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

Good afternoon. Welcome to the Ionis Pharmaceuticals 2025 Annual Shareholders Meeting Corporate Update. I'm Brett Monia, CEO of Ionis and I'm pleased to provide an update on the great progress we're making at Ionis to improve the lives of patients and to meaningfully drive shareholder value. These are my forward-looking statements. So let's start at the beginning, and I mean the very beginning. Ionis was created to establish a new paradigm in drug discovery based on oligonucleotide approaches, targeting -- targeted against RNA. And although this was a formidable path, we persevered and we ended up succeeding when many others failed. We were first to create industry-leading medicinal chemistry and manufacturing capabilities. We were first to optimize and validate delivery to several organs in humans, including the liver and the CNS for human therapeutics. We optimized and validated multiple mechanisms of action in humans, including RNase H and splicing, and we led the way discovering and early -- and conducting early development of first-in-class medicines for serious diseases. Our business strategy at the time was to focus entirely on the science behind oligonucleotide therapeutics and to partner all our programs to support late-stage development and commercialization. This was the original vision for Ionis. Now let's fast forward to the year 2020 when I'm moving to the role as CEO of Ionis. As a founding scientist, I, of course, recognize the importance of scientific innovation for Ionis and was committed to not only preserving it but to strengthen it. However, I also recognize we needed to do more to drive far greater value for shareholders and for patients. And I believe that what we needed to do to accomplish this, could be summarized into two strategic objectives. First, we needed to deliver the drugs that we conceive and discover directly to patients, to bring our medicines through Phase III development ourselves and to commercialize our drugs ourselves. We needed to build and integrate a commercial organization to successfully commercialize Ionis medicines independently. We needed to prioritize and advance the wholly owned pipeline to maximize commercial success, to prioritize and strengthen Ionis' culture of innovation in parallel and always to maximize shareholder value. And of course, we needed a strategy to evolve Ionis into a fully integrated biotechnology company. We have to establish -- we set out to establish as our first step of co-commercialization collaboration with AstraZeneca to leverage a partner to ensure the global commercial success for a rapidly emerging product to the market, eplontersen for ATTR amyloidosis. And we also set out to leverage, as part of our strategy, the AstraZeneca partnership to accelerate and build our internal commercial capabilities for upcoming independent launches in parallel to establish commercial synergies and development synergies by prioritizing specific therapeutic areas, cardiovascular diseases and neurology and our strategy involved focusing initially on the U.S. market with plans to expand outside the U.S. with future medicines eventually. And the second strategic objective was to expand and diversify our platform technology to strengthen differentiation from emerging competition to expand the scope of our technology and deliver even more medicines to patients with commercial success and to solidify our leadership in RNA-based therapeutics. All of it to drive substantial and sustained revenue growth and positive cash flow and value to shareholders. This is the new vision for Ionis, and I'm pleased to report that we've made very strong progress in achieving our vision to date. We've strengthened the organization to support commercial success. We've built an incredibly experienced and innovative and scalable commercial organization to launch products that we choose to keep for ourselves and to bring to patients directly. We've strengthened key functional areas across the organization to support commercialization, late-stage development to conduct Phase III studies, legal, finance, compliance and so on. We've had a lot of success over the last few years from the medicines that we have prioritized to bring forward ourselves and using new chemistries and technology investments to have tremendous success, a positive Phase III outcomes such as for ATTR-variant polyneuropathy, FCS, hereditary angioedema and in hypertriglyceridemia. We've had 3 transformational medicines approved and launched within -- with 1 additional approval expected in the near term. QALSODY approved for a genetic cause of ALS, SOD1 ALS. WAINUA, Ionis' first launch of a co-commercialized medicine, this being with AstraZeneca. TRYNGOLZA, Ionis' first independent commercial launch and in anticipation of our second independent commercial launch, donidalorsen for hereditary angioedema. And we've also made great progress in diversifying and expanding our technological capabilities. We've expanded our platform with new backbone chemistries and other chemistries for antisense drugs. We've now implemented Ionis additional chemistry and know-how to the siRNA platform, which is now in clinical testing, and we're on the verge of declaring our first development candidate involving gene editing to optimize potency, durability and delivery. We've also optimized targeted delivery to new tissues such as muscle, skeletal and cardiac muscle and to expand and strengthen our leading neurology franchise by allowing us to potentially deliver our drugs to the CNS using subcu or intravenous routes of delivery. And all this has strengthened our leading franchises in cardiology, in neurology, while potentially opening up new therapeutic areas. So we are very proud to report now with the launch of -- the independent launch of TRYNGOLZA for FCS that Ionis has now evolved into becoming a fully integrated commercial stage biotechnology company poised to deliver great value, sustained and substantial value for shareholders. We have an industry-leading neurology franchise. Transformational medicines that are truly making a difference with drugs like SPINRAZA, QALSODY for CNS diseases and we knew for peripheral neuropathy as our anchor programs. And building off of these, we have many, many new potential transformational medicines coming for CNS diseases on the verge of potentially being delivered to patients, our Angelman program about to start Phase III development and our tau program for Alzheimer's disease with Phase II data expected next year and our Phase III program is zilganersen for Alexander's disease, which we expect Phase III data results later this year. And as I mentioned earlier, the technology advances we're making neurology is -- are on the brink of clinical testing that's going to further strengthen our leadership in neurology. In parallel, we have a large and expanding cardiovascular disease pipeline with several key late-stage Phase III programs, eplontersen for TTR cardiomyopathy expected to have Phase III results in the second half of next year. Olezarsen, TRYNGOLZA, poised to deliver for a much larger second indication for patients suffering with severely elevated triglycerides, SHTG with Phase III data expected soon and pelacarsen for LP(a)-driven cardiovascular disease. And again, the technology investments we started making several years ago are now on the brink of clinical testing to further strengthen our leadership in cardiovascular diseases. And we have overall the richest, deepest, broadest late-stage pipelines