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

[Audio Gap] Conference in Miami. With me on stage, I have from Ionis Pharmaceuticals, Brett Monia. If you could start, it's nice to have you here, and give us an update on just the top level on Ionis, what has happened in recent years, I know there's been a great deal of evolution in the company, and bring us up to speed.

Happy to, David, and thanks for the invitation. It's a pleasure to be here today. So yes, Ionis, we've enjoyed a great deal of success over the last 2 to 3 years from the pipeline with several new programs, new drugs approved and launched. And really, we're entering a pivotal stage for the company, putting the final touches on becoming a fully integrated biotech company. About 5 years ago, David, we made the decision to move Ionis to become a fully integrated biotech to prioritize our wholly owned pipeline. And we're very excited about that pipeline today. We're just a couple of weeks away from our first independent commercial launch, olezarsen for familial chylomicronemia syndrome. We have a great data package for that. And the discussions with the regulators, the FDA, are going very well. We're also looking forward to our second independent commercial launch next year. We now have a PDUFA date for donidalorsen, our drug for prophylactic treatment of hereditary angioedema. And we're also looking forward to several Phase III readouts next year that will -- we expect to move into commercialization as well. In addition, simultaneously, our partner pipeline is doing very well. Also, WAINUA for TTR amyloidosis with polyneuropathy, our first-ever branded medicine in our history, co-commercialization partnership with AstraZeneca is off to a great start. And that same medicine, of course, is in development for the much more highly prevalent disease, TTR cardiomyopathy, and that's going well. We're looking forward to 3 Phase III readouts next year, an additional drug approval in donidalorsen next year and then more to come in 2026, setting us up for really a steady cadence of Phase III readouts and new products reaching the market for rare diseases as well as highly prevalent diseases for years to come. So it really is exciting times at Ionis.

Now you have a PDUFA date coming up later this month for olezarsen for the treatment of FCS. Could you tell us about the drug, the disease and your expectations?

Yes. Olezarsen, the NDA went in early this year, received priority review. It's being developed for 2 indications, the rare indication, FCS, familial chylomicronemia syndrome; and then for a much larger indication, severe hypertriglyceridemia, which is not a rare indication, a highly prevalent disease indication. The FCS submission was based on a really robust outcome from our Phase III BALANCE study in which we demonstrated in patients substantial reductions in triglycerides. This is a disease that's driven by severely elevated triglycerides, resulting in high risk for acute pancreatitis, also causes cognitive problems as well as severe body pain consistently. We were demonstrated in that Phase III study substantial reductions in triglycerides, substantial reductions in acute pancreatitis events in patients that were treated with olezarsen, substantial reductions, greater than 90% reductions in hospitalizations and improvements in quality of life. And based on all of that, we received priority review by the FDA. Our PDUFA date, as I mentioned, is just a couple of weeks away, representing our first independent commercial launch. There are no approved treatments in the U.S. for FCS. So we have first-mover advantage here, and we're going to take advantage of that first-mover advantage, and we're ready to go. We're ready to launch. Our medical team has been in the field now for several years. And we've done a good job in identifying patients, and we're looking forward to launching, assuming approval, in a couple of weeks. December 19 is our PDUFA date, we will launch by the end of the year.

This is an ultra-rare disease, approximately an estimated 3,000 patients. What's the diagnostic journey for these patients to actually get to the point where people know they have FCS? And obviously, that will change with the drug available in the market. But how long does it take until people actually identify it in the first place?

It's hard to tell. It's a great question. It's hard to tell how long it will take. And certainly that, as you said, that process will evolve with a new treatment for the first time being on the market in the United States. So there's a reason to test. There's a reason to explore. Certainly, people with severely elevated triglycerides are diagnosed relatively routinely through a simple blood panel testing of triglycerides along with your cholesterol and other endpoints when you get your blood worked up. However, the genetic or the clinical diagnosis of FCS is not common. Oftentimes, because there is a non-FCS form of severe hypertriglyceridemia, as I alluded to earlier, sHTG, oftentimes, a clinician will just consider it as sHTG. There's not much I could do for it. They'll put them on fibrates or niacins, which are not very effective and the diagnosis does not -- is not confirmed. That's not always true. There are endocrinologists, lipidologists who understand this disease and can identify patients pretty efficiently, but that's not common. That's not common. So the work we're doing, we've been doing for years and we will continue to do is to really educate and to educate treaters, HCPs on what to look for to diagnose definitively an FCS patient. So there's work to do there. It's getting better and it will certainly improve when the first treatment, olezarsen, reaches the U.S. market.

Now obviously, it's an ultra-rare disease, can be very expensive. What requirements do you think -- first of all, what will the label -- could the label look like? And what requirements could the payers place on the drug to prevent these severe hypertriglyceride patients from being put on drug right now and keeping it isolated towards FCS?

