Ionis Pharmaceuticals, Inc. ($IONS)

[Audio Gap] and I couldn't be more thrilled to provide an update on the remarkable progress we have made at Ionis to drive accelerating value for all IM stakeholders over the last few years and more importantly, how we are set up to drive even greater value in the years to come. Of course, I will be making forward-looking statements during my presentation. So please take this under consideration in any interest you have in Ionis going forward. The [indiscernible] nucleotide therapeutics is -- has emerged as 1 of the most exciting and important new approaches the drug discovery and drug development in the pharmaceutical industry, and we're proud of the fact that Ionis pioneered this field. Well, accordingly, we have a rich history in discovering and developing transformational RNA targeted medicines for a whole range of medically important diseases. In support of this, we created the industry-leading medicinal chemistry and manufacturing capabilities here within Ionis. We've -- we were the first to optimize and validate oligonucleotide therapeutics of any kind deliver for diseases related to liver-derived factors as well as to the central nervous system for human therapeutics. We are at the forefront of validating, optimizing mechanisms of action of RNA-targeted therapeutics, whether it be mechanisms that result in the degradation of the targeted RNA to block the production of toxic proteins such as through an RMS mechanism or to modulate and improve splicing mechanisms so that we can replace proteins, upregulate proteins that are lacking in loss of function diseases. And this has led to us leading the way in discovery and developing first-in-class medicines for a range of serious diseases. We had remarkable progress across the business over the last several years. And this has set us up very well for accelerating growth, accelerating value creation for years to come. One of the most important decisions we made and a decision that has played out extremely well, great success is the evolution of Ionis from a research and development organization to a fully integrated commercial stage biotechnology company, creating a commercial organization of excellence and has always matched the excellence we've always exhibited in research and development. And this is based on a truly groundbreaking technology, technology that continues to advance forward with state-of-the-art fold-type approaches creating a high-value, innovative pipeline. We have consistently, especially over the last few years, delivered breakthrough clinical results that have enabled highly successful drug approvals and commercial launches and all of this is setting us up that drive revenue growth -- accelerating revenue growth, positive cash flow and value creation for everybody involved in the Ionis onshore. Over the last few years, we've had remarkable success. And just over the last 3 years, some of those achievements are shown in this slide. Six positive as III data readouts that have resulted in 4 approved medicines and medicines with brand names that you can read there on the slide. We're expecting 3 more approved medicines by the end of this year. Two of these approved medicines and independent and launches, commercial launches have been independent. Our first independent launches in Ionis' history, Tringolza for familial conomicronemia syndrome and DAWNZERA for hereditary, there's a lot more coming, and we've created a remarkable pipeline with 11 medicines in late-stage development and many more, of course, at mid Asia just getting started from in the clinical pipeline. We're very proud and very pleased with the on-time approval last August of DAWNZERA, as a prophylactic treatment for hereditary angioedema. Now although there are prior to DAWNZERA's approval, prophylactic treatments for this devastating genetic rare disease -- we also recognized, and this is why we moved on DAWNZERA forward that the unmet need for patients is still vastly large. There's a lot of unmet need here for patients, and we felt that on DAWNZERA and fill the needs of those patients. DAWNZERA is a very novel mechanism of action. Of course, as the first and only RNA-targeted treatment to prevent severe swelling HAE attacks, which can be failed in these patients. And we're pleased that the launch is going very well because this is a market where existing prophy contributes existed prior to the approval of DAWNZERA, as I mentioned. We're moving to a market where the goal is to switch patients. from their existing prophylactic treating where they're dissatisfied to DAWNZERA. And in fact, in this launch, we're seeing the majority of our patients switching from other prophylactic treatments DAWNZERA also patient have managed their disease through other means such as on-demand treatment or even treatment naive patients. We're seeing a growing number of repeats with subscribers or prescribers and launch is gaining significant momentum, and we're proud of the fact that our first quarter results, we achieved 128% improvement over our first quarter launch. And I can tell you that the launch for DAWNZERA continues to be quite strong. We look forward to presenting an update on our Q2 earnings later this year. Now moving on from DAWNZERA, which, of course, is being -- which is a disease hereditary angioedema, it's managed by allergists and immunology is very different than the bulk of our pipeline today. I want to drive -- I want to turn attention to our leading therapeutic, areas of focus, cardiometabolic diseases and neurological diseases. Two areas where we have proven value time and time again from our pipeline, 2 areas that we pioneered, and we've developed drugs and are developing drugs for both rare and prevalent disease indications, several of which have multiple -- several of which have blockbuster potential. Now I want to start by providing some of the progress we're making in cardiometabolic diseases and then I'll move over to neurological diseases, some highlights in neurology as well, starting with cardiometabolic disease and starting with olezarsen. Olezarsen, a transformational medicine or disease indications, all disease indications related to severely elevated triglyceride. There's a high unmet need for better treatments to manage patients with high triglycerides. And we're developing olezarsen, and you'll see this in a moment, our brand name for olozarsen for its first indication is called Tryngolza. And I may go back and forth between Olezarsen and Tyngolza here and there. The first indication is a rare, severe genetic disease call familial kiomicrodemia syndrome or FCS. In the U.S., there's about 3,000 people suffering from this debilitating disease. As I mentioned, it's a genetic disorder, which is a consequence of severely elevated triglyceride through certain mutations in the genome of people. These patients these people suffer from a whole host of comorbidities, but what is most significant is the risk of a potentially fatal and recurring, if not fatal, acute pancreatitis attack. And then there's a second indication, severe hypertriglyceridemia. This is not a rare disease. This is a disease that affects millions of people in the United States long do is defined by very high triglyceride levels. In this case, triglyceride at the