging and to our knowledge, it is the most robust target engagement seen with any of these delivery ligands out there to date. And so the team is working diligently to bring this forward into clinical testing. So it is an exciting time at Ionis and Ionis Neurology. As Sam showed for the cardio franchise, we have a lot of upcoming events in neurology, too, actually 11 between now and the end of next year. And I'll just hit on a few. If we start on the left, at the early stage, we have ION337, our new medicine going into development for Dravet. In our mid-stage pipeline, we have readout for ION464 for alpha-synuclein, first-in-class RNA therapeutic targeting alpha-synuclein for synucleinopathies. We also have our MAPT Tau readout. This is a partnered program and here, again, first time anyone is testing the hypothesis of stopping intracellular production of tau in Alzheimer's disease. That's going to readout next year. The Phase II, we've already shared really exciting Phase I data from that program. Phase III, we have our pivotal study reading out with Ulefnersen. This is for the treatment of a genetic form of ALS plus ALS using a similar trial design that we discussed today with Ulefnersen. And then, of course, we have Salanersen, which is that potential once yearly dose disease-modifying therapy for Spinal Muscular Atrophy. And then zilganersen, approval and launch at the end of next year. At Ionis, our goal is to make disease-modifying therapies for patients. We know that they are waiting for us. And we have the talent and the know-how to execute on our vision of delivering a steady cadence of medicines to those in need. We have done this before, not just once but multiple times, and we have a path to do this again and again. That path is steeped in a strong scientific foundation. We listen to the data. We listen to the patients. We listen to the communities to deliver what's needed most. And I'm so proud to be in ION and represent the team back at Ionis who's responsible for all this beautiful work I shared with you today. So with that, I thank you, and I'd like to invite Kyle back up to the stage to share with you how we're going to deliver these medicines to patients.

Thank you, Holly, and congratulations to you and the team at Ionis. Just amazing to see the advancements in technology, the very focused approach within our neurology medicines platform and where we're headed. I'll just touch on a couple of things here to sum up the commercial situation at Ionis. First and foremost, what Holly touched on is the right commercial fit, right? How do we develop synergies around cardio and around neuro for us to build portfolios of medicines that can obviously benefit from one another and we can advance our commercialization efforts accordingly. What we see within the neurology commercial portfolio now is the ability to focus on centers of excellence, right? These are concentrated areas where there are high volumes of neurologists where we can get in and educate, build relationships, be a part of the work that they're doing and truly partner as Ionis. The other thing that we can do is we can do broad disease education. So this allows us to talk about the things that Holly was just describing in terms of the diseases that need treatments that aren't available today, the innovative approaches that Ionis is taking in ways that we are trying to advance for the sake of these patients, new novel innovative therapies and technologies in order to help them. So each of these neurology programs, whenever you look at zilganersen or ION582 and Angelman are the next wave of medicines that Holly touched on, really unlocks the next one, right? It allows us to build our capability, and it allows us to move forward with creating synergies across the commercial organization. Starting with zilganersen. So similar to what we have been able to do with Tryngolza in FCS and then potentially moving into a broader patient population pending the approval in sHTG into a more prevalent population, we will be able to use zilganersen as a pathway for us to engage with neurologists to understand the community even better, to partner with the HCPs that are treating these patients and to begin creating relationships that are long-standing in order for us to benefit the follow-on programs that are coming. For Alexander's disease specifically, no approved disease-modifying treatments today. You saw the strength in the data that Holly shared with us earlier that this could really be a meaningful and tremendous advancement for people living with Alexander disease and their caregivers. Well-established patient community. Ionis, I think, it represents something very special, and we've done this for 35-plus years. And that is a very close connection to the patient advocacy groups and the patient groups that need support and want to have their voices heard. And in the neurology community, these patient groups are very strong, they're very well organized, and there's a tremendous opportunity for us to continue to partner with those groups, specifically with Alexander disease in order to help them accomplish their goals of helping these people that are living with Alexander's disease. And in terms of reaching these patients, there are a couple of things that we'll need to do, and we'll focus on right out of the gate. First is evaluation and diagnosis. A lot of these patients, because there hasn't been a therapy available today are misdiagnosed. And so focusing on how to diagnose these patients, making sure that they understand that there's a new treatment available, what that treatment represents and how to get that treatment to these patients will be the major focus that we have. Keeping in mind, this is an intrathecal administration for zilganersen. We will do things like mapping where all of these centers are that can actually take care of and help patients with the administration so that we have the right centers in the right locations where these patients have been diagnosed and they don't have to travel long distances in order to get care. And those are the types of things that we're working through right now in preparation for the launch -- potential launch of zilganersen next year. So in summary, when Brett opened up, he mentioned about transforming Ionis into a fully integrated biotech company and what's happened over the last 5-plus years at Ionis. I'm extremely proud of what we've done on the commercial side and the medical affairs side of the business here to be able to hire and attract a top-tier team. It's amazing to see from large companies, from start-up biotechs, the amount of talent that wants to come join the Ionis organization as we're launching Tryngolza, as we're launching DAWNZERA, as we see the future with zilganersen and with olezarsen and sHTG, we've got such a tremendous opportunity here to build on that, the launch momentum and the strength and the execution that we've been able to demonstrate early on with our commercial programs to date. We're also -- we have a scalable organization. There are a lot of synergies here already with our marketing groups, for example, our market access, our patient support programs, but the capabilities that we have from a commercial standpoint to be able to begin layering on additional medicines and being able to capitalize on the know-how and the experience and the talent that we have at Ionis in order to maximize the opportunity to help as many patients around the world as possible with our drugs. So with that, I'd like to turn it over to Beth Hougen, our Chief Financial Officer, to talk about the strength of the financial position of the company and what's coming up next.

