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

Okay. Let's get started. I'd like to welcome everybody out today to Ionis' Innovation Day. I'd like to welcome everybody who's joined us in the room here in New York City, and those who are joining us on the webcast. Today, you're going to learn a lot about Ionis' innovative medicines and our plans to deliver those medicines directly to patients. Ionis is in the business of discovering, developing and delivering innovative medicines to patients. As part of that, it's a risky business, so we will be making forward-looking statements. And if you'd like to learn more about those risks that we'll be talking about today, you can go to our website, download our SEC filings and take a look there to learn more. At Ionis, we know that sick people depend on us. And this knowledge drives everything that we do and our work to help patients with the opportunity to have a better life. And building off of that foundation, we strive to be good corporate citizens. We work to empower our employees to support our communities and to support sustainable planet. If you'd like to learn more about Ionis' commitment to corporate responsibility, I encourage you to go to our website and download our latest corporate responsibility report. Today, you're going to be hearing from a number of leaders from across the company, from senior management to leaders in research, clinical development and on the commercial functions. I'm not going to introduce everybody today here right now, but we're very excited that you're going to have a chance to hear from them and they'll be introduced ahead of their sections. You'll also get to hear today from 2 renowned physicians, Dr. Henry Ginsberg, Professor of Medicine at Columbia University and a Key Thought Leader in the treatment for patients with familial chylomicronemia syndrome or FCS, and severe hypertriglyceridemia, or SHTG. You'll also get to hear from Dr. Raffi Tachdjian, Associate Professor at UCLA and a thought leader in treatment of patients with hereditary angioedema. This is our agenda for today. In the morning session, we'll focus mostly on our late-stage commercial medicines, talking a little bit about our plans to deliver these drugs directly to patients. And we'll also be talking more about our technology and the innovations we're making to -- in our technology pipeline to make those programs even better. In the afternoon, we'll talk more about the next wave of wholly owned medicines that we're working on. And also, Beth Hougen, our CFO, will talk about our clear path to unlocking next level value. We'll have 2 Q&A sessions during the day, one towards the end of the morning session for 30 minutes, and one at the end of the afternoon session for 30 minutes. Our CEO, Brett Monia, will introduce us with some discussion about our strategy and our accomplishments to date, and then we'll wrap up the day with concluding remarks. And with that, I'd like to turn the program over to our CEO, Dr. Brett Monia.

Good morning. Thank you, Wade. It's great to see so many familiar faces in person here live today in New York. And also great to have so many people dialing in remotely through our webcast. We really are excited -- we've been excited for the last several months to provide you with an update on the tremendous progress we've been making over the last really couple of years, several months, progress that we believe that Ionis is poised, positioned to drive substantial value for all stakeholders, patients, our shareholders, everybody that's associated with the Ionis family. So at Ionis, we truly have a rich, rich history, heritage that we are incredibly, incredibly proud of. And what we're most proud of is the fact that Ionis led the way in the creation of a new way, a new modality to treat and tackle devastating, debilitating diseases, diseases that were not approachable with existing platforms at the time. A history that we're proud of because it's poised to help so many patients in the future. It started with antisense, right? Many years ago and for decades, it was antisense with RNA, RNA is our target. Today, RNA is a very exciting hot topic today, but it was a very novel idea back in the day. And today, this sector that we really led the way in creating has helped thousands and thousands of patients already around the globe, benefited many patients. But what's really exciting is it's positioned right now, poised on the cusp of helping millions of patients around the globe. And Ionis, Ionis is leading the way in doing this, and you'll see that today. We did this by focusing on all of the key aspects that needed to be focused on, nailed down, understood and validated to create a new platform for drug discovery, including establishing the world-leading medicinal chemistry platform for oligonucleotide drugs, right? To give these drugs, they're drug-like properties such that they can be effective and safe. We also led the way in establishing leading -- industry-leading manufacturing capabilities. Capabilities to ensure that we can provide our treatments for clinical trials at scale commercially and at acceptable costs. We also dug deep into understanding how these drugs behave in animals and in humans, understanding how they're distributed, what cell types they get into, how they get into those cells, what cell types they don't get into. And that really led the way in identifying where we can apply this technology for drug discovery, organs such as the liver and now the CNS for neurological diseases. We led the way in understanding validating multiple mechanisms of actions such as, for example, the RNAse H mechanism of action, which typically is used to block the production of a toxic protein for gain of function diseases. We also led the way in applying the technology to utilize splicing mechanisms, to modulate splicing such that we can, for example, up regulate the production of a toxic protein in loss of function genetic diseases. And we led the way in discovering and developing first-in-class medicines. We showed the way regulatory paths, clinical paths and so on, getting drugs approved. This was the vision for Ionis from the outset. Right from the beginning, it was the vision to create a new way to discover drugs to treat diseases that were intractable using other modalities, a new sector in the biotech industry. And it was this vision that drew me to Ionis many, many years ago, it was a long time ago. I came to Ionis because I was excited about this vision, and I was excited about the people. And I knew that if anyone is going to make this successful, it would be the people at Ionis. I started as a bench scientist in the beginning of the company. On the bench with my colleagues, addressing all the things that I just covered, how do these things get into cells, how do we make them, what's their mechanisms of action? Splicing. I was heavily involved in splicing in the early days. Fast forward to, I don't know, about 4 years ago -- 4, 5 years ago, as I was approaching my new role as CEO of Ionis, I, of course, was part of and recognized all the greatness and the fabric of the organization of Ionis, right? Dedication, perseverance, unwillingness to fail, to deliver medicines for patients that were in desperate need for new treatments. And of course, as CEO, that was a top priority for me to maintain that, in fact, embrace it and strengthen it. But we needed to do more. We needed to do more to bring Ionis to the next level, to drive substantially greater value for patients, for shareholders for all stakeholders. And I identified 2 key objectives that we needed to pursue and be successful at to drive that value. When you create something great, like a new way to discover drugs and apply treatments for patients, a new sector in the biotech industry, it's inevitable that others will follow, right, following your footsteps. Competition will emerge. When we first started Ionis, which was Isis in the early days for those that remember, there was a handful of other companies working on trying to make oligonucleotides work, or an antisense mechanism of action, for example. Most of those companies quit or failed, we persevered. Today, there are -- I can't count how many -- everybody seems to be in the oligonucleotide space because it has such tremendous potential. I mean, we started with antisense, as I mentioned before, now it's expanded many years later to RNAi, even to DNA editing. These are all oligonucleotide based platforms. And again, I believe we showed the way. So -- but competition emerges when you do something great. And therefore, when I was approaching my role as the CEO, I said, there's one or two things -- there's two things we need to do, and the first thing is we need to invest much more significantly into technology. To expand and diversify our technological capabilities, to not maintain but to extend our leadership position in the field we created, oligonucleotide therapeutics. That was the first thing. And the second thing we needed to do was we needed to deliver our treatments to patients directly, commercialization. I mean, after all, who knows our platform better than Ionis, our people, or who knows our platform -- who knows our drugs. The drugs that our leaders -- our scientific leadership and people conceived and identified and discovered. Who knows them better than Ionis employees. And nobody moves with a sense of urgency as Ionis. We can no longer rely on others to deliver our treatments to patients directly. We have to do it ourselves. And of course, all of this drives -- would drive tremendous greater value for not only patients but to all stakeholders including our shareholders. So that was my vision when I was approaching my new role as CEO, approaching 2020. So that was the vision. We would continue to maintain and strengthen our -- everything that we've always done great at Ionis. Innovation, innovation across all aspects of the company but also -- but in particular, scientific innovation and innovation in clinical development, while also, of course, strengthening our financial stability, our strength and always maintaining our financial responsibility along the way. But adding to that would be to expand and diversify our technological capabilities for drug discovery to extend our leadership position in oligonucleotide therapeutics. That was the #1 priority. And the second priority was to deliver our medicines to patients ourselves directly. Patients like on the left, Mark Irwin. I know, Mark, I've known him for many years. Mark suffers with hereditary TTR amyloidosis. He has polyneuropathy and cardiomyopathy. So he's a mixed phenotype. Hardly a few weeks go by in which Mark does not reach out to me, and this is the truth. Mark does not reach out to me and tell me how grateful he is to be on the drug like eplontersen, a drug that he's been on for several years, and he's always telling me how well he's doing. He's gaining strength in ways that he just never ever expected that he would be able to achieve. And he also often tells me how much he wishes his dad, this is a hereditary disease, his dad had a treatment, had access to a drug like eplontersen. His dad succumbed to the disease eventually as there were no treatments for eplontersen. Or Nicole, Nicole who suffers with FCS and waiting for a drug like olezarsen. Or Kiara, Kiara was one of the first patients to receive SPINRAZA following its accelerated approval after our landmark Phase III study NURTURE, in which we proved that SPINRAZA was providing tremendous benefit to patients with SMA. We ran that study. We conceived SPINRAZA. We developed SPINRAZA. Kiara today is living a normal healthy life. She received SPINRAZA just less than 2 weeks after the approval. And today, she's living a healthy life and she had a form of SMA that was a fatal disease within the first 2 years of life prior to SPINRAZA. Sydney. Sydney with HAE, waiting for better prophylactic options to manage her disease like donidalorsen. Dr. Dennis Leahy, a cardiologist, ironically, suffering with Lp(a) driven cardiovascular disease, a disease that afflicts millions and millions of people globally with this disease, and there are little to no treatment options available for it. Dr. Leahy undergoes -- several times a month, he undergoes a procedure called apheresis to just filter out his Lp(a) to the best he can to help manage this disease. It's a highly invasive procedure, it's not very effective, it doesn't last long. Dr. Leahy is looking -- waiting for a treatment like pelacarsen. And then there's Grayson. Grayson patiently awaiting for someone to come forward with a blockbuster treatment or a breakthrough treatment for his Angelman syndrome, somebody like Ionis. Ionis led the way in conceiving and discovering and bringing forward treatments for every one of these diseases today. And this is just the tip of the iceberg. There's so much more, and you're going to hear about it today. When I refer to million, we're on the cusp of helping millions and millions of people globally. This is what I'm talking about. This is what Ionis is doing, and we're leading the way. And as I mentioned, you're going to hear about that today. And by doing this, we're going to provide great value for patients or shareholders for all stakeholders. And this is what we're laser-focused on. And I'm pleased to say that today, after the investments we've made over the last several years, we're there. We have expanded and extended our capabilities in drug discovery by extending our technology in many, many ways, and you're going to hear about that from Eric Swayze today. We have an outstanding clinical organization that knows how to take our medicines through clinical development through proof of concept and to the finish line. And today, we have all the pieces in place to deliver our medicines directly to patients ourselves, and you'll hear about that today. We have a world-class research and development organization that conceived and discovered 4 treatments today that are truly transformational, that are on the market today. 2 of which are real breakthroughs, real breakthroughs for neurological disease. SPINRAZA, as I just mentioned. And then this year, our approval of QALSODY, for SOD1-ALS, a real breakthrough for the ALS community. And we're expanding our ability to tackle other diseases, not just in tissues that have been approachable in the past, but new organs and new tissues. We have one of the richest late-stage pipelines in the industry. We have 9 Phase III programs in development across 11 disease indications, mostly coming from our leading cardiology franchise and our neurology franchise. And we're ready to go, we're ready to launch. We're ready to bring our medicines directly to patients with our near-term commercial launches, eplontersen, olezarsen and donidalorsen and more that's going to come after that. We indeed have a really outstanding research organization. Our research organization today with the investments we've made to extend and expand our capabilities in drug discovery are optimizing potency, optimizing durability to extend dosing intervals, less frequent dosing for both systemic applications and local applications as well. And today, we are mechanistic agnostic for oligonucleotides, right? ASO mechanisms, many different ASO mechanisms, RNAi and now even DNA editing. Why? These mechanisms, these platforms have more in common than they do have differences. These are oligonucleotide-based approaches, genetic medicine approaches, and nobody has the breadth of capabilities than Ionis researchers do in optimizing and delivering on these types of mechanisms over and over again. So that's what we're doing. We're mechanistic agnostic, may the best drug win for patients. We're optimizing targeted delivery, right? Opening up new tissues, new cell types through targeted delivery strategies such as cardiac muscle for heart failure and skeletal muscle for neuromuscular diseases. And we're even now further extending our leadership in CNS diseases by overcoming and traversing the blood-brain barrier to be able to apply our drugs for CNS diseases by an intravenous route of delivery or a subcutaneous route of delivery. And you're going to hear about all this today from Eric Swayze. And all this lays the groundwork for an expanded and sustained pipeline delivery of transformational medicines for today, tomorrow, for many years to come, from our established franchises, as well as from new therapeutic areas. I'm also pleased to report that after 3.5 years or so, we're ready to launch our own products. We're ready to deliver our treatments directly to patients. We have all of the functional areas that need to be in place at this point to deliver our medicines directly to patients. And this organization that is now being formed and is largely formed at Ionis is outstanding. There is so much enthusiasm to come to Ionis. I mean, look at our pipeline, for people that -- for people who have careers in these areas. It's an outstanding organization to match the excellent across other areas of Ionis, including clinical research and -- clinical development research in other areas. And you're going to hear about that today from Onaiza Cadoret. These are our near-term commercial launch opportunities. Eplontersen for -- to being developed for 2 disease indications, a rare disease indication for ATTRv-polyneuropathy. We reported really remarkable Phase III data, full data set this year in that -- in our Phase III trial for eplontersen in this patient population. This treatment is now under review, both in -- by the FDA and in Health Canada, and we're expecting a decision for approvability by December of this year. And then our CARDIO-TTRansform study, the second indication. We have fully enrolled our CARDIO-TTRansform study for a much broader patient population with TTR cardiomyopathy. This is a landmark study, folks. More than 1,400 patients in this study is never -- a size -- a study of this size has never been done before, not even close. This is with our co-commercialization partnership with AstraZeneca. And then we're approaching our first independent commercial launches. Olezarsen for diseases related to severely elevated triglycerides, both a rare genetic disease, FCS, monogenic disease FCS, as well as a polygenic form severely elevated hypertriglyceridemia, a much larger patient population. You're going to hear a lot about olezarsen and FCS and SHTG today. And then donidalorsen as a potential best-in-class treatment for hereditary angioedema, for prophylactic treatment for hereditary angioedema. And we're very much looking forward to the Phase III results in the first half of next year, and you're going to hear about our progress for NHAE. And if that wasn't exciting enough, today for the first time, we're going to share with you the next wave. At least a glimpse into the next wave of wholly owned Ionis medicines that we're planning to bring to patients directly, with a deep dive into our leading neurology franchise. And that will be covered by Holly Kordasiewicz, as well as Rachel Carnes. So look forward to that. We truly have one of the most remarkable late-stage pipelines in the industry, Phase III pipelines. It's broad, it's deep, we're tackling all kinds of disease indications where the unmet need is very high. 9 treatments, 9 medicines in Phase III development today for 11 disease indications, and this pipeline grew substantially this year. And this week, today -- this week, we announced for the first time our ninth drug to enter the pipeline, a medicine from our wholly owned neurology franchise, Zilganersen for Alexander disease, and you're going to hear about this program later today from the team. We have programs for very large disease indications like pelacarsen for LP(a)-driven cardiovascular disease, olezarsen, and eplontersen and also for severe rare disease indications, such as for FCS, HAE, IgA nephropathy, ATTRv-polyneuropathy, and more. Diverse in the diseases we're tackling. But one thing that these diseases -- that these medicines have in common throughout is that they're positioned to tackle diseases where the unmet medical need is substantial. That the unmet need is great, patients are waiting, there's very few treatment options available. And for most of these, we're in a position to be first to patients, first to market. It's truly a remarkable Phase III pipeline, and a pipeline that we expect to continue to grow. Every year around this time, we sit down -- the team -- the leadership team sit down and asks the question, okay, next year is coming. What are we going to do to drive value? Drive value for our patients, drive value for our shareholders. What are our key strategic objectives going to be for the upcoming year? We did that last year. And the objectives we set for 2023 were particularly aggressive, particularly challenging, and I'm happy to report, very pleased to report and proud to report that we're well on our way to achieving everything we set out to achieve and to deliver everything we said we were going to deliver for Ionis in the beginning of the year. We've had many positive clinical data events readouts this year with positive full data set for our Phase III program for eplontersen, for ATTRv-polyneuropathy. And just last week, we reported highly positive Phase III data for olezarsen in FCS and more. Several important enrollment achievements, really important enrollment achievements. Completion of the Phase III enrollment for -- enrollment of their Phase III OASIS study for donidalorsen and HAE. And then completion of enrollment for eplontersen, our Phase III study CARDIO-TTRansform, again, a landmark for TTR cardiomyopathy, more than 1,400 patients. And we will -- as I mentioned earlier, we also initiated and expanded our Phase III pipeline, initiated a new Phase III studies. Zilganersen, as I mentioned, but also our HBV program in our IgA nephropathy program. And we've had several really important regulatory actions that, again, progressing us forward that we set out to achieve this year, including the approval of QALSODY for SOD1-ALS, a treatment that was conceived and discovered at Ionis. A real breakthrough, not just for SOD1-ALS patients, but a real breakthrough for the ALS community. Eplontersen's acceptance, filing acceptance in the United States by the FDA, and also now in Health Canada and other regulatory achievements as well, including orphan drug -- a couple of orphan drug designation and outcomes. And we're not finished. We have a lot more to do by the end of this year and a lot that we're looking forward to through next year. An incredible agenda ahead of us, set up with really strategic milestones that we're looking forward to achieve such as more Phase II mid-stage pipeline of clinical readouts that we're very much looking forward to, including 3 treatments, 3 programs that, if positive, have the potential to go to Phase III development to further expand our Phase III pipeline. Phase II studies that can go to Phase III, including our drug, FB-LRx for geographic atrophy, ION582 for Angelman syndrome, and ION541 and for sporadic ALS. Important Phase III clinical data events, including olezarsen, the full data set for olezarsen for FCS and the Phase III results for donidalorsen in hereditary angioedema in the first half of next year. Several important regulatory actions coming up, including by the end of this year, the expected decision on the approvability of eplontersen for ATTRv-polyneuropathy. Discussions with regulators are going very smoothly, and we're very much looking forward to that. And next year, the potential approval of olezarsen for FCS in the second half of the year, assuming priority review and much more. And then, of course, our new product launches. Assuming approval for eplontersen in ATTRv-polyneuropathy, we're going to launch. We're ready to go and ready to launch just a few weeks after approval. Olezarsen for FCS, if approved next year through priority review in the second half of the year. And the potential for QALSODY to launch in additional markets for SOD1-ALS outside of the U.S. So it really is -- we really are set up for a really exciting list of milestones that are coming up for Ionis that we believe is going to drive substantial value for everybody. So let me leave you with these 4 take-home messages before handing it over to the next speaker, which there are 4 take-homes here. The first is that Ionis has prioritized our wholly owned -- and established our wholly owned pipeline, and we expect this pipeline to expand well into the future. It's a top priority. We are -- we have everything in place today that needs to be in place at this stage to launch our own medicines, to deliver our own treatments to patients directly. Thirdly, the investments we've made over the last few years to expand and diversify our technological capabilities to extend -- substantially extend our leadership position in oligonucleotide therapeutics is on track, and we're leading the way. And finally, we have a financial position that's strong, enabling us to make all the investments we need to make to be successful. So now before handing it over to the next speaker, I'd like to tell you a brief story. And I promise to be brief. I don't know, 2018, 2019 or so, I was approaching my new role at Ionis as CEO. Thinking about all the strategic imperatives I just took you through. What are the key objectives to drive value for the company. And it was obvious, sure it was obvious to all of you. We needed somebody -- I needed somebody, to build a commercial organization, to set strategy, to execute on that strategy, somebody with a lot of experience in this -- doing this successfully. And I pursued Onaiza Cadoret. I knew Onaiza from the past, from years past. We knew each other, we interacted on several occasions. And I pursued her and I asked her, can you do this? You're a perfect fit. And Onaiza was not surprisingly very excited to do that. And she would often cite like what a great platform, what a great technology, what a pipeline. I mean, who wouldn't want to bring medicines like this to patients to commercialize a pipeline like this. And what great people at Ionis. They're smart, they're dedicated, they persevere. Of course, this is exciting. But over the period of months, she would often ask me the same question at the end of our meetings, the same 4 questions actually, which were, are you really going to do this? Is the Board behind it? Are the employees behind it and are you behind it? And every single time I concluded the meeting with simple answers. Yes. Yes. Yes. And most of all, yes. All right. So there I was, 2020 -- January 15, 2020, I was in San Francisco at the JPMorgan Healthcare Conference. I see Jess here, Jess introduced me, representing Ionis for the first time as CEO. And presenting on the corporate update, corporate overview, what my vision was for Ionis. And folks I laid out the same thing I just said to you -- I just reviewed for you today, our key strategic goals and imperatives. I said it at that time. You can look it up. We're going to invest and extend our leadership position in technology, and we're going to build our commercial capabilities and deliver our treatments directly to patients, bring our medicines directly to patients. And there was Onaiza in the front row. And when I was -- when I stepped down and finished, she came up to me and she says, okay, you're on the record now. So let's do this. I'm all in and sign me up, I couldn't be more excited about it. So Onaiza was my first hire as CEO, and she's been working on this ever since she started in January 2020. And here she is, Onaiza Cadoret.