definition of SHTG in the U.S. are triglycerides above 500 per deciliter, normal triglyceride below 150 although this is not a genetic disease, it's not a rare disease, these patients suffer from the same most significant risk that FCS patients suffer from the risk of a potentially fatal acute pancreatitis attack. They also suffer from risk of ASCVD cardiovascular diseases. And although there are some generic treatments for high triglycerides for SHTG today, they're grossly inadequate. They cannot get triglyceride for the most part, the vast majority patients cannot get patients triglyceride down in any meaningful way that puts them out of risk for acute [indiscernible]. Late 2024, we were thrilled with the first FDA-approved medicine for a drug medicine for familial chylomicronemia syndrome in the United States. That is Tryngolza. And last year, we launched Tryngolza in January. It was our first year of launch and our first independent launch in our history. The approval of Tryngolza for FCS was based on remarkable groundbreaking results, efficacy results, substantial reductions in triglycerides and acute pancreatitis with a very attractive city profile, and offers the convenience of once per month administration using a low-volume auto-injector. Patients can administer themselves very simply. In addition to the U.S., we're also launched in the EU with a commercial partner, and the launch is off to a great start. We reported our Q1 revenue of $27 million, which was substantial growth compared to the first quarter of our -- of 2025. the launch continues to go exceptionally well, and we're looking forward to providing an update like and our Q2 earnings in a few months. Turning attention to severe hypertriglyceridemia now, Tryngolza for this large indication, which represents first potential multibillion-dollar wholly owned medicine. As I said, there are more than 3 million people with SHTG in the United States, and there's about 1 million or more than 1 million, slightly over 1 million people that we refer to as high-risk patients, patients that have had AP event in their history and chances of having the other event is very high or the rates are so high. Above 80 or so such that they have chylomicronemia, epidemia at even higher risk for acute pancreatitis as -- what we demonstrated presented published last year was groundbreaking results from our core and CORE II Phase III studies evaluating [indiscernible]. We showed a highly -- a substantial and highly statistically significant clinically menial reductions in truck. This drives many of the patients in our study, we were actually able to normalize their triglycerides from very, very high levels down below that 150-milligram per deciliter target that I mentioned before and nearly 90% of patients, we were able to get them below the definition of severe hypertriglyceridemia, below 500 milligrams or the best later. But what was really grounded, what was really remarkable and unprecedented was the first time anyone ever demonstrated that you can reduce acute pancreatitis events. By lowering train people with SHTG, 85% production in acute pancreatitis in our study after only 12 months of treatment -- groundbreaking results. like for SCS, we will -- and we administer all Lazaretos, using a simple once-per-month self-administration auto injector. We're well ahead of any potential competition to be first to the market using this mechanism of action targeting APOCIII for SHTG. Our field team is fully deployed already -- of course, marketing SCS, but also educating and not surprising considering the groundbreaking results for this study and the unmet need. The FDA granted not only priority review, but also breakthrough therapy disease for this program and granted us a date on June 30, 2026. As I said, this is the potentially the first multibillion-dollar wholly owned product opportunity for Ionis and our history. And recently, we increased peak product sales in the United States guidance beyond greater than $3 billion. We have an exciting quarter met our pipeline. And I would just scratch the surface. This pipeline will continue to grow and expand. Today, we have 6 medicines in clinical development in cardiometabolics. I highlighted or I also want to highlight the fact that we have a follow-on molecule that is on the verge of starting a Phase II study in severe hypertriglyceridemia. That's ION 775, Bank target APOC3, but what this drug is our first advancement of an Ionis discovered Ionis know-how in chemistry SIRA into the clinic as -- and in this case, as a follow-on molecule. The efficacy of a olezarsen and HCTG is tough to be -- that's really the objective. The objective is to relax dosing such that we can get to maybe even once per year. dosing to add convenience for patients. Now we have several others from our own pipeline that we started Phase I study shortly in our partner pipeline is very exciting as well. I want to highlight 2 programs in which we are expecting Phase III data in the second half of this year, eflontersen, which is already approved under the brand name or hereditary ATTR polyneuropathy is in Phase III development for ATTR cardiomyopathy, where we're expecting data in the second half of this year. That's a co-development, co-commercialization partnership with AstraZeneca and then, of course, telecare in development, faster development with our partner, Novartis, for Lp(a)-driven cardiovascular disease, another cardiovascular outcome trial with data expected in the second half of this year. Turning attention to our leading neurology at our leading neurology portfolio, a portfolio that has a strong track record in delivering first-in-class neurology medicines, breakthrough treatments like SPINRAZA, the first ever FDA-approved medicine for spinal muscular atrophy. Like Calsonithe first disease-modifying treatment for any cause of ALS and the first FDA-approved medicine for a genetic cause of ALS, also and then WAYNUA, as I already mentioned, on the market for hereditary ATTR polyneuropathy. And we're well positioned to deliver a steady cadence of medicines in neurology. We have a strong pipeline fully owned as well as partnered medicines, and we're anticipating our first independent launch in neurology. In the second half of this year, and I'll get to that in a moment. We have a focused strategy to expand our wholly-owned neurology portfolio. Our wholly owned pipeline is the priority. And we're really excited about the innovations we're making in science to further extend our leadership in neurology in various ways, including moving to once per year dosing using an intrathecal route of delivery or using approaches that allow us to deliver our drugs to the CNS by subcutaneous or intravenous administration, overcoming the blood brain barrier. We are very proud of the data that we reported last year, Phase III data for zilginersen for the treatment of a severe commonly fall, typically fatal neurodegenerative disease called Alexander disease. [indiscernible], our data demonstrated the first -- to be the first and only investigative medicine to demonstrate clinically meaningful disease-modifying impact on patients living with our standard disease. This is an ultrarare disease indication. We received in the U.S. EU orphan designation. And again, like for sHTG