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

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, clear vision to drive substantial value for shareholders for all stakeholders. In that vision, is to substantially extend the leadership position that we created in RNA-targeted therapeutics. And we're doing so by focusing on 3 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 a 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 2 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 III readouts this year, the BALANCE study, for olezarsen in familial cilomicronemia syndrome or FCS, we presented that data, the full data set, the ACC in April and published the results in the New England Journal of Medicine. And then 2 positive Phase III results from -- for donidalorsen for hereditary angioedema, the OASIS Phase III study as well as the OASIS+ 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 III studies already this year. The CORE study, our pivotal study for olezarsen, hypertriglyceridemia and the supporting study ESSENCE. To support the potential approval of olezarsen in severe hypotriglyceridemia, with more than 1,000 patients in the SNC 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 one study and the DL2 study. And then we've also had to made positive mid-stage pipeline readouts this year. Today, we're very proud of the fact that we have one of -- it's not the richest late-stage Phase III pipelines in biotech. Here's what that pipeline looks like, 9 medicines in -- across len-disease indications for highly prevalent diseases as well as severe rare indications. We knew it in development and now launched for hereditary polyneuropathy. It's off to a great start and is also in development for a much larger indication in ATTR cardiomyopathy in Phase III development. Olezarsen for 2 indications, familial chylomicronemia syndrome, with the potential approval late this year, assuming priority review and then our SHTG study for a much higher -- highly prevalent disease indication, severe hypertriglyceridemia. donidalorsen, our program for prophylactic treatment hereditary angioedema. As I mentioned, we read out that Phase III data last week and we're preparing to submit for approval in U.S. and Europe. 2 programs -- 2 severe rare programs from our neurology -- whole neurology pipeline, Zilganersen for Alexander disease, and Ulefnersen for FUS-ALS are progressing nicely with 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 Protein A, with Phase III data expected next year. I already touched on bepirovirsen for chronic HBV, now fully enrolled with data expected in 2026. And our Factor B-LRx program with Roche in IgA nephropathy with data expected down the road and then tofersen, which is now, as I mentioned, launched in the U.S. and Europe for symptomatic SOD1 ALS is also in face development for presymptomatic SOD1 ALS by our partner, Biogen. Our 3 near-term commercial opportunities are progressing exceptionally well. I already touched on WAINUA. WAINUA is part of a codevelopment cocommercialization partnership with our long-standing partner, AstraZeneca, the first time in our history that we 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 a potential launch and potential approval and launch by the end of this year. and then the much larger indication severe hypertriglyceridemia. In combination, those 2 indications represents blockbuster opportunity and represent -- and this program also represents the first potential independent commercial launch for Ionis in our history and following right behind olezarsen and is [indiscernible], our prophylactic treatment for hereditary angioedema with the expeditions to submit for approval in the U.S. 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 [indiscernible] 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 -- in our co-commercialization co-development arrangement with AstraZeneca, the launch is off and running starting in late January and is 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 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 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 III 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 we now to deliver the richest data set in this broad patient population with Phase III 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 prime -- most important is the risk of a potentially fatal acute pancreatitis attack. We are developing olezarsen for 2 indications: One, for the rare indication called familial chylomicronemia syndrome S and then two, 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 trends of [indiscernible], people with severely elevated trackers. We reported in April, very positive Phase III 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 the launch date this year, our first independent commercial launch. And we're also planning to file in Europe in the second half of this year. As I mentioned, olazarsen represents our potential first independent commercial launch in our rich history at Ionis. And then the Phase III SHTG study is also progressing well, and I'll touch on that in a moment. We couldn't have been happier with the Phase III results in the BALANCE study for FCS for overs. We demonstrated substantial reductions in the target APOC3 and triglycerides and we were extremely excited about the substantial reductions we demonstrated in acute pancreatitis in this study as well as well as reduction