in the industry that's positioned to provide a steady cadence of near-term value-driving events. We have 10 Phase III studies on track to produce data for several years to come, including this year through 2028 for both rare and broad indications, wholly owned and partnered. This is what our late-stage pipeline looks like today. It's a big pipeline. It's a pipeline we're very proud of. It's a pipeline that offers multibillion-dollar revenue potential. Ten drugs in Phase III development, about half of which are wholly owned today and the other half partnered for a range of indications, principally in neurology and cardiovascular disease, which are the therapeutic areas of our focus for highly prevalent diseases such as Lp(a)-driven cardiovascular disease or eplontersen for TTR cardiomyopathy or bepirovirsen for chronic HBV or TRYNGOLZA for SHTG and for severe rare indications like FCS, HAD and ALS. In all, this is positioned to produce a steady cadence of very important events this year, next year and for years to come in the form of new launches, new drug approvals and new Phase III data readouts. The Ionis wholly owned pipeline is the priority for Ionis today and it's a rapidly evolving and, quite honestly, a very exciting pipeline. These are our near-term commercial opportunities coming from our late-stage pipeline, wholly owned pipeline that offers multibillion-dollar revenue potential. We are launched for TRYNGOLZA -- with TRYNGOLZA launch now for familial chylomicronemia syndrome, but as I mentioned earlier, we're rapidly approaching a second indication for TRYNGOLZA, a much larger indication with Phase III data expected in the second -- in the third quarter of this year for severe hypertriglyceridemia. Donidalorsen for hereditary angioedema with an anticipated approval coming up soon. Our zilganersen program for Alexander disease with data expected later this year. And then -- we're -- as I mentioned, we're about to start the Phase III program with first patient dose for our Angelman syndrome program, and we expect to complete enrollment next year. Four more independent launches in addition to the FCS launch in the next 3 years from our wholly owned pipeline. We couldn't be more proud of the late 2024 approval of TRYNGOLZA for familial chylomicronemia syndrome. This approval, which is the only drug is the first and only FDA-approved therapy for adults living with familial chylomicronemia syndrome, represents a milestone event for Ionis as it does show -- it illustrates the evolution of Ionis into a commercial-stage, fully integrated biotechnology company. Familial chylomicronemia syndrome or FCS is a severe, rare genetic disease that can be fatal. It is the result of genetic defects in one of several genes that cause loss of lipoprotein lipase activity. These -- because of these genetic defects, these patients suffer from severely elevated triglycerides that are 10 to 100x or even greater than normal. And because of this, they suffer from a whole range of symptoms, severe symptoms, including the potential for potentially fatal acute pancreatitis events. Tremendously high burden of disease that causes -- that results in poor quality of life and all kinds of stress, including psychological stress. Again, TRYNGOLZA is the first independent launch for Ionis in our history, and we're pleased to report very encouraging results from our first 3 months of the launch back at our earnings in March with over $6 million in revenue in that first quarter, beating consensus estimates for the launch of TRYNGOLZA in FCS. We -- what we've demonstrated, of course, for this -- in this program was robust efficacy, tremendously clean safety and with significant reductions, sustained reductions in triglycerides and substantial reductions in acute pancreatitis events. The first time ever shown that pharmacological intervention to lower triglycerides can actually reduce the risk of potentially fatal acute pancreatitis event. TRYNGOLZA is administered very conveniently by patients themselves using a simple self-administered auto-injector once per month. The successful encouraging launch of TRYNGOLZA to date, is the result of several aspects or areas, first, strong patient uptake. We've gotten quite a bit of prescriptions written from a whole range of different patient populations or approaches. First, we were able to convert the patients from our expanded access program in our open label extension patients in the U.S. to commercial drug rapidly. We also did a lot of work prior to the approval of TRYNGOLZA to identify and diagnose and help diagnose patients with FCS, and we were able to convert those patients to commercial drug fairly rapidly. And we also did a good job, although we still have much, much more work to do to identify new patients, newly diagnosed patients with FCS and get them on to the drug. Physician engagement on the Phase III results and the experience that they're having with TRYNGOLZA through their patients has been very positive. We have a good, broad scope of prescribers today, cardiologists, endocrinologists and lipid specialists and even some internal medicine doctors, and the payer dynamics has worked very well for us, too, to date with a good balance of both government and commercial payers covering SPINRAZA. And that is for both clinically diagnosed FCS as well as genetically confirmed FCS and the out-of-pocket expenses that we've been able to manage with our patients has been attractive for patients. As I mentioned, we're rapidly approaching a much larger patient population for TRYNGOLZA or olezarsen as the generic name goes. Severe hypertriglyceridemia or SHTG, and equally serious disease due to high triglycerides with high unmet need. SHTG is defined by having triglycerides 500 milligrams per deciliter and above, normal triglycerides are 150 and below. And these patients, like FCS patients are at high risk for acute, potentially fatal pancreatitis. Very broad population, high unmet need, large prevalence, impacting 1% of people in the United States, with no effective treatment. Most of these patients are already being -- doctors are already trying to treat them through fibrates and omega 3 fatty acids, but without much success. Those drugs are not very effective. So they're looking for an effective drug like TRYNGOLZA. High unmet need, as I mentioned, treatments today are not very effective. Our Phase III program is comprehensive to support the SHTG approval, Phase III results and subsequent approval. We have two pivotal studies, CORE and CORE 2. These are patients that have SHTG. They have triglycerides in the range of 500 milligrams per deciliter or greater. Our mean baseline demographics shows us that our triglyceride on average, are about 800, mean values in this study. We reported that in a publication earlier this year. These are registrational studies, about 1,000 patients in total between CORE and CORE 2. We're on track for data from these studies in the third quarter of this year. And assuming the data supports submission, we expect to submit our supplemental NDA by year's end. In addition, the ESSENCE study is a key part of the SHTG olezarsen Phase III program. It's a supportive Phase III safety study. to support the exposure database necessary for an approval by the FDA for a highly prevalent disease. It is not as SHTG patients but patients with mildly elevated triglycerides, 150 milligrams per deciliter to 500 milligrams per deciliter. Nearly 1,500 patients in this study, and we reported very positive top line data in May for this program. And here's a snapshot