with Tringolza, olezarsen. We received breakthrough therapy designation and priority review for Silgan Nursing with a PDUFA date of September 26, 2023. From 2026 later this year, and we're prepared to launch. And this launch represents, again, our first independent launch prionis in neurology. Coming up right behind diginersen for Alexander's disease, is another really exciting wholly-owned program that we're in phase development for Obadanerson for Angelin syndrome, a very promising medicine addressing a disease and neurodevelopmental disease with incredibly high unmet need. There's more than 100,000 people in major tographies today. With inulin syndrome, and there are no effective treatments for this disease today. We reported multiple times updates on the HALOSPhase I/II study in patients treated with Obadanterson with Angolan syndrome, which we showed consistent and meaningful improvements in a range of clinical outcomes. At only 6 months of treatment, and I'm pleased to say that we also shared long-term data from our long-term extension that continues to support the benefits that Obedannerson appear to be delivering on from this 6-month Halo Phase I/II study certainly supporting continued development Phase III development. Again, another breakthrough therapy designation for our Ionis discovered medicine. We expect to complete enrollment in the REVEAL Phase III study this year with data expected next year. And this is what our neurology clinical pipeline looks like today, and I said it was robust. It was deep and broad. And I think this slide really reflects that. Today, we have 13 medicines in clinical development, more than half of which are wholly owned today. I touched on already [indiscernible] for Alexander disease, [indiscernible] syndrome, you could read the rest the programs that are in Phase II development for devastating genetic diseases. And I guess I'll just highlight 1 other program, which we just began clinical testing on user base and ION 337. We just got that started over the last month or so. our partner pipeline also is very exciting, of course. We're expecting Phase III data for ALS driven by mutations in the gene Golfs later this year. We reported just today, our partner Biogen reported breakthrough therapy designation for salines, and a follow-on molecule for spinal muscular atrophy, spinal muscular SPINRAZA that supports once per year intrathecal dosing with faster onset of action and potentially even greater efficacy than SPINRAZA in SMA. And we also reported positive Phase II data with our partner Biogen, for Dir Anderson, targeting tau and Alzheimer's disease just 2 weeks ago, and we will be presenting that Phase II data with Biogen AIC in July. There's a lot going on at Ionis, a lot of positive momentum, a lot of success of late and 2026 was set up to be a highly eventful year with many value-driving events -- clinical events, Phase III I've already mentioned some of them. In January of this year, we and our partner, GSK, reported very positive Phase III data for bepariversen and chronic PV, which was presented in which the data was presented in detail last week at EASL and published simultaneously in Neng Journal of Medicine, data, which showed the first time unprecedented results on functional cures, functional cure for people living with a cures on the order of 20% in the overall population, really remarkable. I already mentioned pelacarsen planters in the Phase III data later this year, and Fein Phase II data. We're also expecting Phase III data for SUFAXAsimulated this year for gnephropathy with our partner, Roche, and we've initiated Phase III studies now for samplers, erasers on for SMA, as I mentioned, and so on were also expecting more Phase II data this year. Along those lines, our regulatory affairs group is very busy with new submissions, approvals and so on. The most important, of course, is the approval of all are in the U.S. for severe hypertriglyceridemia, began nursing U.S. approval for Alexander's disease and better reverse in U.S. approval for chronic HPV, which we expect this year. And of course, following this our product launches -- these are exciting times at Ionis. A few companies can boast the steady cadence of new medicines that we expect to reach the market in the near term as we can here at Ionis, building on the success of and ATTR Polyneuropathy [indiscernible] angioedema, we're expecting 3 new product launches this year. I already mentioned olezarsen sHTG [indiscernible] for chronic HPV. And assuming Phase positive Phase III data, later this year. We can anticipate new launches next year. Four, pelacarsen for cardiovascular disease, perceptor cardiomyopathy, IgA nephropathy and the FUS-ALS drug that I mentioned. And then the data for Obadanterson or Angelin Syndrome next year as well. So obviously, with so much success from our pipeline and our commercial launches, wholly owned and partnered. We're in a very good position to continue to drive and accelerate in the drive for revenue growth. Ionis over the relative near term. At peak sales, just for the medicines that I just highlighted on the previous slide, we anticipate more than $5 billion in annual peak product revenue for Ionis matched with partner royalty revenue that goes beyond more than $2 billion. summing up to more than $7 billion in product revenue just from those near relative near-term programs that I just highlighted on the previous slide. I also want to highlight the fact that these guidance to this revenue is also probable such that we not assume every program is going to be successful in Phase III are the launches as we hope them to be. So this is a relative conservative estimate of revenue growth for the company at peak for those programs in the relative near term, very, very exciting for the company that's going to continue to drive value for all of our stakeholders. And based on the pipeline performance, the launch performance and the revenue growth that we anticipate, that's again probabilized, we are well on track to achieve breakeven cash flow in 2028 with positive cash flow, accelerating cash flow and following breakeven and growth -- continued growth for years to come, driven by the product launches, some of which I highlighted already, royalty revenue -- we're in a very strong financial position today, building on that foundation and, of course, disciplined expense management. So to conclude, Ionis has had a great deal of success over the last few years. But more importantly, we are positioned to drive far greater value in the near term this year, next year and for years to come, accelerating growth. And that's based on our leadership in cardiometabolic and neurological drug discovery and development. The steady cadence of positive clinical trial results we have delivered successful product approvals we've delivered and the launches we have delivered and will continue to deliver. And the fact that we're retaining so much more value for the company today as a fully integrated commercial-stage successful biotechnology company. This is driving accelerated revenue growth, which is producing a clear path to sustained positive cash flow with breakeven cash flow in 2020. So that's my presentation, and thank you very much for your attention. And now we can open it up for Q&A session.