in hospitalizations, all with a favorable safety and tolerability profile, and we are very proud to have published the state 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 proud of. As I said, this is just a [indiscernible] of some of that data. We demonstrated substantial reductions in APOCIII levels that were durable in the Phase III BALANCE study at both the 50-milligram per month as well as the 80-milligram per month dose cohorts, highly statistically exit reduction in triglycerides at the 80-milligram dose, as I mentioned, very pleased to have demonstrated substantial reduction in acute pancreatitis hospitalizations, all with a favorable safety and tolerability profile. And then the big study, one of the largest studies we've ever conducted in our history, overs 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 CORE2 with 390 patients in which we're expecting to complete enrollment soon. And then the supporting study called ESSENCE study with mildly elevated patients with mildly elevated triglycerides with cardiovascular disease in which is intended to satisfy the necessary safety exposure as needed for approval for a highly prevalent disease like SHTG. We're expecting data from all these studies midyear 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 III 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 a great patient and caregiver support to help patients through the journey including reimbursement, making sure reimbursement goes very smoothly. And we're building a highly efficient and rightsized commercial team to launch in FCS. And then following FCS, assuming approval in SHTG, we're going to take advantage of and build 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 going to 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 the preferred treatment for SHTG and we have a very good handle on what our commercialization strategy needs to what 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. Heridetary 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 treatment to prevent HAE as well. And we believe donidalorsen is set up to meet the needs for many patients living with HAE, both from an efficacy standpoint as well as the safety and tolerability standpoint with a patient-friendly once per month or even every 2-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 for commercialization of donidalorsen in Europe with our partner, Otsuka, with very favorable economics to Ionis. Launches planned, assuming approval in 2025. This is what the Phase III program for donidalorsen looks like. There's 2 main studies: the OASIS study and the OASIS-Plus study. The OASIS study is our randomized pivotal Phase III 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 III study at the New England Journal of Medicine in the New England Journal of Medicine, and we also presented the results in the late-breaking presentations at the AACE Conference in Valencia Spain. The other study that we're conducting [indiscernible], to support the Phase III program is the OASIS study. And there's 2 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. We're 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 in the SWITCH study, we also demonstrated strong preference at donidalorsen, which -- and all of this, we think, will be very useful and informing positions who are convinced that their patients should be undone ore in the future and we'll 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 the study in gray area is the randomized Phase III portion of the study, which was done for 25 weeks in which we had a placebo in gray. And then we had 2 dosing cohorts, every 2 months dosing shown in orange, orange diamonds and then the monthly dosing shown in purple squares. And what you can see is that both treatment groups were highly effective in reducing HAE attack rates and the dosing had a faster onset of action, but eventually they the month that does caught up to the monthly dosing with respect to reducing attacks. And 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 bimonthly treatment arms, you can see how rapidly the placebo groups improved. We were able to reduce their HAE attack rates extremely fast. And it mired really was very similar to that of the monthly and the bi-monthly with respect to HAE attack rates, we demonstrated 93% reduction in HAE attack rate to placebo for the monthly dose and 92% improvement for the bi-month dose. And then in the OASIS-Plus study, the SWITCH study. As I already alluded to, we couldn't have been more pleased with the 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 previous prophylactic treatment such as lanadelumab, berotralstat and C1 inhibitor, but we are also able to demonstrate further reductions in attack rates, 60 -- minus 65% for lanadelumab. Lanedelumab 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 in as a prophylactic as their previous prophylactic treatment and then 41% improvement would see over C1 inhibitor. And then very importantly, how the patients feel about donidalorsen. Well, we've conducted an independent administered survey and ask patients how they felt about the previous prophy treatment versus donidalorsen. And we are very pleased to see that 84% of patients preferred donidalorsen and well over 60% of patients strongly preferred donidalorsen over their previous program 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 reduction in HAE attacks, improvement in quality of life, and with almost all the patients well controlled. The flexibility of dosing as monthly or every 2 months, those 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 in the next year. We're already building towards this, and we're focused on a concentrated prescriber base. 