Good afternoon. Welcome, everybody, to the 2024 Annual Shareholders Meeting Corporate Update for Ionis Pharmaceuticals. My name is Brett Monia. I'm the Chief Executive Officer of Ionis, and I'm thrilled to provide an update on the remarkable progress we're making at Ionis today. These are my forward-looking statements that I recommend to you at your convenience. So at Ionis, we are executing on a clear vision to drive substantial value for shareholders, for all stakeholders. That vision is to substantially extend the leadership position that we created in RNA-targeted therapeutics. We're doing so by focusing on three specific and highly important investment areas. First, is to extend and diversify our technology for oligonucleotide therapeutics. The second is to prioritize and expand the Ionis wholly-owned pipeline.
And thirdly, to deliver Ionis medicines from our wholly-owned pipeline directly to patients, commercialization, while supporting our partnered pipeline. All of this with financial responsibility in place, of course, driving value by delivering a steady cadence of potentially transformational medicines now, in the near term, and in a continuous manner. We're off to a very strong start in 2024, and here are some of the highlights of the achievements we've made already. Already this year, we have two product launches. Late last year, WAINUA for hereditary TTR polyneuropathy was approved by the FDA, and in late January, WAINUA was launched. In addition, just last week, QALSODY, our treatment that we discovered, that we conceived, discovered, and developed, and is now commercialized by our partner, Biogen, was approved in Europe.
That's in addition to the U.S. approval and launch, and is now launched in Europe as well for SOD1 ALS. We've also had 3 very positive phase 3 readouts this year: the BALANCE study for olezarsen in familial chylomicronemia syndrome or FCS. We presented that data, the full dataset, at the ACC in April and published the results in the New England Journal of Medicine. And then, two positive phase 3 results from, for donidalorsen, for hereditary angioedema, the OASIS phase 3 study, as well as the OASIS-Plus study. And I'll go into, the details of the results of those studies, momentarily. In addition, we are executing on our rich, late-stage pipeline, very well. We've completed enrollment in 4 phase 3 studies, already this year.
The CORE study, our pivotal study for olezarsen in severe hypertriglyceridemia, and the supporting study ESSENCE, to support the potential approval of olezarsen in severe hypertriglyceridemia, with more than 1,000 patients in the ESSENCE study now fully enrolled. And then just last week, our partner, GSK, completed enrollment in the program, our program in hepatitis, in chronic hepatitis B, the B-Well 1 study and the B-Well 2 study. And then we've also had 2 positive mid-stage pipeline readouts this year. Today, we're very proud of the fact that we have one of, if not the richest, late-stage phase 3 pipelines in biotech. And here's what that pipeline looks like.
Nine medicines in across 11 disease indications for highly prevalent diseases as well as severe rare indications. WAINUA in development and now launched for hereditary polyneuropathy is off to a great start and is also in development for a much larger indication, ATTR cardiomyopathy, in phase 3 development. olezarsen for 2 indications, familial chylomicronemia syndrome with the potential approval late this year, assuming priority review. Then our SHTG study for a much higher, highly prevalent disease indication, severe hypertriglyceridemia. donidalorsen our program for prophylactic treatment of hereditary angioedema. As I mentioned, we read out that phase 3 data last week, and we're preparing to submit for approval in the U.S. and Europe.
Two severe rare programs from our neurology, wholly-owned neurology pipeline, zilganersen for Alexander disease, and Nuvtamsein for FUS ALS, are progressing nicely with their scheduled readouts. Pelacarsen, with our partner, Novartis, for a highly prevalent disease, millions of people suffering from cardiovascular disease due to high levels of a risk factor called lipoprotein(a), with phase 3 data expected next year. I already touched on that bepirovirsen for chronic HBV, now fully enrolled, with data expected in 2026. Our Factor B-LRx program with Roche in IgA nephropathy, with data expected down the road. Then tofersen, which is now, as I mentioned, launched in the U.S. and Europe for symptomatic SOD1 ALS, is also in phase 3 development for presymptomatic SOD1 ALS by our partner, Biogen.
Our three near-term commercial opportunities are progressing exceptionally well. I already touched on WAINUA. WAINUA is part of a co-development, co-commercialization partnership with our long-standing partner, AstraZeneca. It's the first time in our history that we've actually launched into a co-development, co-commercialization partnership, and the partnership is going very well. Olezarsen for diseases related to severely elevated triglycerides, with potential launch and potential approval and launch, by the end of this year. And then, the much larger indication, severe hypertriglyceridemia. In combination, those two indications represents blockbuster opportunity and this program also represents the first potential independent commercial launch for Ionis in our history.