[Operator Instructions] Great. So I think several people have figured out how to submit questions online. We have a number of questions in the queue that we'll go through. The first question comes from Tom. He's asking about our strategy for China. He wants to know we still have some rights to some of our drugs that we haven't licensed out to for China market. If and how we plan to commercialize Ozarsen or these other drugs in China, and the second part of this question is big pharma has done several deals for SIR's with Chinese companies in the last year, how are these deals impacting your business model?

Thank you for the question. So our focus for our independent wholly-owned launches is to focus on the U.S. market for now. We will be emerging to both commercialization of our own products outside the U.S. eventually. But today, we are relying on partnerships for commercialization of our partner our products today. China is not a top priority for us, honestly. We have excellent partnerships for Tringolza already for the majority. For the global -- for the geographies that we have prioritized EU, Japan, Middle East, on Canada. China is not a top priority, but we continue to discuss potential commercialization partnerships for China -- for all of our wholly owned programs, and there's interest, but it's just not the highest priority right now. Impact of China, big pharma partnerships with China really has been done. We have seen nothing that has come out of China that we can't match or exceed with respect to science and innovation. As I mentioned in my presentation, we have a follow-on molecule for all those are sensing that's supporting -- twice a year, once a year dosing upon dosing with remarkable efficacy based on Phase I data. We're doing the same thing for our other wholly owned programs, follow-on programs, and we've seen nothing coming out of China. That matches our innovation. I'll also tell you, we're doing the safety in neurology. We have follow-on programs, as I mentioned, for salinersen, that supports once per year intrathecal dosing. New approaches that are going to allow us to dose subcutaneously for CNS diseases overcoming the blood brain barrier. I've seen nothing in CNS that's coming out of China that matches the expertise or the advancements we're making here, at Ionis and CNS diseases. So not dismissive, but paying very close attention to it, but so far, no concerns.