Thank you, Kyle. Good morning, everyone. In my 25 years at Ionis, I can honestly say I've never seen our financial foundation stronger or our financial outlook more promising. We're sitting here today at a very important time for the company in which we are looking to use our innovative technology and be able to generate substantial value. We're going to use that strong financial foundation and the financial profile that's very unique to Ionis to deliver not only medicines to patients, but also to drive accelerated growth and substantial value creation. Today is a watershed moment for Ionis. We've been delivering success across our business consistently, and the momentum is continuing to grow as we bring more and more of these medicines forward to patients. And that momentum is what's going to drive the substantial revenue growth and substantial value creation that we're seeing in front of us today. At Ionis, financial discipline has been a top priority for most of our history, for all of our history and that's what's enabled us to really execute on the value-creating opportunities ahead of us. It's enabled us to be well capitalized. So today, we have $2 billion in cash projected at year-end. And that cash enables us to continue to invest in our ongoing and planned launches, and to continue to invest in our R&D pipeline to bring more and more medicines to patients. We have an efficient and cost-effective capital structure, including low-cost, well-structured debt and our strong financial position and outlook means that we can continue to manage that capital structure very effectively going forward. Our top capital allocation priority is to invest in growth, and we do that with discipline, ensuring that every dollar is directed toward opportunities that have substantial value-creating potential. That means that we're investing in our R&D expenses. They're going to stay stable while we continue to bring forward our late-stage, mid-stage and earlier-stage medicines as well as investing in our technology. We're also going to continue to invest in our sales and marketing expenses, and they're going to grow consistent with the scale that we see from revenue from our wholly owned pipeline. What this all means is that we can see a very clear path to sustained positive cash flow. What you see here is the power of our diverse sources of revenue. We see the potential for peak annual revenues from product revenues and royalties of more than $5 billion. Two points I want to highlight about that $5 billion. First is that it is generated from numerous medicines comprising product revenues as well as royalties and that, I think, is really important because it means we're not dependent on 1 or 2 medicines to reach this level of peak annual revenues. Second is that the $5 billion is actually in view today because it's only generated from our approved medicines and our late-stage medicines that we've been talking about today. So let's dive in a little bit deeper into the components of this. We see in our late-stage wholly owned medicines, the potential for $3 billion or more of annual peak revenues. These are valuable revenues. These are product revenues. So that's really important. The other thing you see on this slide is the consistent pace in which we're bringing these medicines to patients. So you can see that, that revenue as we bring those new medicines to patients is going to continue to grow on top of each other and build on top of each other. I think it's also important to point out that there are multiple billion-dollar opportunities in this pipeline. So Tryngolza, you've heard Kyle talk about, is already launching very well. It's -- the launch is off to a strong start for all the reasons that Kyle has highlighted and notably, we've been outperforming expectations in that launch, and we're on track to achieve our revenue guidance for Tryngolza of $75 million to $80 million in this year. Secondly, DAWNZERA, that launch is obviously in early days, but it's off to a strong start to a very encouraging start already. For all the reasons that Kyle talked about, we have confidence that DAWNZERA can be the treatment of choice for many people living with HAE and in doing so, can generate in excess of $500 million of revenue to Ionis. The exceptional Phase III data for olezarsen combined with the commercial strategy and the strong foundation that we're building with Tryngolza in FCS