Following right behind olezarsen is donidalorsen, our prophylactic treatment for hereditary angioedema, with the expectations to submit for approval in the US and Europe in the second half of this year. Following our 3 near-term commercial opportunities in which Ionis is participating or conducting entirely the commercialization of those products, is the next wave of wholly owned medicines from our wholly owned pipeline, driven predominantly from our leading neurology pipeline. A pipeline and a platform with a proven track record of delivering first-in-class disease-modifying medicines. I will go into more depth in a moment on all these, WAINUA, olezarsen, donidalorsen, and in neurology. We couldn't be more proud of the approval of WAINUA for hereditary polyneuropathy that was achieved around Christmas time last year.
And as I mentioned, with our co-commercialization, co-development arrangement with AstraZeneca, the launch is off and running, starting in late January, and it's going very well, meeting all of our expectations in the United States. We're also expecting approval in Europe and in Canada later this year, and WAINUA is also under review for this indication in several additional territories. We're very proud of the efficacy that WAINUA has consistently demonstrated in this disease, and we're also pleased with the fact that we have an exceptionally attractive profile from a tolerability and safety perspective. It's a very clean label, and it is. WAINUA represents the first approval of our targeted delivery platform we call LICA.
And we think that this bodes very well for the rest of our LICAs that are rapidly progressing towards potential approval. In addition to the poly, the rare polyneuropathy indication, WAINUA is under development and going very well for a much larger, highly prevalent disease indication, TTR cardiomyopathy. We're conducting a global phase 3 development program that is the most comprehensive ever conducted in this disease indication, a highly fatal disease. It is the largest study conducted in ATTR cardiomyopathy ever. It was fully enrolled now for over a year, with more than 1,400 patients, and all of this positions WAINUA to deliver the richest data set in this broad patient population, with phase 3 data expected in 2026.
Right behind WAINUA is Olezarsen, our potential breakthrough medicine for diseases related to severely elevated triglycerides, with blockbuster potential. This is a disease that causes a variety of comorbid conditions in patients with severely elevated triglyceride-driven pancreatitis. Most importantly is the risk of a potentially fatal acute pancreatitis attack. We are developing Olezarsen for two indications. One, for the rare indication called familial chylomicronemia syndrome, FCS, and then to the much broader millions of people in the United States alone suffering with severe hypertriglyceridemia. There's a substantial unmet need. There are no effective treatments today to substantially lower triglycerides in people with severely elevated triglycerides. We reported in April very positive phase 3 data in FCS, which we demonstrated achieving all of our primary goals in that study, including efficacy and safety.
The NDA has been submitted now, to the FDA for FCS, with assuming priority review, we would anticipate an approval late this year and a launch, late this year, our first independent commercial launch. We're also planning to file in Europe in the second half of this year. As I mentioned, WAINUA, olezarsen represents our potential first independent commercial launch in our rich history at Ionis. Then the Phase 3 SHTG study is also progressing well, and I'll touch on that in a moment. We couldn't have been, happier with the Phase 3 results and the BALANCE study, for in FCS for olezarsen.
We demonstrated substantial reductions in the target, apoC-III, in triglycerides, and we were extremely excited about the substantial reductions we demonstrated in acute pancreatitis in this study as well as reductions in hospitalizations, all with a favorable safety and tolerability profile, and we were very proud to have published this data in the New England Journal of Medicine. In addition to the regulatory status that I just highlighted, we've also opened up an expanded access program in the U.S., and that's going well, as is the long-term open label extension. Based on the data, based on the results, and the unmet need, there are no treatments for FCS in the United States today. We were granted U.S. breakthrough therapy for olezarsen and FCS, and we've also had orphan drug designations, and we are prepared to launch.
The results were very positive. As I said, this is just a snippet of some of that data. We demonstrated substantial reductions in apoC-III levels that were durable in the phase 3 BALANCE study at both the 50 milligram per month as well as the 80 milligram per month dose cohorts. A highly statistically significant reduction in triglycerides at the 80 milligram dose, as I mentioned. Very pleased to have demonstrated substantial reductions in acute pancreatitis, hospitalizations, all with a favorable safety and tolerability profile. Then the big study. One of the largest studies we've ever conducted in our history, olezarsen, in severe hypertriglyceridemia. As I mentioned, millions of people suffer from comorbidities associated with severe hypertriglyceridemia in the United States alone.
Because this is a large indication, a single pivotal study is not sufficient. We're conducting a pivotal study called CORE, with more than 600 patients now fully enrolled, and then a confirmatory pivotal study called CORE, CORE2, with 390 patients, in which we're expecting to complete enrollment soon. And then a supporting study called ESSENCE, a study with patients with mildly elevated triglycerides, with cardiovascular disease, in which is intended to satisfy the necessary safety exposure that's needed for approval for a highly prevalent disease like SHTG. We're expecting data from all these studies mid-year next year. As I mentioned, olezarsen represents our first independent commercial launch for Ionis, and we're ready to launch.
We're building a tremendous momentum from the phase 3 results through a lot of work being done to improve disease awareness, patient identification campaigns, extensive market research to identify those physicians that actually see these patients, and we're building great relationships with these physicians today. Also great patient and caregiver support to help patients through the journey, including reimbursement and making sure reimbursement goes very smoothly. We're building a highly efficient and right-sized commercial team to launch in FCS.
