Good afternoon. Welcome to the 2026 Annual Shareholders Meeting Corporate Update. My name is Brett Monia. I'm Chief Executive Officer of Ionis and Board Director at Ionis, 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 Ionis 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 field of oligonucleotide therapeutics has emerged as one of the most exciting and important new approaches to drug discovery and drug development in the pharmaceutical industry, and we're proud of the fact that Ionis pioneered this field.
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 were the first to optimize and validate oligonucleotide therapeutics of any kind to liver or 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 the mechanisms that result in the degradation of the targeted RNA to block the production of toxic proteins, such as through an RNase H mechanism, or to modulate and improve splicing mechanisms so that we can replace proteins, upregulate proteins that are lacking in loss-of-function diseases.
This has led to us leading the way in discovering and developing first-in-class medicines for a range of serious diseases. We've had remarkable progress across the business over the last several years, 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 that has always matched the excellence we've always exhibited in research and development. This is based on a truly groundbreaking technology that continues to advance forward with state-of-the-art oligonucleotide 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. All of this is setting us up to drive revenue growth, accelerating revenue growth, positive cash flow, and value creation for everybody involved in the Ionis sphere. Over the last few years, we've had remarkable success. Just over the last three years, some of those achievements are shown in this slide. Six positive phase III data readouts that have resulted in four approved medicines with brand names that you can read there on the slide. We're expecting three more approved medicines by the end of this year. Two of these approved medicines and commercial launches are independent. Our first independent launches in Ionis' history, TRYNGOLZA for familial chylomicronemia syndrome and DAWNZERA for hereditary angioedema. There's a lot more coming.
We've created a remarkable pipeline with 11 medicines in late-stage development and many more, of course, at mid-stage and just getting started 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. 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 DAWNZERA forward, that the unmet need for patients was still vastly large. There's a lot of unmet need here for patients, and we felt that DAWNZERA could 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 fatal in these patients. We're pleased that the launch is going very well.
This is a market where existing prophylactic treatments existed prior to the approval of DAWNZERA, as I mentioned, we're moving into a market where the goal is to switch patients from their existing prophylactic treatment where they're dissatisfied to DAWNZERA. In fact, in this launch, we're seeing the majority of our patients switching from other prophylactic treatments to DAWNZERA, also patients that have managed their disease through other means, such as on-demand treatment or even treatment-naive patients. We're seeing a growing number of repeat subscribers or prescribers. The launch is gaining significant momentum. We're proud of the fact that our first quarter results, we achieved 128% improvement over our first quarter launch. I can tell you that the launch for DAWNZERA continues to be quite strong. We look forward to presenting an update at our Q2 earnings later this year.
Now, moving on from DAWNZERA, which is a disease, hereditary angioedema, that's managed by allergists and immunologists, very different than the bulk of our pipeline today. 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. Two areas that we pioneered, and we've developed drugs and are developing drugs for both rare and prevalent disease indications, 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 diseases and starting with olezarsen. Olezarsen, a transformational medicine for all disease indications related to severely elevated triglycerides.
There's a high unmet need for better treatments to manage patients with high triglycerides. We're developing olezarsen. You'll see this in a moment. Our brand name for olezarsen for its first indication is called TRYNGOLZA. I may go back and forth between olezarsen and TRYNGOLZA here and there. The first indication is a rare, severe genetic disease called familial chylomicronemia 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 the consequence of severely elevated triglycerides due to certain mutations in the genome of people. These people suffer from a whole host of comorbidities. What is most significant is the risk of a potentially fatal and recurring, if not fatal, acute pancreatitis attack. There's the second indication, severe hypertriglyceridemia. This is not a rare disease.
This is a disease that affects millions of people in the U.S. alone. It, too, is defined by very high triglyceride levels. In this case, the definition of SHTG in the U.S. are triglycerides above 500 mg per deciliter. Normal triglycerides are below 150. Although this is not a genetic disease and 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. Although there are some generic treatments for high triglycerides for SHTG today, they're grossly inadequate. For the most part, the vast majority of patients cannot get patients' triglycerides down in any meaningful way that puts them at a risk for acute pancreatitis.