gives us confidence that olezarsen can be a $1 billion-plus opportunity. And now with Phase III data in hand for zilganersen, zilganersen is on track to launch next year. This is a really important launch because it opens up the neurology pipeline, and it's really the first neurology launch. And by opening that door, it enables us to bring more and more of our neurology medicines to patients, including Angelman syndrome that Holly talked about earlier, which like olezarsen could be a blockbuster opportunity. So together, all of these medicines continue to strengthen our revenue -- our potential for revenue growth and give us a clear path towards sustained positive cash flow. There's also more though, because we have an enduring R&D engine that is generating a deep and rich mid- and early-stage pipeline. And that early and mid-stage pipeline also has the potential for some blockbusters in it, as Holly mentioned earlier today as well. So this is, I think, together bringing us substantial high-value product revenues on a sustained basis as we bring these medicines to patients, and we drive revenue growth and our path to sustained positive cash flow. So let's look at what our partnered medicines can do for Ionis. Our partnered medicines are really important because they build on top of our high-valued product revenues. And in doing so, we think about them, those royalties and those milestones, we think of those as financial accelerators. I want you to think about them in that way as well. They build on top of the substantial product revenues that we see in our future. Importantly, there are 3 points I want you to take away from this slide this morning. First is that the attractive economics that you see on this slide in terms of the $6 billion or more in milestones and the royalties that extend into the 20% range is a testament to the value of our innovation and our ability to negotiate substantial economics with our partners. Second, it's really important that $3 billion or more of those milestones are in view today. They're milestones that we anticipate being able to earn in the next several years as we bring these medicines on this slide forward to patients. And third, importantly, the revenue that we anticipate from royalties and milestones is very important to Ionis because it drops directly to the bottom line. It comes at literally little to no cost to Ionis and as such, it really augments our revenues, our earnings and our cash balance. So now what does this look like over the next several years? For the first time today, we are sharing with you our projections for peak annual royalties for our late-stage partnered medicines. And as you can see, those amounts are considerable. When you add those amounts to the revenue that we're generating today from our approved partnered medicines, we see peak annual royalties in excess of $2 billion. You can see why I think about our partnered medicines and the revenues from royalties and milestones as powerful financial accelerators for the company. So you've heard me talk this morning about the clear value drivers for Ionis. And for the first time this morning, we're positioned to be able to project cash flow breakeven in 2028. That's an important inflection point for us. And it really reflects the fact that we have a very differentiated financial profile that includes substantial revenues from recurring R&D revenues. We have expanding royalties and sales milestones from our partnered programs, and most importantly, it reflects the substantial growing revenues from our partnered program -- from our wholly owned programs. Those key drivers together really reflect our ability to move Ionis forward into sustained positive cash flow and create substantial value for shareholders and for patients. So what you've heard today is that we have a strong foundation and a very promising outlook across all aspects of our business. And from a financial perspective, we're sitting here today with the ability to generate substantial revenues using disciplined expense management and together, driving the company to sustained positive cash flow. And that can mean that we're moving into an important new era for the company, an era in which we are delivering life-changing medicines to patients and generating, accelerating and substantial sustained value for shareholders. So thank you. And with that, I'll ask the team to come back up to the Q&A.