Next question comes from James. He's asking -- it appears that Ionis recently received patents for half duplex ASO architecture and family and technologies. Can you elaborate a bit on what this architecture technology is about? And how do you plan to use it also how would you -- how would this compare to standard siRNA in terms of potency like knockdowns and dose duration?

So these are double-stranded approaches that we -- our outstanding research team uncovered the potential for that they have shown remarkable durability and potency in animal models that, in many cases, not in all cases, but in many cases, match the durability and potency that we see with state-of-the-art antisense and state-of-the-art ester names. We don't know how we're going to use this technology today. We don't -- we're looking at it much more carefully. We have a lot more to learn about this technology, but it's just another example of our own innovation from our research organization. We think it has the potential to be as good and potentially better for certain applications, but we still have a lot more work to do here.

Our next question -- actually, a slew of questions comes from Denis Reznik, asking on behalf of Gary Nachman from Canaccord Genuity. We'll break this up into a couple of parts. There's the first part. This is deal with trigs and hold ours. Please provide an update on sHTG discussions with the FDA as we get closer to the upcoming PDUFA date. Any color you can provide on how labeling discussions are progressing and what patients should be covered in the indication will SAGA data be included somewhere and any potential updates to warnings and precautions.

So I'm sorry to say that my answer is quite sure. It's -- we don't comment on -- we're obviously waiting discussions at this stage. We at PDUFA between 30 and we don't comment on labeling interactions with the FDA at this stage as we approach approval. All I can say is that our discussions with the FDA are going very well.

The second part related to olezarsen, how will payers be treating these communication? Will they be largely sticking to the label? And will they be requiring any sort of step edit prior authorization documentation, prior to approving Tigo for use in the different STG patient groups of varied risk profiles.

Yes, we don't expect payers to support nor would we promote any off-label use for for the indication, SHTG as defined by triglyceride 500 and above, I mean we're talking millions of people in the United States. There's -- the opportunity here is enormous. So we don't expect that. We're not going to promote that or we expect payers to support that. But the other part of your question was step edit. So most of the patients -- many of the patients that sHTG are already being treated with generic medicines inadequately 5 rigs, Omni fatty acids and fist oils. Some even statin those sorts of things. These patients are -- all patients essentially were in our Phase III trial are on these drugs already. So although I wouldn't necessarily call it a step at the vast majority of the patients that we're going to be targeting initially, certainly, the high-risk patients who are already on these drugs. Olezarsen and Tryngolza goals have demonstrated the results that I highlighted, the groundbreaking results on top of these medicines already. For newly diagnosed patients, but they have to go on a generic fibrate or something like that, possibly, maybe not, we'll see. That's something that we're going to have to work through. I don't -- whether it's required or not, it wouldn't take long after a couple of months, it will be clear that these patients are not getting to target and they're going to need to get content recolor their treatment. So we don't -- more important -- most importantly, we see this as a barrier achieving our peak product revenue goals of $3 billion plus at in the U.S.

Continuing on the questions from Dennis at Canaccord. What are your expectations for the pelacarsen Phase III readout to Lp(a)? And what are you hoping to show with the outcomes data and what's the latest timing of that data?

So the timing of the data has not changed. Our -- what we're guiding to us in Novartis in the second half of this year. We're very confident that, that data is going to come out in the second half of this year. We're looking forward to it. As far as expectations, just let me remind everybody that -- there has been a baseline demographic paper published by Novartis with the clinical trial design and study rationale design rationale. The study is powered to achieve a 20% relative risk reduction in the total population, a 25% risk reduction in patients that are at greater risk in the study, high-alpha in the study. What do we expect to be a clinically important outcome in this study would be a clinically significant benefit on outcome, which is a composite mortality and hospital CV events in the study compared to placebo. Why is that? The line was the magnitude of risk reduction, not so important because the unmet year is enormous. There's 8 to 10 million people in the United States suffering from cardiovascular disease artifacts and drugs, they are very high levels, and it's not manageable with any medicines that are out there today. shelling benefit in this patient population would be groundbreaking for the cardiovascular field, where there's bestoneed for treatments for calculating cardiovascular disease -- and that's what I expect in the study, I expect it to be positive. Follow on, if the data are positive, how soon can this be filed for regulatory approval by the end of this year.