And then following FCS, assuming approval in SHTG, we're gonna take advantage of and build on and leverage all the great progress we expect to make in FCS and apply all of that and then expand on all that for the much larger indication, SHTG. We're gonna leverage the treaters that treat FCS and build on those treaters to build to capitalize on the SHTG disease opportunity as well, and to spread out from there. We believe that olezarsen will be established very quickly as a preferred treatment for SHTG, and we have a very good handle on what our commercialization strategy needs to be implemented for this indication to achieve blockbuster status that we're expecting for this treatment. Right behind olezarsen is donidalorsen, our second anticipated independent commercial launch for Ionis.
Donidalorsen has the potential to be the preferred treatment, prophylactic treatment for people living with hereditary angioedema. Hereditary angioedema is a genetic severe disease that results in patients being afflicted with unpredictable and severe swelling of various tissue beds that can include the larynx, and if it does, can cause suffocation and can be fatal. There are prophylactic treatments on the market today, but new prophylactic treatments are needed, better prophylactic treatments to provide better efficacy for patients and better tolerability, and patients want simpler routes, simpler administration profiles for treatments to prevent their HAE attacks as well.
We believe donidalorsen is set up to meet the needs for many patients living with HAE, both from an efficacy standpoint as well as a safety and tolerability standpoint, with a patient-friendly once per month or even every two-month administration, self-administration, using a simple auto injector. We believe that donidalorsen has the potential to be, as I said, treatment of choice in the United States, where we're planning to launch independently. We also secured a new partnership late last year for European commercialization of donidalorsen in Europe with our partner, Otsuka, with very favorable economics to Ionis. Launch is planned, assuming approval, in 2025. This is what the phase 3 program for donidalorsen looks like. There's two main studies, the OASIS study and the OASIS-Plus study.
The OASIS study is our randomized pivotal phase 3 trial. In that study, we demonstrated substantial reductions in HAE attack rates with favorable safety and tolerability. We also demonstrated markedly improved quality of life, high levels of disease control. We've received U.S. and EU orphan drug designations, and last week, we published the results of the OASIS phase 3 study at the New England Journal of Medicine, in the New England Journal of Medicine, and we also presented the results in three late-breaking presentations at the EAACI conference in Valencia, Spain. The other study that we're conducting, that's for donidalorsen to support the phase 3 program is the OASIS- plus study. And there's two cohorts in OASIS- plus.
The first cohort is the long-term open label extension cohort, in which we've now demonstrated that long-term treatment continues to improve. We continue to reduce HAE attack rates and continue to improve quality of life measures. The effects are durable. And then the second cohort in OASIS-Plus is what we refer to as the switch study. Patients that are on existing prophylactic treatments were invited to move into donidalorsen treatment, switching from their existing prophylactic treatments over to donidalorsen. In this first, of its kind clinical trial done in HAE, we demonstrated in the switch study improved HAE attack rates. That means improved compared to the level of control they were getting from their previous prophylactic treatment.
We also demonstrated improved quality of life compared to what they were experiencing prior to coming on donidalorsen, and improved disease control. Based on patient surveys from the, in the switch study, we also demonstrated strong preference for donidalorsen, which we... And all of this, we think, will be very useful in informing physicians who are convinced that their patients should be on donidalorsen in the future, and will provide the data necessary to switch them safely and effectively. And as I mentioned, the filings are on track for this year for both U.S. and Europe, and we will be prepared to launch in 2025. This slide shows a snippet of data from our open-label extension study from the OASIS-Plus study.
What you can see in this study, in the gray area, is the randomized phase 3 portion of the study, which was done for 25 weeks, in which we had a placebo in gray. Then we had 2 dosing cohorts, every 2 months, dosing shown in orange, orange diamonds, and then the monthly dosing shown in purple, squares. What you can see is that both treatment groups were highly effective in reducing HAE attack rates, and the monthly dosing had a faster onset of action, but eventually they caught up. The bi-monthly dosing caught up to the monthly dosing with respect to reducing HAE attacks.
Then once the patients rolled over into the open label extension, not only did we show continued durable reductions, remarkable reductions in HAE attacks in the monthly and bi-monthly treatment arms, you can see how rapidly the placebo groups improved. We were able to reduce their HAE attack rates extremely fast, and it mirrored, it really was very similar to that of the monthly and the bi-monthly with respect to HAE attack rates. We demonstrated 93% reductions in HAE attack rates compared to placebo for the monthly dose, and 92% improvement for the bi-monthly dose. As...
And then in the OASIS-Plus study, the switch study, as I already alluded to, we couldn't have been more pleased with how well donidalorsen performed in patients previously on prophylactic treatments who switched over to donidalorsen. Not only were we able to safely transition patients from their previous prophylactic treatments such as lanadelumab, berotralstat, and C1 inhibitor, but we were also able to demonstrate further reductions in attack rates, 60-65% for lanadelumab. Lanadelumab is what patients are mostly taking in the United States today.