We've assembled the team now for our Q&A session, the second one of the morning, and we'll get started. Jess, do you want to start us off with a question?

Great. Jeff Fye, JPMorgan. Can you first just elaborate a little bit on how the NMA technology works to achieve these long dosing intervals? And then second, a couple on 337. I think for STK-001 01:00:42, it took them a while to get up to an effective dose, maybe in part related to some nonclinical findings that led to a partial hold in dose cap. Did you guys have any similar findings in the NHPs with 337? And given that you'll be coming from behind relative to Tominersen 1:00:53 -- how do you expect to differentiate beyond dosing frequency?

ION337, the NMA technology, the way that it works is it improves potency, so we have about a 3x potency shift and by improving the potency, you can then extend the dosing interval. And we have a manuscript up on BioArchive that explains the details of this, so there's more chemical details in there as well. So recommend everybody check that out. And then in terms of the NHP, we're very happy with our NHP profile. We're up to go -- able to go up to high doses as we do for most of our programs. And the only finding that we have there is our typical acute transient fully reversible finding. So we are very happy that we'll be able to dose the full dose response curve going right into our human clinical testing. And this is based on the experience we have with oligos. We know what to look for preclinically to make sure that we have a molecule and achieve that. And then in terms of differentiating, so in addition to that extending the dose interval, we also won't be leaving any efficacy on the table, so we'll be able to get maximum efficacy and provide the greatest benefit is our hope.

This is Julian Pino working with Paul Matteis at Stifel. Just a couple of questions on Angelman. So your competitor has already announced completion of enrollment. So I'd love to hear a potential status update on how enrollment is progressing there and when you expect to complete enrollment next year, if you have any more specific guidance. And we've also sort of seen some recent updates that suggest this FDA may be more willing to be flexible from a regulatory perspective, when it comes to rare disease. Do you maintain a dialogue with FDA just because you announced alignment on the registrational trial almost a year ago. And there's been a number of updates since then. And then one more quick question, if you don't mind, just on the status of your collaboration with Biogen. The blood brain barrier technology that you presented today seemed really exciting, so I would love to hear, are you encumbered from any targets that you re going after with your BBB tech and would love to hear any color on that.

Yes, there's a lot of questions. So I'll try to remember them all. Holly, why don't you talk about how enrollment is going? And then maybe also talk about a little bit about how we see ION582 from a differentiating standpoint from other programs. And then I'll talk a little bit about the regulatory question in Biogen.

Yes. So ION582, our Angelman program, the enrollment is going extremely well. We had announced that we would begin dosing in June, we did. We're still on track to complete enrollment next year. So there are many KOLs and patients in this community who want to participate in trials, actually many more than we'll be able to enroll in the trials that are available. So that is not a challenge. Our molecule also has an excellent safety profile. Again, it's built on our known established platform that you guys have been hearing about today that have gone through our rigorous screening paradigms to make sure that it's a safe molecule. So we have a safe molecule that's showing activity across domains. And so we have in all the different domains that we've looked at, benefits in our ION582 HALOS study, which isn t the case for everyone else.

Shifting gears, we have an outstanding relationship. I'd call it a partnership with the neurology division at the FDA. We were the first to bring oligonucleotide-based drugs to the FDA for neurological disease applications, and they have worked tirelessly with us to help us not only get these drugs to patients, but also to help us in our clinical trial design, so we've been very flexible. I'm not talking about cutting corners, but I'm talking about supporting us and helping us along the way. As they did with SPINRAZA, the first ever infant delivered intrathecal oligonucleotide in the history prior to us doing it as they did to find a way to get QALSODY approved, the drug that was clearly demonstrating benefit for ALS patients, but the clinical trial design was not the right design, but they knew it was helping patients as they did in our Alexander's program. I mean, a single clinical trial that they agreed to, a Phase I,II, III study that they agreed to would -- that if it showed benefit, they would support it going forward, so -- and the same is going to hold, we believe, for Angelman's and so on. So we have a great relationship with them as we do with Biogen. Biogen is a long-standing strategic partner of ours, and they've done a phenomenal job with the programs that we have delivered to them, whether they were responsible for late-stage development or we were or the commercial launches. They've done a great job with SPINRAZA. They've done a great job with Salanersen in our other programs, our Tau program and so on. We have a long-standing partnership with Biogen that lasts a couple of 3 more years or so. However, we have a lot of unencumbered neurology programs that are wholly owned by Ionis, and we expect to have more going forward that includes Alexander disease, that includes our Angelman's program, that includes our alpha-synuclein program and so forth. I mean Biogen has their capacity and their focus, and we have ours, and there's plenty for both. Blood brain barrier, we're working closely with Biogen on BBB, but we're also working on independent programs for blood brain barrier ourselves and Holly actually showed you an independent unencumbered program today that we're working on in blood brain barrier there too. So we don't really have an encumbrance on using technology for the blood-brain barrier going forward.