of those results. First is the largest study ever conducted for an RNA-targeted treatment to target and reduce triglycerides. And of course, what we were able to do here was to fully explore the potential for lipid lowering for olezarsen for hypertriglyceridemia patients in this mildly elevated triglyceride patient population and most importantly, to support the exposure database that we needed for the SHTG indication. We demonstrated really substantial reductions in triglycerides, 61% in the dose that we expect to be the commercial dose for olezarsen, 50 milligrams was quite good too, had a 58% reduction in triglycerides in placebo corrected at 6 months. And we met all the key secondary end points, and we're looking forward to presenting all this data in detail at a medical congress later this year. In addition, the vast majority of people that were participating in the trial, we were able to normalize their triglycerides to below 150. And very importantly, all with a very favorable safety and tolerability profile. So as I mentioned, we're looking forward to presenting this data as well as getting our CORE and CORE 2 SHTG data in the third quarter of this year, and we look forward to presenting the CORE and CORE 2 data at a medical congress later this year as well. So to wrap up olezarsen, it really is a breakthrough not only for FCS patients, but a potential real breakthrough for this highly prevalent SHTG patient population with high unmet need, has the potential to be a real blockbuster for patients -- for Ionis as well as for a really meaningful -- providing real meaningful difference for patients suffering with high triglycerides. We have first-mover advantage for both FCS and SHTG and we plan to take full advantage of that. The launch for FCS is going well, which bodes well for SHTG. And we're looking -- as I mentioned, we already have Phase III -- positive Phase III data in ESSENCE, which helps derisk the CORE and CORE 2 outcome, and we're looking forward to the CORE and CORE 2 data very soon. Moving on to our anticipated second independent commercial launch for Ionis. Donidalorsen, a potential advance -- a real advance for people suffering from hereditary angioedema, positioned as a prophylactic treatment for this disease. Hereditary angioedema is a rare genetic severe disease that can be -- that is potentially life threatening. And it is also often hereditary, so it's passed down from generation to generation. These patients experience recurring unpredictable, severe swelling of various tissue beds and if it affects the throat, it can be fatal due to suffocation. Patients that have this genetic disease often experience their first attacks at a very young age of most commonly before their 18th birthday and often within the first year or 2. The prevalence of this disease is just expected -- is estimated to be around 20,000 in the U.S. and Europe. There are treatments available today, prophylactic treatments on the market for hereditary angioedema but it's very clear that these treatments are inadequate for patients. New treatment options for HAE are desperately needed. And that has been solidified, that position has been solidified very recently through various patient surveys that have been conducted as well as Harris Poll, the Harris Poll that was conducted, really reinforcing the need for new treatments for hereditary angioedema. So examples of the outcome of these surveys in its poll, 91% of patients that our survey expressed an interest in trying a new prophylactic therapy that had a profile that they thought would be better than the one that they had. 89% of patients have reported even with the treatments that they're on missed or avoided activities of daily living over the past 12 months, 65% of patients reported that they cannot find, they've still not found the prophylactic treatment of choice for them. And what we also know in the U.S. market alone is that more than 20% of the patients switch today to alternative treatments because they are unsatisfied with the treatments that they have, and they often switch back to the treatment that they were on, if they continue to be unsatisfied. The point is that this is not a sticky market. Patients are looking to find better alternatives to manage hereditary angioedema, and we believe donidalorsen has the profile to meet the needs of patients. This slide shows some data from our Phase III study, OASIS and our Phase III open-label extension OASIS-Plus, which demonstrates sustained reduction in HAE attacks are durable but with extended treatment. In the gray in this slide is our Phase III results. In this study, we examined a dose of 80 milligrams either once every 4 weeks or once every 8 weeks. In this study, every 4 weeks is shown in dark purple and every 8 weeks is shown in orange versus placebo in black. And what you can see is that both dosing regimens produce substantial and rapid reductions in HAE attacks during the course of the Phase III study with the every 4-week dosing regimen having a faster onset of action over the every 8-week dosing regimen. However, with long-term treatment in the open-label extension, what we also see is that the every 8-week dosing ends up being as good in reducing HAE attacks as the every 4-week dosing. We believe that this is a very important advantage. It provides flexibility in dosing for patients be able to dose themselves using a simple auto-injector once per month or once every 2 months. We demonstrated 93% improvement in our open-label extension, improvement from baseline in every 4-week dosing, which was essentially matched with that 92% improvement in reductions of HAE attacks with the every 8-week dosing, with no emerging safety or tolerability issues with long-term treatment, very, very exciting profile for patients. In addition, we conducted a very novel study to further differentiate donidalorsen from the rest of the prophylactic treatments that are available today for HAE. I mentioned that there are prophylactic treatments today available in the U.S. market and in fact, more than 70% of people with HAE are on some form of prophylactic treatment today in the U.S. So unlike TRYNGOLZA for FCS, where we're first to market, donidalorsen represents a different commercial strategy in which we're going to be focused on switching patients from their existing prophylactic treatment, which are unsatisfied to donidalorsen. . So to support this commercial strategy, we implemented the first of its kind, a prospective Switch study in which we invited people with HAE who were on prophylactic treatment, whether it be lanadelumab, berotralstat or a C1 inhibitor, to enter a trial and switch over to donidalorsen. And of course, why would patients do that? Well, at this time, we ended our Phase II data that was out and published and we're excited about what we saw in Phase II. . The purpose of this study was to provide guidance to safely switch patients to donidalorsen. How do we switch safely from one prophylactic treatment to donidalorsen and prevent attacks from happening as we go through that transition period? In addition, we wanted to generate long-term donidalorsen efficacy and safety and we also wanted to understand what the patients prefer. Did they prefer their original treatment or did they prefer donidalorsen in this study? We were pleased that we were able to enroll this study quickly, which we believe reflects the fact that patients are unsatisfied with their current treatments and they're very much looking forward to a new potential option to treat their HAE. The next slide shows a snapshot of the results from the donidalorsen Switch study. What we demonstrated was not only were we able to safely transition people -- patients with HAE from their existing treatment to donidalorsen without any breakdown or any gaps in protection, we were actually able to further improve or reduce the number of HAE attacks compared to their baseline value, 65% further reduction compared to what they were experiencing with lanadelumab. 