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. And we are -- we believe we have the right drug and the right strategy to reach a good number of patients in the U.S. 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 partner programs from our leading and validated neurology brands. I say validated because we have 2 breakthrough treatments already approved 2 drugs that were discovered and developed at Ionis are now being commercialized by our partner, Biogen. SPINRAZA for spinomuscular atrophy and [indiscernible] 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 OE-owned medicines in clinical development. Our next wave is focused on several sub groups or sub domains, if you will, in neurology. We're building a pipeline of rare pediatric neurology, medicines, Zilganersen for Alexander disease, now in Phase III data 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 III study sometime early next year. Our ION356 for PMD, a first-in-patient study that's now underway and our MECP2 duplication syndrome Medicine 940 expected to start clinical testing later this year. Our second pillar is top priority for our wholly owned pipeline 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 -- 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 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 that 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) a little later, cardiovascular disease or rare indications such as IgA nephropathy as well as I mentioned, using Zilganersen and very importantly, olezarsen for SHTG. And this will continue with additional medicines down the road, such as per version for HPV and then AUA for TTR cardiomyopathy and more. All of this sets us up in a clear direction and clear path to drive value creation. We've added our -- 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, amending our technology to drive a steady cadence of new medicines and all this set of sub 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 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 oligonucleotides chemistries with new backbones to targeted delivery strategies neural approaching clinical testing. We're very excited about expanding into new mechanisms, type therapeutics such as RNA our first RNA 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 of 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 to shoes like skeletal muscle for neuromuscular diseases, and we're very excited about the work we're doing to deliver our medicines to CNS systemically overcoming the blood-brain barrier further strength and designed to further strengthen our leadership in neurological diseases. So 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 III side of things, I already touched on the very successful Phase III outcome for donidalorsen and HAE with full presentations now behind us in the publication as well. Olezarsen, the strong Phase III data has been achieved, and we presented that data. And we're also looking forward to fully enrolling the SHTG Phase III study shortly. Phase 2 has also been very productive so far this year. We've reported positive data for INCT4 in NASH. As well as in Angelman syndrome top line, and we're looking forward to presenting the detailed Phase II data in agents syndrome later this year. We also reported a disappointment from our Phase II pipeline, IN-541 in sporadic ALS IM1 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. And we've already filed, as I mentioned earlier, WAINUA for ATTR polyneuropathy in several territories outside of the U.S. We're looking forward to the approval -- the acceptance, I should say, olezarsen NDA later this year. And if we receive priority review and approval for FCS, and we're also preparing to file outside the U.S. as well. Similarly, we're planning to file us for donidalorsen in the United States. And as I mentioned earlier, our partner at Otsuka prepared and is preparing to submit for European approval later this year as well. And we achieved the approval of calcite our partner, Biogen, for 51 ALS in Europe. We've launched WAINUA within our Coco with AstraZeneca for ATTR polyneuropathy and now QALSODY launched a Biogen in Europe for SI1. And we're looking forward to potentially launching olezarsen for FCS late this year, assuming priority review. So all this is 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 all of our strategic priorities, of which there are four: one, our wholly owned pipeline is a top priority. Banking growing our wholly owned pipeline and especially in the areas of neurology and in cardiology; number two, to integrate to now, as we are a fully integrated biotech company to deliver our medicines directly to patients and build all the capabilities necessary to have to be highly successful on the commercial front for the programs that we prioritize to keep our sellers; thirdly, to expand and diversify our technology and to deliver these new technologies, these new approaches for all immunophenotype therapeutic 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, and all of these investments are on driving next total 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.