Just one other thing to highlight for the FDA is we have breakthrough designation for ION582 for Angelman. Will help us with those conversations.

All right. Yanan, another question, and then Yale, after.

Yanan Zhu, Fargo. I wanted to thank the team for the clarity on the peak royalty, peak sales and cash flow breakeven. Those are super helpful. My question is maybe a follow-up on Angelman's syndrome. I was wondering, have you looked, in terms -- of course, great data on expressive communication. I was wondering, on the cognition [indiscernible] component side, is the profile that you see competitive? Maybe separately, on zilganersen, it sounds like there's -- there are only 100 to 300 patients in the U.S. What's the pricing strategy there?

So for Angelman, we have benefits across domain. So yes, cognition is one of the domains that we have benefits in.

One other thing I'll just add to that -- Holly, is -- one thing that we know is that if you can improve communication, it has a trickle-down effect on improving all other aspects of the disease. As you can imagine, your ability to learn, to communicate, to go into a classroom and communicate either expressively or receptively, this helps with cognition. So it's actually a trickle-down effect too there. But as Holly said, we're very pleased with our cognitive domains and our Bayley-4s assessments, Vineland-3 assessment our as well in the Angelman's program. So we think we'll do just fine in that. Before turning it over to Kyle, I just want to highlight the fact that -- and sorry if you were going to say this, but rare genetic diseases where there are no treatment options available today are historically underestimated with respect to prevalence, right? Beth reminds me all the little time about how we started with SMA with 35,000 patients for estimate and where we are now?

20,000.

20,000. We are now pushing 100,000 patients with SMA today with the various treatments that are available today. So we don't know what the prevalence is. But we have a real disease-modifying treatment that is going to make a big difference. And Kyle is doing all the -- his team is doing all the pricing work, but it's early days though, right?

Yes, it is. There are estimated to be about 350 patients in the U.S. today. There is an ICD-10 code for this, not always aligned directly to the disease yet. Again, that's part of the education that we need to do. We anticipate knowing where about 150 or so of these patients are, about half of the potential prevalent population. This is going to be a rare disease price drug, right? So it's going to be greater than $500,000. We don't have a final price point yet. We'll do more work with the payers based on the body of evidence that Holly shared earlier, and making sure that we price it appropriately so that there is unencumbered access for patients and for physicians to be able to get this drug to the patients that need it.

Yale Jen from Laidlaw & Company. I have a question regarding the DAWNZERA. And you guys mentioned that you are in discussion with the payers to accept coverage policy, probably will be done by next year. So two questions here. When do you think -- can you get a little bit more tighter time line for that? And second is that, what specific sort of features or aspects you can share with us for that discussion before you get finalized?

Yes. So the payer discussions are ongoing. Typically, they'll review a class at a certain time. And that's why it takes some time in order to have the formal policy get put in place. The good news is, is that prophylactic treatments are -- have been widely available for quite some time. So a lot of the policies have already been established. It's a question of will they cover DAWNZERA under the policy that's in existence today. So that's the work that we want to do with them. As we've had already initial conversations, the profile of DAWNZERA is very appealing, the first RNA-based technology that could potentially make a difference for patients, the profile, as we've talked about in terms of efficacy, tolerability and convenience and also the switch data. The switch data is very meaningful to the payers because they want to know when they can stop paying for one treatment and when they can start paying for the next treatment. And right now, they're telling us that there's quite a bit of overlap in terms of their costs associated with multiple therapies and they would like to do better in that regard. So we've got the right strategy in place and we're working with payers and it's more of just a time and a process element for when they'll review the class.