Late 2024, we were thrilled with the first FDA-approved medicine for familial chylomicronemia syndrome in the U.S. That is TRYNGOLZA. Last year we launched TRYNGOLZA in January, and 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 in acute pancreatitis with a very attractive safety profile. 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. 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 2025.
The launch continues to go exceptionally well, and we're looking forward to providing an update, like DAWNZERA at our Q2 earnings in a few months. Turning attention to severe hypertriglyceridemia now. TRYNGOLZA, olezarsen for this large indication, which represents Ionis' first potential multibillion-dollar wholly owned medicine. As I said, there are more than 3 million people with SHTG in the U.S., 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 an AP event in their history and chances of having another event is very high, or their triglycerides are so high above 80 or so, such that they have chylomicronemia and xanthomas at even higher risk for acute pancreatitis event. What we demonstrated, presented, published last year was groundbreaking results from our CORE and CORE2 phase III studies evaluating olezarsen in SHTG.
We showed substantial and highly statistically significant clinical meaningful reductions in triglycerides. Many of the patients in our study, we were actually able to normalize their triglycerides from very, very high levels down below that 150 mg per deciliter target that I mentioned before. In nearly 90% of patients, we were able to get them below the definition of severe hypertriglyceridemia, below 500 mg per deciliter. What was really groundbreaking, what was really remarkable and unprecedented, was the first time anyone ever demonstrated that you can reduce acute pancreatitis events by lowering triglycerides in people with sHTG. 85% reduction in acute pancreatitis in our study after only 12 months of treatment. Groundbreaking results. Like for FCS, we administer olezarsen, TRYNGOLZA, 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 APOC3 for SHTG. Our field team is fully deployed already. Of course, marketing FCS, but also educating on severe hypertriglyceridemia. Not surprising considering the groundbreaking results for this study and the unmet need. The FDA granted not only priority review, but also breakthrough therapy designation for this program and granted us a PDUFA date of June 30th, 2026. As I said, this is potentially the first multi-billion dollar wholly owned product opportunity for Ionis in our history. Recently, we increased peak product sales in the U.S. guidance to beyond greater than $3 billion. We have an exciting cardiometabolic pipeline, and we've just scratched the surface. This pipeline will continue to grow and expand. Today, we have six medicines in clinical development in cardiometabolic diseases. I highlighted olezarsen.
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 ION775, same target, ApoC-III. What this drug is our first advancement of an Ionis discovery using Ionis know-how in chemistry, siRNA, into the clinic, and in this case, as a follow-on molecule to olezarsen. The efficacy of olezarsen in sHTG is tough to beat. That's really not 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. We have several other from our wholly-owned pipeline that we start in phase I studies shortly, and our partner pipeline is very exciting as well. I want to highlight two programs in which we're expecting phase III data in the second half of this year.
eplontersen which is already approved under the brand name WAINUA for 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. Of course, pelacarsen. pelacarsen in phase III 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 platform, our leading neurology portfolio. A portfolio that has a strong track record in delivering first-in-class neurology medicines, breakthrough treatments like olezarsen, the first-ever FDA-approved medicine for spinal muscular atrophy. Like QALSODY, the first disease-modifying treatment for any cause of ALS, and the first FDA-approved medicine for a genetic cause of ALS, QALSODY. WAINUA, as I already mentioned, on the market for hereditary ATTR polyneuropathy.
We're well positioned to deliver a steady cadence of medicines in neurology. We have a strong pipeline, wholly 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 we reported last year, phase III data for zilganersen, for the treatment of a severe, commonly fatal, typically fatal, neurodegenerative disease called Alexander disease. zilganersen in our data demonstrated to be the first and only investigational medicine to demonstrate clinically meaningful disease-modifying impact on patients living with Alexander disease. This is an ultra-rare disease indication. We received a U.S. and EU orphan designation. Again, like for SHTG with TRYNGOLZA, olezarsen, we received breakthrough therapy designation and priority review for zilganersen with a PDUFA date of September 22nd, 2026, later this year. We're prepared to launch. This launch represents, again, our first independent launch for Ionis in neurology.