Thank you, Brett. We're going to pause for a minute and let people take a minute to let people go into the online portal and submit questions and we'll get 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 e-mail 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 [indiscernible]. How do you see donidalorsen fitting into the already crowded HAE market and how will donidalorsen differentiate from existing and new products also facing in the market.

Very important question. So the HKD prophylactic market is somewhat credit. I mean there are treatments on the market today, especially in the U.S. We have principally 2 treatments to case tech 0 in BioCryst or Lideo. What we've learned from extensive market research, direct interactions with physicians as well as the patient community. Despite the availability of these prophylactic treatments for HAE, there remains a substantial unmet in the eyes of patients in the eyes of treaters and that unmet need comes in several forms. One, patients are still having attacks tax and attacks can be highly debilitating and can be -- can land a patient in a hospital for an extended period of time, and it can be potentially fatal. These are unpredictable attacks. Patients are looking for better efficacy despite the availability of proper treatments today. In addition, patients are looking for better tolerability the 2 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 want to get into the details here, but it's clear that patients are seeking better tolerability of existing profile 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 the auto-injector like orders and offers. We believe donidalorsen has the potential -- and certainly, the Phase III data supports August 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 switch study. They're staying on donidalorsen in the switch study, and they -- and in addition, they have demonstrated strong preference for donidalorsen in the patient space. So we think donidalorsen has a good chance to be really effective and preferred treatment for HAE.

The next question that came in is about the launch of WAINUA what the status of the launch of WAINUA is?

So WAINUA is also a really good start. We're really proud and happy with what we're seeing. We're hitting all our key -- 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 a no we're pleased with the interest, enthusiast and the questions that we're getting from treaters, how they can get to get their patients on WAINUA. All the enthusiasm for the drug, we're pleased with the types of patients that are now are moving on to WAINUA and that includes patients that are newly diagnosed to hereditary ATTR polyneuropathy as well as patients switching from existing treatments for hereditary angioedema. So it's certainly dates, but we know the launch is also a really solid start.

Great. Another question we have that's come in is about finances. And the question is going forward, when do you expect to be cash flow positive?

Yes. Great question. We are in an investment period today. We're building our commercial capabilities, and we're finishing up some very large Phase III studies, olezarsen and sHTG, WAINUA, TTR cardiomyopathy and bringing these near-term commercial opportunities to the market is positioned to provide multibillion-dollar potential, along with our partner pipeline on top of our substantial and sustained revenues that were already achieving today. We think that far down the road, all of this will power our move to becoming cash flow positive.

The next question is about Helios about the data Helios-B study that's coming along from a competitor? And what kind of read-through that will have from -- for our study that's currently in Phase II.

Yes, it's hard to say. We're very much looking forward to the Helios results, considering it's the first cardiovascular alcom 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. Not only the largest by far of the study ever done, we also have the right population for today's for today's patients. We have a substantial number of patients in 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 or combination human is very important and also have a good balance of naive patients not on tafamidis. We also have several sub-studies in progress to look at the mechanism of amyloid accumulation and the effect that it has on cardiac performance in the cardio transform study, imaging studies substudies. 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 is the -- 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. And we think that the [indiscernible] will we'll demonstrate the efficacy that I just alluded to. It's hard to say what we're expecting or how it will 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 Asian program, and they are: Is there any change in the company's relationship with Biogen, given this recent decision not to license with agent drug and what's the status of the program and intend to advance it independently.

Our partnership with -- we even partner with Biogen for a decade now and started with SPINRAZA and the ALS resulted in QALSODY and so much more. The partnership provides as strong as ever. 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 is a top priority in their pipeline. And they're really excited we remain very excited about QALSODY and SPINRAZA and the rest of the pipeline that we've delivered to them basically. The Angelman program, it was a different view as to risk and reward for the program. We were aligned in most areas, honestly, on the -- what the results are 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 the -- now that we're in control of the Angelman program, this was a gift that we 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 strong as ever. We intend to keep this program for ourselves. We think that this would be -- is going to represent a centerpiece in our wholly enterology 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 are no treatment options available today. A prevalence that's more than double that of final 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 an Angelman Syndrome Foundation meeting in July. And 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 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 misunderstandings about it, I would have to say the olezarsen program. There are some misunderstandings about diseases and what we're trying to correct 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 in the blockbuster potential for olezarsen in 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 and the really strong FCS 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 work to do there to really drive appropriate appreciation for the value of 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 clear development? And what targets are you pursuing with siRNA and why?