And any time, maybe second half or first half of next year?

It depends on the payer. That's why I say 2026 just to give a little bit of room, but it really is dependent upon the payers. We've got some that could potentially put policies in place before the end of this year, for example, right? But some of those will take time next year. Just depends on when they get to the review. But it shouldn't limit the ability for patients to have access to DAWNZERA, right? So the ones that have policies in place physicians know exactly what to do. If it's a prior authorization process, et cetera, they'll be able to support it through that process. And be able to get DAWNZERA through a medical exception process. So it shouldn't limit the ability to have access to the treatment.

We got Debjit next, and then we'll do Shelby and Ryan.

Debjit from Guggenheim. So a couple of questions for Holly and then one for Beth and Brett. But the remarkable NFL reduction, is that unique for SMA? Or can this be extrapolated to triplet expansion diseases like Huntington's? Number two, if you think about where the neurology portfolio is going, say, 2 years from now, do you think intrathecal dosing is a thing of the past and everything is going to move towards -- or Ionis can move to IV or subcu? And then more on the business side, given where you are financially, do you think you would need to partner any programs going forward?

All right, neurofilament. So neurofilament, and that remarkable effect in SMA, we've also seen with QALSODY in ALS. So it can happen with other neurodegenerative diseases. In both those instances, they have high levels of baseline neurofilament, quite high. Huntington, you asked specifically about, and other triplet diseases. Some do have higher neurofilament levels, like SCA1, Huntington is less elevated. And so the question that we don't have data on yet as a field is, in those slight elevation diseases, not the severe elevation, how much of that will be reflected in the treatment effect? So I think the jury is still out on that. There are some hints that neurofilament can be affected in those diseases, but how much into what magnitude and how that translates, we still need to learn as a field. That said, I'm personally very excited about neurofilament as an unbiased biomarker in these degenerative diseases given our experience with SMA and ALS. And then to the other question, which I...

Huntington.

The Huntington is -- yes, I think I hit on that one. What was the other question? Sorry.

Just going forward, would you think...

Oh, yes. So subcu -- I think it's going to depend on the program. So there's going to be programs where you want to target and you have a target that you can hit in the whole body that it isn't going to be detrimental to lower it. There's going to be other targets where you just want to hit centrally. So for example, things like LRRK2 is a target where you want to hit it just centrally because you don't want to target the lung and the kidneys because of on-target liabilities. So there's going to be examples where intrathecal is favorable. There's also once-yearly intrathecal is an attractive approach from the research that we've done. So it will be a mix depending on the indication, depending on exactly what the patients need and what the target is. But we will be seeing, hopefully, more and more subcu and IV delivered oligonucleotides going forward.

And not all targets are the best targets for systemic administration too. I mean some targets can bring on-target liabilities systemically, and you only want to deliver them into the CNS. There are several examples of that. But we're pushing on both, but we think intrathecal has a long life ahead, especially once we go to semiannual/annual dosing. As far as partnering, so your question, Debjit, was, do we need to partner? The answer to achieve the vision that -- the expectations that Beth laid out for breaking even, achieving positive and growing cash flow, the answer is no. We don't need to partner. Will we partner? Probably. We have a prolific R&D engine, and we will continue to prioritize the wholly-owned pipeline, but there may be assets, programs in the future that we believe will take us out of our comfort zone. We may not be the perfect choice to bring these forward to the market ourselves and maybe they fit better with someone else. We have the ability to do that. And as Beth laid out, there is economic upside to partnering at times, and we'll probably continue to do that. But do we need to do that to achieve the vision that Beth laid out. Is that right?

Yes, that's absolutely right.

This is Shelby working with Luca Issi from RBC. How should we think about pricing for Alexander's disease? And then I know you guys mentioned that this program can kind of help your entry into the neurology space. So how have those interactions been with health care providers? And what were some of their initial reactions on the data?