So it is an ultra-rare indication; upwards of 3,000 individuals in the United States today, no treatment options available. That prevalence, of course, is not certain because it's a poorly understood disease. It's possible that there could be more patients; we'll see. Most are unidentified today. Our discussions with the FDA are progressing on track. They're going very well. We expect a rather broad indication statement, which will include the ability of patients to go on to olezarsen if they're confirmed either genetically or clinically. And there are ways to diagnose this disease clinically that are now established. But you asked about payers. Payers, because it will be a -- it will have rare disease pricing associated with it, payers will be more reticent to cover unless they are convinced that this is a patient with truly FCS and not MCS or sHTG, which is a much more highly prevalent disease. So we do believe that payers will require a confirmatory -- go through a confirmatory process to diagnose FCS patients for coverage. But we also think that, that can come in the form of genetic testing or clinical diagnosis. So -- but that will be the key. We expect a broad indication statement, but payers will require a definitive FCS diagnosis.

With data for severe hypertriglyceridemia coming in the second half of next year, what would we expect to see? What can we extrapolate from what we've seen in FCS? And what should -- how should we set our expectations?

Yes, sHTG is severely elevated triglycerides, obviously, much like FCS, except that it's -- there's no known genetic cause of sHTG. It's estimated 2 million to 3 million people in the United States with sHTG today. And again, there's no effective treatment options available. Although the prevalence is much different, these patients suffer from really the same comorbidities and risks that FCS patients suffer from. That is consistent, constant body pain, cognitive defects and also a serious risk for acute pancreatitis, which, if it occurs, often puts them in an intensive care unit for a week or more or can be fatal. So they suffer from the same problems that FCS patients are, it's just more highly prevalent. I touched on the strong Phase III data earlier from our FCS Phase III BALANCE study. We're looking at the same endpoints for sHTG, and we expect to achieve the same outcomes. Primary endpoint is triglyceride reduction. We expect substantial reductions in triglycerides. And in fact, we expect even greater reductions in triglycerides in FCS because of the fact that these patients have an intact lipoprotein lipase pathway unlike FCS patients. And our mechanism by targeting APOCIII and lowering APOCIII, we think we'll get even added triglyceride reductions because APOCIII works in part through the lipoprotein lipase pathway, which is, as I said, is intact in sHTG. So even greater TG reductions, we expect substantial reductions in acute pancreatitis as well. Even though the rate of pancreatitis in sHTG is somewhat lower than in FCS, the study is 10x the size. So we're accumulating AP events in the study. And we had 11 AP events in the FCS study in the placebo and 1 event in the treatment group. If that reads through to the sHTG core studies, we expect most of these AP events to be in the placebo group. We also expect -- and we'll also be looking at quality of life endpoints and other endpoints as well. But those are the 2 main endpoints is triglyceride lowering as well as acute pancreatitis. And we expect that data in the second half of next year.

Do you think that the acute pancreatitis data needs to be on label and the initial approval to be for doctors to be willing to use the therapy? Is that something we can expect to see in the top line release?

We expect to have acute pancreatitis improvement in our label for FCS. FCS is a form of sHTG. So the sHTG NDA will be a supplemental NDA. So it will be an expansion of the label. If what we're expecting holds true in FCS, it will already be on the label. Would the added benefit of an AP outcome in sHTG be -- would benefit us? Of course, absolutely. It would just drive down the belief, the data would support that lowering triglycerides will provide an outcome benefit in acute pancreatitis. So it will be very helpful, not necessary for approval. We already have AP in the -- we expect to already have AP in the label with FCS, but we'll be able to strengthen that. So it will be very helpful to demonstrate that. I also want to point out that the BALANCE study, the FCS Phase III study that we conducted, which we showed a reduction in acute pancreatitis, was the first time that was ever demonstrated. It's been a strong belief in the field that if you can reduce triglycerides, you can reduce the incidence of acute pancreatitis. We were the first to demonstrate it, and we expect to have similar outcomes in sHTG.

Now let's jump over to HAE. Could you tell us about donidalorsen? That's at the FDA, I believe a PDUFA date in August. Tell us about the drug. It's a very different market than FCS. And what are your initial thoughts now of the drug's profile and how it might fit into this market?