Thank you, Brett. That was fantastic introduction. And most of it is actually really accurate. Great to see all of you. I'll add a little bit that's a little different than what he said, but I definitely interrogated Brett, quite a deal on the strategy for the company. It's a transformational vision, right, and very different than where the company had been in the last 30 years. So his commitment was just relentless. And I have to say, since I've been here, for the last 3.5 years, his commitment is steadfast. And there is one thing I know about Brett. When he commits to getting something done, he gets it done. So a bit more around the commitment. First of all, it's been a great collaboration with the people at Ionis. They are ready. They want to do this. They've been really great partners. And there is change that comes along with the commitment. And I have been very pleased with the level of change we're making. The one thing that did surprise me from the story that Brett said was the pace. He's a pace setter. The pace at which we have gone has been incredible. I really didn't think we'd be here in 3.5 years in this measured manner, to be launch ready for this organization for 3 programs, 5 indications in the next 3 years. It's pretty remarkable. And I have to say, we have a great team in place to be able to deliver on this transformational vision that has been set out. So I have been on a journey. I've been in Life Sciences for about 30 years. And I actually started off my career right here across the street, at Pfizer about 25 years ago, where within the prime, I would say, of bringing small molecules as a modality into the marketplace. Conquering kind of cardiovascular and CNS diseases. But I've had the privilege to work across very many modalities. So it was really only fitting that I went over to peptides next, and I was at Amylin, where we discovered GLP-1. And as we know now, GLP-1 is right square in the heyday of where it is right now. And actually, I'm one with the first to bring a GLP-1 to market, which is Byetta for diabetes. And then I had the fortune of actually going to the birthplace of biotechnology. I worked for Genentech for many years, and that was prosecuting monoclonal antibodies to get to undruggable targets, right? Proteins, very, very different. So it's really only fitting that I am just here at Ionis, which is kind of the next modality that's just on the cusp of entering its prime. Just on the cusp, right? The RNA platform is really prosecuting rare diseases, as Brett just went through diseases that are intractable, have not had the opportunity to have even a single treatment for these patients. And then we're also in our prime and on the cusp of getting to large, broad prevalent diseases where the standard of care just isn't sufficient enough for patients anymore. So we're really at the cusp of entering this wonderful new modality and in a new era as well. It's exciting. So the first thing we did when we came in was said, okay, well, we want to go commercial, great vision, what's our strategy and how do we actually take this pipeline that we have that's coming forward, and really focus on the things that are really going to make a difference where Ionis can be very successful in terms of reaching all the patients in these indications that really deserve it in that disease area. So as a result, we came in and looked at the late-stage portfolio, and we said, "Wow, these actually look very exciting." Here are the things that we think we can do really well, and we chose cardiovascular and neurology as our 2 areas of focus. I would say they are 2 pillars. They are 2 pillars here. And we did that with also thoughtfulness as to not what was available just in the late-stage portfolio, but also what's coming behind it. So we did a really big review of the portfolio strategy we prioritized to the things that we were going to bring to commercialization as Ionis on our own, and really thought about the cadence within which this would come, so we could actually build our commercial capabilities alongside of that and really deliver and execute well. So through that,exercise. We took that to the Board, got it approved, and we started building. And I'm pleased to say, and you'll see some of the core capabilities that we've established are really thinking about how we're going to be innovative in our approach, do the rightsizing of our capabilities that are gated to good, as we call it, asset stage milestones, and then really have the ability to scale as we need. And as a result of that plan, well, I can't do it by myself. So I have a team. And we have been able to really recruit a lot of exceptional and experienced talent. Much of which I'm going to actually go through today with you is the work of really a great team in Carlsbad and actually in our Boston office as well. I have a couple of members here I would like to introduce you to as well. First of all, Rachel Carnes. Rachel has been the Head of Global Product Strategy for about a year now. She came from Celgene and has really launched a really fantastic products in oncology over there, ABRAXANE, being one of our major accolades. But Rachel is going to be responsible and has been responsible for our early and mid-stage portfolio. So she's thinking about the next wave of medicines that will be coming, and you'll hear from her a little bit later. About I guess 48 hours into the role, we have our new Chief Commercial Officer, Jonathan Birchall. Jonathan has just joined us as well. And Jonathan will be leading our late-stage portfolio, primarily the 3 eplontersen, and a co-co with AstraZeneca, olezarsen and donidalorsen, and preparing those capabilities and markets for launch as well. Jonathan is a classic leader, been in sales and marketing throughout his whole career, started off at Sanofi. So he has a lot of global experience, but spent about another dozen years here at Genentech, and has also launched a really -- a lot of products in rare disease type of -- launches Kadcyla for HER2 breast cancer, and then broad scale types of launches such as Lantus for diabetes as well. So he brings a good core set of capabilities. As you can see, these other leaders who are not here today are functional leaders that have been placed for the last, I would say, 2 years or 1 year, depending on their role. We've got the Head of Medical Affairs, Shay Bujanover; Chris, who heads Market Insights and Portfolio. And then very importantly, what you see in the next row is really the heads of each of the brands. We've got a Vice President of Marketing for olezarsen, one for donidalorsen and eplontersen and for neurology. So everybody is really in place and structured and focused in their therapeutic areas. We also have the functional leaders who are building the capabilities that are necessary. I call it the machinery that's necessary to launch the strategy and the products, and that includes patient services, commercial operations, omnichannel, and obviously U.S. market access and reimbursement for our payer strategy as well. So as I said, there's a really great team in place and really I have the opportunity and the privilege to really present the work -- the great work that they're doing. So this is our launch cadence. This is probably the best recruiting tool I've had to get the top talent in place. There is very often time, I do not -- I've been here 30 years, I don't think I've ever seen a cadence of launches such as that's coming up in such unmet needs, as Brett said. And this is coming -- again, we've got eplontersen followed by olezarsen and followed by donidalorsen. So that's 3 programs, 5 indication launches in the next 3 years. And that's exciting. It's exciting because we get a pipeline that's as large as what you get in big pharma, but we get it in a small, nimble, agile company such as Ionis. So you can actually create the right blueprint of what you need to get done to launch these products well. Very exciting times. We'll talk about each one of these as we get through the day. So hold on to that. And let me tell you a little bit about our innovative model to bring these products to market and to our customers. So you know what, great thing is we've got a lot of talent. They've come from large pharma. They've come from small biotech. They've done rare diseases. They did it in broad scale launches. And one of the great things about this team is, we all look back in our careers and say, if I could, I wish I would have. And guess what, over here, you get to do that. And we are building the blueprint from all the learnings that we've had through so many different launches we've been through to make sure that not only are we capturing those learnings and making sure that we're doing this differently this time around, but also we're looking to the future. And the future looks different in our marketplace, particularly since COVID and really thinking about how we're going to deliver this wonderful set of products through an excellent customer experience along the way. At the center of it all is really focusing on the people living with the disease. We must. But we also know in order to get to the patient, we actually have to really delight a lot of different care providers and treatment influencers along the way. We know that our health care providers are really kind of centric to be able to get the right decision made and also given the right care along the way. We do work in genetic diseases. So our influencers are really broader than, I would say, most others. As rare diseases, we hit treatment centers of excellence, we need to work with geneticists, and then our market influencers are obviously wide from payers also to advocacy groups as well. What you see here to the right, our table stakes. These are table stakes in terms of everything we need to get done to be able to be ready to launch. Every company does that. Okay? If you don't do that, you're not going to make it. To the left is what we're doing in addition to table stakes. This is really thinking about how we're going to use innovative techniques to create that delightful customer experience along the journey so our patients really get the product. We're doing a lot on data. We're really looking at data and optimizing the insights that we can get from them and integrating very different data sources. Data is great, and it's all available. But how you integrate it and how you get the insight is really important. So that includes your traditional claims data, but also looks at integrating EMR data. It also looks at looking at lab data. And this gives us insights into rare disease, particularly where these patients are because there's a lot of patient finding that goes into it. And also in terms of how do we want to communicate to our customers at the right time, at the right level. And as a result, complementary to that data integration is omnichannel. We're going to be big in digital. We're not going to do it exactly with everybody feet on the street. But omnichannel in a very bright way to be able to, again, reach our customers in these influencers that we have in a very broad manner. We obviously are in rare diseases, so we need a patient hub and patient support services. That is a big heavy cost sometimes. So we're thinking about what biotech does, is keeping some of those case managers, you would say, outside. But then you kind of lose the integration with your internal team. So we've got a novel way to bring everybody in here, get the efficiency that we need but also the integration and the teamwork that it takes to get all of the insights and the products to patients as well. So as you can see, this has been really set up. But the blueprint in mind for ensuring that, although we have these great products, and we can talk about our products all the time in order to make it meaningful to the person living with the disease, we actually really have to delight everybody all along the way from influencers to care providers to get there. So we have 3 near-term commercial medicines. I'm going to talk about the commercial opportunity for each of them. But I'll leave you maybe with some top lines as we go into the day. So for ATTR, we are well poised to be the leader with eplontersen. We have an ambition and a goal to be the leader for both polyneuropathy and cardiomyopathy as we launch this. And we believe that our clinical data, the strength of what we have seen to date, alongside the complementary capabilities that come with both AstraZeneca and Ionis together is really magic. And that's what's going to make it happen. For olezarsen, we've seen unprecedented data last week. It was just about a week ago that we were going through the FCS data. This unprecedented data that we've seen in reduction of acute pancreatitis really gives us a good foothold into the marketplace for our first independent launch, and the team is just chomping at the bit and ready to go. They also have a great line of sight into where they're looking for the next larger scale up launch for severe hypertriglyceridemia. For donidalorsen, we've seen our Phase IIs. We're going to review that again. We have a potential best-in-class profile. We are really on track for getting that data in the first half of 2024. And this is a very attractive market for us, very concentrated set of prescribers and we're, again, very excited to launch for donidalorsen and preparing for our next wave of wholly owned medicines, which Rachel will talk to you about later. So key takeaways from the morning. We've got a great team, they are in place. We are commercial-ready. We have a very unique way to think about bringing our commercialization process into medicines and directly to patients, and this team is prepared for multiple upcoming launches. So I hope that you're feeling as ready and excited as we are. And we'll talk about again each of these medicines as we go forward for the rest of the morning. So I'd like to now invite Sam Tsimikas, he's going to walk you through our eplontersen program. Sam?

Good morning, everybody. Thank you, Onaiza, and thank you for joining us today. Let me just first start out by saying that as a practicing cardiologist who've seen many kinds of cardiovascular disease, I'm very, very proud to be part of the team that's going to patients a drug for a very morbid and deadly disease, which is transthyretin amyloidosis. Transthyretin amyloidosis is also called ATTR and it's caused by a production of transthyretin from the liver. That misfolds, aggregates and causes deposition of the transthyretin in multiple tissues and organs, which is the cause of the disease. Eplontersen is designed to inhibit the production of that protein and treat the root cause of the disease. We have been waiting as cardiologists and also neurologists for a long time to have a way to treat this disorder. And I think we're finally at the cusp of offering these patients some important therapies. Now there are 2 versions of this disease, there's a hereditary version and there's a wild-type version. The major manifestations of polyneuropathy and cardiomyopathy. And this is why we are targeting those 2 indications with eplontersen. So I'm going to review for you in the next 15 minutes our polyneuropathy program and our cardiomyopathy program. And I hope at the end of my 15 minutes that you feel as excited as we are for what a great advances should be for our patients. Now if you look at the slide on the right side, let me give you a sense of what these patients feel and function like. So if you look at the bottom, they have peripheral neuropathy, and that's manifested in motor, sensory and autonomic dysfunction. So what does that mean? That means they have numbness, tingling and pain in their legs and they develop imbalance. So they initially need to have a cane or a walker, and eventually end up in a wheelchair, okay? The next manifestation that's major is cardiovascular manifestation. What is this? The transthyretin accumulates between the muscle fibers of the heart, and the heart actually enlarges, gets very thick and gets very boggy. This creates arrhythmias, it creates heart failure, and it creates -- ultimately, it leads to death. In the past and even until recently, the treatment for this has been liver and lung transplantation as the only viable approach. And obviously, we're going to have -- we're going to be able to overcome that and provide better therapies. Now the other part of this is that, in my practice in interventional cardiology, I performed many biopsies. Cardiac biopsies in these patients to diagnose them with cardiomyopathy. Luckily, we no longer have to do that. We have noninvasive ways to detect amyloidosis in the heart. And with noninvasive testing, and that has allowed us to diagnose these patients much, much earlier versus when they come in and experience heart failure in the hospital. So this is why you can see here that the prevalence of this disease is going up very rapidly because we actually can find the patients way before they're at the very end stage of the disease. The other part of this disease is very important to understand, that these patients develop cachexia. This is the same kind of cachexia that you see in patients that are undergoing chemotherapy. And why is that? Because there are GI manifestations of the disease. It affects both the parasympathetic and sympathetic nervous system, and these patients get alternating bowels of constipation and diarrhea, and eventually can't eat. They start losing weight. And they start losing weight, and ultimately succumb from that as their kind of end stage manifestation of this disease. So I'm going to show you how we're going to be able to treat all these cardio -- all these manifestations that you see here. Now, if you look at the middle of the slide, you see the prevalence is about 500,000 patients, okay? And that seems to be growing as we're able to diagnose these patients. As I mentioned, there are 2 versions of the disease. So it's important to understand this. So the major version is the wild-type TTR. The transthyretin here has no mutations on it, but it misfolds, and it occurs mostly in older patients, and their main manifestation is cardiovascular. The other version of the disease when there are multiple mutations in the transthyretin gene or protein gene and ultimately, the protein that then misfolds, those patients tend to have neuropathy. And you see on the bottom there, that about 40,000 patients estimated to have neuropathy, but these patients can also have cardiac involvement. So we call that a mixed phenotype. So what you -- so the bottom line is, there's a lot of patients with the wild-type TTR, and there's other patients with hereditary or variant TTR. Our drug does not discriminate against each one of those. It treats the same problem in those patients. Therefore, we can use it for both indications. Now we have a very robust development program to address these 2 major clinical manifestations. The first program on the top right is our NEURO-TTRansform study. This is for ATTR hereditary version of the polyneuropathy. I'm very pleased to tell you, and you probably have seen this already in the last week. We published the main findings from this study in the Journal of the American Medical Association. So you can look at that and see all the details from that. It met its 3 co-primary endpoints, and 4 of its secondary endpoints, highly consistent and highly statistically significant results. As you know, the ND has been accepted. We look forward to having approval in a couple of months and bringing this drug to patients very soon after that. The second indication is ATTR cardiomyopathy, which is a much larger indication. We think we have the best study design in the field, and I'll go over that in more detail. It's going to allow us to get very rich data set to analyze all the different varieties of amyloidosis that the patients are coming in with. That study has fully enrolled as of July, and it can read out as early as the first half of 2023. Now along with this, we have several other profile enhancing studies and life cycle management studies. We have open label extensions for both, and we have imaging studies that we'll review for you in a bit of detail. And then we have plans for additional life cycle management studies going forward. So let me now review for you our polyneuropathy program and show you a summary of the data that we just published. This study is called NEURO-TTRansform, and this has the hereditary version of TTR, and it's polyneuropathy is the main manifestation, okay? Now it's unethical or felt to be unethical to do a placebo trial because these patients have such a poor prognosis. And so the design is a little bit unusual from the perspective of what you typically see with placebo-controlled trials. So what you see here is 144 patients were treated with 45 milligrams of eplontersen monthly. The control group is from Neuro-TTR, which is a prior study, and this is a historical control that you see has 60 patients. So that's going to be a comparator group. There's another group in between there, inotersen, 24 patients, that the regulators have a contemporary cohort treated with inotersen. This is to basically just have some qualitative data. This is not going to be into any of our analysis that I'm going to show you. These patients were treated for 35 weeks and then switched over to eplontersen after that. Now the study design has had an interim analysis at week 35. The full analysis was at week 66, but you also had a prespecified end of treatment analysis that you see there at week 85. There are 3 co-primary endpoints, and I'll go over those for you on the next slide with a little more detail. So the first co-primary endpoint is TTR concentration. Why do we want to know that? Because this directly tells us how the drug is working, okay? And we're going to look at this as a percentage from baseline. And I just want to make a point here that we measure the levels right before the next dose. So this is a conservative measure of the actual effect of the drug. The other 2 co-primary endpoints are based on evidence of nerve fiber involvement and then how the patient feels and functions. So the first one of those is called the Neuropathy Impairment Score or mNIS+7, and this measures objectively how much TTR is getting accumulated into the nerves. And you can do that in the motor neurons, the sensory neurons and the autonomic neurons, and you can see some of the tests on the right how that is done, okay? So this is an objective measure of TTR accumulation. So we're going to measure that and see if it gets better. The other part of this is the Norfolk Quality of Life questionnaire. This allows us -- the patients to tell us how they're feeling and how they're functioning. All of these are highly validated for this field, and so they are widely accepted as proper end points. These are the baseline characteristics. A lot of stuff here. Bottom line is there were some minor differences in the groups, but essentially very well balanced. I just want to point out a couple of things because this is a hereditary version of the disease, the patients are showing up about 20 years earlier than the cardiomyopathy patients. So notice here, their age is in the mid [indiscernible] okay? So they're starting from birth with this disease, and it's finally accumulating when they're 50 years old and causing them symptoms. On the bottom, you'll notice here that about 70%, 60%, 70% were actually previously treated with stabilizers. And on the right side, you can see the stages of the disease, and there's one particular version of the disease called the V30M that was predominant in these patients. On the bottom right, you see the actual scores of the mNIS +7 and Norfolk, the higher the number, the worst the patient is doing. But keep that in mind when I show you the data as the percent change from baseline. So this is the first co-primary end point, we're looking at the mean percent change in the TTR level in the plasma, in the historical placebo group in orange, and then in the purple color are eplontersen data. Notice a couple of things. Placebo group data is declining. And this is not a fluke of variability. This is a sign that the patient is actually getting worse because they're getting more cachexia. On the eplontersen arm, what you see here is that there's a massive decline or rapid decline, I should say, in the TTR level that actually goes down by about 3 -- sorry, by about 13 weeks. And then the level is sustained and stays all the way down to week 85. Notice that the air bars are very small here, which means that there's very little variability between doses of the level. And so this is a very robust finding that should now translate to other clinically relevant measurements. And what are those? So mNIS+7. So remember, I said, if the level -- the number goes up, the patients are doing worse. So in this case, this is a neuropathy score. So this is the objective measurement. That means there's more accumulation of TTR in the nerve fibers. Now look at this interesting part of this disease. Every single week, the curve, the orange curve and the placebo is going up. That means that relative that these patients are watching them degrade week by week by week. So by that 35-week time, when we measure, you see already a rapid progression of these patients in their neuropathy score. And then the curve, even the slope of that curve grows up even faster from 35 to 66 weeks. So in 1 year, you're seeing a rapid accumulation or more TTR on the nerve fibers that's manifested in the test that we're doing. Now on the bottom, you see here, we completely halted the disease from using eplontersen. There's absolutely no change. In fact, by week 85, you see here that the actual levels are declining -- the numbers are declining, means that the patient's nerve test actually is improving. And so we don't have data beyond this, but presumably, as we're going to treat these patients for a lifetime, these curves should continue to separate. Now the quality of life data looks even better. As you see here that not only do we have a halting of progression, but from quality of life, the data is actually improving. The patients are feeling better before their objective findings on the neuropathy scores are changing. This is a great sign that tells us that not only these are all aligned, but the patient is actually telling us they're feeling better than their scores are. So a large number of patients that you see on the top left actually had a significant improvement. Importantly, for both mNIS+7, and this score, all of the subgroups that were prespecified and all of the domains of the Norfolk and the mNIS+7 went in the same direction. So very robust findings. Now, one important aspect of the disease I mentioned is cachexia. I want to make 1 point here, on the top right is a secondary endpoint. The modified BMI score. BMI is a combination of height and weight. The modification here is that we add albumin to this measurement. And so if your body stops making albumin, that means you're nutritionally deficient. So you're losing weight and your liver stops making proteins. So that number becomes negative. And you see here on the purple curve, completely flat. That means that nutritional status of the patient is maintained when it entered into the study. Okay. What about safety and tolerability? Bottom line is there were no serious adverse events in this study. There was no imbalance of ocular events. I know there's been some talk about this. Let me explain this real briefly. One, we did the placebo group, the patients have to -- the physicians and the patients have to be blinded on their vitamin A levels, right? Otherwise, we wouldn't know who was on the drug and who wasn't. So there was no way for the patients or the physicians, I should say, to check a box that says the vitamin A level is low. However, in the current study, we did not blind the study, right? So they could get a report that says vitamin A level is low. Now, everytime you inhibit transthyretin, the vitamin A level is going to go down because that's disfunction. We supplement vitamin A in these patients as a way to mitigate that. So what this basically was, was there was a check box for the vitamin A that basically said there was an ocular event, but it wasn't a clinical event. It was just a lab test. If you take that lab test out of the equation here, you see that the events are fairly balanced. There was also no other imbalances of any other things that we worry about that you see here that are listed on this slide. There were 3 deaths. These were all related to disease progression and not related to drug. So what is the bottom line here? The bottom line, I think, is that we have a very potent therapy to reduce TTR levels. We have objective evidence of nerve function improvement, and we have quality of life that goes along with that. We have a favorable safety and tolerability profile, and we are now ready to have approval for this drug and launch it as we go forward. Okay. Now let me transition over very briefly to cardiomyopathy. I'm not going to have any data to show you, but I'm going to show you the trial design, and explain to you why we think this is a fantastic design. Now we're going to be able to take our neuropathy data and have it read through into our cardiomyopathy. And why is that? Because we're using the exact same dose. So we're going to know about how much TTR reduction we're going to get, okay? Also, we have the safety and tolerability data that we can read through into what we're going to see in the cardiomyopathy program. So we expect the drug to be safe and tolerable and to have a fantastic TTR reduction. So this is the design of this study. It's about twice as large as other studies that have been done in this field. It's global. It's randomized. It's going to have 45 milligrams of eplontersen versus placebo. It can go as long as 140 weeks, but we have the optionality to bring that back based on various criteria. It has hard endpoints, cardiovascular death and cardiovascular events. It's going to have a lot of patients on tafamidis, a lot of patients off tafamidis, and we're going to have the largest number of hereditary patients with cardiac involvement in this study. So we expect to be able to have a positive trial at the end and have a very rich database to be able to analyze all of these other things that are important to you, and to the patients, and to the physicians to show that the drug works in various clinical scenarios. Now built into this study, we have 2 sub-studies that are going to tell us how well the drug is working in the heart itself above and beyond the clinical outcomes, okay? We have an MRI sub-study, that's 128 patients. We have serial imaging. Why do we use MRI? MRI can pick up the fluid between the TTR fibrils. Think of the heart as a swollen ankle, right? The MRI will image that and fluid. As you remove the TTR, the fluid is going to decrease. We can image that and tell us, we're actually having a removal of the TTR from the myocardium. So this is going to tell us how well we deplete the TTR because that's what we expect to have the benefit from this drug ultimately. We also have a complementary study using nuclear scintigraphy, and that does the very same thing. The nuclear isotope called pyrophosphate accumulates in the myocardium and binds for the fibrils. So when we image that, we can tell how much TTR is there. So let me show you some very exciting data using this technique that just got published in Europe, or presented at the European Society of Cardiology. This is 6 patients from the NEURO-TTRansform study. Remember, this is open label, so we know these patients are on eplontersen. This is an investigator-initiated study. We had nothing to do with it. The investigators did it themselves. Notice here that when you have a high score on the left, there's a lot of accumulation in the heart relative to the lung, okay? And an average of 144 days, notice here that there's a significant reduction in the accumulation of the pyrophosphate label in the myocardium. So what this tells us is that we're already depleting the amyloid using this imaging technique, and we can demonstrate it in only 6 patients. We're going to have 150 patients in our cohort, and we're going to have 1438 patients in our study. So this makes us feel very good that the drug is already working, and we can have an idea how it's going to be working. So to summarize then, we have a fantastic drug. We have 2 programs that address the most relevant parts of this disease. And we are ready to go forward with a fantastic program to get these drugs to our patients that need them. So thank you. I'm going to hand now the podium back to Onaiza, who's going to tell us how we're going to achieve that last part.