On the pricing side, we expect it to be rare disease pricing, greater than $500,000. We'll dial in the number as we do more pricing research and obviously announced upon the approval. But with the patient population of several hundred patients, that will probably be an acceptable range and reasonable for payers to cover and reimburse.

And then in terms of the community response, it's overwhelmingly positive. The outreach from the families and parents and patient advocacy organizations and the KOLs has been just overwhelming. Hearing things like "I can breathe for the first time knowing that this is coming." And so it's really wonderful.

Yes, I'll just mention we also have our medical affairs team that's been in the neurology space. And so we're interacting with a lot of the key centers. And the feedback has been very positive from the HCPs. And a lot of questions around how fast will this get to the market and when can we start treating more and more of these patients. So there's a lot of interest in trying to bring the therapy forward quickly. And also at Ionis, I'll just share with you, every year we do what's called [ Why Week ], why do you do what you do and what does it mean to you? And we had an Alexander disease, a parent that was there and talking about this program, and she subsequently sent a letter to Ionis after the data announcement. And it's very heartwarming.

Ryan?

Ryan Mcelroy here for Mani Foroohar at Leerink Partners. I appreciate you taking the question. Maybe just one more on Angelman. Your Phase III program is obviously enrolling a broader patient population than competitors. I'm just wondering when you think about this commercially, what are your expectations for whether this is predominantly a pediatric treatment or one that obviously can expand into adult patients? And then just separately, thinking about the Phase III salanersen trial, is that one where we'd see a head-to-head against SPINRAZA? Is this a placebo-controlled trial? How are you guys thinking about that development plan?

So let me take the first one. Biogen has not released details on what that Phase III trial design will look like. That will come out probably early next year. So stay tuned for that.

In Angelman, for that, it is a disease of all ages. Individuals are affected for their entire lives. And what we're seeing in the HALOS is the adults are responding as well as the children. And so given that we are seeing that positive results -- response, and it's not entirely surprising, because UBE3A is a protein that's involved in synaptic health and so that we even saw this in preclinical models, even in adult brains, if you improve that synaptic health, you can have growth in repair. And so because of that, really treating the entire Angelman community should be our goal. And that is our goal at Ionis.

Okay. I think we have time for one or two more questions. Jay?

Jay Olson, Oppenheimer. For your BBB penetrant ASOs, can you compare and contrast your two approaches, VHH antibodies versus bicycle peptides? What are the pros and cons of each? Or does it depend on the specific program?

Yes. They're on a different time line. So the VHH program is more advanced, and then the BBB is coming. We're still in development to optimize that, to make that able to do the delivery that we wanted to do to differentiate. So right now, we're really focusing on VHH for the clinical candidates just given the profile that we have in the advancement. Eventually, the idea that the bicycle is going to circumvent that and really take over for all the future programs, if we can get everything to work the way we want it to work.

Yes. We're taking, as Holly said, multiple approaches. They are on different time lines and we are moving urgently to move our first BBB for proof of concept in the clinic. So the VHH will probably be the first. The bicycle, think about GalNAc for the liver, the molecular weight of GalNac. That's what bicycle brings to us, a very low molecular way ligand attached to an ASO siRNA that offers a lot of advantages from a manufacturing standpoint, cost standpoint. Also the ability to use low-volume injection, subcutaneous, because it's such low molecular weight. So we like both platforms. We are doing head-to-head comparisons, but one is ahead of the other based on pure time lines.

This is Zaki on for Akash at Jefferies. Just one on Angelman's. So with kind of thinking through the broader -- the larger Phase III trial that you're doing, is there anything we should know about maybe heterogeneity in response among the Bailey-4 sub-domains that prioritized choosing expressive communication? And then number two, just on the TRYNGOLZA launch into sHTG, I'm not sure like how much you've commented so far, but just any sense on the cadence there given that there is overlap in the prescribers between FCS and sHTG? And how much your -- the current manufacturing footprint can address that entire sHTG population relative to what we have now?