Next question is on ATTR-cardiomyopathy. -- which should investors expect to see in the talent results, specifically with the combination subgroup that would be considered meaningful compared to the HELIOS-B data and if positive, how to be filed. So

This is a co-development commercialization partnership with AstraZeneca partnership that now over a decade old. We have a great partner -- we work very closely together on this program. We're looking forward to the come of the study, which started largest study ever conducted in ATTR or cardiomyopathy position to deliver the richest data set not only the primary endpoint but of course, but in the secondary endpoints, including the combination with tafamidis subgroup that you referred to. The reason for your question for the benefit of others, of course, that nobody has ever shown has ever designed a study that can actually determine whether or not the combination of a silencer with a stabilizer will provide added benefit versus either agent alone or versus families alone most importantly, which is the standard of care in the market today. All patients on traits are progressing. Some are progressing a lot. Faster than others, but they're all progressing, although defendants provides benefit to these patients. That's why the combination growth was so interesting can actually add further benefit in combination group. We have not worked through the -- what we're going to share in our top line announcement. But what I can say is that we believe that Well, we will present the data at a medical congress as soon as possible after the data comes out, and publish in simultaneously in a reputable journal. So all I can say is a thing for that. What we share with respect to secondary endpoints in top line results is something that we're going to have to work through with with our partner.

And positive how soon could this be filed?

Also, we expect to flow by the end of the year.

All right. Next, we have a few of questions from James. First 1 is, when do you plan to start clinical trials for your first B2B crossing drug?

We plan to initiate our first BBB crossing drug, which I can tell you is a wholly owned neurology medicine complete to start and complete -- we'll start tox studies this year to complete them sometime next year to enable a first-in-human study second half of next year.

Next question is it seems like Ionis's chemistry is much more potent than the competition. Can you elaborate more on this? And also in the concept of MSPA chemistry be applied to your SIRNAs.

Yes, we have a remarkable medicinal chemistry toolbox when SPA is 1 of those tools. And we have been and concert apply it to siRNA as we do a single strand as we do and have with single-stranded emphases and all I could say about our siRNA capabilities or that we've seen nothing that's out there Yes. can beat what we've done, whether we're better or not, that's to be termed a lot more experience in the clinic. But right now, you're right, early clinical returns have been extremely supportive of our capabilities I want to emphasize that this I don't know of any company that has the expertise to do both, state-of-the-art, single-stranded antisense for applications where Amexes works best, in double-stranded siRNA applications for applications or siRNA could work best. And we're developing both mechanisms depending on the target, depending on the application. And as I said earlier, we have several SIs in the clinic already, and we're expecting to have more later this year and next year.

Another question for James. What is your strategy for follow-on drugs with your more advanced chemistry and technology?

For all of our wholly owned programs, that we have achieved a key inflection point, let's say, proof of concept in the clinic as an example. Based on the advancements we're making in science, we have a high priority, we prioritize follow-on programs. If we believe those advancements can be applied to a fall molecule that will meaningfully differentiate versus the existing molecule or competition emerging competition. We recognize the fact that there's a lot of smart people in the world out there and everybody watches what Ionis is doing because we tend to be first in the diseases we get the targets we go after -- so all on molecules to build a franchise around an indication is a top priority for the company. And I gave you an example already I'll give you 2 examples. One example was the follow-on we have the Tryngolza, which is now about to start Phase II testing in sHTG support once per year dosing. And I mentioned as a follow-on to SPINRAZA, that's in Phase III development with our partner, Biogen and Ionis discovered medicine that supports once per year intrathecal dosing with potential for even greater efficacy than SPIRANZA, in SMA. We're going to do that for all of our programs.

James has more questions on the technology. It looks like you've developed several technologies that can compete with competitors' modalities, do you have plans to showcase these technologies? And what are your strategic plans for them to showcase to investors.