All right. Thanks, Sam. Happy to. So it's great to have actually Sam onboard. His depth of clinical acumen that he brings as a cardiologist is fantastic for our programs. The other thing to know about Sam is he's actually still a practicing physician at UCSD. And with that, I think he brings in a very real-world perspective of what is the type of data that will be really compelling that physicians need, as well as what patients really need to be able to treat them really fully. So it's fantastic to have him lead our eplontersen development program. So we are ready to bring eplontersen to patients. We're a short, I would say, less than 3 months away from a PDUFA for polyneuropathy on December 22. And we are entering this market with a growth mindset. Growth because as you will see, and Sam went through it, the prevalence is high, both in polyneuropathy, mixed phenotype and cardiomyopathy. But not all of these patients have been found, and not all of these patients have been treated. So we have a lot of headroom over here. As Sam also explained to you, this is a systemic disease. That means it manifests in different parts of your body. That means the pain is going to show up differently, and our patients are going to present in a variety of different physician settings. They're going to show up at the neurologists, the cardiologists, the GI, the hand surgeon, carpal tunnel. And that means, we have to use some of the techniques I described just earlier about really integrated data and insights to know what these patients are, where they may show up next, and where they may be stuck in the system and misdiagnosed as well. With the excellent data that we have in polyneuropathy, really great on all 3 co-primary endpoints, TTR neuropathy impairment and quality of life, we believe eplontersen will be the preferred treatment in this space. We are confident that the global partnership we have with AstraZeneca is really the right thing to do here. It complements Ionis in a very meaningful way. We know ATTR. We've been in this market for more than a decade. We know the investigators. We know the KOLs. We know where the treatment patterns are going. We are also very adept at rare disease. And as this sits in AstraZeneca's global cardiovascular business unit for the commercialization, we believe that both of those items are really necessary to really fully, fully realize the potential of eplontersen and treating this disease. So I'll point you to 1 number here, which is the 20%. Currently, less than 20% of ATTR patients are treated. So we've got, as I said, a lot of work to do. Our goal is to become the preferred choice for patients for new to silencer treatment. And as a result of the clinical profile that Sam just shared and our self-administered auto-injector profile, we will be the preferred choice in this marketplace. Let's deeply take a look at the clinical profile. What are the things that we're actually testing in the market right now, we're still preparing and waiting for our label and the discussions going on, that's really resonating well with the physician community. First of all, our targeted knockdown of TTR. The knockdown with very consistent and tight sustained suppression on a month-to-month basis. If you remember, the curve was like this and just flat. As Sam said, this is a disease when you looked at the placebo line, it gets worse. Patients are progressively getting worse. So the ability to halt the progression of the disease, as many of our KOLs when they saw the data was very exciting. It's like, we really didn't think that could actually materialize, you've halted the progression for these patients. And then, with our Norfolk Quality of Life, we actually saw improvement. We saw improvement in a substantial number of patients on their quality of life measured through Norfolk QoL. And we've seen that sustained over 85 weeks as well. So the duration of the data is really strong. In cardiomyopathy, again, largest clinical trial in cardiomyopathy. Many of our KOLs are calling it a potential landmark trial over here. Why is that important? Well, there are 300,000 to 500,000 estimated hereditary and wild-type cardiomyopathy patients, right? If you think about it, they range in a variety of different ways. It's heterogeneous. They're not all going to be the same. And we will have the clinical data to be able to bring to physicians how best to treat these patients, be it that they're mild in their severity, to be it in they're severe in their severity, you need how Class 1, 2 and 3. It's going to be really important to have some subcuts of population data. Second, I would say, what does it mean to treat a hereditary patient versus a wild type? And what types of things can I expect in their treatment journey. And very importantly, in the United States, particularly, how do you see a benefit of cardiovascular risk reduction benefit on top of tafamidis, which is a lot of stabilizers you use here? And what can I expect to see for patients who are naive to any treatment? This is going to be very compelling. This, alongside our significant commercial reach, the global partnership, the patient support these rare disease patients need, and being a very high-touch organization in their journey, along with our administration profile really sets us up for success. So we're ready to execute. We have everything in place, both the Ionis team and AstraZeneca team is ready to go, and we have a shared strategy to bring eplontersen to patients around the globe. We're filing in the -- we filed in the U.S., but we're also filing in Europe and Canada and other global markets with AstraZeneca scale. We're actually going to be first in filing in regions such as China as well as Japan. And really get into this very large $10 billion market opportunity worldwide. We have a 1 customer team approach that's designed to drive some rapid adoption and broad uptake. Many of the teams that you see here are complementary between the 2 teams. Our field medical team has been in market for the last 2 years, really creating the disease awareness and the signs and symptoms that one should see around the manifestation of polyneuropathy for example, that can be very new to different types of physicians. Our patient education manager team is hired and trained. This is what Ionis is actually leading, and they're going to be very complementary to the sales team that AC has already hired and trained. And as of last week, they were actually in field and talking about, again, the disease and signs and symptoms. So this team is ready to go. We're waiting on our last few weeks from a label discussion and getting things prepared in advance at risk for what these materials are going to look like in anticipation of the label. We launched recently, I think, a very compelling disease awareness campaign. As you can see, it talks about seeing the patterns very clever play on ATTR. And it's a showstopper. It was launched at the ESC meeting at the Congress. And it really grabs an attention on the patterns, but really gets you to think about the consequences, the consequences of not accelerating the diagnosis of this disease, and what does that mean if you have a delayed diagnosis or a misdiagnosis for patients. And we are very excited that we have a publication that was just published in JAMA, and that will be available at the time of launch for the sales reps as well to bring to their physicians. Of course, in every rare disease, patient and caregiver support is extremely important. We're assisting the patients through their journey, including genetic testing, our patient education manager team is going to be there post the prescription decision to actually help them all the way through their journey and our self-administration program. We're going to just train the patients, so they're really confident on their first try to do this. Given that this is so different and unique in our profile, we did extensive market research to understand what the needs of the patients and the health care professionals are around the self-administration. As I'll share with you now, 2/3 of the patients indicated that going into an HCP office for their administration is actually difficult in the sense they can't do it on their own. They often need to be accompanied by a caregiver. And given that right now, much of the treatment is in centers of excellence, they're not really close by. So they have a long drive. And this actually adds a lot of financial burden for them. Sometimes they have to come in the night before, stay in a hotel to be able to just see their physician and get in administration. We also talked to HCPs, and about 2/3 of them said that this is actually a negative impact on the lives of people living with ATTR. And why is that? That is because it doesn't get the freedom and the independence really to take care of their own disease. And it does impact their quality of life in a negative way. So we really do believe this is going to be a preferred option for HCPs and for patients, and it's a much more important factor than just infrequency. So what are the next steps to bring eplontersen to this market? Well, first of all, we've got a lot of completes on this slide, which is exciting, right? The NEURO-TTRansform data was presented at AAN. We saw the positive 85 durability of the data. as well as the recent JAMA publications. What we're really waiting for is December 22. And the road to December 22 is our PDUFA and really getting into just finalizing the label and getting into discussions with the FDA on that. Alongside of that, we're preparing regulatory submissions. As I said, EMA, Health Canada and others that AstraZeneca will be leading in global markets. And more importantly, just at the turn of the calendar year, this team is ready to go for the PN launch in the United States as well. And then for Cardio-TTRansform that Sam reviewed with you, waiting for the readout as early as the first half of 2025. So as Brett opened this morning, we have been very inspired by Mark. He has come to our team meeting as the brand teams have been getting ready to really give us a day in the life of a patient with polyneuropathy and how meaningful it has been for him to be in the clinical trials for eplontersen. He's been courageous actually, and been on this journey for many years because it is hereditary. He did see his father die from this. And he was courageous enough to go get a genetic test and really know what was coming in the future. And was really activating himself to find the right clinical trial to get into, so he could get the treatment he needed. And out there right now, he is doing really well on eplontersen, which is great to see. But he's also a real patient advocating others to go out and get their genetic tests done and really be courageous enough to kind of enter into a treatment pattern as well. Very, very inspiring for us. And so I'd like to now invite Brett up to introduce our next speaker. Thanks, Brett.

Thank you, Onaiza. Thank you, Sam. So now we're going to move into the next segment of our morning. The next near-term commercial launch opportunity for Ionis. Our first potential independent launch for Ionis is olezarsen. And the diseases that olezarsen is set to treat, diseases related to severely elevated triglycerides. We're honored to have one of the key opinion leaders in the cardiometabolic space, Dr. Henry Ginsberg from Columbia University, Professor at Columbia University. He's an endocrinologist, a leading physician, a leading investigator who evaluates potential new treatments for diseases related to cardiometabolic diseases, and in particular, diseases related to like lipoprotein abnormalities, lipid -- high lipids and so on. Dr. Ginsberg will cover for us today the unmet medical need in patients suffering with high triglycerides and the changing medical landscape. Following Dr. Ginsberg, Sam Tsimikas will take us through the olezarsen clinical development program. In particular, the top line data that we reported last week for FCS. And then Onaiza will come up again and present to you our strategy to deliver olezarsen to patients in need. So no longer -- no further delay, Dr. Ginsberg.

Good morning. I'm here to present an overview of FCS and SHTG. As you heard, I'm an endocrinologist who became a -- I call myself an ex-endocrinologist, now I'm a lipidologist. But I've been in this field for half a century and have seen many patients with this disorder that I'm going to talk about today. And so severe hypertriglyceridemia and familial chylomicronemia syndrome unmet needs and current treatments. These are my disclosures. Ideal without getting too much into the weeds with things called lipoproteins. And probably some MD PhDs in the program will know as much as I do about this, and there are some with MBAs who don't know very little -- who know very little about lipoproteins. So here's what I tell my patients. Think of tiny little golf balls. They're actually submicroscopic, you need electron microscopy to see them, and we have them circulating in our bloodstream because we move triglyceride fat and cholesterol, a waxy like fatty substance through our bloodstream. Now think of oil and vinegar, those 2 substances would phase out in the blood, which is salt water plus cells and proteins. And so to allow the movement of triglyceride and cholesterol through the bloodstream, Mother Nature gave us lipoproteins with this little droplet of oily substances covered with something called phospholipid, you don't have to remember that. But that's the coating to the golf ball. And then it gets a little more complicated, and I'll get back to that because I have to talk about APOCIII. But on this slide, what you see are the ApoB lipoproteins. So you don't see HDL here, which you all know about at varying degrees. And what you see in the lower left of the screen are the chylomicrons, and they are the largest and lightest and most triglyceride-rich golf balls. They're made as I'll show you in the intestine when you eat fat. And the upper panel shows very low-density lipoproteins to also triglyceride-rich spheres coming out of the liver, the chylomicrons coming out of the intestine. APOCIII is a small protein that is found on chylomicrons, on very low-density lipoproteins, and on the golf balls I didn't show you on the last slide HDL because they don't really play a role in what we're talking about today. And APOCIII plays a key role in determining serum chylomicrons, VLDL and triglyceride levels. And that's because APOCIII inhibits the activity of the most important part of this discussion, which is lipoprotein lipase, an enzyme that we make in our fat cells and in our muscle cells, including heart muscle cells. And that enzyme gets out into the capillary beds, the smallest blood vessels we have, and sits there waiting for a chylomicron or a VLDL to come along to take out their triglyceride. APOCIII also inhibits the uptake of particles that we call triglycerides lipoproteins, and more specifically remnants, and I'll show you what I mean by that in a moment. So it has 2 roles. Both of them not helpful in terms of what your plasma triglyceride levels will be because one is -- one role is to inhibit the enzyme that moves triglyceride out of the bloodstream. The other is inhibiting a process that removes the whole golf ball out of the bloodstream. And this is a schematic of that. And on the right side of the screen, you see a little squiggly tube, and that's your small intestine. You've eaten some fact. And in the intestine fat, the triglyceride is broken down through its components called fatty acids and glycerol, they're taken up by the wall of the intestine, put back together, and what emerges from the intestine is the chylomicron. And these are just balls of triglyceride. It's an oil droplet with that phospholipid coding and some proteins on them. And that chylomicron gets to the bloodstream. And now if you look down at the bottom, it's pretty complex. Essentially, you're in that little capillary bed, and there's lipoprotein lipase, a little golden circle with LPL there. That's the key enzyme. It sticks on to a chylomicron, and it's going to chew up that triglyceride and send out its components, the way the enzymes in the gut did, but now it's not in the guts, it's all over the body, particularly the adipose tissue and muscle beds, and those fatty acids are going to be taken up by those tissues, either stored for energy and adipose tissue are used for energy in skeletal muscle or cardiac muscle. And what emerges from that is something we call the chylomicron remnant, which is taken up by the liver. So it's a 2-step process to move from the intestine to the liver. Get back to the bottom of the slide, surrounding that chylomicron and surrounding the LPL are a number of acronyms. And there's APOCIII, there's APOCII, ANGPTL 3/4/8 apoA5. Some of them are activating lipoprotein lipase. Some of them, like APOCIII, are inhibiting lipoprotein lipase, okay? And that is where all the complexity of the system comes from. But simplify it, if lipase is working, you move from a chylomicron to a chylomicron remnant, which goes into the liver, simple. What happens if you have no lipoprotein lipase, okay? Well, you never get from the chylomicrons to the chylomicron remnants, and they accumulate in the plasma. And as I said, they are the largest of the lipoproteins, but they're still very small, but they accumulate in very large amounts. And you can actually -- in patients that I see who have FCS or SHTG, when they come in with triglycerides that should be -- if you're very healthy, triglyceride-wise, your triglyceride might be 100 milligrams per deciliter. If you're not so healthy for whatever reasons, you might have a triglyceride of 200 milligrams per deciliter. These individuals have triglycerides of 2,000, 3,000, 5,000, 10,000 milligrams per deciliter. And as I draw their blood, it's coming out and looking like cream of tomato soup. And if I just let the tube lie on its side, I get the oil and vinegar effect. But this is like the chylomicrons are phasing out just because they're so light, they float up to the top of the tube or the side of the tube above the blood. So that's what we see clinically. There are other -- many other sequela that we'll talk about, the worst, of course, being pancreatitis. So in the absence of LPL, none of those activators or inhibitors can do anything. On the other hand, we have more than just LPL total loss of function. We have the severe hypertriglyceridemia, and I'll get back to that. But here is a way to look at this as a pyramid of triglyceride levels starting from 150, which experts decided about 25 years ago would be the upper limit of normal. And people from 150 to 500 have a simple hypertriglyceridemia. They're mostly individuals with what we call metabolic syndrome, with diabetes, they have multiple risk factors for cardiovascular disease, which are added to by hypertriglyceridemia. And they are very common in the population I'll show you, probably 20% or 25% of the population falls in that range. Above that, we have those with severe hypertriglyceridemia, 2 flavors, the lesser severe of 500 to 880 milligrams per deciliter, to more severe, greater than 880 milligrams per deciliter, and they smear into the FCS, the familial chylomicronemia syndrome. So if we look across those panels toward the right, you can see the differences. The most common group of hypertriglyceridemia, their major risk is cardiovascular disease. Although some of them are under certain circumstances, can explode their triglycerides up to the thousands and actually get pancreatitis. But as you move higher, then the pancreatitis story becomes more and more prevalent, more and more likely and more and more difficult to prevent all the way to the FCS patients. Along the way, there's -- we're all genetic. Sometimes we're 100% genetic or something like FCS patients. Sometimes we're 50%, 60% to 70% and you can see that, that brings in the environment, alcohol intake raises triglycerides. If you're overweight, your triglycerides will be higher. Diabetes, particularly poorly controlled diabetes your triglycerides will be higher. Dietary-wise, that gets more complicated, but certainly saturated fats and refined sugars both raise triglycerides, and certain medications that I'll get back to briefly. So here's the overview of the prevalence of these disorders, FCS, 1 to 2 per million individuals. I now have in my practice 6 individuals with FCS, okay? That's a lot for 1 physician in the United States because there are a lot of us. In some countries in Europe, small populations and few lipidologists, they may have 20 or 30, but this is a very rare disorder, okay? It's monogenic, associated with efficient LPL activity and complete loss of these patients are homozygous, the loss of function mutations, and you see the genes there. And the most common one leading to FCS would be lipoprotein lipase itself. And then there were those activators of lipase's activity that if they're absent, the lipase won't work. The TG levels, as I said, can go into the 5,000 to 10,000 milligram per deciliter range, but mostly in the 2,000 to 4,000 milligram per deciliter range. Quality of life is very remarkably reduced. Beyond the risk of pancreatitis or the events of pancreatitis that they have, there are debilitating symptoms. There's often abdominal pain that's not quite pancreatitis and it's a little bit poorly characterized. There's -- many of them have a fog associated maybe with thickening of their blood because all those chylomicron are circulating. And clearly, FCS is unmet medical need. There are no approved treatments. They're refractory to any of the treatments that we can use off-label, such as fibrates or omega-3 fatty acids. And the standard of care is to become an aesthetic essentially in your lifestyle. I have a couple of patients who have BMIs of 18, if you know what that means, that's in the low normal to almost abnormal range, that's where they keep themselves. They eat almost no fat. And if you look at labels, like many people do today, take a look at the labels of how many grams of fat are in some of the products you eat. Pick up a little portion of Haagen-Dazs ice cream, and look at how many grams of fat are in there, 15 to 20 grams of fat is hard to reach. And our patients actually need to go lower than that, 5 to 10 grams of fat, excuse me. No oil is good for them. All fat is bad for them. What about SHTG, Well, here, we have a broader population of about 1 million individuals who run triglycerides over that 880, and another 2 million between 500 and 880. And this is a complicated disease. Polygenic, that's the word -- the term we all use today for everything that's wrong with us, 99.9% of the time, polygenic disorder. And it's also lifestyle impacting on polygenic risk. There is a risk for acute potentially fatal pancreatitis as there was in FCS. There's also a risk depending on other factors for ASCVD. This is a double bad disease to have, associated with chronic daily symptoms as it is in FCS and again, depending where they fall on this broader spectrum of TGs and it leads to poor quality of life. And the care of these patients is not as intractable as it is for FCS, but it's very difficult, okay? And they have to work hard at the diet. Fibrates and fish oils may be beneficial, but they may not get to the point where they're totally healthy and their sense of daily living or they're totally outside the risk for pancreatitis. And there were situations, particularly in women, on getting anything that raises estrogen, whether it's oral contraception or whether it's pregnancy itself that can push them way up into the pancreatitis stage of the disease. So this is another way of looking at this. This is from a Danish population of 100,000 individuals. It looks at the distribution of triglycerides. And as I've said, when you get above 500 to probably 880 or above, you're in this polygenic range. Many genes involved, some of the same genes, but they would not have a full loss of function. The environment is much more important. And the HTG, SHTG group can smear over, can move over into the same levels of TG in the same risk of pancreatitis, depending on the polygenes, depending on their lifestyle. And the monogenics are there all the time. So what does olezarsen do in this situation? Well, here's the patient who has no lipoprotein lipase, and this was, to us in the field, I don't know what it was to people at Ionis, but us in the field, this was unexpected. You didn't have lipoprotein lipase, we wouldn't expect knocking down an inhibitor of lipoprotein lipase to have any efficacy at all, and yet it did. And that's because of that second pathway that's affected by CIII, and that's uptake by the liver. It's not been definitively shown in people, but the TGs are falling in people with FCS when they're given olezarsen. There's not much else that could be doing this, except uptake of chylomicrons that have been maybe remodeled somehow in the blood without LPL around and being taken up by the liver. In the SHTG population, olezarsen is going to hit both of the problems. Remember, they have lipase. But it's somewhat reduced for a number of reasons, polygenic reasons, environmental and dietary reasons, and knocking down CIII is going to allow that lipase to work better, knocking down CIII will allow the remnants to get into the liver better. So here it's clear, it's a double benefit in these patients with SHTG. Importantly, when you look at the risk for pancreatitis. Logically, the higher your TG, the greater the risk. And this is another Danish study where they took people in the mid-80s, they have incredible epic kind of medical record system there for everybody. They looked at the TG at 0.0 and followed them for 15 to 20 years. And if -- wherever you started, the higher you started, the greater your chance of having pancreatitis later in your life. Here's a way to look at the more likely group to have pancreatitis so as with SHTG and FCS with ranges of triglyceride of, in this case, 750 up to over 2,000 and greater and greater risk for pancreatitis. These are some of the most important data that I'll show you, and that is here, we see that compared to people who have pancreatitis due to gallstones or alcohol, too much more common causes of pancreatitis. People with pancreatitis due to hypertriglyceridemia, too much worse, the green bars. That's because they're mostly SHTG who also have diabetes and hypertension and cardiovascular disease. But even the FCS patients do worse, not exactly clear why, maybe the people with gallstone pancreatitis have a surgery and that takes care of that problem, and the alcohol pancreatitis stop drinking while they're in the hospital, but those are the data. Also importantly, once a patient has an episode of pancreatitis, their risk of having a second and a third and a fourth is markedly increased. So we've got to keep them from having the first event. So lastly, the unmet need here. I mentioned fibrates and omega-3 fatty acids. They worked to lower TGs between the 2 of them, maybe 30% to 40% in people with not FCS, but all of the types of hypertriglyceridemia. But mostly modest reductions, and you don't get to the point where they can't blow up at in some environmental way and get pancreatitis. The statins, they have a very modest effect on TG levels, and so they really don't play a role in this population. GLP-1 receptor agonist, the rage these days. What happens if you lose 20% of your body weight and your TG was 2,000. While you're losing weight on those drugs, it will probably fall. They haven't shown any of those data for a population like this. They haven't studied people who have SHTG or FCS and obesity, but it's not going to be enough, and not going to normalize that TGs in most cases. So the takeaways, FCS and SHTG, both defined by very high TG levels in the top 1% of the population at most, but they have a genetic and mechanistic differences. FCS, monogenic mutations, homozygous, complete absence of LPL and -- but they do have that clearance in the liver that allows this drug to work. SHTG, polygenic mutations, a bad environment on top of that, reduced LPL activity and reduced TRL clearance by the liver, both can be improved with olezarsen. Both patient populations at high risk of pancreatitis. The current treatment options do not provide adequate benefit certainly for FCS patients and also for many SHTG patients. Thank you.