73% further reduction compared to what they were experiencing with berotralstat or 41% versus C1 inhibitor. . And what was also really insightful was an independent survey that was conducted at the end of the study of patients, 84% of patients who switched to donidalorsen said that they prefer donidalorsen over their previous treatment. And I'm pleased to report that these patients have now entered into a long-term open-label extension and have stayed on donidalorsen -- vast majority have stayed on donidalorsen long term. So donidalorsen, we believe, is positioned to be a preferred treatment for patients with HAE -- for many patients with HAE. A really exciting product profile and there's a clear and unmet need, robust clinical profile, well-defined patient population, and we have data to support the switching -- the rationale for switching patients from their existing treatment over to donidalorsen. We have a very efficient launch approach. We know we have a concentrated prescriber base with about 1,000 allergists immunologists as our targets, and it's relatively straightforward to manage this. We have a PDUFA date of August 21 this year. And assuming an on-time approval, we will launch soon after the approval of donidalorsen in August. Moving on to a third very important medicine that has recently reached the market, WAINUA, a novel treatment for ATTR amyloidosis. As a reminder, WAINUA is being developed to address a disease called ATTR amyloidosis where there is a very high unmet medical need. This disease is caused by the accumulation of a toxic protein that's produced in the liver called TTR, transthyretin, which accumulates in various tissues and extracellular various tissues, causing a whole range of phenotypic issues, problems, including the eye, the spinal cord, GI and the kidney and so forth. But what we're really focused on are two indications. One is peripheral neuropathy, which greatly affects the quality of life and can be fatal for these patients, and cardiomyopathy, TTR cardiomyopathy, which, of course, affects the heart due to the accumulation of TTR amyloid in the heart. It is estimated that there are about 40,000 people in the U.S. and Europe that have TTR polyneuropathy -- or I'm sorry, hereditary TTR polyneuropathy and approximately 300,000 to 500,000 people with TTR amyloidosis worldwide, including both hereditary forms, which is a mutation in TTR gene that causes this. For patients that do not have a mutation in TTR gene, it's called wild-type TTR amyloidosis and principally wild-type disease affects the heart -- TTR cardiomyopathy. Late in 2023, we were thrilled with the approval of WAINUA for ATTR-variant or hereditary polyneuropathy. Again, this is our first step toward -- this represented our first step towards commercialization for Ionis. It's a co-commercialization partnership with a long, trusted partner, AstraZeneca, was approved in December 21, 2023, for hereditary TTR polyneuropathy. And we're very pleased with the launch of WAINUA for TTR polyneuropathy. The first full year 2024 was very strong, very positive, and we're looking forward to a very positive growth year -- continued growth year for WAINUA for TTR polyneuropathy through 2025. And this is based on really good experiences by the patients as well as by the physicians that prescribe WAINUA. And then comes the next indication for WAINUA, the much larger ATTR cardiomyopathy disease population. We are conducting a global Phase III development study called CARDIO-TTRansform, it's the most comprehensive, the largest study ever conducted in ATTR cardiomyopathy, this fatal disease and desperate need for better treatment options. And because of the size and the design of the study, we're positioned to deliver the richest data set in this population ever conducted to date, more than 1,400 patients fully enrolled with data expected in the second half of next year. So I've touched on olezarsen and I've touched on WAINUA for TTR cardiomyopathy, olezarsen for SHTG and WAINUA for TTR cardiomyopathy. Those are two late-stage programs from our leading cardiology franchise. Our third Phase III program is pelacarsen for LP(a)-driven cardiovascular disease. Today, our cardiology franchise boasts 5 medicines in clinical development, 3 Phase III studies, the 3 that I just mentioned, 2 of which are involved in cardiovascular outcome trials, eplontersen and WAINUA and pelacarsen. Two of these are wholly owned medicines by Ionis, and we're continuing to advance key technology advancements forward towards the clinic to further strengthen our leadership in cardiology, including subcutaneous administration using semiannual or annual dosing for follow-on programs and new programs. And we're on the verge of clinical testing of our first targeted delivery of cardiac myocytes for CV indications, such as heart failure. As I mentioned, I've discussed olezarsen and WAINUA and eplontersen from our cardiology franchise. However, before closing out the cardiology section of this presentation, I want to touch on pelacarsen because pelacarsen is a very exciting program, Phase III development, addressing a major independent risk factor lipoprotein(a) for cardiovascular disease, which reflects more than 8 million people worldwide suffering from cardiovascular disease due to high LP(a) levels, and that's because LP(a) is an independent genetic risk factor for cardiovascular disease. It's not related to other risk factors such as hypertension, LDL cholesterol or diabetes. It can cause heart attacks, strokes and other forms of cardiovascular disease at a very young age, if you have very high levels of lipoprotein, LP(a). Our partner, Novartis, is conducting the Phase III HORIZON study with more than 8,000 patients with high LP(a) fully enrolled last year. And with the recently published baseline demographics paper recently published demonstrating that study has been very well executed, and we're looking forward to data in the first half of next year with the potential if the study, get the results support a regulatory filing in the second half of next year. So now moving on to our leading neurology franchise anchored by 3 approved medicines, SPINRAZA for spinal muscular atrophy, QALSODY the first-ever approved medicine for a genetic form of amyotrophic lateral sclerosis or ALS, 2 CNS diseases. And then WAINUA, which I already touched on for peripheral neuropathy. These are the anchors and right behind these medicines are 13 medicines in clinical development for a range of neurological diseases, including large indications such as our Tau program for Alzheimer's disease and ION464 for multiple system atrophy and ION859 for Parkinson's ease and severe, rare diseases with high unmet need like our Angelman program and our Prion program and our Alexander disease program. Eight of these 13 medicines today are wholly owned, enjoying the benefits of a proven validated platform to target CNS diseases. And like in cardiology, we continue to advance our leadership through technology for CNS diseases. Today, our drugs are administered intrathecally. That is a quick, fast spinal cord injection procedure. And