So the investments we've been making over the last 4, 4.5 years in backbone chemistries, you targeted delivery strategies as well as new siRNA are really delivering and are rapidly approaching clinical development. On the siRNA, we have 2 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 an Ionis -- 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, 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 2 new approaches -- technology approaches. One is an siRNA using Ionis siRNA chemistry, and it's coupled bound or it's linked to a bicycle peptide from our collaboration with Bicycle Therapeutics, and we're utilizing the bicycle peptide siRNA molecule to go after a target in the heart, cardiac minoytes, opening up cardiac myocytes for an indication in heart failure. That program was licensed late last year by our partner, AstraZeneca, and now is in manufacturing toxicities. So stay tuned for them. 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 of muscle tissue. Cardiac myocytes is now in preclinical development for Hartfield. There will be more coming behind that. In addition, we're making -- 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 be [indiscernible] 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 NSTA that are really providing several advantages. One notably is the durability, allowing us to get siRNA ability, semiannual dosing, potentially and we're expecting our first PA molecule for a CNS target to reach clinical testing in the second half of this year. And then lastly, I'll mention the really encouraging results that we're getting or 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, siRNA into the CNS using a subcutaneous administration or [indiscernible] route 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. We're making great progress with metagenomic and in 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. Move into IND-enabling toxicology study. So the investments we started making for 5 years ago in science technology are really set up now to deliver molecules for clinical testing and can wait.

I think a few other questions are coming in now on mid-stage pipeline questions. And specifically, programs that we've reported positive Phase II data on, but we said that we don't plan to develop ourselves. So this is AGT Factor XI and DGAT2. And so the question is what are the status and what are the plans for those products?

All of those -- all 3 of these programs were 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, Ionis on programs that we keep for our wholly owned pipeline programs that we partner and programs that we stop. And we have -- we strongly believe that these 3 programs fit better with a partner, maybe like a large pharmaceutical partner or another type of company. So we're looking to partner the AGT program, the DGAT2 program in MASH in the Factor XI program. And those activities are well underway.

Excellent. We've had a couple of questions on the Mycronic 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 backbone chemistries, SIs 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?

Yes, 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 data from the high-dose SPINRAZA study. But some color, the study is going well. We have gone through the dose escalation phase of the study. We're going -- 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 gone well. But as far as timing, when we'll get to see some of that data that's really a question to provide...

Just a question on WAINUA. How do you feel when WAINUA compares Amvuttra from a convenience standpoint.?

There are several advantages that our market research has informed us on for WAINUA that we think really sets WAINUA up to be -- eventually be the preferred treatment for TTR amyloidosis of all forms. The first is the Phase II according myopathy 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, that will serve us extremely well with the richest data set now. 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 us working very closely, we know TTR amyloidosis as well. We know our platform well and taking advantage of the global strength of AstraZeneca in heart failure is a very important advantage for 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, a well-tolerated auto injector and not have to rely on a health care provider to administer a treatment for their disease is a third big advantage that only when New offers today. We think the combination of all 3 of these of course, the highly competitive efficacy and a really clean safety profile, physicians Anoa, we believe the AstraZeneca eventually the preferred treatment for GTR and mitosis.

I think we have time for one more question, and that one will be which program are you most excited about?

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 programs that are most excited about. WAINUA. We've invested in TTR miosis 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 or Ionis is paying off. And we -- and I'm excited because the new it demonstrates our perseverance to deliver life-changing medicines and to never develop when we think we have our 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, 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 up for a different reason. Here, we are moving into a market that already has several treatments that are in place. We're looking -- 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. switch market. And then lastly, I would say, pelacarsen. Pelacarsen is another blockbuster potential blockbuster from our pipeline. This drug has been in development for several -- many years now. because the size of the Phase III trial, which reflects the size of the unmet need, 8 million, 10 million people around the globe suffering from cardiovascular disease due to no other cause except elevated levels of risk -- CV risk factor lipoprotein [indiscernible]. Well, after all these years and the enrollment of more than 8,000 patients globally in this cardiovascular alcom trial, we are now positioned with our partner, Novartis, who is 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 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. Goodbye.