Dr. Ginsberg. It's really an honor to have Dr. Ginsberg here because he called himself a triglyceride nerd. So after today, you have unanswered questions. Go to Starbucks, get 2 large coffees, and go visit him, and he'd be glad to talk to you for hours about triglycerides. All right. So with that, I'm going to actually review for you our olezarsen data. And so for those of you who have children, you know that you absolutely positively cannot choose favorites. And so I feel the same way about olezarsen and eplontersen. Really in the same realm in my franchise for treating patients with unmet needs. Now as a quick aside, I think a lot of you probably don't know this, but Ionis right now is #3 with having cardiovascular drugs in development in the industry, okay? My goal and my hope is by the end of the decade, we'll be #1. We'll see if we can pull that off, but we're conceiving a lot more children in this area. And so stay tuned because there's going to be a lot of important things coming across as a decade goes on. Now let me just briefly summarize how we think olezarsen work. Dr. Ginsberg very elegantly showed you the mechanisms. And so 2 natural questions you might have. Well, if the problem with FCS is just having too much dietary fat, why don't you just prevent the gut from absorbing it? Or why don't you just give back lipoprotein lipase and deal with it that way? And the answer is, both of those have been tried and failed. So we have to outsmart Mother Nature here. And the way we're going to do that is by inhibiting APOCIII, because APOCIII is a key regulator of the clearance of chylomicrons and other triglyceride-rich lipoproteins. Now I want to emphasize that the mechanism is going to be a little different in FCS and SHTG. In FCS, we're missing lipoprotein lipase. So we're dependent entirely on the clearance of these very large particles. APOCIII, you can think of it as an visibility cloak, okay, going back to Harry Potter. It coats these particles and hide them from the receptors. So they just circulate forever essentially, okay? What we're doing with olezarsen is, we're pulling those APOCIII particles off the surface, and all of a sudden, they're recognized by the receptors and clear. So you don't need to have lipoprotein lipase for FCS to get a benefit. In SHTG, you do have lipoprotein lipase activity, so you can bring both mechanisms into the clearance of these particles. And theoretically, that should be even a more effective approach by doing that. So now, why do we think APOCIII outside of the pathophysiology, do we have evidence that actually -- that will work. And the answer is yes. This is a natural history study that was published in 2008, and really led the way to develop an APOCIII antagonist. So what did Mother Nature do for us here, there are patients in the Pennsylvania Amish community that are missing APOCIII. And so what do they look like? They have very low triglyceride levels and actually have a low rate of cardiovascular disease. So if you look at this slide here, and you look at the dash line, these are noncarriers of a loss of function mutation in APOCIII. So that 50% of the function. Notice their triglyceride level started 60, probably like most of you here, a lot of you here. And now they were given a fat load. So a big milkshake, and then you measure their triglycerides, which is mostly chylomicrons over the next 6 hours. And you see here that the levels peak at about 4 hours, and this starts coming down. If this is an FCS patients, the levels would start at 2,500 and skyrocket to about 5,000. So what happens now if you're missing APOCIII. You noticed the levels now started about 35, okay? And then when they eat the fat, the levels are suppressed. So the delta between those curves increases. This is what we're going to replicate with olezarsen, okay? Except we're going to set a much higher triglycerides levels, because we want to treat patients with disease, not the so-called normal triglyceride levels. So that's going to be the basis for what we think olezarsen is actually going to work in both of these indications. Now let me give you an overview of the programs, and then I'll go over the data. So for FCS, I'm going to go over the Balance study, which is a pivotal trial. And then, I just want to summarize for you that we have a Phase IIb study ongoing, which is an SHTG population that's going to be a supporting safety database study for the NDA submission. So the NDA is going to go in with the Balance, and it's going to go in with this Phase IIb. We're going to have data very soon on the Phase IIb, so stay tuned for that. Everything is on track for appropriate regulatory filings and launch preparations, as you'll hear from Onaiza when she comes up. Our much larger program is SHTG. So the FCS is 1 million to 2 in a million. The SHTG in the U.S. alone is about 3 million to 4 million, okay? So orders of magnitude, more patients. And we have 2 pivotal trials in this indication. We have CORE and CORE2, okay? The regulators expect us to have 2 trials in this indication because it's more common, and it's not outcome based. It's based on triglyceride lowering, which is accepted as a regulatory filing. And therefore, we need to have 2 trials. That's why you see CORE and CORE2. They're in patients with triglycerides over 500, and that both of these are pivotal registration trials, and you see the numbers of patients in each one. They're fairly large, 540 and 390. Now we need to have a supportive database for this. We size those patients, so we have another 1,300 patients in the Essence trial, which is going to be patients with triglycerides over 200. And that -- those 3 trials all form the basis for NDA submission. These trials are going very well. They're recruiting rapidly. The data is expected in about a year from now or early 2025, and we should have an NDA in 2025 based on the findings. Okay. So let me show you the Balance. You -- I suspect a lot of you saw this in the webcast. This is a rare population. These are genetically defined FCS patients. So they had to have a known mutation that we know is associated with lack of lipoprotein lipase activity. It's randomized, double-blind, placebo-controlled. Our initial going-in approach was to have only 1 dose, the 80-milligram dose. But in discussions with regulators, they wanted a lower dose. And this is why you're seeing here 2 doses of 50 and 80-milligram every 4 weeks, along with the placebo group. So this is a 2:1 randomization. The primary outcome is a percent change in fasting triglycerides at 6 months. And we have key secondary endpoints that you see here, which are changes in fasting triglycerides at 12 months, and a reduction of pancreatitis events, and we have a series of other secondary endpoints that are not on this slide. So this is a patient disposition. The patients tolerated this drug fairly well. There were over 90% of patients completed the study. There were 2 voluntary withdrawals and there was 1 patient in the placebo group where the investigator wanted to stop the drug. So essentially, there are only 3 patients that had any significant withdrawal from the study. Now very importantly, and this is an index of how the patients like being on the drug. Every single patient that finished the study went into the open-label extension. So that should tell you both that there's a significant need for this kind of drug and that the patients are liking it and tolerating it and are willing to now go on open-label extension. This is based on characteristics. Again, this is a genetic disorder, so people are born with this problem, right? So they have the issue for a long time. A lot of them have problems in childhood with pancreatitis, teenagers. But in this study, there are adults, we chose adult patients who noticed in their low 40s for their age. A couple of important things on this slide. Notice on the bottom here, the body weight is normal or low, okay? Like a lot of you in the audience, okay? Their BMI is 24. This is very typical of FCS, okay? These patients don't have the typical metabolic parameters that SHTG patients have. So they're genetic disorder. On the top right, notice about 70% have already had a pancreatitis episode, at least 1. Sometimes these patients have 10, 20, 30 episodes. And the mortality, as Dr. Ginsberg mentioned, it can be fairly high. Sometimes it's even higher than acute MI. And so also in this particular study, about 40% of these patients were treated with volanesorsen. And this is at least 1 year prior, not recently treated. So they are pretty much washed out of volanesorsen. So this is a key finding for the target. I noticed there are a couple of things that are very important. We're going to be looking at the mean percent change in APOCIII levels over the time course of the study. Notice in the placebo group, the levels are fairly flat, and then they start to rise at 6 months and 12 months. So this is an index of dietary intake. It's extremely difficult to have 5, 10, 20 grams of fat a day. So when you see the APOCIII levels going up, that tells us the patients are not able to keep their low fat diet, and the APOCIII is accumulating on triglycerides. It's extremely important when you do these studies to do placebo correction, because everything the patient eats goes into the bloodstream. And then if you measure that as a biomarker, you have to know how much input there is, and it's extremely hard to control that in a day-to-day in these patients. If you notice, there's a dose-dependent reduction in APOCIII levels reaching 74% at 6 months, with the 80-milligram dose, and 66% with a 50-milligram dose. That data actually continued to improve over time with a 77% reduction in the 50% and an 81% reduction in the 80-milligram doses. Now these are the key findings from the study. Now this is top line data. We have not closed our database yet. So we're not sharing everything that we can share. We will do that at the next major cardiovascular meeting. A couple of things I want to point out. We had a highly statistically significant reduction in triglycerides that you see the p-value there. We barely missed our triglyceride lowering with the lower dose. We're going to see the reason for that. We'll share that with you later, but apparently had to do with the variability at that specific time point. On the bottom shows the most important and really unprecedented findings for the study. Dr. Ginsberg has been waiting 50 years to see this. And I'm glad to say, Ionis finally delivered to you and your patients a way to inhibit pancreatitis. This is unprecedented. Nobody has ever done this before in the 50 years in the field. And so what you see here, with both doses, we had massive reduction in pancreatitis. We had 11 events in the placebo group in 7 patients. We had 0 events in the 80-milligram dose, and we had 1 event only in the 50-milligram dose despite the fact that you see there, we missed our primary endpoint for the 50-milligram dose. This tells you that over time, when you look at the time average reductions, they're actually very significant. And we'll be able to provide more data for this for you in the future. In terms of safety and tolerability, what you're seeing here is that the GalNAc drugs are safe and tolerable as a class. We're not seeing some of the issues we've seen in the past. Most of these issues are balanced. What's important in this study, which tells us that the drug is working outside of the endpoints, is there was actually an imbalance of treatment-emergent adverse events in the placebo group with higher numbers. And most of these were related to GI side effects. So these patients are feeling ill, they have a lot of GI side effects. So they actually tended to be more in the placebo group. So, sorry, let's just go back a second and make a couple of other points. The rest of the points here in terms of other significant adverse events were fairly low. There was 1 death in the 50-milligram dose. This was unrelated to the study drug. So in summary, I think what you can see is extremely good data on APOCIII. Statistically reduction on triglycerides with the 80-milligram dose that we were going in with. We have a tremendous effect on pancreatitis, and the drug looks like it's going to be very tolerable. So with the supporting data from the other trial, we're on track to complete at the end of this year. We have an expanded access program to capture these patients that are coming off the trial. Our regulatory findings should be on track and launch preparations are now underway. So now I want to invite my tag team partner, Onaiza to come back and tell us how she's going to get this direct to patients. Oh, I'm sorry. I finished too soon. I had a little brain disconnect here. Yes. Let me give you some -- sorry about that. Let me give you some details on the CORE program. I apologize. So I mentioned briefly the data on this. So we have the 2 trials, as I mentioned, complementary. They have very similar trial design, okay, as the Balance study. So we're going to be able to read through some but not completely because it's a different population, as I mentioned. We have a 50-milligram dose. We have an 80-milligram dose. We have a placebo. We have -- the primary endpoint here is going to be triglyceride, lowering it from baseline to 6 months. You do not need hard end points or syndication, at least in the U.S., anything over 500, if you lower triglycerides, that's good enough for a regulatory submission, if your drug is safe. We're going to be able to take these 2 studies and look at them individually and also combine them. Okay? So we've got 930 patients to be able to get great data on a variety of different things. About 25% of these patients are coming with a history of pancreatitis. So we're going to have really, really good power to not just look at triglyceride lowering, but also the pancreatitis effect of these drugs. So these 2 are the pivotal trials. The supportive study is called Essence. This is going to be much larger. It's going to be in patients with triglycerides over 200. It's going to have a very similar design, and you can see here. And this is recruiting extremely fast. We built into it several important imaging studies, including MRI of the liver. And we've shown recently that volanesorsen reduces liver steatosis. And we also have built into a CT angiography study to look at plaque burden. Those are kind of like profile enhancers, they're not part of the main safety parameters that we need for the CORE and CORE2. So the data for this is expected in late 2024, early 2025. And so bottom line, I think, is that we have a great drug. We have beautiful data, particularly on pancreatitis in the Balance study. We have a great program acting for them to take this drug and expand it to a very, very broad population, and we have now preparations for going forward to patients. So thank you very much. Onaiza?