Coming up right behind ZOLGENSMA for Alexander disease is another really exciting wholly-owned program that we're in phase III development for, obudanersen for Angelman syndrome, a very promising medicine addressing a neurodevelopmental disease with incredibly high unmet need. There's more than 100,000 people in major geographies today with Angelman syndrome, and there are no effective treatments for this disease today. We reported multiple times updates on the HALOS phase I/II study in patients treated with obudanersen with Angelman syndrome, which we showed consistent and meaningful improvements in a range of clinical outcomes at only six months of treatment. I'm pleased to say that we also shared long-term data from our long-term extension that continues to support the benefits that obudanersen appeared to be delivering on from the six-month HALOS phase I/II study, certainly supporting continued phase III development. Again, another great breakthrough therapy designation for an Ionis-discovered medicine.
We expect to complete enrollment in the REVEAL phase III study this year, with data expected next year. This is what our neurology clinical pipeline looks like today. I said it was robust, it was deep and broad, and I think the 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 ZOLGENSMA for Alexander disease and obudanersen for Angelman syndrome, and you could read the rest. The programs that are in phase II development for devastating genetic diseases. I guess I'll just highlight one other program, which we just began clinical testing on, Dravet syndrome, ION337. We just got that started over the last month or so. Our partnered pipeline also is very exciting, of course.
We're expecting phase III data for ulefnersen for ALS, driven by mutations in the gene FUS later this year. We reported just today, our partner Biogen reported a breakthrough therapy designation for salanersen, a follow-on molecule for spinal muscular atrophy, a follow molecule for Spinraza that supports once-per-year intrathecal dosing with faster onset of action and potentially even greater efficacy than Spinraza in SMA. We also reported positive phase II data with our partner Biogen for diranersen targeting tau in Alzheimer's disease just two weeks ago. We will be presenting that phase II data with Biogen at AAIC in July. There's a lot going on at Ionis, a lot of positive momentum, a lot of success of late. 2026 was set up to be a highly eventful year with many value-driving events. Clinical events, phase III events, I've already mentioned some of them.
In January of this year, we and our partner GSK reported very positive phase III data for bepirovirsen in chronic HBV, in which the data was presented in detail last week at EASL and published simultaneously in The New England Journal of Medicine. Data which showed for the first time unprecedented results on functional cures for people living with chronic HBV. Functional cures on the order of 20% in the overall population. Really remarkable. I already mentioned pelacarsen, eplontersen phase III data later this year, and ulefnersen phase III data. We're also expecting phase III data for atrasentan later this year in IgA nephropathy with our partner Roche. We've initiated phase III studies now for sapablursen, polyisoprenylphosphate synthase inhibitor, salanersen for SMA, as I mentioned, and so on. We're 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 olezarsen in the U.S. for severe hypertriglyceridemia, ZOLGENSMA U.S. approval for Alexander disease, bepirovirsen U.S. approval for chronic HBV, which we expect this year. Of course, following this, our product launches. These are exciting times at Ionis. 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 WAINUA in ATTR polyneuropathy, TRYNGOLZA for FCS, DAWNZERA for hereditary angioedema. We're expecting three new product launches this year. I already mentioned olezarsen for SHTG, ZOLGENSMA for Alexander disease, bepirovirsen for chronic HBV.