For berotralstat, we were able to demonstrate a further improvement of 73% compared to what they were getting from berotralstat, as a prophylactic, as their previous prophylactic treatment, and then, 41% for improvement with C1, over C1 inhibitor. And then, very importantly, how do patients feel about donidalorsen? Well, we conducted an independent, administered survey and asked patients how they felt about their previous prophylactic treatment versus donidalorsen, and we were very pleased to see that 84% of patients preferred donidalorsen, and well over 60% of patients strongly preferred donidalorsen over their previous prophylactic treatment, whether it was lanadelumab, berotralstat, or C1 inhibitor. So donidalorsen has the potential to be a preferred treatment choice as a prophylactic for people with hereditary angioedema based on its overall profile.
Substantial and sustained reductions in HAE attacks, improvement in quality of life, and with almost all the patients well controlled. The flexibility of dosing as monthly or every two months dosing using a simple self-administered auto-injector, with really, really impressive efficacy that's durable and all with a favorable safety and tolerability profile. We will be ready to launch donidalorsen next year. We're already building towards this, and we're focused on a concentrated prescriber base. A lot of these... Most of these patients are found in centers of excellence. We know where to find them in the U.S., and they're mostly managed by allergists. We will build an efficient field team, under 100 persons, customer-facing team. That includes field sales reps, as well as patient education managers and more.
We are, we believe we have the right drug and the right strategy to reach a good number of patients in the US with HAE. In addition, our partner Otsuka, as I mentioned, is preparing to file for approval in Europe, and they also are gearing up for commercializing donidalorsen in Europe. Following WAINUA, following olezarsen, following donidalorsen, is a wave of wholly owned programs as well as partnered programs from our leading and validated neurology franchise. I say validated because we have two breakthrough treatments already approved, two drugs that were conceived, discovered, and developed at Ionis, and now being commercialized by our partner, Biogen, SPINRAZA, for spinal muscular atrophy, and QALSODY, for a genetic cause of ALS, SOD1 ALS.
In addition, we have many additional 11 medicines in clinical development today for both broad indications such as Alzheimer's disease, as well as severe rare indications like ALS, Huntington's disease, prion disease, and more. Today, Ionis has 5 medicines in clinical development in their wholly owned pipeline in neurology, and by the end of this year, we're expecting to have 7 wholly owned medicines in clinical development. Our next wave is focused on several subgroups or subdomains, if you will, in neurology. We're building a pipeline of rare pediatric neurology medicines, Zilganersen for Alexander disease, now in phase 3, with the data expected next year. We're thrilled to be in control of our Angelman syndrome program, ION 582, and we're looking forward to starting a phase 3 study sometime early next year.
Our ION356 for PMD, a first in-patient study that's now underway, and our MECP2 duplication syndrome medicine, ION440, expected to start clinical testing later this year. Our second pillar that's top priority for our wholly owned pipeline is dementia, prion disease. Symptomatic prion disease, ION717, is now underway in the clinic, and we are also planning to start in the second half of this year a new clinical study with a target with a much larger, quite a large patient population in dementia. Target has not been disclosed yet, but we'll disclose that target when we start the clinical study later this year. Following rare pediatric neurology, following dementia, is the next...
Is another wave of key areas of focus for our wholly owned neurology pipeline, which are neuromuscular diseases, peripheral neuropathies, as well as motor diseases, and these are not that far down the road. All of this progress, all of the progress we're making for our near-term commercial opportunities, the progress we're making with our partner pipeline, as well as the rest of our pipeline, is setting us up to achieve the vision that I laid out at the beginning of this presentation to deliver a steady cadence of medicines to patients to drive substantial value, revenue growth for our shareholders, for all stakeholders. You can see in the near term, we're expecting to add olezarsen for FCS into our commercial pipeline.
And then, in 2026, 2027, we're looking forward to potential approvals and launches for medicines for broad indications such as pelacarsen for Lp(a) and cardiovascular disease, for rare indications such as IgA nephropathy, as well as I mentioned, zilganersen, and very importantly, olezarsen for SHTG. And this will continue with additional medicines down the road, such as bepirovirsen for HBV, and then WAINUA for TTR cardiomyopathy and more. All of this sets us up in a clear direction, a clear path to drive value creation.
With a solid financial foundation and a robust, innovative pipeline, that will continue to drive value well into the future, to invest in bringing these important medicines to patients is a key area of focus, of course, to drive substantial value, advancing the pipeline, advancing our technology to drive a steady cadence of new medicines, and all this sets us up for positive cash flow, powered by substantial revenue growth. And then finally, we are very excited about the progress we're making in science and innovation and in our technology to expand and diversify our technological capabilities. The investments we've made over the last few years to do exactly this are delivering. They're paying off, expanding our technology platform.