Wonderful. So it's been really a pleasure to hear from Dr. Ginsberg. He taught me a lot and hopefully, you appreciated his teachings of triglyceride biology and the different mechanisms that are at play in both the FCS population and the severe hypertriglyceride population as well. So we are with olozorsen, as you know, as Sam just went through the legal trial program addressing 2 distinct populations, 2 distinct indications. The first one in FCS is really about treating the significant risk these patients have for acute and potentially fatal pancreatitis, and this comes from really them having no and 0 lipoprotein lipase activity as Dr. Ginsberg just went through. We are -- we are going to enter this market with a first-mover advantage. We will be the first to bring a treatment where there hasn't existed a treatment for these FCS patients, so a real honor to be able to do that for many of the patients that have been waiting for many, many years for a treatment option. We are then also have a line of sight into severe hypertriglyceridemia. Here the job is different. We're addressing a very large population of about 3 million patients -- and one of the things I really liked about this is when we went to the indices to studies and discussions with the FDA. They were very clear about, please do the right study here, do the right study for all patients over 500 in SHTG. There was a thought process that we had that we might actually look at 80 and above or other guideline indicators and above. They were like no. These are all severely hypertriglyceridemia patients, do the right study and the biomarker that's really important here is triglyceride reduction. So we have a clear regulatory path. It's important to know. The other thing that's actually very, I think, unique, at least from my experience in different launches in this area is the treatment guidelines already set. Usually, you're looking for the data that comes out that's very robust and you go back to the guideline committees and you have the guidelines updated as a result of that. Here, the risks are known. The risks are known because these patients are at risk for acute pancreatitis and as Dr. Ginsberg said, because of the remnant floating around also for ASCVD and both the ACC guidelines, the endocrine guidelines and other guidelines really reflect this treatment. The only challenge here is that the treatment guidelines are there, but there are no great options for these physicians to get them down to the levels of goal of triglycide reduction that is needed. So this together really represents a fantastic blockbuster opportunity for olezarsen across both of these indications. Starting with SCS, you've heard a lot. It's rare, it's severe, it's debilitating. Let me just spend a couple of moments on the debilitating piece because I think it's really important to get. We heard a lot from both Sam and from Dr. Ginsberg about the physical and the physical symptoms that these patients have, the severe nausea, vomiting and abdominal pain and It is absolutely true. But in addition to that, they really carry a lot of emotional symptoms as well. There's cognition abilities that are really difficult. And you can imagine when you have to be on a strict diet as they have to do each and every day, which is like a handful of maybe fat intake of 5 almonds, 1 to 2 tablespoons of olive oil. It is really hard to have a really normal social life. They can't actually go out and engage and enter restaurants and kind of eat at will. And it really does impact some of their emotional well-being as well impacts their relationships and their ability in terms of productivity and showing up work because they're usually, have some of those physical symptoms that are debilitating as well. So we're very, very honored and excited to bring a treatment option with the results of the balance data, potentially getting that approved in rapid fashion for a patient population that had no effective treatments to date. Our market research that we did with HCPs, patients and payers really leased to a couple of things about olezarsen that's very exciting. First of all, patients don't even need to measure their triglyceride level. They know when their body is in danger. They say my body tells me, and there is very little I can do about it. Patients are a fear for having an AP attack, and they are very, very motivated to take action. Very pleasingly surprising, the payers of this area actually understand the disease, and they know there's nothing there. We tested our target product profile which we expected, which showed significant results in terms of trends in improving acute pancreatitis. But we actually got a hard outcome and a statistically significant outcomes data for them was supposed to be a home run. I'm very excited to know that we don't believe that this is going to be a real problem from an access perspective and payers are going to really recognize the value proposition of our product recently. So FCS patients are at increased risk for acute pancreatitis as we've seen. In fact, 2/3 of FCS patients have experienced an AP event in their lifetime and as a result of having an event, they're 10x more likely to have a recurrent attack. You could imagine if you know that, that you're always living in fear in anxiety that you wind up in that ICU again with another attack. And then the attacks that they do have are 2x more deadly because they're more likely to result in depth versus other acute pancreatitis causes. So what are we doing to get ready? Well, this is a rare disease, 1 million to 2 million patients per million. And we have looked at some of the registries for FCS patients, and they're smaller actually lighter than where we would expect the prevalence to be in the United States. So we're doing a lot of work through that data integration tools that I said to identify FCS patients to figure out where they are in system. And that's been a core activity of our launch readiness plan over here. We also have field medical that had been out in talking to lipidologists, but also endocrinologists and cardiologists to really kind of prepare the market from an understanding of disease and symptoms. And then with the data that we have from the balance, we could actually now start engaging with payers to let them know that this product is coming. Post approval, we'll do all the usual things of sales and marketing execution. Here, given the rare disease nature of this, the access, the distribution, the specialty pharmacy are really key things that we need to just really nail down and we will, and the patient services are going to be really important. So this is that circle of our customer model. We're entering it in. You just saw it for eplontersen. We have a very similar philosophy for the olezarsen team. It's a 1 customer team. One key thing that's different here is that the sales account management team will be the Ionis sales account management team because this will be our first independent launch. And then alongside of that, we have all the additional field-facing, customer-facing resources to create a very delightful customer experience on their journey. Moving to SHTG. This is also a severe disease. It's just much more prevalent and still has a significant unmet need. It is common. As I said, there are about 3 million patients in the United States, and it is severe. These patients are also, as Dr. Ginsberg went through, at risk for fatal pancreatitis. And when I had a conversation with him last evening. He said he goes, "Well, we actually see many more of these in the ICU for acute pancreatitis with SHTG. And that's just because there's so many more, right, absolute number of them as well. This has a high disease burden. These patients -- I often get the question is like it's a silent TGs [ restilent ], right? It's a silent biomarker, like -- are they going to go and do something about this? Well, in fact, it actually is silent has patients who suffer from lots of physical symptoms, abdominal pain and reduced quality of life as well. So this is not going to be a silent as, let's say, LDL was. And these patients are also very underserved. By current treatment options, you're looking at fibrates, niacin and fish oil is really as available. And it's really important to know, and I'm sure -- and Sam highlighted this, but our studies in Core and CORE2 are designed to show the benefit of olezarsen on top of those treatments that are already available to them. So I really do think this is going to be a significant change in the treatment paradigm for severe hypertriglyceridemia. As you can imagine, with 3 million patients, we have to think about how do we target these patients. We're not expecting we're going to get all the 3 million patients on olezarsen, but in order to understand where we're going to go and where we're going to get the adoption, we did some really great work to understand where the highest degree of unmet need is. And as you can see that the higher risk of greater than 880, which is a nice demarcation line in the treatment guidelines is where the higher-risk SHTG patients are -- not to say that the SHTG patients on greater than 500 are not at risk either, they just present differently and some of the risks are different around ASCVD that they carry as well. So we're going to actually robustly target both parts of this population. And what we're not going to focus on is hypertriglyceridemia patients that are in the 150 to 500 patients. That is not where our strategy nor our indication or our clinical trials are designed to. I've mentioned the guidelines a few times. It's really important to see how they put this into the guidelines. For patients, they that demarcation line of 880. And there for high-risk SHTG, they recommend that you do your weight loss and diet -- diabetes, but you initiate treatment with fibroids to reduce triglycerides. And we expect if we have an olezarsen in the market, those are the types of things you will see in the guidelines as well. And then they also have recommendations for patients who are at the 500 to 880 mark. We're -- they're also recommending the weight loss but also statin therapy to reduce CV risk and initiate treatment with omega fatty acids and fibrates as well. So great to know that the guidelines already exist. I think with the advent of the data we have for [ olezarsen ], we expect that this to be really mainstream and updated as a result of our data. So as usual, we do a lot of market research. Here, it's a large market. So we really went deep. We talked to 200 HCPs, 600-plus patients and 20 payers that cover about 100 million-plus life, most of the United States. Payers view the target product profile very favorably, suggesting potential for broad access in more in that high premium kind of cardiovascular prevalent disease range. For the HCPs, they understand the association between TGs and the risk -- the risk of acute pancreatitis and ASCVD. And very many physicians really told us, I get the guidelines, this is great, but I really don't have any effective treatment options here. From a patient perspective, they're motivated. They're motivated take on a new medication, one that really works and is effective for them and they understand the underlying medical need. These patients also live with some of the emotional symptoms that we have. The physical areas are well known. But as a result of an anticipated attack, as a result of an anticipated admission into the hospital they live with increased stress. It impacts their quality of life from a sleep perspective and their ability to work. And these -- in the cloud or some of the words that really came out that keeps them really socially isolated. And because the disease isn't taken as seriously, they feel that they really don't have a good support system around them as well to really help them through this journey. As we're preparing to address this market with SHTG, we can see to the right is the cutoff in the United States for the patients who are greater than 880 milligrams per deciliter. That's about 1 million patients. And then to the left, the 500 to 880 compromise -- comprises of actually 2.5 million patients. Now one of the things I really want to leave you with here is this is not a static demarcation line, and we have a little dotted line around these patients. And the reason is, the way triglycerides are measured is that fasting. And all of our measures when you go into the doctor, you go in fasting and you get your blood drawn. But we know that as soon as we eat during a day, the fasting actually changes because you have post-prandial fluctuations that happen through the date, which accompanies your meals. And these levels change during a day. So you can easily be in that kind of intersection right there of being in the 500 range and all of a sudden, you're up into that 880 range during the day. And once patients are in the higher-risk segment, they are often unable to reduce their TGs and remain a higher-risk patients. So our plan really is to do the education that's needed with the physicians to understand this post-prandial level that is fluctuating as well and really address both segments in parallel for rapid adoption. We also needed to understand who the treaters are because this is actually wide. And instead of going well, we've got lipidologists and cardiologists and endocrinologists, we really wanted to think about the behavioral segmentation here. Like what want to make you actually treat SHTG over here. And the behavioral segmentation comes out like this. We have a very nice portion of physicians who are we call aggressive treaters. And we call them aggressive because they understand the 2 underlying risks of this biology, and they are ready to treat all patients over 500. They will certainly be a priority in our launch focus as well. And then we have the active and the actives are also going to be a priority because they get the TGs, but they're really more on the line. I want to treat the patients who are really high risk at over 880. So we're going to actually focus on both of these segments as we launch. And we always know when we get to launch phases over time, the actives become aggressive, and this changes. But right now, this is how the market is playing out and this will consist of, again, lipidologists, cardiologists and endocrinologists, and we're really looking for cardiologists here that have that preventative mindset. So our launch is designed already. We're launching an FCS first. Here, our goal is to establish Ionis' first commercial presence in the marketplace. We're going to cultivate advocates for olezarsen. And this gives us an opportunity to deploy and optimize our commercial capabilities ahead of the broader SHTG launch. For the launch in SHTG, our priority launch phases that I just went through will be our focus. We're going to leverage existing treatment practices of priority treaters and quickly establish olezarsen as preferred treatment. And then over time, we will extend our physician engagement and really get to more broadly reach more than the patients with SHTG. So Sam went through our balanced data. It is complete. It's exciting unprecedented data as we saw -- and as he also explained where we're just waiting for the completion of the Phase IIb study, which is just to give us the additional patient exposure for the full filing of FCS. We expect the regulatory filing to be very early in 2024, just in the turn of the year. And then with that filing, we also believe we have a very strong potential for priority review here. Huge unmet need, great unprecedented data. And we are planning for that. And that is the way we're planning for a launch expected for FCS at the end of 2024. In parallel, we're waiting for the completion of our severe hypertriglyceridemia program, and the readout is going to be in late 2024 or early 2025. And then we expect that to be an [ SNDA ] and get that ready for an Olezarsen launch in mid to late 2026. I conclude and leave you with a patient, a patient that Bret actually opened with the call in hearing from FCS patients, again here, I think the thing that I am left most with is the kind of social isolation, these patients really live with and same for SHTG, just kind of the emotional cloud. I hope that remains with you in terms of what they really face on a day-to-day basis. With a robust APOCIII reduction, significant triglyceride reductions and substantial reductions in acute pancreatitis in the BALANCE Phase III study we are ready for our FCF filing and launch ready in late in 2024. And then Olezarsen, we expect will be the first of many medicines that you should expect to launch from our wholly owned pipeline. And with that, I'd like to actually invite Wade Walke, kind of Investor Relations up.

A little bit behind schedule. So I'm going to ask everybody if they could come back here and we'll restart again at the bottom of the hour for those that are on the East Coast, that's 10:30. All right, I see in a bit. [Break]

The opinion leaders -- key opinion leader as well as -- in addition to covering the unmet medical need in HAE, Dr. Tachdjian will also review for us the treatment landscape for this disease. And following Dr. Tachdjian will be Ken Newman. Ken Newman leads are kind of on working Phase III of development program for HAE. And then after Tachdjian will be -- we'll bring Onaiza back up to talk about how we plan to deliver on [indiscernible] to patients in need. So Dr. Tachdjian, it's all yours.

Good morning, everyone. Thanks for the opportunity to speak to you on hereditary angioedema. I'll give you a quick comparison with allergic angioedema. So word angioedema, as you know, is swelling. And if you have a allergy. A penicillin allergy or you got stung by a bee that you're sensitized to you have an allergic reaction, and that swelling usually would be taking course over 24 hours whereas with hereditary angioedema, you'll see kind of picture is a little different. So I'll be talking about unpredictable debilitating and potentially life-threatening and in some instances deadly, this condition can be -- these are my disclosures for speaking as well as research on our area. And so we'll dive right in. This is obviously a rare and potentially life-threatening condition. It is genetic, hereditary in it's autosomal dominant. So each patient that is identified as a 50-50 chance of passing that on to their next progeny it's hallmarked by painful, but most importantly, unpredictable attacks of swelling -- like I mentioned at the outset, if you have peanut anaphylaxis. Today, you could say I'm not going to get anything at this hotel, et cetera, and we can predict that you're not going to have a swelling attack. The HAE patient opens their eyes and is not sure if it's going to be a smooth day, or if they're going to miss their daughter's graduation. There's significant others, job promotion party, their birthday. And so with the -- at the cost of this condition is C1 esterase, which is a protein that's either deficient or dysfunctional in these patients, and that drives the majority of HAE . What does that look like? So on the right side of your slide, you'll see attacks that can occur at any part of the body. Obviously, the laryngeal ones can be life-threatening and there have been deaths reported on the way to the emergency room or blamed on something they ate and so on and so forth. The stomach or abdominal attacks can mimic anything under the sun. So these patients typically get appendectomy done, open laparotomy, laparoscopy, et cetera, unnecessary procedures and the rest of the body when it's your hand, your feet, you might think, "Oh, well, suck it up or what if that's your flight attendant, your surgeon or my hair stylist. So as I mentioned, C1 esterase inhibitor is at the center of this condition. And you'll see in the gray bar in the middle of the right diagram, that it's there to block the progress after prekallikrein, which is the zymogen or the precursor of kallikrein, can then facilitate the release of bradykinin from high molecular-weight kininogen. Bradykinin is responsible then for loosening up or opening up the blood vessels on the venous side of the body to then release fluid extravasate that's what causes the swelling, Obviously against a hard surface such as the back of your hand, cheekbone, that swelling will be more prominent than, say, in the intestinal area where you've got a lot of room to expand. What does that look like when I get called to the emergency room. Here's a young lady [indiscernible]. Time she gets to the emergency room, our first concern. She's drooling, meaning she is not able to swallow some simple as her saliva. And what follows there is not being able to pass the airway. And so the airway can be compromised. Fortunately, she's caught in time. Plus or minus intubation, and you could see the resolutions start to happen. Now this patient could look like and allergic angioedema patients to the untrained triage nurses, for instance, in the emergency room. But there's no hives, so no early carry associated with HAE and there's no itching. So there's no pruritus associated with HAE attacks. And so this patient can be given all the antihistamines you want, corticosteroids, even epinephrine does not really help this condition because -- you remember from the diagram I showed you earlier, there's nothing about histamine, IgE, et cetera, that hints to allergic. This is purely an immunologic complement-based condition. As far as [indiscernible] this is a condition that occurs in one in approximately 50,000 patients or individuals across the world. And I've seen pretty much every race and ethnicity represented, remember, it's 50-50 for gender because it's autosomal dominant, it tends to affect women a little more than it does men due to hormonal differences. But when you calculate that sum there should be over 20,000 patients across the U.S. and Europe combined. In the middle panel, you'll see, again, focus back on the basis of this condition. So type 1 patients comprise about 85% of the pool, and those are the folks who have not enough C1 esterase inhibitor. And I call it not enough wheels on your car, so it's not going to run well, 1 wheel is missing. Type 2 looks like it's got 4 wheels, should run like a car, but they're actually triangular wheels, right? So that's not going to be a smooth right. So it's this functional C1 inhibitor. So the number is fine, and this got diagnosed or classified later in the last 30 years. Lastly, extremely rare and less than 1% of this total population, is the HAE with normal C1 inhibitor, which we formally called Type 3. And these patients have genetic mutations and extremely rare, like I said. So the focus is more on type 1 and type 2. Now age of onset, it's great that we can the condition, but are we missing it. So if someone who did pediatrics, this was not on my radar simply because it's only been about 13, 14 years that we've got the novel era of therapeutics. And we were stuck with mainly anabolic androgens in the past and archaic forms of treatment. But 50% of patients will experience their attack -- their first attack under the age of 10. And in that last bullet point, you'll see that there are a good amount of individuals that will have their first attack in infancy in the first year of life. And it could be something as daunting as scrotal swelling or labial swelling that warrants 1 million workup from urology nephrology and so on. Now that's for just detecting someone who may or may not have a family history because remember, it's hereditary. And you may have a patient above you and a patient below you as family members. Now 25% of individuals are de novo mutations. So that means there's no parental or great grand parental history. And so that makes the challenge of diagnosing these patients even greater. And you can see on the right that patients will in a number of years meandering through the system -- the health care system, seeing multiple specialists until they get to the immunologist, who knows what to draw because think about it, if you're in the emergency room, you don't have time to follow through. You just stabilize the patient -- but then we always ask the emergency room physicians to at least refer them for the workup that might take a week or so to come back. What does that work up? Essentially, what I mentioned, the tires on the car, check the C1 esterase inhibitor level, check the function. Oftentimes, we check complement 4, which also gets run down in the immune system. And less commonly, because it's cost prohibitive and access-wise might be difficult to attain. Genetic testing is available. For instance, I have a young female patient who's now in her teens but we diagnose her right of birth using cord blood, matched her mutation to her dads. Her older brother was fine. So the dad that essentially got a 50-50, one child without 1 child with HAE. The problem is for the normal C1 inhibitor. That third portion that I told you, the less than 1%, their labs look essentially the same as most people here who do not have HAE. And so there's no approved diagnostic testing for that category of patients. Now on the attacks hit, the patients in a recent study from the hereditary angioedema association, and this is a big organization, patient organization that is amazing in how it works. And MyClinic is actually the referral center for Southern California for patients that are identified through that venue. So this is a recent study that's just gotten into the publication. You'll see that patients were responding as saying the majority of them have gone to the emergency room, so 87% utilization there. Over 2/3 have been hospitalized. A good amount of folks have been in the ICU with or without intubation and then 16% have had unnecessary and inappropriate abdominal surgery simply when laboratory testing could have been done at that more earlier. And when you look at a quote of a patient saying, "I've been intubated 3 times and the very first time they had to resuscitate me because they had trouble getting the tube down. And I stayed in the ICU for 3 days. I actually have a female patient whose husband is a hunter. And this gentleman practices on a deer every time you -- I'm not a pro hunting guy, don't judge me, but he sits there and does, he does his little surgical exercise every time he brings down a deer because he's had to assist with his wife when she shut down their airway in the past. So it's that extreme of a condition. Mind you, these guys diagnose their HAE before we had novel medications, but to tell you that we've come a long way and still have a long ways to go as an understatement. On the right, you'll see that attacks may last up to 5 days. Remember back to the peanut, the honeybee, the penicillin allergy that I told you that angioedema lasting 24 hours. Here, the uptick of angioedema in hereditary or HAE could be up to 2 days, so you can still continue swelling. The downtrend can take up to 3 days -- and there's nothing you can do at that point to accelerate resorption of that fluid. It's through the lymphatics. And so a typical HAE attack could put you out for 5 days. So you're out of the pocket as far as being present, having presenteeism in society. Moving forward to the treatment landscape. It's divided into 2 portions. I will start with the right side, acute therapies. So every patient according to the guidelines, the HAEA guidelines are stipulated to have 2 on-demand therapies available to them -- or 2 doses, I should say. And on the left, you'll see that the move is more and more towards -- we should try to control the condition rather than this disease controlling the patient, and that's through prophylactic therapy to prevent attacks. And if there are breakthrough attacks, to really dampen them so that the severity is reduced. And so approved prophylactic therapies to date include daily, twice weekly, biweekly and for few select patients maybe up to every 4 weeks dosing. Why do I mention that? I showed you a lot about the burden of disease, but there's also a burden of treatment that's a real thing there where patients might get fatigued from twice a week infusions, injections and so on. And so from that patient-reported survey of over 500 participants reported that they've used a prophylactic medication in the past 12 months, a little over 1/3 said that they had more than 2 attacks per month, which that in the majority of HAE specialists will say that's severe HAE, phenotype. And 13% reported they had good control of their disease with less than or equal to 1 attack per year. And so I hope you take these key takeaways, mainly the sense of urgency in the HAE community to help these patients who have this unpredictable disease that's making an impact, not just in their lives, but really in their community. So their teachers affected the coach, et cetera, young kids with their siblings. And then on average, it takes multiple years for patients to be diagnosed. And remember that 25% of them don't have a family history. So when they show up to that emergency room or whichever portion of the medical world that they present to, there isn't that extra hint of like, "Oh, yes, it's a family based condition that you may realize or you may find out on my labs. And then despite approved prophylactic therapies on the market today, less than 15% of these patients are reporting good control of their disease, which tells us that there's still an unmet need and patients are looking for better treatments to reduce the disease burden, as I mentioned, and the treatment burden. And so at this point, I'd like to invite Dr. Ken Newman from Ionis to take us into the next phase.