we're rapidly moving new chemistries into the clinic that we believe will support semiannual or even annual dosing intrathecally moving from monthly to quarterly to now semiannual and potentially annual dosing. In addition, we're making great progress overcoming the blood-brain barrier. The blood-brain barrier, of course, that forces us to deliver our drugs intrathecally because these drugs do not cross the blood-brain barrier when systemically applied but we're making great progress in overcoming that barrier, potentially enabling us to deliver our medicines to the CNS through subcutaneous or intravenous administration. We're also making great progress opening up new tissues for neurology, including skeletal muscle allowing us to potentially tackle neuromuscular diseases in the not-too-distant future. Now I'd just like to touch on a couple of our ongoing Phase III programs from our neurology franchise. First, zilganersen for the treatment of a severe genetic leukodystrophy causing -- called Alexander disease, a devastating neurological disease with no approved treatments today. As I mentioned, this is a rare disease. It's a rare leukodystrophy. These patients suffer from a range of symptoms, including cognitive -- major cognitive defects, major defects in gross and fine motor function, speech, constant seizures that can be severe. And as I mentioned, it's a fatal disease, typically median survival between 14 and 25 years of age. Our Phase III program for Alexander's disease is well along and we're expecting data from our Phase III pivotal study in the second half of this year. So stay tuned for that. And then our next wholly owned Phase III program in neurology is our Angelman syndrome program, a severe neurodevelopmental disorder with an enormous unmet medical need, more than 100,000 people in major geographies are estimated to have this severe disease with no meaningful treatment options available. It's caused by a loss of function of a gene called UBE 3A and symptoms usually start being detected after a couple of years after birth. These individuals live -- have normal life expectancy. However, the burden on families and caregivers is enormous. They have profound developmental defects, cognitive delays, require full-time supervision throughout their life. It's a tremendous unmet need. We think we have a potential treatment for this medicine -- for this disease called ION582. There are no effective treatments today, but we're hoping to change all of that. Why we feel great about ION582? Well, we believe it has the potential, as I mentioned, to address this awful disease. Based on the data we presented last year from the HALOS Phase I/II study, very positive, encouraging results from this study. What we demonstrated in the study was consistent and meaningful improvements in essentially all areas of clinical function that we measured, including communication, cognition and motor function across age groups, across genotypes with favorable safety and tolerability. Our Phase III study, called REVEAL, is about to start recruiting any day now with the first patient dose imminent -- with expectations to complete enrollment in this study, which is about 200 patients looking at 2 dose groups with a placebo control across age groups, children and adults looking at, as I mentioned, 2 dose levels, 40 milligrams and 80 milligrams quarterly versus placebo. And again, this is a priority wholly owned program for Ionis. We have a lot going on right now. A lot of positive results over the last few years, setting us up for an exciting second half of 2025 and 2026 and for years to come, a lot of key value-driving things. Phase III studies, I already mentioned the Phase III results that we're anticipating in the second half of this year from our olezarsen, TRYNGOLZA SHTG Phase III study and our zilganersen, Alexander disease program and the start of our Angelman Phase III study. And next year, we're anticipating 5 Phase III readouts from -- for pelacarsen, eplontersen in cardiomyopathy and the bepirovirsen, sefaxersen, ulefnersen and the completion of enrollment for Angelman's. And all of this translates to a whole host of support of regulatory actions, including the approval of donidalorsen anticipated later this year for HAE. And then approvals in other geographies. And then as we look to 2026, additional approvals based on the Phase III readouts that we're anticipating this year and next year and what follows, of course, are the launches. The donidalorsen launch this year, the European launch for TRYNGOLZA in FCS this year, and then next year, we're looking to the SHTG olezarsen Phase II launch and potentially the zilganersen launch for Alexander disease, assuming, of course, the Phase III results support these launches. So we are at an inflection point for Ionis. In 2025, we're positioned to deliver a steady cadence of new important medicines over the next few years. From our wholly owned pipeline, we anticipate 3 independent launches over the next 3 years. And from our partner pipeline, we're anticipating for -- also 4 key partner launches over the next few years. Again, severe, rare indications as well as highly prevalent disease indications. And when you look at this slide, you can see the steady cadence of expected launches that's coming -- that's anticipated for Ionis from our both partner pipeline as well as our wholly owned pipeline. And what you can see just through the next few years, with SPINRAZA, QALSODY and WAINUA for ATTR polyneuropathy as our anchor, now TRYNGOLZA for FCS and then as we look to the expected launches for additional medicines next year and the year after, we are positioned to achieve more than $2 billion in annual peak royalties from our partner pipeline and more than $3 billion of potential annual peak product revenue from our wholly owned pipeline. In total, estimated -- expected to be more than $5 billion in potential annual peak product revenue from our wholly owned pipeline as well as from our partner pipeline through royalties. And this does not -- from our partner pipeline, this does not even include expected milestones that we would receive as our programs advance through approval and launch from our partner pipeline. And then there's so much more coming even after this -- after the next few years with drugs like our Tau program, our MECP2 program, our Prion disease program and of course, our Angelman's program that I already touched on setting us up again, for a steady cadence of expected launches that we are positioning to power revenue growth and positive cash flow and ultimately, profitability in the not-too-distant future. So to conclude, we're making tremendous progress at Ionis. We believe we're delivering great value to patients and that are setting us up to drive meaningful shareholder value in the near term and sustainably. We have established a proven and prolific discovery and development engine. Our pipeline has been delivering consistently at all stages, in particular, our Phase III programs. We've now built a highly experienced, innovative commercial organization. We just recently increased our 2025 financial guidance, and we have a clear path through the progress we're making in our pipeline to positive cash flow in the not-too-distant future. All of this is setting us up to improve the lives of millions of patients through the transformational medicines that we can see, we discover and now we deliver for years to come, which will drive tremendous shareholder value in the future. Thank you very much. And with that, we'll open up for questions.