We are advancing the very best ASO, antisense oligonucleotide chemistries, with new backbones, new targeted delivery strategies, and they're all approaching clinical testing. We're very excited about expanding into new mechanisms of oligonucleotide therapeutics, such as siRNA. With our first siRNA molecule now in preclinical development, toxicology studies, and our first clinical study to expect in the second half of this year. We're also excited about the progress we're making in gene editing. All this focused on optimizing potency, durability for systemic and local applications. Delivery is very important, of course. We think we're leading the way in targeted delivery strategies or LICA strategies, opening up tissues such as cardiac muscle, opening up tissues like skeletal muscle for neuromuscular diseases.
We're very excited about the work we're doing to deliver our medicines to the CNS systemically, overcoming the blood-brain barrier, and designed to further strengthen our leadership in neurological diseases. All of this is to support our leading franchises in cardiovascular and neurology, as well as to open up new potential areas such as in pulmonary diseases and in renal diseases. There has been a lot of achievements already this year in key value-driving events and more work to do in the second half of this year. On the phase 3 side of things, I already touched on the very successful phase 3 outcome for donidalorsen in HAE, with full presentations now behind us in the publication as well.
Olezarsen, the strong phase three data has been achieved, and we presented that data. And we're also looking forward to fully enrolling the SHTG phase three study shortly. Phase two has also been very productive. So far this year, we've reported positive data for ION224 in MASH, as well as in Angelman syndrome, top line, and we're looking forward to presenting the detailed phase two data in Angelman syndrome later this year. We also reported a disappointment from our phase two pipeline, ION541, in sporadic ALS. ION541 demonstrated substantial engagement of target with good safety and tolerability. Unfortunately, it just did not demonstrate the efficacy that was needed to progress this program forward.
On the regulatory side, we're looking forward to the approvals of eplontersen, WAINUA, for ATTR polyneuropathy in Europe and Canada later this year. We've already filed and as I mentioned earlier, WAINUA for ATTR polyneuropathy in several territories outside of the U.S. We're looking forward to the acceptance, I should say, of olezarsen's NDA later this year, and if we receive priority review, an approval for FCS, and we're also preparing to file outside the U.S. as well. Similarly, we're planning to file for donidalorsen in the United States. And as I mentioned earlier, our partner Otsuka is prepared and is preparing to submit for European approval later this year as well.
And we achieved the approval of QALSODY with our partner Biogen for SOD1-ALS in Europe. We've launched WAINUA with our, in our co-co, with AstraZeneca for ATTR polyneuropathy, and now QALSODY is launched by Biogen in Europe for SOD1-ALS. And we're looking forward to potentially launching olezarsen for FCS late this year, assuming priority review. So all this is positioning, positioning Ionis, for great success in the near term and well into the future by building on the momentum that we've achieved over the last several years, including this year, and by focusing on our, all of our strategic priorities, of which there are four. One, our wholly owned pipeline is a top priority, advancing and growing our wholly owned pipeline, especially in the areas of neurology and in cardiology.
Number two, to integrate and now, as we are a fully integrated biotech company, to deliver our medicines directly to patients and build all the capabilities necessary to be highly successful on the commercial front for the programs that we each prioritize to keep ourselves. Thirdly, to expand and diversify our technology and to deliver these new technologies, these new approaches for oligonucleotide therapeutics into the clinic and into patients, to expand existing franchises and to open up new therapeutic areas. And fourthly, to continue to be responsible in our financial strategy and to take advantage of our financial strength and to deliver the medicines that are in our pipeline today and in the future to drive substantial revenue growth, positive cash flow well into the future.
All of these investments are focused 100% on driving next-level value, great value, for patients, for shareholders, for all Ionis stakeholders. Thank you. That's my presentation. And now we'll open it up for our Q&A session. And I'll ask, Wade Walke, Senior Vice President, Investor Relations, to manage the Q&A queue.
Thank you, Brett. We're gonna pause for a minute and let people take a minute to let people go into the online portal and submit questions, and we'll gather those questions and be right back. All right, we have some questions that are coming in. We also have some questions that people have submitted via email to us, and so we'll start off with a few of those as people are putting in questions on the online portal. The first question we have is from investors congratulating us on the positive donidalorsen data that was reported recently at EAACI. How do you see donidalorsen fitting into the already crowded HAE market, and how will donidalorsen differentiate from existing and new products also advancing in this space?
... Very important question. So, the HAE prophylactic market is somewhat crowded. I mean, there are treatments on the market today, especially in the U.S. We have principally two treatments, Takeda's Takhzyro and BioCryst's Orladeyo. What we've learned from extensive market research, direct interactions with physicians as well as the patient community, is despite the availability of these prophylactic treatments for HAE, there remains a substantial unmet need in the eyes of patients, in the eyes of treaters. And that unmet need comes in several forms.