Assuming positive Phase III data later this year, we can anticipate new launches next year for pelacarsen for cardiovascular disease, eplontersen for ATTR cardiomyopathy, IgA nephropathy, and the first ALS drug that I mentioned. Then Phase III data for obudanersen for Angelman syndrome next year as well. 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 the drive for revenue growth for 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 partnered royalty revenue that goes beyond more than $2 billion, summing up to more than $7 billion in product revenue just from those relative near-term programs that I just highlighted on the previous slide. I also want to highlight the fact that this revenue guidance is also probabilized, such that we do not assume every program is going to be successful in phase III or on their launches as we hope them to be. This is a relative conservative estimate of revenue growth for the company at peak for those programs in the relative near term. Very exciting for the company. It's going to continue to drive value for all of our stakeholders.
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 achieving break-even cash flow in 2028 with positive cash flow, accelerating cash flow following break even, and 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. To conclude, Ionis has had a great deal of success over the last few years. 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.
That's based on our leadership in cardiometabolic and neurological drug discovery and development, the steady cadence of positive clinical trial results we've 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 break-even cash flow in 2028. That's my presentation, and thank you very much for your attention. Now we can open it up for Q&A session.
Great. 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. If you want to submit a question, please log on to the webcast and post a question on the webcast. The first question comes from Tom. He's asking about our strategy for China. He wants to know, since we still have some rights to some of our drugs that we haven't licensed out for China market, if and how we plan to commercialize olezarsen or these other drugs in China. The second part of this question is, Big Pharma has done several deals for siRNAs with Chinese companies in the last year. How are these deals impacting your business model?
Thank you for the question. Our focus for our independent wholly owned launches is to focus on the U.S. market for now. We will be emerging to commercialization of our own product outside the U.S. eventually. Today we are relying on partnerships for commercialization of our products today. China is not a top priority for us, honestly. We have excellent partnerships for TRYNGOLZA already for the geographies that we have prioritized, EU, Japan, Middle East, Latin, and Canada. China's not a top priority, but we continue to discuss potential commercialization partnerships for China for all of our wholly owned programs. There's interest, but it's just not the highest priority right now. Impact of China, big pharma partnerships with China really has been none. 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 olezarsen, TRYNGOLZA, that's supporting twice a year, once a year dosing, subcutaneous dosing with remarkable efficacy based on phase I data. We're doing the same thing for our other wholly owned programs, follow-on programs. We've seen nothing coming out of China that matches our innovation. I'll also tell you we're doing the same thing in neurology. We have follow-on programs, as I mentioned, for salanersen 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 going on in China that matches the expertise or the advancements we're making here at Ionis in CNS diseases. Non-dismissive, but paying very close attention to it. So far, no concerns.
Thanks. Next question comes from James. He's asking: It appears that Ionis recently received patents for half-duplex ASO architecture and family of technologies. Can you elaborate a bit on what this architecture technology is about? How do you plan to use it? How would this compare to standard siRNA in terms of potency, like knockdowns and dose duration?
These are double-stranded approaches that 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 siRNAs. We don't know how we're going to use this technology today. 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 Ionis 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.
Thanks. 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. Here's the first part. This has to deal with TRYNGOLZA and olezarsen. 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 SHTG AP data be included somewhere, and any potential updates to warnings and precautions?
That was a long question, so I'm sorry to say that my answer to you is quite short. We're obviously in labeling discussions at this stage. We have a PDUFA date of June 30th, 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.
Thanks. The second part related to olezarsen is how will payers be treating that SHTG indication? Will they be largely sticking to the label, will they be requiring any sort of step edits or prior authorization documentation prior to approving TRYNGOLZA for use in the different SHTG patient groups of varied risk profiles?
Yeah. We don't expect payers to support, nor would we promote any off-label use for the indication SHTG as defined by triglycerides 500 and above. We're talking millions of people in the U.S. The opportunity here is enormous. We don't expect that. We're not going to promote that, nor will we expect payers to support that. The other part of your question was what?
Step edit or prior-.
Oh, sorry. Step edit. Most of the patients, many of the patients that have SHTG are already being treated with generic medicines inadequately. Fibrates, omega-3 fatty acids, fish oils. Some even statins and those sorts of things. All the patients essentially in our Phase III trial were on these drugs already. Although I wouldn't necessarily call it a step edit, the vast majority of these patients that we're going to be targeting initially, certainly the high-risk patients, were already on these drugs. olezarsen and TRYNGOLZA have demonstrated the results that I highlighted, the groundbreaking results on top of these medicines already. For newly diagnosed patients, would 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. Whether it's required or not, it wouldn't take long.