We've got quite a few questions actually. We'll try to get to all of them in the time we have left, if not, you can always contact us here at -- in the IR department, and we'll try to answer your questions the best we can. The first question we have actually comes from analyst from Raymond James. He's asking us regarding the donidalorsen PDUFA in August, how have your communications with FDA be going? And what is your level of optimism and the timely approval with a favorable label with all the necessary data that will help you differentiate doni, do you expect to include both once monthly and every other month dose in the label.

Yes. We are -- we, of course, are monitoring the FDA and the changes at the FDA very closely. But I'm happy to say that at this point, we've seen no disruption in the review time line or the quality of the review for donidalorsen in -- by the FDA for the expected approval -- on-time approval of August 21. So far, we are exactly where we should be, in the review process about 2 months ahead of PDUFA, and all things are green light go. Yes, we absolutely expect to have provided the option that's in the label for every month dosing or every 2 months dosing, that's because both dosing cohorts were highly statistically significant. So the FDA -- we're very confident that the FDA will support this dosing regimen in the label. And we also are reasonably confident that we'll be able to refer to some of the Switch data that I talked about in my presentation in the label. How much, is to be determined but our confidence is growing.

[Operator Instructions] Our next question is from an investor who's asking us what is holding up some of the rollout of your preclinical work to start clinical trials, how many new drug targets do you plan to start, clinical trials in the remainder of this year?

We continue to have and we've actually strengthened our research organization. It's a prolific organization that typically delivers 3 to 5 drug candidates each year, and we're continuing to do that. We're anticipating a number of candidates to reach IND supporting comp studies this year in that range, 3 to 5, and this includes -- these are entirely focused on cardiology as well as neurology, which is our therapeutic focus and it involves new technologies, new targeted delivery strategies, new drugs for new target disease indications as well as follow-on programs, follow on programs for the drugs that we brought forward ourselves. We're continuing to advance the technology and to support further improvements and to strengthen these franchises. We're bringing on follow-on molecules as well. We don't report targets and drugs in Phase I development typically anymore. It's a very competitive space. And there are a lot of others that follow what we do and we monitor it very closely. But rest assured, we are incredibly prolific these days, and we're continuing to advance 3 to 5 new programs into development each year. So stay tuned for that.

There's a couple of questions from investors that are related. I'll kind of read them together so they're kind of are related. When we have a bicycle muscle targeting compound enter the clinic, what's the target? Is it wholly owned or subject to the Biogen collaboration. And then a separate related question, I think is when will you develop a LICA drug to target DMPK and when we start rolling out your preclinical drugs to start clinical trials.