One, patients are still having attacks, and patients and attacks can be highly debilitating, and can be, you know, can land a patient in a hospital for an extended period of time and can be potentially fatal. These are unpredictable attacks. Patients are looking for better efficacy despite the availability of prophylactic treatments today. In addition, patients are looking for better tolerability. The two main treatments that are on the U.S. market today have room, a lot of room for improvement with respect to tolerability. I don't wanna get into the details here, but it's clear that patients are seeking a better tolerability of existing prophylactic treatments.
And then thirdly, patients are also looking for more simple approaches to drug administration, less frequent administration, and a simplicity of treatment in other forms, such as using an auto-injector like donidalorsen offers. We believe donidalorsen has the potential, and certainly the phase 3 data supports all this to meet all these needs for patients. We think that that is also reflected in the switch data results that I presented earlier. Patients are switching to donidalorsen in the switch study. They're staying on donidalorsen in the switch study, and in addition, they have demonstrated strong preference for donidalorsen in the patient survey. So we think donidalorsen has a good chance to be a really effective and preferred treatment for HAE.
Great. The next question that came in is about the launch of WAINUA and what the status of the launch of WAINUA is.
So, WAINUA is off to a really good start. We're really proud and happy with what we're seeing. We're exceeding all of our key performance metrics here in the United States, where it's launched. We're pleased with what we're seeing on the speed to reimbursement. We're pleased about the number of patients that are now on WAINUA. We're pleased with the interest, the enthusiasm, the questions that we're getting from treaters, how they can, you know, get their patient on WAINUA. All the enthusiasm for the drug. We're pleased with the types of patients that are now on, are moving on to WAINUA.
That includes patients that are newly diagnosed to hereditary ATTR polyneuropathy, as well as patients switching from existing treatments for hereditary polyneuropathy. So it's early days, but the WAINUA launch is off to a really solid start.
Great. Another question we have that's come in is about finances. The question is, going forward, when do you expect to be cash flow positive?
Yeah, great question. We are in an investment period today, and, you know, we're building our commercial capabilities, and we're finishing up some very large phase three studies, olezarsen and SHTG, WAINUA and TTR cardiomyopathy. And bringing these near-term commercial opportunities to the market is positioned to provide multi-billion dollar potential, along with our partner pipeline, on top of our substantial and sustained revenues that we're already achieving today. We think that not too far down the road, all of this will power our move to becoming cash flow positive.
Great. The next question is about HELIOS-B, about the data from the HELIOS-B study that's coming along from a competitor, and what kind of read through that will have, for our study that's currently in phase 3?
Yeah, it's hard to say. You know, we're very much looking forward to the HELIOS-B results, considering it's the first cardiovascular outcome trial conducted in this patient population with a silencer. As I mentioned in my presentation, we believe that we have the right trial design for TTR cardiomyopathy. It's not only the largest, by far, of a study ever done, we also have the right population for today's patients. We have a substantial number of patients on which we're studying WAINUA on top of tafamidis, which is now the standard of care in the United States. So combination treatment is going to be very important. Having data for combination treatment is very important. We also have a good balance of naive patients not on tafamidis.
We also have several sub-studies in process, in progress, to look at the mechanism of amyloid accumulation and the performance and the effect it has on cardiac performance in the CARDIO-TTRansform study, imaging studies, and sub-studies. We think we have the right trial design to provide the richest data set ever in this patient population. The outcome of the HELIOS-B and how that influences Ionis and our partner, AstraZeneca, will depend on the details of the data. We believe that the silencer class will be the preferred class from an efficacy standpoint in this patient population based on its mechanism of action, blocking the production of a toxic protein right at the source.
We think that the silencer class will, you know, demonstrate the efficacy that I just alluded to. It's hard to say what we're expecting or how it'll influence us. It's nuanced. It's going to depend on the details of what data comes out and also what data is shared. So it's really hard to say at this point. We're focused on our study, but we're looking forward to the readout of that study.
Great. So the next question is actually a couple of questions about the Angelman program. And they are: Is there any change in the company's relationship with Biogen, given this recent decision not to license the Angelman drug? And what's the status of the program, and do you intend to advance it independently?
Our partnership with... You know, we've been partnered with Biogen for a decade now, and started with SPINRAZA, and then ALS resulted in QALSODY and so much more. The partnership with Biogen is as strong as ever. We, you know, we work very closely with Biogen on the research side. We're advancing the technology together as well for CNS diseases now. They've also prioritized the tau program as a top priority in their pipeline, and they're really excited, remain very excited about QALSODY and SPINRAZA and the rest of the pipeline that we've delivered to them, basically. The Angelman program, you know, there was a different view as to risk and reward for the program.
We were aligned in most areas, honestly, on what the results were telling us. But the question really just came down to internal metrics on what is necessary to advance the program to Phase III. We believe, now that we're in control of the Angelman's program, this was a gift, that we're couldn't have been more pleased to have this program as a centerpiece in our pediatric neurology pipeline today. But the relationship with Biogen is as strong as ever. We intend to keep this program for ourselves. We think that this would be, is a, is going to represent a centerpiece in our wholly owned neurology pipeline, now and well into the future. We're excited about the data.