After a couple of months, it'll be clear that these patients are not getting to target, and they're going to need to get onto TRYNGOLZA for their treatment. Most importantly, we don't see this as a barrier to achieving our peak product revenue goals of $3 billion plus at peak in the U.S.
Thanks. Continuing on with questions from Denis at Canaccord Genuity. What are your expectations for the pelacarsen phase III readout in Lp(a)? What are you hoping to show with the outcomes data, and what's the latest timing of that data?
The timing of the data has not changed. What we're guiding to Ionis and Novartis is 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, excuse me. 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, higher Lp(a) in the study. What do we expect to be a clinically important outcome in this study would be clinically significant benefit on outcome, which is a composite of mortality and hospital CV events in the study compared to placebo. Why is that?
Why is the magnitude of risk reduction not so important? The unmet need here is enormous. There's 8 to 10 million people in the U.S. suffering from cardiovascular disease, heart attacks, and strokes at very high Lp(a) levels, it's not manageable with any medicines that are out there today. Showing benefit in this patient population would be groundbreaking for the cardiovascular field, where there's a desperate need for treatments for Lp(a) for treating cardiovascular disease, that's what I expect in this study. I expect it to be positive.
Follow on, if the data are positive, how soon can this be filed for registry approval?
By the end of this year.
Next question is on Rayneuva for ATTR cardiomyopathy. What should investors expect to see in the top-line results, specifically with the combination subgroup that would be considered meaningful compared to the HELIOS-B data, and if positive, how soon could it be filed?
This is a co-development, co-commercialization partnership with AstraZeneca, a partnership that is now over a decade old with a great partner. We work very closely together on this program. We're looking forward to the outcome of this study, which started in 2020. Largest study ever conducted in ATTR cardiomyopathy, positioned to deliver the richest data set, not only in the primary endpoint, of course, but in the secondary endpoints, including the combination with tafamidis subgroup that you referred to. The reason for your question, and for the benefit of others, of course, is that nobody 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 tafamidis alone, most importantly, which is the standard of care on the market today. All patients on tafamidis are progressing.
Some are progressing a lot faster than others, they're all progressing, although tafamidis provides benefit to these patients. That's why the combination group is so interesting, is can we actually add further benefit in combination group. We have not worked through what we're going to share in our top-line announcement. What I can say is that we will present the data at a medical congress as soon as possible after the data comes out, and publish simultaneously in a reputable journal. All I can say is stay tuned 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 our partner.
If positive, how soon could this be filed?
We expect to file by the end of the year.
All right. Next we have a slew of questions from James. First one is, when do you plan to start clinical trials for your first BBB-crossing drug?
We plan to initiate our first BBB-crossing drug, which I can tell you is a wholly owned neurology medicine, start on detox studies this year to complete them sometime next year to enable a first-in-human study, second half of next year.
Next question is, seems like Ionis' siRNA chemistry is much more potent than the competition. Can you elaborate more on this? Also, can the concept of MsPA chemistry be applied to your siRNAs?
Yeah. We have a remarkable medicinal chemistry toolbox, where MsPA is one of those tools, and we have been and can certainly apply it to siRNA as we do with single-strand, as we do and have with single-stranded antisense. All I can say about our siRNA capabilities are that we've seen nothing that's out there that can beat what we have done. Whether we're better or not, that's to be determined. We'll get a lot more experience in the clinic. Right now, you're right. Early clinical returns have been extremely supportive of our capabilities. I want to emphasize 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 antisense works best and double-stranded siRNA applications for applications where siRNA could work best. We're developing both mechanisms, depending on the target, depending on the application.
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.