Thank you, Dr. Tachdjian for your really insightful comments about what it's like to actually treat patients with hereditary angioedema. It's actually a reminder of the first patient that I ever saw with HAE. I was a fellow with John Hopkin some decades ago. And a young woman was admitted into the intensive care unit with massive laryngeal swelling, with major effort we were able to intubate her, put a endotracheal tube into her airway, save her life. It was a great reminder that this is a fatal disease. In fact, in the days before effective therapy, 30% patients would actually die at the [indiscernible] due to their disease. There was no effective therapy for acute angioedema attacks until 2008. The only thing we could do was supportive care. It's always a reminder that this disease continues at high morbidity, anxiety, depression and sadly occasionally still mortality. The importance of the k–inin-kallikrein system was pointed out by Dr. Tachdjian. What Ionis scientists did was they produced antisense oligonucleotides to every step in the pathway in order to determine which of these were the most important proteins to be able to reduce, therefore, determining which was the most effective therapeutic cards. They determined that prekallikrein was the best target for a therapeutic intervention. So prekallikrein is metabolized activate the kallikrein, kallikrein cleaves bradykinin from high molecular-weight kininogen, therefore, producing the characteristic submucosal and subepithelial swelling that characterizes hereditary angioedema. So we're going to walk through why donidalorsen is such a compelling HAE prophylactic therapy potentially. It can be dosed every month or every other month and in a patient-friendly auto-injector, meaning the auto-injector has a low volume and has an ultra fine needle. We're going to walk through the striking Phase II data at a high level, which was so unique that it was accept for publication in the New England Journal of Medicine. We're then going to show you some new open-label extension data from the Phase II trial. And then we're going to walk through the Phase III program, which is the OASIS study. OASIS stands for oligonucleotide antisense and symptoms of HAE. This is a Phase III study, which is fully enrolled for which we expect data in the first half of next year. Then we're going to talk about the open-label extension study called the OASIS plus. The study actually has 2 parts, one of which is an open-label extension. Another part is a unique switch protocol, which we will talk about. This is an overview of the Phase II study with donidalorsen. This was a randomized, double-blind, placebo-controlled study of monthly subcutaneous injections of donidalorsen or placebo. So what you can see is patients entered into a screening period of up to 8 weeks during which time they needed to have at least 2 attacks. After they had their second attack, they were then randomized in a 2:1 ratio to either dotted donidalorsen or placebo given every 4 weeks that the primary endpoint was at week 17, which is 16 weeks after the first dose. At that point, they could either enter into a post-treatment period or roll over in an open-label extension. There were 20 patients that participated in this study, 17 of them were 85% rolled over into the open-label extension. This was remarkable and compelling. It showed a rapid and sustained improvement in HAE attacks. Specifically, starting from the first dose, there was a 90% reduction in the rate of HAE attacks. We know with antisense oligonucleotides that often will take 2 doses in order to get maximum efficacy. So we can pre-defined a key secondary endpoint being the efficacy starting from the second dose. From that dose, there was a 97% reduction in the rate of HAE attacks. In fact, every patient but 1, was completely attack-free. But 92% of the patients on active drug versus no one -- none of the patients on placebo. Importantly, this was associated with a statistically and clinically significant improvement in their quality of life. At the same time, there was a favorable safety and tolerability profile. Specifically, the adverse events were actually lower in the active group than they were in the placebo group, and there was no safety signal of any type. Following the completion of the Phase II double-blind study, patients could enter into the open-label extension study, and this is the design of that study. There was a fixed dosing period during which time patients received donidalorsen 80 milligrams every 4 weeks for 4 doses after which the dose could be varied depending on how the patient was doing. The patients could continue on 80 milligrams every 4 weeks or if they were doing really well, the dose could be extended to 80 milligrams every 8 week. If for some reason, the patient was still having attacks so were symptomatic, the dose could be increased up to 100 milligrams every 4 weeks. We now have 2-year data from this. I will only show you a little bit of that data. The rest of this date or we presented at upcoming congresses. For the first time I am showing you is striking data. This graph basically says it all. What you can see on the y-axis here is the HAE monthly attack rate and on the X-axis, you see time in the study. So starting on the left, you can see the time in the double-blind study and after the dash line, you can see year 1 and year 2 in the open-label extension. And you can see the rate of attacks go down dramatically. In fact, it's reduced 96% over 2 years. The rate of attack is 0.06 attacks per month. It's remarkable. If you remember what I said on the prior slide, was 97% reduction starting with the second dose. What we see now is that is sustained and durable over 2 years of the study. As Dr. Tachdjian mentioned, the goal of therapy is to improve quality of life for these patients. This is the quality of life data. This is for year 1. Year 2 data will be has been submitted and accepted for presentation at an upcoming congress very shortly. So this is the angioedema specific quality of life question here. The minimum clinically important change is 4 points -- I'm sorry, 6 points. And what we found in this study is we had a change of 4x that much. There's an improvement of 24 points. So what you can see on the right is what's called a radar block. I think it was really cool. So on the top is the total store for the angioedema quality of life questionnaire. And on the side, you see the subscales, nutrition, fear shame, functioning, fatigue and mood. And there is dramatic improvement in every one of these endpoints. This is remarkable, especially for such a small study to see these sort of effects. Turning to the safety data. What we found is that the drug was well tolerated. Specifically, there's been no serious adverse events. There have been no treatment emergent adverse events that have led to discontinuation. And the only TEAE that's occurred in more than 1 patient was injection site reactions or discoloration, which have occurred in 2 patients. There have been no changes in any laboratory parameter, no changes in ECGs. So with this data being so striking, we urgently move to a Phase III study. This is a fully powered, well-designed study of donidalorsen in hereditary angioedema. This is a global randomized double-blind placebo-controlled trial of monthly and bimonthly doses of donidalorsen in patients age 12 and up This study is fully enrolled. There were 91 patients that have enrolled in this trial. The design is what you see on the bottom. Patients enter into a screening period, during which time they need to show at least 2 attacks after which they are randomized to either donidalorsen 80 milligrams every 4 weeks, donidalorsen 80 milligrams every 8 weeks or matching placebo. At the completion of the trial, which is 24 weeks, they can continue into a post-treatment period, which is an additional 13 weeks or they go into an open-label extension. The primary outcome as an oral study of this type are time normalized number of HAE attacks. The open-label extension trial has been termed OASIS plus. This is a continuation of dosing for patients in the Oasis from I can say that more than 90% of the patients in OASIS have been rolling over into OASIS-PLUS. This study patients will continue getting the dose that they received in the prior study. So they received 80 milligrams every 4 weeks or 80 milligrams every 8 weeks. The primary outcome is safety. So it's the incidence of treatment emergent adverse events, but the key secondaries are, of course, efficacy and durability of effect. This is a totally unique part of the study, and there's almost like 2 studies in 1. This is what we term a switch study. And what it basically says is that we're taking patients that were on treatment with other HAE prophylactic therapies, whether it's lanadelumab, berotralstat, whatever. And then they are switched to donidalorsen 80 milligrams every 4 weeks for at least 1 year. And the reason for doing this are multiple. First of all, we want to be able to show comparable efficacy, a way of being able to say, what is the efficacy of what you were on previously and what's the efficacy while you're on donidalorsen. In that way, we can measure patient satisfaction. We can say how well are you satisfied with the medication that you're on versus how satisfied are you with donidalorsen. And we can ask them their preference, the Coke versus Pepsi question. Do you prefer donidalorsen or do you prefer what you were on previously. And finally, it gives physicians guidance on how to switch medications. Right now, there is no data out there on how physicians should switch from one prophylactic therapy to another. So we're going to fill that gap. So, the takeaway message is we have a really compelling and robust story. We have great data to date. We have a Phase III program, which is fully enrolled. We are planning on taking all of this data, both the Phase II and the Phase III program and using it to file an NDA in the middle of next year. If we are fortunate enough to get approval from the FDA, there will then be our responsibility to bring this medication as a therapeutic option to patients. And for that, I turn it over to Onaiza.

Donidalorsen, the last over 3 near-term opportunities and much more to come in the next wave. I hope that you were struck by some of the patient illustrations of what it means to actually live with this disease. What really struck me was the patient that can treat it when he was a post-doc at John Hopkins. I can't imagine what it would feel like if you're really getting this shortness of breath while your layering is actually swelling up and you only have just that much time to get yourself to the hospital. And I cannot imagine what that feels like as that construction in your airways continues to happen on that journey. So the whole thing about this area is prophylactic treatment to prevent that. And I have to say that the market dynamics and I'm thankful actually to all the prophylactic treatments that have done a really nice job of moving patients out of acute treatment into prophylactic treatments. And as a result, we have a very well-defined population. Yet there continues to be significant unmet need. The increasing rate of prophylaxis treatment is actually very high, and it's growing in the United States. We're at about 70%. We expect to be at 70% by the time donidalorsen enters the marketplace. This is not the case actually in Europe, which is still another sad state for these patients. And I'm encouraged to see that it is increasing, but we're not there yet. The other thing to note about this patient population is they're really searching for the efficacious product that are going to prevent the attacks alongside the convenience that they need for their lifestyle. [ Dr. Tasian ] actually told us how young these patients are. They're like average attack at the age of 18, they're on the go. They need something really that's accompaniment to them. Not refrigerated and not obviously going into a physician's office to do that. So we've seen patients switch both ways to find both of those things together. And then lastly, the launch plans for this is simple. We actually really know where the physicians are who treat these patients in the United States. They're very concentrated and about 1/4 of the allergists and immunologists only treat HAE. So easy for us in a very efficient commercial model to get to them. So Sydney is your typical younger population for HAE. We have about 20,000 patients and from a prevalence perspective in Europe and United States, about 6,600 of them are in the U.S. We believe with our very strong profile that we see in the Phase IIs where the product is designed to reduce the source of the problem, which is the production of prekallikrein. Our studies have actually shown some really great data you saw from Ken, where you see a rapid that's in 1 to 2 doses of rapid reduction of HAE attacks. Rapid is actually really important here if you're going on a prophylaxis treatment, right? And then as we just revealed with the 2-year data, we see that sustain reduction over 2 years is pretty compelling. So we really feel like we're in a very, very strong position to deliver a compelling HAE prophylaxis product to the marketplace. Now the question I get asked sometimes is there, well, there are already these prophylactic agents, is there an unmet need? And [ Dr. Tachdjian ] also revealed to you a study that was done by the HAE actually just got published in online and it was a study of about 500 patients, right? We did similar market research. Ours is much smaller, but the nice thing to know it's really corroborated and on average, half of the patients that are on prophylaxis treatment still experience about over 3 attacks in an 18-month period. There's still unmet need. There are obviously approved treatments that require more frequent administration as a standard of care. I'm very excited about our once-monthly self-administration here. And then it's important to know, again, these patients are really looking for something on the go. They want freedom from their HAE and importantly, just improve their quality of life. So here's the data that we did that was a smaller subsection. We ran a market research study to understand well, are patients still having attacks and about half of the patients in the U.S. have had 3 or more attacks in the past 18 months. And if you look at that chart to the right, you see that only 22% of the patients said they did not have any attacks in the past 18 months. And if you look again deeper in kind of the raspberry portion of this, you see that 25% of the patients having 6 or more attacks in a period of 18 months, pretty substantial. In Europe, the situation is even more dire. We have about 70% of the patients have 3 or more attacks in the past 18 months. The other question we really wanted to know, are these patients willing to switch, and we see that about 80% of these patients have actually switched treatments. And we've seen the switching driven by wanting more efficacy. They want fewer attacks. They want more predictability. And as I said, they're really looking for that improved convenience. Getting deeper on the reasons for switching, what are the top drivers for switching, we really see at 72%, it's equal. Like I said, I want fewer attacks and I want more convenience. And then, of course, some of the other things that are really important to them, side effects, safety, having it be available and lower out-of-pocket costs for the medications also become a choice in their factor as well. I cite some of the quotes here. I think they're really telling us to what's going on for these patients. Clearly, efficacy, my prior medication didn't work properly. I would have breakthrough attacks good reason for switching. And the other one is just that the self-administration they've had, but the injection actually really hurt, I had to do it myself, and so I switch and had to be stored in the fridge, and that just was very complicated. So when we no doubt bring the donidalorsen blinded profile to patients, they have a very strong interest in saying, I'd like that product. Almost 98% were moderately or very enthusiastic about doni. And going from dosing from once every 2 weeks, which is where standard of care is right now, to once every 4 weeks is going to be a really nice step change for them. And then as Ken said, we might have the possibility of even seeing this every 8 weeks as well. And we asked them about, again, their switch and said it was available tomorrow, I'd go ask my doctor about it. And as [ Dr. Tachdjian ] said, this is really a shared decision-making process between the physician and the patient, and we can see that coming through. Health care professionals view the profile, again, in a very blinded fashion with our target product profile as a meaningful advance in treating HAE. What do they like about donidalorsen? Well, it was favorable across all dimensions, which is reduced attack frequency, attack severity and very importantly, what they look at is the attack-free rate. They also like the onset of action because getting a prophylactic on board, particularly in a switch situation and having them be controlled and have no breakthrough attacks is really important. And as I said earlier donidalorsen reaches kind of this MAX clinical efficacy in 1 to 2 doses. And as a result, they're very excited about the once monthly dosing you said, "Oh, my patients are finally going to be compliant." So the feedback on the expected TPPs has been very positive by health care professionals. As I said, we know where these physicians are. We know who treats them. It's very concentrated, actually about 1,000 allergists and immunologists manage about 70% of HAE patients in the United States. So we really feel like we can get to all of them with a field team, when I say field team, not just salespeople, but on the other customer-facing teams that you need to get to including your patient education managers, your field reimbursement managers and all the support that these patients need, we believe we can get there in less than 100 customer-facing team size. And of course, here, high-touch patient service is going to be really important, and the direct-to-patient engagement activities are being planned. And we're going to be building from all of the high-touch patient engagement activities we're going to be launching for FCS and then 6 months later is our time line to get them ready for donidalorsen. So it leverages really, really well. So what are the next steps for donidalorsen? Well, I'm pleased to say we've got a lot of things that are complete on this list. As Ken just said, we just finished our 2-year OLE data and that will be presented in the second half of this year, before end of the year, we expect the Phase III OASIS-HAE data readout in the first half of 2024. We also are very excited in the commercial setting to get the SWITCH study data readout as well, and that's going to be mid-2024. That's going to be very important for physicians to understand how to make a switch in this marketplace and that lines us up for a filing in the second half of 2024 for HAE and expecting a second half mid-2025 launch. So I leave you with a very dynamic marketplace for donidalorsen, lots of things going on in terms of unmet need and switching and continued rate of attacks for these patients. Our product profile will really deliver very well against that unmet need. Quality of life and switch studies that we have in the data set are going to be really informative for physicians to actually really make the right choices for their patients and then we will support the patients in terms of what's most important access patient support hub and patient engagement. All right. So to wrap up the morning of our near-term commercial opportunities, I'd just take you back to what we covered. In summary, we are poised and ready to launch eplontersen, olazarsen and donidalorsen. Eplontersen PN right around the corner in just a few months and the turn of the calendar year for ATTR continues to be a very underserved in growing population, prepared to launch both indications for FCS in the heels of the unprecedented data and preparing for SHTG. And just as I covered right now, the continued unmet need in HAE and a great best-in-class potential profile coming up as the Phase III readout. We are ready, starting first with the co-commercialization and then followed by our independent launches for olozarsen and donidalorsen. All right. With that, the morning is concluded. I'm going to invite Wade Walke to come back here and lead the Q&A session.

So I am going to invite the speakers from our morning session so far to come up here and join us on stage. And as we get to this Q&A session, we're going to have about 30 minutes and so probably likely want to ask questions, so I'm going to ask the people if there's questions. [Operator Instructions] Okay. So we'll kick it off, Debjit.

Debjit from Guggenheim. So a question for Dr. Ginsberg, in your practice and in the history of treating SHTG patients if you were to segment patients between above 500 and above 880, what would be the rate of pancreatitis events in those patients versus those over 1,500 or 2,000?

It's not a simple question to answer because these patients move. Certainly, there is some divergence in the phenotype related to genetic background and environment. And so we have some patients who are SHTG who have genetically much more complicated than the FCS, but almost as much of a loss of LTL is FCS. And we have those who have a much more complicated polygenic and environmental. So I'd say 500 to 1,500, that group will have less of a chance of having -- less risk of having pancreatitis than someone 1,500 to 2,500 who's not FCS. Obviously, that's -- because to get up there, they're more likely to have just a much more severe genetic background and then those who are lower. But again, the patients I've seen most often are women who would never diagnosis having even hypertriglyceridemia who start on all contraception or become pregnant or having fertility treatments and on those estrogenic approaches have TGs that go to 2,000 get pancreatitis. And so it's very difficult to put a nail on the box, but if somebody shows up with a 2,000 regardless of what their genetics are, they're more likely to have over the lifetime, more severe disease. That's, I think, obvious. I hope that's an answer. I'm not sure exactly if that's what you were looking for.

How do you think that we [indiscernible] .

Yes. So what the treatment patterns for those 2 groups, so we do genetics. And obviously, 99.99% of the time they come back as some mixture of poly genes, maybe some of them are the big genes for FCS, but the heterozygous. Others are just variance. Those people would get fibrate, omega-3 fatty acids, diet,, whereas the FCS would get diet, but probably not the other 2. And then we watch them and we see where they go. And so there are many of them who will drop below 1,000 or if they're below 1,000, drop below 500 but if they come -- and many -- and there are those who won't. So I think in that group, it's trial by error in terms of what drugs they will need. But there, again, several million of them in the population. So there'll be a lot of people who won't succeed at the existing treatments.

I don't know if my mic is on or not, but I'd like to just add to that. I must be adding my problems today. Something Sam touched on in his presentation, it's important to remember that the patients in our core and CORE II studies are on top of the standard of care. So these patients are in the above 500, many of them are above 1,000 or 2,000, and that's in our study already. That's on top of fibrates, tissue oils, what have. Is that right?

And if I could add one color -- a little bit of color to your question on pancreatitis. We because we're doing these SHTG studies in the COMPASS trial in patients who are in their 40s, about 25% have already had pancreatitis just to give you a sense of the lifetime risk of SHTG versus the control robust stage. So it's a sizable proportion is SHTG patients to get pancreatitis and the higher the value of the tragic more of the risk.

One of the things I would add just to make sure is that when we talk to physicians about how are they going to treat this? It really comes down to treating the risk, right? They're really not necessarily thinking about I got to treat the disease. It's the risk and the prevention mindset. And hence, we get these treaters that are very aggressive and very active, as I said, in terms of our behavioral segmentation.

Okay. Let's go have Yanan, then Kostas and Eli.

Yanan Zhu, Wells Fargo. I have a question for Dr. Ginsberg. Just to follow up on the prior question, what proportion of your patients are those that have above 500 despite having been on standard of care and what proportion are above 880? I also have another question on pricing, Dr. Ginsberg, could you comment on what kind of price will payers be willing to pay for the severe HTG population. We understand FCS is obviously is a very awesome disease. But just trying to understand you think payers level of acceptance of pricing points.

So I'll take the first one, I don't think I can give you an answer of 500 versus 800. Those people move back and forth. The day-to-day variability of triglyceride on a percentage basis, can be 25%, depending on what you eat in the previous day. It's a very dynamic situation. And so these people, they're not 500 to 799 or 879 for all their lives. They move back and forth. And so I don't -- again, the higher they are, the more likely there's a stronger genetic background, less likely that I'll be able to get them below 500 and permanently just on the standard therapies. I can't -- so I have a handful of those patients, and when they get a PG that's better and they're further away from their pancreatitis, they don't show up for a while. That's the big problem. We've seen a lot of diseases where there's no symptom every day, but then they come back in again with pancreatitis. As far as payers go, I'm sorry, you touched on it, a soft point. I just would point out that I've had patients who have been in the hospital for 6 months in an ICU, on dialysis intubator with pancreatitis. So when they get out, I have trouble getting a fibrate or omega-3 fatty acid from the payers. And I have to fight with them on the telephone convincing them that patient will cost them another $1 million if they don't let me treat them. So I'll probably have the same battle.

Maybe Onaiza, you could provide a little more precision.

Sure, be happy to. I think my mic is on, right? So we just actually recently completed a pretty extensive payer and pricing research to understand kind of where payers are going to land on both indications. Again, with the blinded profiles that we tested for olezarsen, both FCS and in severe hypertriglyceridemia. I'm very pleased to see they see the value proposition of the product. They know it's going to be really an add to the armamentarium of what physicians really have right now and they clearly see that rare disease for FCS and you could imagine that we're thinking then the value proposition lines up with other rare disease pricing alongside that corridor. On the SHTG, where we get pegged mostly is on the premium priced cardiovascular agents that are there for more prevalent conditions. And I can certainly point you to a few analogs, inclisiran happens to be one of them. And then and some others that have come close to that. So I would take a look at that, and that's where it's being impacted as well.

Great. I have my second and last question for Dr. Tachdjian. Thanks for the very helpful reference about the unmet need, which is apparently consistent with what the company's own research on. I was wondering could you speak to your patients who are -- who have access to Takhzyro? Is that level of unmet need still exists in that population? And also, could you compare donidalorsen with the Factor XII antibody as well as the YTE engineered half expanded Takhzyro, so to speak?

I'll start with Takhzyro, which is currently approved in the market. That is -- so in the trenches, it starts off at every 2 weeks. And if someone has no attacks for 6 weeks -- 6 months, then they can go on to every 4 weeks as shared decision making between the patient and the physician. That said, I'm not going to comment on how we think it is to go back if they start having more attacks, okay? And the other 2 that you alluded to hitting Factor XII activation at the top of the cascade as well as the YTE engineered extension of the monoclonal. Those are in clinical trials. How that pans out remains on the outcomes that are published essentially. So unmet need wise, all of those -- all 3 including the Ionis product will at least increase the interval and so decrease the burden of treatment for the patients.