We're excited about the potential ability to be able to deliver a really meaningful, potential transformational medicine for this devastating disease, which there are no treatment options available today. A prevalence that's more than double that of spinal muscular atrophy, and SMA, of course, as you know, is a blockbuster medicine. We're looking forward to sharing the phase II data at the ASF meeting, the Angelman Syndrome Foundation meeting in July. We're looking forward to an end-of-phase II meeting with the FDA to settle on our phase III design later this year, and to get the phase III program started as soon as possible.
Excellent. So the next question that we have is, what program do you think is most undervalued today?
Well, there are probably several. But the one program that I would, I think considering its blockbuster potential and, and misunderstandings about it, I would have to say the olezarsen program. There are, you know, some misunderstandings about, diseases and what we're trying to correct for diseases related to severely elevated triglycerides, such as SHTG specifically, and the market opportunity for that. So we think under olezarsen, is probably the most undervalued program, especially considering, the substantial unmet need, the blockbuster potential for olezarsen and SHTG, and the fact that it's wholly owned by Ionis. So we're going to really we expect to really drive substantial value for all stakeholders, for this program.
The really strong SCS data lends even further confidence of a highly successful SHTG outcome next year. With that said, we're also pleased with the progress we're making. Olezarsen is far more appreciated today than what it was just a couple of years ago, but we still have some work to do there to really drive appropriate appreciation for the value that this program we expect to deliver to all stakeholders.
Great. The next set of questions are clearly. There's clearly interest in the new technologies that we're developing for our platform. So we have several questions related to that. The first one is about siRNA and our siRNA efforts that we're developing. Where are you in advancing this technology in clinical development, and what targets are you pursuing with siRNA and why?
So the investments we've been making over the last four and a half years in new backbone chemistries, new targeted delivery strategies, as well as new siRNA, are really delivering and are rapidly approaching clinical development. On the siRNA front, we have two lead programs. Unfortunately, I can't give you the targets right now. We have not disclosed them, but I can give you a little bit more color. We expect to start our first clinical study for a wholly owned siRNA in the second half of this year.
This is a Ionis siRNA utilizes Ionis siRNA chemistry and know-how, and we expect this molecule to be highly potent based on our preclinical data and highly durable, potentially allowing us to dose semiannual or maybe even annual in the clinic. We have to prove that, as it is our first siRNA in the clinic, but the preclinical data supports that conclusion. Our second lead molecule is actually utilizes two new approaches, technology approaches. One is the, it's an siRNA using Ionis siRNA chemistry, and it's coupled, bound, or, or it's linked to a Bicycle peptide, from our collaboration with Bicycle Therapeutics.
And if we're utilizing the Bicycle peptide, siRNA, molecule to go after a target in the heart, in cardiac myocytes, opening up new cardiac myocytes for an indication in heart failure. That program was licensed late last year by our partner, AstraZeneca, and now is in manufacturing tox studies. So stay tuned for those. And then there will be more coming behind that. And then, with respect to efforts to target other tissues other than the liver, as I mentioned, we're making great progress in opening up muscle tissue. Cardiac myocytes is now in preclinical development for heart failure, and there'll be more coming behind that.
In addition, we're in lead optimization for several programs targeting skeletal muscle for neuromuscular diseases, using targeted delivery strategies, ASOs, siRNA, for targets in the skeletal muscle. And we're expecting those to move to toxicology studies soon and then into clinical development, possibly next year. We've also now have developed some very exciting backbone chemistries for antisense oligonucleotides, novel chemistries, such as MsPA, that are really providing several advantages. One notably is the durability, allowing us to get siRNA-like durability, semiannual dosing, potentially, and we're expecting our first MsPA molecule for a CNS target to reach clinical testing in the second half of this year.
Then, lastly, I'll mention the really encouraging results that we're getting, we're achieving, to overcome the blood-brain barrier using targeted delivery strategies to target endothelial cells in the blood-brain barrier to deliver our payloads, ASOs, siRNAs, into the CNS using a subcutaneous route of administration or intravenous route of administration. And this positions us very well, we think, to further extend our already substantial leadership position in CNS diseases. And there's a second last, one more last. We're making great progress in metagenomics in our gene editing.
We're moving through several targets now in preclinical models, and we're hopeful that early next year, we should have our—we may have our, we expect to have our first gene or drug candidate in gene editing to move into, you know, IND-enabling toxicology studies. So, the investments we started making 4-5 years ago in science technology are really set up now to deliver molecules for clinical testing, and we can't wait.
Yeah. I think, a few other questions are coming in now on mid-stage pipeline questions, and specifically, programs that we've reported positive phase 2 data on, but we've said, that we don't plan to develop ourselves. So this is, AGT, Factor XI, and DGAT2. And so this question is: What, what are the status and what are the plans for those programs?