Thank you. Another question from 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 follow-on molecule that'll 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 target, the targets we go after. Follow-on molecules to build a franchise around an indication is a top priority for the company, and I gave you an example already. I gave you two examples.
One example was the follow-on we have to Spinraza, which is now about to start phase II testing in sHTG to support once per year dosing. I mentioned the follow-on to Spinraza that's in phase III development with our partner Biogen, an Ionis discovered medicine that supports once per year intrathecal dosing with potential for even greater efficacy than Spinraza 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 them to investors?
Yeah. To be determined how best to do that. Of course, we publish a lot at Ionis. We present at a lot of scientific conferences. Our research team is very active in doing that. I understand the question, can you pull it all together and really present 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. 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. Maybe, in the second half of this year, we can do a podcast or some sort of webcast in focusing on the science.
I guess the bottom line is it's something we want to do. We just need to find the right time to do it.
Thank you. Another question from James. Are you building your own internal ligand or peptide library? If 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 molecular weight peptide-like molecules for muscle targeting as well as for blood-brain barrier, where we have exclusive rights for all oligonucleotide strategies, ASOs, siRNAs. It's working really well. Our first bicycle siRNA is actually in phase I testing today for a heart indication targeting cardiac myocytes. That's with AstraZeneca. We have our own internal programs, too. I just can't talk more about them. It's a very competitive space, as I'm sure you know.
One more question it looks like from James is, do you or GSK have plans to develop a follow-on drug for hep B using MsPA, assuming that this chemistry would have better efficacy in 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 EASL and published simultaneously on functional cure rates in the order of 20%-25%, it's just the beginning. As groundbreaking as those results are, and important for the HBV community, that's the beginning. GSK is committed to this drug, bepirovirsen, in this area, and are already in clinical testing with combination approaches that sets bepirovirsen up to drive even greater functional cure rates. You can see some of that on clinicaltrials.gov, but also, there's more in the works, I can tell you, that's being planned.
If 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 furthering clinical trials involving bepirovirsen.
Thank you. A question from Howard. Do you have any updates on the development of oral drugs?
We're not pursuing oral drugs at this time. We've been down that road many times. We've invested extensively. I think we've done by far the most substantial work and the most innovative work in oligonucleotide oral delivery, whether it be ASOs or siRNAs and so on. It's just really problematic. 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. In the CNS, once per year, intrathecally or even subcutaneously. If subcutaneous administration works for CNS diseases, that too will be extremely infrequent. That's not going to be a frequent dosing regimen. We question the value of oral drugs versus once per year dosing or twice a year dosing.
That's very convenient for patients and doesn't cause the burden of oral delivery that often, frequently every day or so. We've pretty much moved away from oral delivery.
Thank you. Another couple of questions from Tom. Where do things stand with respect to your collaboration with Metagenomi and other gene editing efforts? Will you bring a gene editing drug into the clinic?
Our partnership with Metagenomi continues to go very well. We have late-stage programs in research, so drug discovery research. Ionis has not disclosed targets that we've prioritized yet. We expect to have a candidate by next year, probably the first half of next year, our first candidate involving gene editing. I want to emphasize that the know-how of Ionis with respect to chemical modification of nucleic acids and understanding nucleic acid biology and nucleic acid-related drug discovery is something we're taking full advantage of with Metagenomi in developing state-of-the-art gene editing approaches, our just general know-how of understanding how to discover drugs involving nucleic acids. It's going well. Our first candidate discovery efforts are going well. We expect the candidate not too far down the road. As far as when we initiate clinical studies, that's to be determined, it's not going to be next year.
Thank you. Last question from 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 new targets at this stage until they reach posting on clinical trials where we start the phase I study. I did mention already, we just started a Dravet syndrome phase I/II, first-in-man, first-in-patient study. We refer to that as a phase II study. That's underway. We expect additional first-in-human starts this year. Typically, we move three to five new drug candidates into development each year. That has a trickle-down effect of a similar cadence of new clinical trial starts each year. 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.