Yes. So to be determined how best to do that, we, of course, we published a lot at Ionis. We present at a lot of scientific conferences. Our research team is very active in doing that. But I understand the question, can you pull it all together and really presents the overall strategy and the progress you're making overall. To be determined, we have been incredibly busy with the late-stage pipeline and the launches that I highlighted earlier and even our mid-stage pipeline today, but we are looking forward to maybe a component of our biannual Innovation Day that we've been holding to really do a real focus on science and the advancements we're making there. And maybe in the second half of this year, we can do a podcast or some sort of webcast in focusing on science. So I guess the bottom is something we want to do. We just need to find the right time to do it.

Another question, james, are you building your own internal ligand or peptide library. And so can you elaborate on the strategy for this?

All I can say is yes. We have our own programs internally. We also have a strategic partnership with Bicycle Therapeutics, using very small low-rate epti like molecules, for muscle targeting as well as for brain barrier, where we have exclusive rights for all organically type strategies, ASOs RNAi's working really well. Our first bicycle siRNA is actually in Phase I testing today for a heart indication target cardiac msite and -- but we have our own internal programs, too. I just can't talk more about them. It's a very, very competitive space, as I'm sure you know. And 1 more question,

Looks like from James is do you or GSK plans to develop a follow-on drug for hep B using MSP assuming that this chemistry would have better efficacy and dosing.

Not at this time, but I wouldn't rule it out for the future. What I can say is this. The groundbreaking results that GSK reported from the Phase III studies at ES published simultaneously on functional cure rates in the order of 20% to 25%. It's just the beginning. GSK is committed to as around breaking out of those results are and important for the HBV community. That's the beginning. GSK is committed to this drug, our version in this area. -- and are already in clinical testing with combination approaches that sets that favors enough to drive even greater functional cure rates. So you can see some of that on clintrials.gov, but also there's more in the works, I could tell you that's being planned. So the question really is about how are you going to ensure growing success and real leadership in chronic HBV for many years to come. GSK is doing all they can in that space with respect to combination approaches and further clinical trials involving that arise.

A question from Howard, do you have any updates on the development of oral drugs?

We're not pursuing ours at this time. It's -- we've been down that road many times, we've invested extensively. I think we've done the by far the most substantial work and the most innovative work in organically tire oral delivery, whether it be ASOs is RNAs and so on it's just really problematic. Instead, several years ago, we pivoted to less frequent dosing. As I mentioned for certain targets, we're on the cusp of potentially delivering drugs once per year using a low-volume subcutaneous injection once per year. And in the CMS once per year, particularly or even subcutaneously, which will, if subcutaneous administration works for CNS diseases, that 2 will be extremely infrequent. That's not going to be a frequent dosing regimen. We questioned the value of oral drugs versus 1 per utes or 2-year dosing. I mean that's very convenient for patients and doesn't doesn't cause burden of oral delivery, walking frequently every day or so. So we pretty much moved away from oral delivery.

Another couple of questions from Tom. Where do you things stand with respect to the collaboration with Medogenomi and other gene editing efforts. Will you bring a gene editing drug into the clinic in the next year.

Our partnership with Metagenomi continues to go well very well. We have late-stage programs in research, drug discovery research. We haven't disclosed -- Ionis as not those targets that we prioritized yet. We expect to have a candidate by next year, probably the first half of next year, our first candidate involving an editing I want to emphasize again that -- or I want to emphasize that the know-how of Ionis with respect to chemical modification of nucleic gases and not understanding nucleic acid biology and drug drug discovery, that's related story, is something we're taking full advantage with Medigenomi in developing state-of-the-art gene editing approaches, in our just general know-how of understanding how to discover drugs involving nucleic acids. So it's going well. We expect our first candidate discovery efforts are going well. We expect candidate not too far down the road. And as far as when we initiate clinical studies, that's to be return, but it's not going to be next year.

And the next last question for Tom is -- how many Phase I trials do you plan on initiating within the next 12 months? And can you tell me what the targets for these drugs are?

I can't talk about targets at the target at this stage where until they reach posting on in trials or we started a Phase I study. And I did mention already, we just started a Dravet syndrome Phase III first in man first patient study to for that as a Phase II study, that's underway. We expect additional first-in-human starts this year. Typically, we move 3 to 5 new drug candidates into development each year, and that has a trickle-down effect of a similar cadence of new clinical trial starts each year. So that's the ballpark for new trial starts for Ionis. And we're well on track for that this year as well as next year.

We have a couple of questions for Ted, who's asking about tissue deliver. First question is where do things stand with Ionis targeting skeletal muscle esketamuscle targeting drugs entering the clinic in the next year.