So we're moving rapidly forward with multiple oligonucleotide drugs using bicycle conjugation, technology towards the clinic. The first one that we expect to reach clinical testing, and we're reasonably confident that we'll initiate this year is actually partnered not with Biogen but with AstraZeneca. And we're utilizing this technology to target cardiac myocytes for heart failure indication. The target is confidential, but we anticipate that to start clinical testing potentially this year. We have wholly owned bicycle programs as well, several -- for both cardiac myocytes for heart failure types of indications as well as for skeletal muscle for neuromuscular, we've declared our first candidate actually already wholly owned. That will be moving into manufacturing and then moving to IND tox studies. And then we have 1 or 2 more after that, that are coming. That's where -- in the new ones, these ones to follow the first one are for neuromuscular indications. So stay tuned. It takes time to move these things forward but they are advancing. We're looking at 3 candidates using bicycle technology, including the one that -- partner that I mentioned to be moving into IND tox studies and into the clinic very soon. We're not commenting on what those targets are. Obviously, we're very experienced with DMPK and a whole range of other targets that are relevant to neuromuscular diseases as well as cardiac myocytes. So stay tuned, we'll declare the targets at the appropriate time. Again, it's a very competitive space. And we just got to protect -- we got to protect ourselves and our shareholders as much as we can to fend off competition.

So a related question about bicycle technology targeting transferrin receptor. Can you give us an update on how you're using this technology to deliver drugs via the blood-brain barrier and do you have a breakthrough in this technology? And when can we expect drugs to be in clinical trials using this technology?

So for blood-brain barrier, we're using several technologies, not just bicycle, to really optimize delivery across the blood-brain barrier for CNS diseases. Bicycle is one of them. We are getting close to declaring a candidate -- development candidate for a CNS disease that's wholly owned. And that will probably happen by the end of the year if not early next year, and then we'll move into IND tox study. So don't expect our BBB drug to reach the clinic this year or the next, not next year because we have to do the manufacturing and toxicology studies but they are moving forward and right behind the first one is the second one and the third one and a fourth one. So it's really a prioritization. We're in a great position that we have to prioritize, which ones are going to go first, and we're really excited about the first target that we're going to move forward. And again, it's a wholly owned CNS disease that we're targeting that we think we really have a great strategy for overcoming the blood-brain barrier.

A question from investor related to CNS targeting. Many of your competitors are using conjugated siRNA to target CNS. How are you addressing this competition since your drugs are not conjugated and have not been conjugated a disadvantage?

As I mentioned in my presentation, the second -- in addition to full integration, for Ionis is a key objective for the company and the new vision for the company. The second objective is to expand and diversify our technology to really extend our leadership position in oligonucleotide therapeutics. And that means that Ionis is now utilizing new chemistries, is using antisense mechanisms of action. We're also delivering to the clinic new siRNAs using Ionis siRNA using medicinal chemistry discovered at Ionis with Ionis know-how for siRNA applications as well as I mentioned gene editing in my presentation, too. Our first siRNAs are in the clinic. We have a lot of experience with siRNA, especially over the last few years, CNS diseases as well as systemic applications. We believe that there are applications where antisense oligonucleotides are the preferred choices. We can get into -- I don't want to give you all the details here but we have a very clear path to where -- what types of targets and the types of drugs are preferred for antisense mechanisms of action. And then we also see applications for siRNA technology that offers significant advantages, and that's why we're pursuing siRNA too. We have a wholly owned Ionis discovery siRNA already in the clinic. We're looking forward to sharing data in that program later this year. The bicycle conjugate with AstraZeneca that I mentioned that's targeting cardiac myocytes as an siRNA, conjugated to bicycle. And we also have antisense oligonucleotide bicycle conjugates that we're moving forward ourselves. For CNS applications, the conjugate you're referring to using intrathecal deliveries of C16 lipid. The reason why siRNA uses a C16 lipid is because it has to have acceptable distribution in the CNS following high conjugate delivery. Using the chemistries we use for antisense oligonucleotide in CNS, we don't need that lipid for distribution. We get rapid and deep uptake of oligonucleotides ourselves. But like I said, we have plenty of experience with C16 siRNAs in CNS, and we're on top of all that and where we get the best drug win, if you will. We look at ASOs, siRNAs and so on. And then for blood-brain barrier is the same thing. We're using conjugates with antisense oligonucleotides with novel chemistries with antisense oligonucleotides as well as siRNAs and we're characterizing both. So we -- our philosophy at Ionis is we have the best oligonucleotides, medicinal chemists and biologists and we will pursue and bring forward the very best drug, very best mechanism, agnostic to antisense or siRNA.

Thank you. We've got a couple of more questions from our current analyst at Raymond James. One is on TRYNGOLZA in FCS and one is on pelacarsen. The first question is on the TRYNGOLZA launch in FCS, how challenging has the process been thus far for identifying new patients and bringing them on drug? And what are some of the initiatives that you're using to achieve that? And as you've been promoting for FCS, what have you been hearing from physicians about the extent of the unmet need in SHTG and how they would use TRYNGOLZA if it were approved for that?