Thank you. We have a couple of questions from Ted, who's asking about tissue delivery. First question is, where do things stand with Ionis targeting skeletal muscle, any skeletal muscle 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 siRNA for muscle targets for neuromuscular diseases that are, as I said, in late-stage drug discovery. They have the potential to get through tox next year, assuming everything goes well, and maybe get into the clinic in the second half of next year. That's to be determined. We don't have the drug candidates yet. If everything goes smoothly, I wouldn't rule out a clinical start next year.
Thanks. Second question that Ted has is about lung. Where do you think stand with Ionis' inhaled drug programs, and will Ionis be moving any inhaled drugs into the clinic soon?
We have our first medicine using Ionis advanced chemistry, MsPA chemistry in particular, using an antisense oligonucleotide with that chemistry incorporated for a target. I don't believe we've disclosed the target yet. That candidate, it looks great in pre-clinical models. That's our first re-entry into pulmonary diseases using the inhaled route of delivery. We're hoping to start IND tox studies second half of this year, and then you could do the timeline. If the tox goes well, if we complete it next year in enough time in advance, maybe we can start a clinical study into next year. Maybe it'll be 2028. We'll see about that. Pulmonary is advancing forward nicely.
All right. I think we have one more question, and it's from Denis on behalf of Gary Nachman from Canaccord. Where are you currently with the Angelman 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 it compares to the original phase I/II trial you ran? Go ahead.
Let me back up. Our phase III program for Angelman syndrome has a pivotal study for people, I believe it's between the ages of 2 to 18, nearly about 200 patients or so, give or take, all being dosed at 80 milligrams quarterly in that study. That's the dose that showed the best evidence of efficacy in our phase I/II HALOS study. Across all measurement tools as well as all clinical measures for each of those tools, Bayley-4, SAS, CGI as examples. Very encouraging data there. Enrollment's going really well. There's a lot of enthusiasm for our phase III study, 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. I forget the other part of the question, but I think that pretty much covered it. Oh, 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. In our phase I/II HALOS study, we actually showed good evidence, strong evidence, that even the adults were benefiting, not just the 2 to 18-year-olds in the study. 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. We believe that the greatest benefit will actually be getting to those newborns as quickly as possible.
That's why we initiated the infant study, which is now underway.
The second part of these questions are about the competitor's readout this year. He wants to know, what are the read-throughs that we could expect from the trial readout later this year for the competitor drug, and is there anything you could do to change your phase III trial after seeing those results?
Let me just start by saying that we're pulling for all modalities to have success for the treatment of these devastating diseases that we're tackling. We think options for patients is best. It's best for all parties, patients, HCPs, as well as sponsors. It just lends to greater success for everybody. I will also say that let's not forget the fact that Ionis has been in CNS diseases for multiple decades now with great success. I talked about the drugs that are already approved and 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 program that's essentially identical to Spinraza and QALSODY and tau, all the drugs that have shown value, ZOLGENSMA for Alexander disease. It's a proven platform.
The competitor that is going to have phase III data later this year is a very different platform, very different approach, very different dosing in their study. We are very much looking forward to their results later this year because it will be the first randomized controlled study using an oligonucleotide approach for Angelman syndrome. Can we learn from that? Sure, we can learn from it. Can we modify our study in certain ways? Within limits we could potentially. Do we expect to? Probably not. We like the design of our study. It's very well-designed. It's based on our phase I/II HALOs study, which was very successful, and it's using a platform that's proven. Certainly, we'll be paying attention to it, and we're very hopeful that they have success.
We have time for one last question from Ted. Is there a priority review voucher associated with the approval of the Alexander disease drug?
No, there's not. We do have breakthrough therapy designation and priority review.
That's a wrap.
Okay. Well, those are all great questions. I 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 well-positioned to really drive tremendous value, accelerating value for all Ionis stakeholders, our shareholders, HCPs, the medical community, and most importantly, to the patient community. Thank you for listening. Really proud of the update we've been able to give today, and stay tuned. There's a lot more coming from Ionis.