All three of those—all three of these programs, we're planning to partner. We do not believe that... First of all, we, as I highlighted in my presentation, we have a very rich and growing wholly owned pipeline today. We take a very, methodical, thoughtful approach to portfolio prioritization today at Ionis on programs that we keep for our wholly owned pipeline, programs that we partner, and programs that we stop. And we have—we, we strongly believe that these three programs fit better, with a, with a partner, maybe a large, like, a large pharmaceutical partner or, or another type of company. So we're looking to partner the AGT program, the DGAT2 program, and that DGAT and MASH, and the factor XI program, and, and those, those, those activities are well underway.
Excellent. We've had a couple of questions on the myotonic dystrophy program, and if we still are pursuing that?
... Yes, we are. Absolutely. And we think that myotonic dystrophy, as well as several other indications, are set up very well for some of the advances we're making in technology that I referred to earlier, opening up skeletal muscle and other... And using new backbone chemistries, size, and so on. So, stay tuned for that. But yes, we are still committed to myotonic dystrophy.
There's a question that's come in about the high-dose SPINRAZA trial, if there's an update on that.
Yeah, that's programmed, the DEVOTE study. I can certainly provide an update. As far as timing, that's a question for Biogen, when we would see new data or when we would see data from the high-dose SPINRAZA study. But some color, the study's going well. We've gone through the dose escalation phase of the study. We've gone to doses that are more than double that of the commercial dose, with good safety. And now, the high dose has now expanded into an expansion cohort in patients with SMA. And so far it's going well. But as far as timing, when we'll get to see some of that data, it's really a question for Biogen.
There's a question on WAINUA. How do you feel WAINUA compares to Amvuttra from a convenience standpoint?
You know, there are several advantages that our market research has informed us on for WAINUA that we think really sets WAINUA up to be the eventually be the preferred treatment for TTR amyloidosis of all forms. The first is the phase III cardiomyopathy design that I already went into in my presentation. We think we have the right trial design for this vast patient population. And we think that will serve us extremely well with the richest data set when it comes out. The second advantage is to have a great partner, like AstraZeneca, which is a powerhouse in the area of heart failure globally.
And we think that, you know, us working very closely, we know TTR amyloidosis well, we know our platform well, and taking advantage of the global strength of AstraZeneca in heart failure is a very important advantage for WAINUA to reach as many patients as possible globally. And then thirdly, to your question, we think the ability of patients to self-administer wherever they are, at home, in the office, on vacation, using a simple, well-tolerated auto-injector, and not have to rely on a healthcare provider to administer a treatment for their disease is a third big advantage that only WAINUA offers today.
We think the combination of all three of these, plus of course, the highly competitive efficacy and the and the really clean safety profile positions WAINUA, we believe and AstraZeneca believes to be eventually the preferred treatment for TTR amyloidosis.
I think we have time for one more question, and that one will be: Which program are you most excited about?
Oh, boy! That's like picking your favorite child. So that's a tough one. I can't give... I don't think I can give you one, but I can give you several but different reasons for why these are programs that I'm most excited about. WAINUA. We've invested in TTR amyloidosis for so long, for over a decade. And we've had our bumps along the way. However, we think that the perseverance that is hallmark for Ionis is paying off. And I'm excited because WAINUA demonstrates our perseverance are to deliver life-changing medicines, and to never give up when we think we have a strategy to deliver a really life-changing medicine. So I'm excited to see that play out for WAINUA.
Olezarsen, I'm really excited because, as I highlighted earlier, it's wholly owned and represents really our first wholly owned blockbuster medicine since we've made the move to full integration and to build our wholly owned pipeline. So that's a different reason. Donidalorsen is certainly a program I'm very excited about for a different reason. Here, we are moving into a market that already has several treatments that are in place. I'm looking forward to seeing our commercial team being able to utilize the strong profile that I highlighted earlier for donidalorsen, and to reach and to win in this market, and demonstrate their savviness, their persistence, their perseverance in delivering donidalorsen to patients in this U.S. HAE market.
Then lastly, I would say, pelacarsen. Pelacarsen is another blockbuster, a potential blockbuster from our pipeline. This drug has been in development for several many years now because of the size of the phase III trial, which reflects the size of the unmet need. 8-10 million people around the globe suffering from cardiovascular disease due to no other cause, except elevated levels of a CV risk factor, lipoprotein(a). Well, after all these years and the enrollment of more than 8,000 patients globally, in this cardiovascular outcome trial, we are now positioned with our partner, Novartis, who's running the study, for data in 2025.
This is certainly ranks up there with some of the most exciting programs in our pipeline. Not far from behind all these could be the Angelman’s program. We're looking forward to sharing the phase II data for Angelman’s in July, as I mentioned, and then to move into phase III development. And with that said, thank you for all the really great questions. Very thoughtful. I'm sure you are all as excited as we are at Ionis about the great progress that is being made here, as well as what the future is set up to bring. Great value for shareholders, for patients, for all stakeholders.
And I really look forward to providing further updates in the second half of this year, as well as for many years to come. With that said, thank you for attending, and have a great day.