Thanks for the very helpful presentations. Kostas Biliouris here from BMO Capital Markets. A couple of questions, one for Sam the other one for the HAE experts. Some on ATTR cardiomyopathy, we recently saw that ONPATTRO's benefit on top of tafamidis was not significant. And given the robust clinical trial design of eplontersen, I'm wondering, in case you see a significant effect of eplontersen on top of tafamidis. Do you think this would be representative of all the silencers or there is any reason to believe that this effect could be specific only to eplontersen and not representative of the silencers?

Yes, it's a great question. It's going to be hard to compare because the trial designs are a little bit different from BridgeBio and the Alnylam trial. There are some differences, even though they all have hard endpoints, we're focusing on cardiovascular mortality as part of our key part of that end point besides all the heart failure hospitalizations. So if the trial designs give you different data, then it's going to be hard to say if it's a broad effect of just the target or the drug. So I think I can't commit them one way or the other. I think we have the best design, as you have seen. We're going to have multiple hundreds of patients on and off to tafamidis. So we'll be able to answer that question fairly definitively, I think, based on our trial design. And hopefully, that will help answer your question once we get the readout.

And I'd like to just add to that simple way I think about it is that you need 2 things to demonstrate best-in-class efficacy and a profile that patients really, really prefer and physician preferred one is you need a great drug. And we believe we have a great drug in eplontersen and we believe the silencers class at the end of the day went out on efficacy. The second thing you need is you need to be able to prove it. You need a trial design in which you actually have the data that actually supports the conclusion that your drug works well on top of a silencer, which in the United States, we all know, tafamidis is a standard of care or your drug works really well alone and maybe better than a stabilizer. So we believe in silencers, we believe in eplontersen, but we also need -- We believe in our trial design, which is as important as having a great drug. Then you have a follow-up question?

Great. Yes. Before we go to HAE, Sam, you mentioned Ionis is the third cardiovascular company. Maybe you can give us the other 2 on top of Ionis?

Sure. I think it's BMS and Daisy.

Perfect. And for HAE, you mentioned the importance of the unpredictability of the attacks some wondering in the Phase III trial, what would be most important end point for you, the reduction of the attacks on average or the percentage of people with 0 attacks? And obviously, both are great here, but because we have larger sample size in Phase III, these numbers may be a little bit.

Yes, I can. Yes, I think it's a combination. Really the primary endpoint is the reduction of HAE attacks. But you're right, what patients with HAE want is they want to have a normal life. They don't want to have to wake up and worry am I going to have an attack today. And for that, the attack free rate becomes critically important. And that's why we're so pleased that in the Phase II trial, we had 92% of patients, every patient but one that was attacked through. So I think it's the totality of the data, which is most important. Having said that, it's clearly upon what our primary endpoint is.

Eliana Merle UBS. Just on the question of combinations in ATTR, maybe just from a clinical perspective as well as a commercial perspective in terms of what is meaningful on top of tafamidis. I guess how are you thinking about what would be a clinically meaningful benefit of the combination versus tafamidis alone? And then from a commercial perspective and some of maybe your early work discussing this with the payers. Is there any expectation of potential step edits or demonstration of, say, progression on standard before say a witch or going on to a branded combination?

Sure. I think if you look at heart failure trials in general, which is basically what it is, we have the field in cardiology has really focused on hard end points. We want to see cardiovascular mortality, and we want to see heart failure hospitalizations. That's what physicians are expecting to see from a drug that will impact their patients' prognosis. And we have designed the study to do that. If you look at the tafamidis data, note that in the ATTRACT trial, the placebo group had 45% or 44% mortality rate and the treatment group had 30%, okay? So that means 30% of people on tafamidis are dying. So we think we can now take that 30% and get it further down. So we hope that we've designed our trial in the right way. We have cardiovascular mortality, we have heart failure hospitalizations and we have very serious arhythmias, and these are the kinds that bring patients to the hospital, they get cardioversions, they get defibrillators and those are the sort of arhythmia as in comp is clinically meaningful. So those 3 things, I think, will be the key for what we'd be looking for in the cardiology.

Yes. It's a really great question on what payers are going to think and how they're going to treat it. It's one of the first questions we had as we went into the trial design. So the way to think about this is they actually recognize what a serious debilitating and terminal disease business, right? So at the end of the day, they say, if a physician is going to test that you need both mechanisms on board to keep the patient in control. We will approve both mechanisms. So they do view these as different classes as a result of the different class designation of a stabilizer and silencers, there was a new kind of thought process of step-added treatment in that way. We also think that we are -- our design -- we'll have both subgroup data, like naive to tafamidis as well as on topic tafamidis. And it's a clinically meaningful kind of improvement that we are expecting to show on top of tafamidis as Sam just described. So that also becomes really relevant in the payer conversations to be show a cardiovascular risk reduction on top of that's clinically meaningful will be really important in the value proposition of the product.

Just a quick follow-up. I guess, is there a scenario where HELIOS-C would be positive that you still would take the analysis after the first half of 2025 such as if you wanted more powering on the combination. I guess how should we kind of think about that decision nature?

Well, everything is on the table. We are monitoring. We're mostly laser-focused on our study, of course, how the study is going, and it's going very well. We have a laser focus on blinded event rates, which are going well as planned. And we'll continue to monitor that and make sure the study is properly powered. If there's something that emerges externally, the competitive landscape or elsewhere that teaches us something new that might cause us to make a decision to end early. We certainly have that option. Or, to your point, we may say, okay, we got a drug now we want to really round out this profile. We really want to bring it to the finish line or to a later point to make sure we have the most robust data set possible. As Onaiza always tells me, this isn't a sprint, okay? This is a race to get the best possible data in a market that is enormous and untapped.

Yaron Werber from TD Cowen. So I have maybe just a quick follow-up, maybe, Brett, to you. On cardio transforms, when you're thinking about what we just learned from the last panel, are you thinking that patients on tafamidis, what's going to be the profile? Are they sort of patients who have recently been diagnosed and been on tafamidis and now they're getting enrolled into the study? Or they're typically patients who've been at tafamidis, maybe they're not doing that great. And as a result, they're getting the word in the study? And then secondly, would you announce if you've done an interim analysis? Or would you do want to either announce it if it's positive or continue the study. I have a follow-up.

Thank you, Yaron. I'll actually ask Sam to take the first one, I can address the second part.

Yes. So we're -- one of the things that we've designed in this trial, that's unique is we did not limit the amount of tafamidis use at baseline. And we think that is the best approach because we don't want to interrupt the standard of care wherever was in that geography. So in the U.S., for example, there's a lot of patients on tafamidis versus some other countries. And so we're going to be analyzing how long they've been on it and how many patients drop in or take tafamidis afterwards? But the bottom line is everybody that's sort of in the trial that on tafamidis has been on for a while. We're not -- we didn't screen for patients that are like failing on it. If you were on it for any reason, you can get into the trial. So we'll be able to look at that granularity at the end of the trial, we'll be able to understand that much better.

And I think we've also shared that it's been very interesting following the demographics in the cardio transform study. We're not seeing a lot of drop-ins and very, very low percentage of patients that are actually coming on to tafamidis that weren't on tafamidis stably coming into the study. We don't prevent that from happening, but we're seeing almost none of it. As far as interim analysis, we're not planning an interim analysis in cardio transform, but we would have several options to read the study out early. That's different, right? There's no statistical penalty or reading the study out early. And if we decide to end the study early because we think we have all the data, with all the powering we need for a successful study, we'll certainly make that an announcement.

And study early means before the 36 -- before, everybody is on 36 months? Or is it -- you want to have at least 4 -- well, you already have 1,400 patients?

That's right. Yes. We have all the patients. So the longest duration of the study is going to be 140 weeks, which is about 32 months, but we can pull that back to early 2025, if we want to.

So we would have patients that would have -- we already have patients, obviously, in the open-label extension that have completed and so on. So it would be a snapshot in time at that point in the study. Does that answer your question?

Patients in the OLE are able to continue to get dosed?

Yes.

I'm way past my 2 questions. I'll count the second one is the second comp. On the OASIS study, it's a question about HAE. You're going to have data in the first half and mid next year. from the Q8 weeks and also from the SWITCH study, can you file for label for both of those 2? one label for monthly, Q2 months and switch?

Yes, that's it. Net of the intention is to file for every 4-week dosing and if the data is supportive to also file for 8-week dosing.

And it's just important to note that we actually don't need the switch study for filing, but it's really important for commercialization and also, obviously, for physicians direction of use, so.

Gary Nachman at Raymond James. So I have a broader question about the transition to becoming a commercial company. So when you talk about the omnichannel approach versus having a targeted sales force. And when you think about the unmet need and improving diagnosis rates, maybe give us a better sense of how much headroom there is in some of these markets, whether it's ATTR or FCS or SHTG or HAE. And what you think is reasonable with the approach that you have in order to get to the kinds of targets maybe that people are thinking about and I guess, specifically with ATTR, just because there's going to be multiple competitors in that market, how you see that sort of coexistence given that it is so untapped at this point?

Yes, as you're asking that question Gary, my mind just kind of raising back to all of the other products I worked on in terms of where we tend to peak out. So I think if you have really good data tools, as I said, great diagnostic tools, right? And Sam spoke to this in ATTR with scintigraphy actually being really much more available now. And as the diagnosis and treatment rate extends out of the centers of excellence into the community, you start seeing the treatment rate going up. So those are kind of the fundamentals to really think about I do not see treatment rates really going up beyond 80% versus virtually in any category I've worked in. And I think the only place I've seen it is in HER2 which Jonathan worked on HER2, where a specific diabetes such a dusting disease were in the 90s. And even they can get to 100%. So you're never going to get to 100%. 80% is really optimally great. And but what it takes is really thinking through what I said is just doing your data analysis, getting the reps to go where they need to go, but also very importantly, the diagnostic tools, the disease awareness and all the other things that multiple -- when there are multiple companies actually all boats are rising at that point in time. And I think that's what it's going to take for TR. That is why we're so excited about having such a large-scale partners such as AZ on board alongside with us to really capture the market opportunity for...

Okay. And then just a follow-up for Dr. Tachdjian. Specifically on HAE, I think someone put up the number, less than 15% or so of patients or effectively treated or satisfied with the current treatment regimen. Is that more to do with the effectiveness of the treatments or because of the administration and maybe a lack of compliance in getting where they need to be and how you think donidalorsen will help address that?

Sure. one thing I always emphasize with the patient is I'm not a patient, so I got to best empathize and feel what it's like to have HAE and HAE is particular because the minute you put a tourniquet on someone to get the blood draw for instance, for a clinical trial already there and is just a big sponge and turn in just blue compared to an average person. So to correct that pathophysiology to me already innately make renders them normal-ish. So quality of life is contains that factor of that in each sense of just wellness that some of these meds can attain. And so I don't think it's so much the efficacy that, that survey reflects but more the burden of treatment because you look at some of these daily versus -- I mean, the first drug that got approved in this era 14 years ago now was something that reduced the attack rate by 52%. And that was how screaming the new areas coming on in 22 patients that finished the study, but it's ID-1 inhibitor given twice a week. That's -- I mean, that's a tall order now. Back then, it was great. It was an overall moment. So now especially when the Q8 weeks approval should occur presumptively, I mean that changes the paradigm at that point to have 6 injections a year with efficacy that goes with it and obviously, safety. So that's the huge 80-some percent unmet need for me.

I apologize, we're running low on time. So Jess and then Myles will be our last question for this session, and then we'll have to get back on to our presentation schedule. Go ahead, Jess.

Great. Jess, JPMorgan. You flashed up the treatment guidelines for the SHTG population for 500-plus and 880 plus. What's your expectation for all Arsen's inclusion in those guidelines? And what's the path to get it added there?

So I mean based on kind of what I've seen, Jess, is that once you have a robust data set, and you have a novel mechanism as we do right now, you're really then taking it to the advisory committee of the medical guidelines and really reviewing the robust data set that you have. And it's really up to them in their decision whether they're going to want to include it or not. But what I've seen is that particularly in areas such as in SHTG, we haven't really had tons of innovation in here. We had Omega 3 fatty acids, and they were added in one of them. And in right fashion or so we expect the same for olezarsen to bring that in. Our medical affairs group will be working on that with [indiscernible] group. And hopefully, they will see the robustness of the data and make the right decision.

Myles Minter from William Blair. Just on the symptography sub-study curious as to whether you're enrolling patients in that substudy that are taking tafamidis as well? Any resume say that is there some emerging data coming out that tafamidis [indiscernible] can actually reduce paracrine grades? And there was some talk at the AdCom that they might want to use that as a biomarker for potential efficacy should these studies be positive. And so I'm wondering whether or not you'll actually have enough patients in that study to show that or whether enrolling patients on tafamidis might actually confound the potential findings there because you're already reducing amyloid burden in the heart in those patients.

Sure. Sure. I can take the question. So we're stratifying the entry or was already stratified by tafamidis use. So we anticipate any subsequent analysis. There's going to be equal distribution of tafamidis use. We're not restricting tafamidis use in the symptography. We'd like to have equal numbers, let's say, of on and off tafamidis in this 2 weeks study. We're a wave of powered, as you saw 6 patients give you a difference. So we think we're going to have great data with and without tafamidis symptography and we'll be able to see if it's one, the other, both or neither in terms of the final analysis.

Okay. That's all the time we have for Q&A today for this session anyway. We'll have another one in the afternoon. And let the speakers go back to the seats, and we have one more presentation before lunch break, and I'll have Brett introduced [indiscernible].

We have one more -- as Wade said, we have one more presentation before completing the morning session before lunch. We've covered a lot already. We've really focused on Ionis' the building of our commercial organization. Our preparations to launch and the status of our pre near-term launch opportunities, which we're very excited about. Now for something a little different, we're going to really move into the advancements we're making in research. Again, consistent with what I laid out in my introduction, one of our key strategic imperatives is to invest heavily in advance and expand and diversify our technological capabilities to extend our leadership position in oligonucleotide therapeutics. And Eric Swayze will lead us and Eric Swayze, is Executive Vice President of Research, Ionis. He started at Ionis a long time ago as well, he came in as a medicinal chemist and then soon progressed to run the dismal chemistry and really establish our medicinal chemistry organization today. And today, he's now Head of Research. So with no further delay, Eric, it's all yours.