Yes. We -- again, the launch of TRYNGOLZA is very encouraging to date. We did a lot of work prior to the approval of TRYNGOLZA for FCS and doing our best to identify potential patients. Of course, you can't confirm that they were FCS patients until you actually have a drug with label. But we identified the large pool of potential patients and of course, we had -- as I mentioned, we have the patients that converted over from our clinical trials to commercial TRYNGOLZA. And we're using the same methods that we use to identify prior to approval now to identify patients. And that is basically to start with a funnel that begins with severely elevated triglycerides. Do your patients have severely elevated triglycerides? And the -- and of course, that can be measured with a simple routine blood smear, blood panel. I mean, and if they have severely elevated triglycerides then the next step is, okay, can -- let's now move on to FCS diagnosis either genetic or clinical using one of several -- one of the two tools, the North American FCS scoring tool, which can provide a clinical diagnosis of FCS or in Europe, they're using a criteria called the Milan criteria, which -- and we're using those. So it's really a funnel. First, severely elevated triglycerides, now is confirmed those patients with FCS. That's how we identified them prior to the launch, and that's how we're identifying them going forward. It's estimated that there are up to 3,000 people with FCS in the United States. And what we're hearing from physicians is that their patients are doing remarkably well. We have so many treaters that are reauthorizing treatments. They're bringing in new patients. After their first experience with TRYNGOLZA with their first patient, the feedback has just been remarkably positive. And the estimates of about 3,000 in the United States is -- appears to be pretty confirmed by these treaters. And then with respect to SHTG, yes, it's a great question. I was at the north -- the National Lipid Association Annual Meeting this past week, last week. And I had the pleasure to meet with a whole long list of lipid specialists, cardiologists, endocrinologists that manage FCS patients, SHTG patients. And not only have they -- not only was TRYNGOLZA the center piece at that meeting, attendance was increased 20% compared to past years, which was totally based on new treatment available to manage a terrible lipid disease due to triglycerides. Not only is their FCS experience has been incredibly positive, they were just waiting for a treatment like TRYNGOLZA to become available to manage their patients with SHTG. And what we've heard consistently is that there's a patient prioritization that they believe they will enact on starting with patients that are above 880 or 1,000 milligrams per deciliter, if you will. These are patients with severely elevated triglycerides that are high risk for acute pancreatitis or patients that have had an acute pancreatitis attacks in the past, so they have a history of AP. Those are the patients they're going to focus on initially. . And that's a large number of approximately 1 million people in the United States that meet that criteria. And again, they emphasize that they're already treating these patients. They just can't -- they don't have effective treatments. They treat them with fibrates and omega-3s and they can't get these patients under control. So they're just waiting to add TRYNGOLZA to the armamentarium. And as a reminder, our Phase III study in SHTG, virtually all patients are already on fibrates and omega-3. They just -- their triglycerides are still very high. So it's not working. So TRYNGOLZA will just be -- they're just waiting for it, but they're particularly focused on patients with a history of AP or patients that are in that 880 to 1,000 range or higher to treat with TRYNGOLZA, but the reception was very, very strong, very positive.

That's great to hear. So related to this, I know we're running out of time but the question related to this was that what are your expectations to the key endpoints, primary triglycerides lowering. There is a key secondary endpoint of pancreatitis. We have to get this question, do you expect to see benefit in pancreatitis?

So now let me also bring us back to the experience I had last week at the National Lipid Association meeting because it's related to that question. I sat down with a long list of HCPs who manage these patients, and I asked each one of them individually, do you need to see a statistically significant or even a major reduction in acute pancreatitis in the CORE and CORE 2 studies to prescribe it to patients with SHTG. And uniform 100%, 14, 15 HCPs that I sat down with and met, uniformly each one of them said no. What I need is a drug that lowers the triglycerides, cut it in half, 50% reduction in triglycerides on top of standard of care. And I'm ready to prescribe. Why is that? They already now that these patients are at high risk for acute pancreatitis and they have many patients that have had AP events. They want to -- and in other patients, they want to prevent that first AP event from happening, they don't want to have that first AP event. So HCPs don't need that AP data to prescribe. As a reminder, we do have AP data in our label. This is a supplemental NDA. We got that in the label with FCS and also, with that said, we're also feeling reasonably confident that we'll see trends in the Phase III study, reducing -- showing the reduction of AP events compared to placebo in our study. Although the rate of AP in SHTG is lower than an FCS because FCS patients' triglycerides are much higher. Our study is more than 10x the size of our FCS Phase III study. So just based on pure numbers, we expect to have a good number of events -- AP events in this study. And if the FCS Phase III study is an indicator of what you're expecting, SHTG, most of those events should be in the placebo group and not in the treatment group. So we know that showing a reduction in AP events is very important for a segment of the investor community but -- and we're going to have that data. But in the eyes of the HCPs, all they need to really see is substantial reductions in triglycerides to prescribe TRYNGOLZA.

Thank you. So I know we're over time, so we're going to end on one last question. And for the other questions that we didn't get to, we'll reach out to you -- we have your contact info. So we'll reach out to you and provide you with some answers to those questions offline. The question -- the last question is for pelacarsen, what type of outcome in that study in terms of improving CV risk you're hoping to see? And what would you consider a major success for patients with high LP(a)?

So aside from supportive attractive safety and tolerability, what Novartis has published and based on clinical manuscript that recently came out is that they're looking for an overall relative risk reduction in that study on the order of about 20% in the overall population, that is patients with LP(a) 70 milligrams per deciliter and above and the subgroup of patients, 90 milligrams per deciliter and above, which represents a sicker population, they estimate a relative risk reduction of 25% in the study. So anything in those ranges would be a highly successful outcome. As a reminder, there are no treatments that lower LP (a) and get patients out of harm's way for LP (a)-driven cardiovascular disease. That includes LDL-lowering therapies or other therapies that are available today. So this represents -- pelacarsen represents a potential breakthrough in the field of cardiovascular therapeutics and we are very much looking for the data, the Phase III readout in the first half of next year.

Thank you.

I want to thank everybody for their time. I think you all agree with me that the progress that we're making at Ionis is remarkable, and we continue looking forward to providing updates on further progress as the company goes forward this year and well into next year in the future. Thank you for all your support, and have a great day.