Yes. So for the Angelman question, for the Bailey data, we shared last year the 6-month data, the end of the MAD data, and there we could see a response across the Bailey domain. The expressive communication had the biggest change from baseline because the baseline is stable, where in the cognition domain, for example, there is still an improvement over the younger age groups. There is still that growth that's happening. And so having that delta is attractive from an endpoint perspective. But it's also that this is a domain that is most important for families. And as Brett mentioned earlier, this is also a domain that involves all different functions. You need to have motor skills to be able for speech and expression. You need to have cognition to be able to understand what is being said so that you can respond. And so it's a domain that even though it's a single measure on the Bailey, it's taking into account a lot of aspects of neuro development. And so it's very attractive from that perspective as well.

And on the FCS launch into sHTG, you're exactly right, it's the same call points, right? It's cardiology, endocrinology and lipidologist. As I mentioned, we were reaching about 3,000 today with our current sales team. We're going to expand our TRYNGOLZA FCS team in order to reach 20,000 HCPs that are high treaters of sHTG. We've just hired our management team and that team is in place. We expect to have the broader team in place the first half of next year. That's going to allow us to educate more broadly on sHTG, and most importantly, get more patients that are diagnosed with FCS on to TRYNGOLZA next year, which is going to be our number one priority. So those scaling of the team and capabilities are underway, and we're very excited about the talent that we're attracting into the organization. If somebody wants to touch on manufacturing, I mean we're -- for sHTG, we're able to...

We are in great shape. I mean we have no issues with manufacturing. We're ready to -- we'll be ready to launch upon approval in the second half of next year. We're in good shape.

Okay. With that, I think we're running out of time. So I'll thank our panelists for coming up here and answering questions. And I'll ask Brett to give us views on what he really thinks about the future of Ionis right now.

Well, I don't know about that. I think we've been doing that all morning. First of all, let me thank all of you for taking your times out of your very busy schedules for spending a few hours with us today and hearing about the great progress we're making at Ionis. So a couple of take-home messages, and I'll show a couple of slides and we'll be done and let you go back to your busy schedules. First of all, I think what you saw today was an incredibly deeply talented bench of people at Ionis that we came up here and presented to you how committed they are to drive incredible accelerating value for patients, for shareholders, for all stakeholders. And I could tell you that, back home in Carlsbad, they're all like that. Carlsbad, Boston, Dublin across the globe, they're all like that. They are committed to drive value for patients and for all of our stakeholders. The second thing that you saw today was that we've had a great deal of success over the last couple of years. But we've just scratched the surface. We're just at the very beginning. We are now entering into a period of accelerating growth for Ionis that's going to be sustainable well into the future. These are just some of the expectations for real value-driving events that are coming next year as a reminder, because we did cover a lot today. We're anticipating 2 NDA submissions next year, both of which are supporting 2 independent commercial launches next year: severe hypertriglyceridemia for olezarsen and zilganersen for Alexander disease. We are also expecting next year five Phase III data readouts from our wholly owned and our partnered pipeline next year, that is setting us up for a continuous accelerated or continuous expectations for Phase III data readouts next year and product approvals there to follow. We're also expecting multiple Phase II readouts next year from our mid-stage pipeline that, if successful, then we'll move into Phase III pivotal studies, both from -- these are all from our wholly owned pipeline today. And we believe that these will set us up for at least two initiations of pivotal studies, our Phase III studies for next year, to drive continued success in Phase III readouts and to the market. As I mentioned in my introduction and as you saw today, we are highly focused at Ionis to drive success. Therapeutically, we are focused on two therapeutic areas: cardiometabolic diseases and neurological diseases. We're leading the way with oligonucleotide-based therapeutics today, targeting RNA. And we're continuing to invest in these platforms to ensure continued success well into the future with new technologies, and you heard about that from Sam and you heard that from Holly as well today. And all of this is setting us up for a really, really attractive financial picture for years to come. Accelerating revenue growth is on the way with a clear path to sustain positive cash flow, as Beth took you through just a few moments ago. So with that, I'll just close with this final slide. Again, thanking all of you for your time today, listening to the great progress we're making at Ionis. We are well on our way for accelerated value creation at Ionis based on everything we're doing and our commitment to drive success going forward and to achieve our vision to transform -- to be the leaders in transforming human health through RNA targeted medicines. So thank you, everybody, and have a great day.