Potentially, we have several late-stage drug discovery programs using the bicycle technology, coupled with an ASO or an RNA for muscle targets for neuromuscular diseases that are, I said, in late-stage drug discovery. They have the potential to get through tax next year. assuming everything goes well. And then you get into the play in the second half of next year, it has to be determined. We don't have the drug candidates yet. But if everything goes smoothly, I wouldn't rule out a clinical start next year.

Second question that Ted has is about that long. Where do you think stand with IOS' inhaled drug programs in reliance will be an inhaled drugs into the clinic soon.

We have our first medicine using Ionis advanced chemistry, NSPA, chemistry, in particular, using antisense organically tied with that chemistry incorporated , I do believe we've disclosed the target that candidate it looks great in preclinical models. That's our first reentry into pulmonary diseases you can be palette delivery -- we're hoping to start IND tox studies in the second half of this year, and then you could do the time line. The tax goes well. We're we deplete it next year and in enough time in advance. Maybe we can start a clinical study in the next year. Maybe it will be 2028. We'll see about that. But preliminary is advancing. Is it balancing forward nicely.

Right. I think we have 1 more question, and it's from Dennis, on behalf of Gary Nachman from Canaccord. Where are you currently with the Angolan study in terms of enrollment completion, is there any color that you can provide on the baseline characteristics enrolled thus far in terms of age gender location? And maybe how many how it compares to the original Phase I/II trial in Iran?

Yes. So let me back up a our Phase II program for Annema syndrome has a pivotal study for people, I believe it's between the ages nearly about 200 patients or so, give or take, all being dosed at 80 milligrams quarter. And that's and that's the dose that showed the best evidence of efficacy in our Phase I/II ALOstudy. Across all measurement tools as well as all clinical measures for each of those tools, daily for SaaS CGI as examples, very encouraging data there. We expect -- roles doing really well. There's a lot of enthusiasm for our Phase III study. And we expect to complete enrollment this year with Phase III data next year. We haven't provided more granularity than that, but we'll certainly announce when we complete enrollment for that study. And for the other part of the question, but I think pretty much covered it. We -- I'm sorry, that's what I was going to say. In addition to the pivotal study, we also have additional studies running in parallel for the newborns between newborn to 2 years of age as well as in adult patients. And in our Phase I/II HALO study, we actually showed good evidence, strong evidence that. But even the adults, we're benefiting not just to 18-year-olds in the study. And of course, we all know based a lot on Ionis research, drug discovery and development that the earlier you can treat neurological diseases, the better you are. So -- we believe that the greatest at that will actually be getting to those new barges as quickly as possible. And that's why we initiated the infant study, which is now underway.

And the second part of this -- these questions are about competitors read out this year. So he wants to know what are the read-throughs that we could expect from the the trial read out later this year for the competitor drug. And is there anything you could do to change your Phase III trial after seeing those results?

So let me just start by saying that we're we're pulling for all modalities to have success for the treatment of these devastating diseases that we're tackling, right? We think options for patients is best. It's best for all parts patients, HCPs as well as sponsors. It just went to greater success for everybody. But I will also say that let's not forget the fact that is has been in CNS diseases for multiple decades now. with great success. I talked about the drugs that are already approved in the proof of concepts and the drugs to be approved later this year as well as proof of concepts that are coming that we've already achieved in neurological diseases. We're using a chemical platform in our Angelman's program that's essentially identical to SPINRAZA and, all the drugs that have shown value, you'll get obinursing for anointed disease. So it's a proven platform. the competitor that is going to have Phase III data later this year. It's a very different platform, very different approach, very different dosing in this study. But -- we are very much looking forward to their results this year because we will be the first randomized controlled study using an oligonucleotide approach for Angelman syndrome. Can we learn from that? Sure, we can for it. Can we modify our study in certain ways within limits within limits, we could potentially do we expect to and probably not -- we like the design of our study. It's very well designed. It's based on our Phase I/II ALS study, which is very successful, and it's using a platform that's proven. But certainly, we'll be paying attention to it, and we're very hopeful that they have success.

We have time for 1 last question from Ted -- is there a priority review vouchers associated with the approval of the Alexander disease drug?

No, there is not. But we do a break therapy designation and priority review. Okay. Well, those are all great questions. I really, really want to thank everybody for listening and your participation in our shareholder meeting today. I very much enjoyed it, and I think you agree with me that based on all the progress that I've summarized for all of you today and additional successes we've had that I didn't have a chance to get to that many of you are aware of. Ionis is really, really well positioned to really drive drive value, tremendous value, accelerating value for all stakeholders, our shareholders, HCPs, the medical community and most importantly, to the patient community. So -- thank you for listening. Really proud of the update we give today and stay tuned is more coming from my Ionis.