Thanks, Brett. So to finish off the morning session, I want to talk about technology, oligonucleotide technology. And specifically, three key things that we're bringing forward, which we hope will lay the foundation for advancing our future medicines that we're bringing into development, the new molecules we're making. So as many of you know, Ionis has a history of technology advances, and this has resulted in a -- we're pretty proud of as a pretty rich pipeline and some medicines that are in the market. that have really some of which have been transformational in some of the molecules you've heard about earlier today. So to do this, we had to first invest what we consider as a best-in-class chemistry that we use as the basis for all of our drugs. For medicines like QALSODY and SPINRAZA, we have optimized delivery to the CNS via local administration, but also pioneered a variety of mechanisms to modulate gene expression and this includes both down regulation, for example, silencing a toxic gene, like we talked about with some of the medicines this morning. QALSODY for example, down regulates SOD1 turns off the expression of SOD1 protein, which is responsible for causing SOD1 ALS. We've also been able to upregulate genes replace function. SPINRAZA does this by modulating gene expression such that it creates a functional protein where there was none in spinal muscular astrophy and that medicine has really transformed the care of SMA. We've also developed a targeted delivery strategies specifically to the liver. And those have made some of the medicines that we've talked about today, such as eplontersen, olezarsen and donidalorsen Possible. But I'm not going to talk about those technologies today. We're going to talk about some new technologies that we're bringing forward, which we think will make a difference in future medicines. Ionis has a really fantastic research organization. I've been privileged to be part of it for almost 30 years. And I don't think people really know and appreciate this, but about 50% of the research organizations total effort is dedicated to enhancing and improving our technology in one way or another. That includes making new things, testing new things, investigating the mechanistic basis for how these things work, applying them to drug discovery problems and ultimately trying to make new medicines for these drugs. Lots of technology research. Some of it is very broad. But when we get close to advancing something into preclinical development, i.e., making a new molecule, we're going to put in people, we focus that. And we focused our technology research on achieving 3 key objectives, which we think will add value to our areas of work and the patients that we're trying to serve. The first is enhancing the profile of new therapies. And the idea here is quite simple, is to make our new molecules to enter our pipeline even better than the ones that we have now. The next is to expand opportunities in existing franchises. And here, we're looking to add new opportunities for our cardiovascular franchise and our neurology franchise. And the last bit is opening up therapeutic opportunities in new spaces and trying to find new areas where we can develop drugs. And here, I'll highlight a couple of opportunities that we think are hopefully upcoming in pulmonary and renal. So this focus has led to really 3 things that I want to cover today that we think are really potentially important advances for Ionis and will be the key for some of the next molecules. And the highlight here is the bright pink slide. So if you can remember one slide, remember, this bright pink, red raspberry slide, it's hard to miss. And the idea is these are the key things that we're going to be bringing forward. The first is MsPA Backbone. And we think this is a potential breakthrough. I'll describe that in a little bit. The next is Ionis' siRNA technology. And here, this really just adds an additional mechanism in chemical class that we can use to make drugs and key for us is that for each new program we bring forward, we'll evaluate multiple different approaches, including siRNA to find the best molecule for the job. And then we'll close with targeted delivery where we're really focusing our delivery efforts on bi-cycle peptides in collaboration with our colleagues at Bicycle Therapeutics to target the heart and skeletal muscle and hopefully potentially enable the future delivery of neurology drugs across the blood-brain barrier. So first up is the MsPA Backbone. This increases duration of effect and improves therapeutic index. This is why we think it's such a big deal. And we think it's going to be broadly useful in all of the new drugs that we bring forward, both existing therapies and also in new areas. So what the heck is MsPA? What is a Backbone? And why do we need a new one? Why we need to improve it? So I'll start with the cartoon labeled. I'll start with the cartoon shown here, labeled Phosphorothioate so this represents a Backbone. And it's actually a dimer. The cartoon just really represents a 3 dimensional shape that [indiscernible] peptides has that interacts with biological systems, I'm a chemist so i got structures. The dimer, there's 10 of these in a drug like Calzati, which is a 20-mer and actually, Calzati has 5 of these dimers that make up the DNA portion of the region of the backbone. And the backbone part is really this part around the phosphorus or the P in the middle, the stuff around the P, that's the backbone. One of the modifications that we've made very early on in oligonucleotide medicinal chemistry is to change an oxygen for a sulfur. So the sulfur is the red S next to the P. This does several things for us. One, it improves stability over DNA. You can't make a drug without it being stable in a biological system. Phosphorothioate helps but it's not quite good enough. It is still the limiting part of it's still metabolized at that linkage and it limits stability, which limits duration of effect. The other thing phosphorothioate does that's very nice is it in parts of basic level of protein binding. That allows the drugs to actually distribute into tissues and stay there where we need the drugs to behave to do their job. There's a 2-edge sword there because that protein binding is not precisely specific. And it combined to the surface of tissues and cells, but it can also bind to things like immune sensors, things we don't want it to bind to. And that can give us some side effects. And so we've kind of had this love-hate relationship with phosphorothioate for a long time. And in fact, I started Ionis, I sustained in 1994 of March. And my first reaction was trying to make one of these XYZ things to replace the phosphorothioate backbone and find a substitute. And so my action work, we made the molecule, but the backbone failed. As in hundreds of other backbones that we've explored at Ionis to try and find something that works better than phosphorothioate and achieves the goals that we have set up here to work well, improve duration and reduce side effects. Nothing worked until we started working with MsPA. And that's why we're kind of so fired up about this particular backbone is we think it can do something that nothing else has been able to do before. So once we started playing with MsPA, one of the first key objectives we set out to ask was, well, does it maintain potency. The next key objective was, well, can it really modulate protein buying like we want it to and demonstrate some improved properties. So some of the experiments we do are described here, and I'll first orient you with a little cartoon. So the cartoons are representing oligonucleotide, and it's a series of little balls that are strung together with little loops. So each ball represents a monomer in oligonucleotide. This one is actually 16 units long. And the color of the ball tells you what type of base chemical it is. In this instance, the backbone that I discussed earlier is represented by the open circles, which is a DNA and the little linkage between it, the mustard color is phosphorothioate and then the MsPA is the little purple color. So with the kind of experiment we did is we take oligonucleotide, and we walk MsPA modifications throughout the molecule. And then we ask, well, what does that do to the properties of the oligo and those are represented by the pink line. So first, potency or activity. If you look at the graph on the left, that shows you that MsPA maintains potency relative to the parent. The pink lines are all to the left of the blue line. The blue line is the dose response to parent oligo. A leftward shift means we're improving potency. So at least definitely, we're not hurting it, and it looks like there's a slight improvement in potency for these types of MsPA molecules. That's good. The next graph on the right shows you that MsPA can also reduce protein binding. Here, the pink lines are shifted to the right that shows reduced affinity for this model protein relative to the blue line. So that's 2 things we wanted it to do. Well, how does that translate? Does this reduce protein binding, do anything of value for us? So the answer is yes, it does. Shown here is data from oligonucleotide that is a model system. We know it's a pro-inflammatory oligo. And we know that because if you dose this oligonucleotide to an animal, what you can see is in large spleen, shown in the blue box, cytokine induction, which measures inflammatory stimuli. We then did the same type of experiment with this particular molecule by walking MsPA linkages through the DNA portion of the molecule and that's shown by the little pink boxes highlighted with the MsPA oligos. And what happens? So if we do that, now highlighted in the pinkish box, we can see that the MsPA substitution, just 3 of them at various points in the DNA reduces immune stimulation, presumably by reducing binding to the TLR-9 driven pro-inflammatory sequence that's causing this immune stimulation it's evidenced by lower screen rate, they're essentially normal, the same as vehicle and lower cytokine induction. So that's nice. That's a model system. Does it have a beneficial effect in a real system. And so to test that, we took a very real system that was also unfortunately a very real problem for us. And some of you in the audience will remember our ENaC program where we had a molecule that was well tolerated in humans and it was showing nice early evidence of activity in humans, but had a problem in a chronic tox program. And the problem it had was due to inflammation in the lung of nonhuman primates. And so we wanted to ask, could MsPA help us fix this type of problem? By putting MsPA in the molecule in much the same design as we used before. And so here, the design in the little pink boxes shows that we have MsPA in each end of the DNA portion. And we wanted to ask 3 questions. Does it have similar activity to the parent drug? So that's shown here. Again, the blue line is the parent oligonucleotide. The pink line is the MsPA drug. Yes, it has the same activity. Next, and the big question is, does it help some of our inflammation problems? We saw complement activation in the monkey lung, does MsPA reduce that? And so here, we did study where we dosed the compounded tox dose -- a fairly high dose for 13 weeks. And you can see the parent oligo is increased. The blue bar is induction of complement in the monkey lung. The little pink dots are the MsPA oligo. Absolutely no activation of complement. So it has addressed and solved our problem. And in this experiment, we also included an siRNA for fun, which is somewhere in between the parent oligo and the MsPA oligo in terms of complement action. And the last thing is, well, did we do inflammation? And this is just an example. Of course, we look at this histopathologically, but we also looked at it with IP-10, which is a cytokine. Again, the parent oligo in blue shows an induction of cytokines. The MsPA is normal, like saline and the siRNA somewhere in between. So this suggests that MsPA, when used in the right design can help us make molecules that target for lung with local administration and do it safely. And so [Audio Gap] suggest that we can advance MsPA in pulmonary indications. We next asked a very similar question for a renal-targeted drug. And this is a molecule that has a reasonably decent profile, but not quite good enough for us, and we ask the same type of question. Here we put MsPAs at just one end of the DNA portion of the oligo. Ask very similar series of questions. Does it work as well as the parent? Yes, it does. Again, the pink line is the same as the blue line, suggesting the MsPA will have the same activity as the parent oligo. Next, we asked how does it tolerated? And again, we did an NHP study at a toxicological dose level and asked what does it look like. And so the parent oligo, we see some induction in kidney injury markers. These are commonly used to assess the potential for kidney injury, both our increase with the parent oligo. MsPA takes it back down, no increase. It looks like vehicle. We then also, of course, look histopathologically in the kidney, and we looked for signs of inflammation and shown in the little chart shows that the MsPA has reduced the inflammation that's observed by a histopathologist in all the measures we looked at, including at the injection site. This also suggests to us that we can use MsPA for some kidney indications and kind of starts to lay the foundation of where we're starting to look for some new places to make potential drugs for patients with the new chemistries. The next question we wanted to ask with MsPA regards stability and duration of effect. And so because we substituted the most metabolically label of point of the molecule, the DNA phosphorothioate with something that we know is more stable, MsPA, it's not recognized by nucleases like phosphorothioate is. We asked, "Well, if we substitute MsPA at these weak points, can we improve stability? And this should improve duration. Can we improve duration of effect?" And the answer is yes, it works. And this is shown in this experiment here. So we did this in both mouse and nonhuman primate. A series of experiments [Audio Gap] just focus on the left graph, this is an experiment where we give a single dose of an oligo and MsPA-oligo or a benchmark siRNA. Those are represented by the curves in blue, pink and green. So the parent oligo, if you just look at the blue curve, the target goes down. Factor XII, we can measure it in the plasma. So it's a nice one for this experiment. And you can see then over time, it recovers. And so at about 6 to 7 weeks, it's recovered back to the baseline. If we make an MsPA-substituted variant to this compound, again, using a design like we had for the renal oligonucleotide, just some MsPAs as evidenced by the pink box in the 5 prime end of the DNA portion, you can see a pretty dramatic improvement in duration. The MsPA oligo reduces the Factor XII target and then recovers much more slowly such that when the blue line is back to baseline, the pink one is still suppressed. And it's kind of on top of the green line. The green line is what I'll call an industry standard siRNA and those are typically dosed quarterly in clinical trials right now, suggesting that the MsPA oligo has the potential to achieve quarterly dosing in the liver. We also then looked at this in primate. So on the right side is the same experiment with the same target in NHP. The blue oligo represents the parent, goes down, returns to baseline and the MsPA oligo is clearly prolonged. Little bit better than the siRNA and the experiment again suggesting that the MsPA has the potential to get us to quarterly dosing for liver drugs. We also wanted to look in the central nervous system. And this is key for us because as you'll hear right after lunch, we are very invested in neurology and have a large suite of neurology drugs. Because our neurology drugs are given locally to the CNS, extending duration here is a big deal, a very big deal for us. And so we wanted to see if the benefits we saw in the liver could translate into the central nervous system. So we did a similar set of experiments. We put some MsPAs in the DNA portion of oligo represented by the pink boxes in the little cartoons and then look at the duration for both the parent oligo, which is currently a quarterly dose drug that's in clinical trials and an MsPA variant of this oligo. And what you can see from the graph on the left is that the ASO reduces this target, again, just a single dose into a mouse. And it recovers over time and returns back to baseline between 16 and 24 weeks post dosing. So that's a nice healthy duration. MsPA does much better. The MsPA oligo is still going down at 16 weeks and then returns back, but even at 32 weeks, it's not yet back to baseline. So we're very enthused about this data suggesting that MsPA can get us perhaps greater than semiannual dosing in the clinic with this type of modification. And the increased duration is due to stability, and that's shown on the graph on the right, where we measure half-life. We've measured the drug in each of these time points. More drug in the peak line, it has a lower slope. That means it stays put longer than the orange line, which has a shorter half-life. And so we think this is due to stabilization of the molecule, more drug increases duration of effect. So MsPA backbone, key points. It maintains and sometimes increases potency, reduces nonspecific protein binding and increases stability over PS backbone. This has the potential to reduce dosing frequency. Targets are greater than quarterly or quarterly in the liver and hopefully greater than semiannually in the CNS. Reduce side effects, and this combined allows us to expand into new therapeutic opportunities in new tissues, for example, the lung and the kidney. The next steps here are to evaluate these medicines in human clinical studies. And as I mentioned, we're broadly using it across the platform for many of our clinical studies or permitting our candidate identification programs. So next up is Ionis' siRNA technology. So here, our objective is to expand the technology base with an additional mechanism in chemical class. So, at Ionis, we have a fairly long history. I think this is a bit underappreciated also in technology development in the RNAi or siRNA space. We started this in 2000. We had an extensive program focused on the siRNA mechanism and this effort led to the invention of several key chemistries that are crucial to the success of siRNAs and we think will be crucial to the success of future siRNAs. One is what I've labeled RNA-free siRNA. And so this uses a modification of the drug with 2-prime methoxy and 2-prime fluoro to eliminate RNA from the molecule. It's very important to make them stable. Another key is the 5-prime vinylphosphonate called mole vinyl P, and that is exceptionally useful for optimal potency and also improving duration especially in nonhepatic tissues. And then the other one I highlighted is fluoroHNA, which is a unique modification to Ionis, this can substitute for 2-prime fluoro. So the siRNA optimization strategy at Ionis is fairly simple. I want to maximize potency, increase stability and reduce 2-prime fluoro nucleoside content be a substitution of other residues. The way we're achieving that is, first, we use the Ionis MOE vinylphosphonate for maximal potency. From there, we then use a whole array of chemistries throughout the molecule to substitute 2-prime fluoro and substitute the ends of the molecule to try and increase stability to maximize duration. We use backbone stabilizing modifications such as MsPA and/or phosphotide at the end to increase stability and increase duration. And for siRNAs alike, it is usually required. An example of that optimization strategy is shown here, use the same Factor XII system that we used before, and we also compared to what I'll call an industry standard siRNA design. That's shown in the red curve. So, again, a single-dose experiment with one dose of the siRNA shown on the red curve that goes down and then recovers back to baseline at roughly 8 to 10 weeks. There's no more target suppression. And just to note, these siRNAs again, are generally given quarterly in the clinic. So that's the profile of a quarterly molecule. We then look what happens if we just put the MOE vinylphosponate out of the molecule. So this is only one simple change. And there's a little orange ball there at the end of the molecule that represents we substituted MOE VP for a regular 2-prime methyl nucleoside. And you can see the orange line now has an increased duration. It stays down much longer than the red line, which is returned by 10 weeks. The orange line is still suppressed after 14 weeks. We've taken that one step further. And that's what happens if we substitute out all of the fluoros on one of the strands with fluoroHNA. This example just has 2 fluoroHNAs in the antisense strand of the molecule and MOE vinylphosphonate and further extends the duration of action over the MOE VP alone. And I mentioned the industry standard designs are generally dosed quarterly, suggesting that hopefully, with this type of design, we can have longer duration of action. And we've then taken this into a follow-on program for hepatic target with the idea to make an siRNA that would have a longer duration for our clinical development and see if we're on the right track. And data from that program is shown here. The red line is a clinical stage siRNA, a surrogate of a clinical stage siRNA. We -- the surrogate is -- we used our GalNAc instead of the GalNAc that's on the molecule. And you can see, much like the previous data, it goes down and it recovers to baseline by about 8 weeks post dosing. And what we were able to do in our optimization program is through a series of chemical modifications, including the MOE VP is produce some siRNAs that have much better durability than the red line, the one that's currently in the clinic. So we're excited about this, and we have translated this into preclinical development and hope to start clinical development with that molecule sometime next year. So for siRNAs, key takeaways. We think Ionis Chemistries are beneficial. The Ionis-optimized siRNA has the potential to reduce dosing frequency. Our target is greater than semiannual in the liver. And it gives us another modality that we can use to make drugs and optimize the profile of the molecule for each target. And as I've said, the next step is to evaluate these in human clinical trials and internally compete with other mechanisms for all new candidate programs. Okay. Last up is targeted delivery and specifically, Bicycle conjugates where we focus our targeted delivery efforts. So many of you may have heard me talk about LICA before. That stands for ligand-conjugated antisense. And as I just discussed, we're well beyond antisense. So we're just calling it targeted delivery. And we had a reasonably broad program. And as we started to advance things towards development, we focused that program. We focused that program on bicyclic peptides in collaboration with our colleagues at Bicycle Therapeutics, really because they work so well. And it also benefits our cardiovascular franchises and our neurology franchises by targeting both the skeletal and cardiac muscle and potentially crossing the blood-brain barrier. So what are bicycle peptides? This is -- they're developed by our colleagues at Bicycle Therapeutics, and they basically consist of a short linear peptide which is -- then reacts with a scaffold and the scaffold orients the linear peptide into a constrained structure. And that's very important because then that constrained structure allows these small peptides to bind biologically relevant structures, to form biological development structures, combine a diverse array of proteins. And these have several favorable properties that we really like. One, they're small. They have high specificity because of this constrained structure. They're chemically synthesized. They can -- drug complex protein targets and they're non-immunogenic, which is very important. And the target that we are interested in and have licensed from our colleagues at Bicycle is Bicycles that bind human transferrin 1. And that's shown in the bottom right-hand figure, that's -- the purple is human transferrin receptor 1 and the red is a Bicycle bound to transferrin receptor. We want to bind transferrin receptor because it's known that, that can translate to transfer cargo into the skeletal muscle and cardiac muscle. Bicycles work. That's shown here. This is an experiment where we made a series of compounds, as shown on the right. One is an ASO, that's the dotted lines. Then we took a fab, which is a piece of an antibody that was known in the literature to transfer oligonucleotides into the muscle and cause of target reduction. We made a positive control. We made 2 Bicycles represented by the pink and the blue. And what you can see in the figure on the left is that the Bicycles work. The potency has shifted to the left as evidenced by the blue and the pink lines to the left of the dotted line, which is the parent oligo. And what you can't see very well is the black line because it's right underneath the blue and the pink ones, that's the fab. So on a molecule-per-molecule basis, it works just as well as the fab. And that's very important. This potency is technically based on the mass of the oligo administer, not the mass of the total drug. Well, I just told you the Bicycles were small, fabs are pretty big. And if you calculate this then on the mass of the total drug administered, I've highlighted what happens here on the slide. The dotted line on the left shows you 3.5 mgs per kg dose based on oligo total weight. The 2 dotted lines on the graph on the right show the data when it's plotted based on the total dose of the drug administered. That corresponds to about 4-5 mgs per kg of the bicycle ASO because the Bicycle is small, it only adds a little bit of weight, whereas the same point that has 3.5 mg per kg ASO on the left is really 36 mg per kg of total drug because the fab is heavy. So most of that is due to the delivery system, not the actual drug. And so based on the total mass administered, the Bicycles are actually much more potent than the fab oligo and maintain their potency advantage relative to the parent where the fab actually gets less potent based on the total drug. We've also shown that Bicycles worked well in -- with siRNAs, and that's very important to us because the siRNAs have been working well in one of our programs. Shown here is data with a fab conjugated to an siRNA in gray compared to a bicycle conjugated to the same siRNA in green. You can see that the 15 mg per kg total dose, which is equimolar, so the same number of siRNA molecules as the green one has roughly the same activity, yet it's 15 mgs per kg versus 4 mg per kg total dose. We've then taken this into NHP and shown the same thing with both oligos on the top panel, in the blue bars and siRNAs in the bottom panel on the green bars. They reduced their target in monkey, quadricep skeletal muscle, heart cardiac muscle. And importantly, you can see on the left that the Bicycle ASOs bind monkey transparent receptor, which enables this target reduction. We've also had success in a follow-up in a new drug program with the Bicycle chemistry and shown here are 2 key bits of data from the program. The first one on the top is a PK study. And the objective here was to demonstrate subcutaneous bioavailability with the Bicycles, which we did. The blue-shaded area shows subcutaneous dosing of an NHP with a Bicycle-conjugated siRNA. The red shaded dosing shows the area under the curve of the IV dosing. And the area under the curve equals the amount that is in the blood circulation over the unit time for the AUC. And if you see the quantitation, the AUC for the subcutaneous dosing is, if anything, higher than the IV. This suggests that we have very good subcutaneous by availability with the Bicycle siRNA and that's made further clear by the quantification of the drug in the tissue at the end of the experiment. The blue bars, which are subcu are the same height as the red bars in both skeletal and cardiac muscle, we have the same amount of drug accumulated. And in the bottom panel shows the activity of this particular construct. We have nice target reductions, skeletal muscles such as quadricep and also in the heart, which is the target tissue. So Bicycle targeted delivery. Key takeaways for the muscle system, bicycle conjugates are small, low molecular weight, which simplifies the system, and they deliver both ASOs and siRNAs to skeletal and cardiac muscle. The next steps for this program is to evaluate our clinical -- our preclinical program in IND-tox studies and ultimately get them into human trials. And we have multiple targets of interest for both neurology and cardiology indications with using the Bicycle strategy. So we wanted to ask what else we can do with the transparent system and particularly in neurology. So as you'll hear right after lunch, we have a very broad and growing neurology program where we aspire to do a lot more than we're already doing. And while this has been enabled by lots of technology advances, we were thinking about what we could do more and what we could do better for neurology. And we really think the next hurdle is systemic delivery of oligonucleotides to the central nervous system, which, of course, involves crossing the blood-brain barrier, which normal oligonucleotides wouldn't -- don't do. So we wanted to ask, well, does transferrin receptor tenant mediate transcytosis cross the blood-brain barrier and bring a cargo with it. And so we started off to have a blood-brain program. The objectives of this program were to understand the characteristics and they are required for crossing the blood-brain barrier, identify systems that could do this and then simplify it as much as we've done with our Bicycle strategy targeting liver. So our strategy here was fairly straightforward, make some surrogates. There's some in the literature that have shown early success, use them as positive controls. They all have antibody-based systems. Figure out what makes them tick and how they work and then identify Bicycles that have those characteristics and ultimately, they cross the blood-brain barrier and modulate their targets. So early evidence that Bicycles could cross the blood-brain barrier was shown in this really nice experiment that our colleagues at Bicycle Therapeutics did. And what they did was implant surgically a dialysis probe into the brains of NHPs such that they could measure the concentration of bicycle in the CNS fluid that surrounds the catheter on the other side of the blood-brain barrier. So they infuse Bicycles into the plasma shown on the top graph, measured the concentration of Bicycles in the plasma. And then the blue bars at the bottom show the concentration of Bicycle in the CNS interstitial fluid on the other side of the blood-brain barrier, providing very nice evidence that the Bicycles can cross the blood-brain barrier and do so by transferrin-mediated transcytosis. So that's nice, but we wanted to ask, well, if they cross the blood-brain barrier, can they move a cargo across? And does that cargo engage and modify and modulate its target? So we first asked with a set of Bicycles that we had used for our skeletal muscle system. This is data shown on the left with the pink bars. And you can see they nicely modulate their target in the skeletal muscle quadricep and in the heart but they don't do anything in the cortex of the spinal cord. So this particular Bicycle design doesn't work across the blood-brain barrier. So we played around and fooled with it a little bit, came up with a couple of other designs that do cross the blood-brain barrier. And this is shown in the graph on the right. The Bicycle designs are shown on the -- in the orangish colors. And if you see in the bottom, they reduce their target in cortex, spinal cord and other regions such as the brainstem. The gray bar is our positive control which actually works a little bit better. So we got a lot more work to do, but we're very encouraged that the Bicycles are lowering their target in the CNS. And just to note, the Bicycles are small. So they're actually -- this is the same equimolar, same number of molecules of conjugate dosed, but it's much higher total dose of the antibody-based system because the antibody-based system is large as opposed to the Bicycles. So in conclusion, we've talked about 3 things that we think can make a big difference for Ionis' technology going forward into new molecules. The first is the MsPA backbone. This increases stability, which can reduce dosing frequency. It reduces nonspecific protein binding, which improves therapeutic index and enables expansion to new tissues. We've talked about Ionis' siRNA technology and shown that Ionis Chemistries can increase stability and this adds a new mechanism for us in a new chemical class, which is really optimal for some targets and applications. And we've talked about targeted delivery with Bicycles, which gets us into the skeletal and cardiac muscle. We think the small size is a huge advantage as it simplifies the structure and we've shown an early preliminary experience that we can cross the blood-brain barrier and this sets up the potential for crossing -- for systemic delivery to the CNS when we optimize the system. So all of these advances are geared towards improving the ultimate profile of our drugs for Ionis' pipeline. Enhancing the profile, expanding opportunities in existing franchises, as I've discussed, and opening up new therapeutic opportunities in new spaces. And I just want to leave you with what I think is really important for our technologies. Ionis is the only RNA-targeted therapeutics company with expertise in multiple modalities, which enables us to make the best drug for a given indication completely agnostic to modality. We're just trying to find the best molecule for our patients for new indications. And thank you.

Thanks, Eric. The opportunities are limitless with the research and the progress we're making in this area. So I'm not going to take any extra time. I know it's been -- we've covered a lot this morning, and I don't need to summarize it for you. But it's been an exciting morning and we're right up against lunch. Let me just give you a quick preview of what's coming after lunch because it's really exciting. We're going to provide for you an overview of a portion of what we see as our next wave of commercial opportunities, doing a deep dive into our neurology franchise and how we plan to bring those products from our wholly-owned neurology pipeline to the market. And then we're going to wrap up with the final presentation, which will be our financial strategy to maximize value to all shareholders to unlock value and that will be done by Beth Hougen. And we will have one more Q&A session towards the end. So with that, let's try to get back here by 12:50, Wade is telling me. We have box lunches out there and look forward to seeing you in a few minutes. Okay. [Break]