Yes, very different market than -- and very different go-to-market strategy because of that for donidalorsen versus olezarsen. Olezarsen, we're first to market. Donidalorsen, we are moving into a U.S. market as a -- with a prophylactic treatment for hereditary angioedema in a market that is established today. There is a well-established injectable, subcu injectable, TAKHZYRO, with about 70% of HAE patients in the U.S. today on TAKHZYRO. There's also an oral drug, ORLADEYO, in which a smaller -- a significantly smaller percentage of patients are on ORLADEYO today. So overall, there's about 70%, 75% of people on prophylactic treatment today in the U.S. So this is a switch market, not a first-to-market strategy. Why do we think donidalorsen will be successful? For several reasons. One is we know that patients want better treatment options. We have seen switching in the market between existing therapies already today. Patients are looking for better efficacy in reducing HAE attacks. They're looking for better convenience. They're looking for less-frequent dosing. They're looking for better tolerability. Whether it's an injectable or an oral, they want better tolerability, and we're already seeing switching around. The second reason is that our Phase III and our Phase II data is very strong, substantial reductions in HAE attacks that are as good, if not better, than anything that's out there today. The convenience of monthly or every 2-month dosing, subcutaneous dosing using a simple auto-injector, the standard of care today is every 2 weeks of subcu dosing, which the -- with the potential of every 4-week dosing. But if you go to every 4-week dosing, the protection against HAE attacks goes down substantially. So we win on efficacy, we believe, we win on convenience and the self-administration using an auto-injector is very well tolerated by the patients as well. We also addressed this idea of switching the switch market directly by conducting the -- first time ever conducted a prospective switch study in which we invited patients from the agents that are on the market today to come into a clinical study and move on to do and asked the question, what is your preference? How well do you do? How well -- how quickly will you sign up? We were pleased to see that patients signed up very quickly. We enrolled a study of nearly 70 patients very rapidly. Patients stayed on treatment. And we demonstrated that -- 2 things: patients, we were able to actually reduce their HAE attack rate further compared to their baseline values by more than 60%; and using an independent survey analysis, patients showed a strong preference. More than 80% of patients said we prefer donidalorsen over our previous prophylactic treatments for the reasons I outlined: better efficacy, better convenience, better tolerability. So that's why we believe donidalorsen could be a real game-changer in the U.S. with a potential launch next year.

Now the Switch study is -- obviously, it's not a double-blind study. It's different than the primary pivotal trial. But it essentially provides an instruction manual for doctors looking to switch. Is that something that can end up on label? How ultimately do you feel it will be used?

We think it has a very good chance of being on the label. Of course, that's a -- I can't speak for the FDA, regulatory authorities, but we believe so because we think that the -- because it is a switch market, physicians are going to want to know how do I safely switch my patients from their existing treatment onto donidalorsen. What do I mean by that is, how do I prevent there being gaps in protection when I wean them off of one treatment, their existing treatment and then move them on to donidalorsen? We actually have thoughtfully created a procedure, an algorithm when we initiated the Switch study, taking into account the durability, the duration of action that's known for existing treatments, when to wean them off and coupling that with when -- our understanding of when donidalorsen will be fully on board to protect them from treatment. That algorithm-- those algorithms worked out perfectly. We didn't have gaps in protection when we switched them from existing treatments to donidalorsen. And we believe that that's a safety issue. So because it's a safety issue to contend with to safely switch patients from one treatment to another, that it warrants being on the label. To be determined, but that was certainly in our filing, which is now accepted by the FDA and with a PDUFA date, as you know, of August of next year.

And I guess as far as overall expectations, given it is more crowded, how should we view the -- what the potential initial revenue might be and where it ultimately might sit within the market? And who, frankly, given of the therapies out there, prospective therapies, who do you believe is the biggest challenge?

So there's estimated to be about 20,000 people in the U.S. and Europe with HAE. In Europe, it's -- the prophylactic market is just emerging. It needs to be developed. We have a commercial partner in Europe, Otsuka, who has submitted for approval in Europe, and they've signed up to develop this market in Europe. And in the U.S., as I mentioned, it's a switch market. These will be -- donidalorsen will be priced commensurate with other HAE prophylactic treatments that are on the market today in the U.S., rare disease pricing. And we expect that patients who are unsatisfied with their current treatments, and as I mentioned earlier, a lot of these patients, most of these patients are unsatisfied, they want to switch to other potentially better treatments. It's going to be focusing on those patients that are unsatisfied and they're willing to try a new treatment like donidalorsen. We have an ongoing Phase II open-label extension study. We have an ongoing Phase III open-label extension study. We also have a small expanded access program going. We have patients on the Switch study. So there'll be an initial bolus that will be the low-hanging fruit, if you will, to switch those patients to commercial in the U.S. once we get approval. But then it will be just getting out there, getting the word out, taking advantage of the fact that our medical team has been out there for several years now, really just talking about donidalorsen, its profile and so forth and getting the word out and making it clear that there are potentially better treatment options out there for patients and for HCPs to consider. As far as emerging treatments today, really, donidalorsen will be the -- we expect it to be the next paradigm shifter in HAE prophylaxis with a PDUFA date of August next year. There are other antibodies coming along, for example, one that's targeting Factor XII, not prekallikrein. We're targeting prekallikrein that are emerging with a profile that appears better than TAKHZYRO, but we don't think it's better than donidalorsen. We think our efficacy is second to none. We think our convenience of offering the potential for every 2-month dosing without a loading dose is very attractive as well as the ability to self-administer using an auto-injector. So we think donidalorsen is the next big thing in HAE prophylaxis, and we're looking forward to getting it launched next year.

So we go through next to 582 in Angelman. You recently announced a Phase III trial design. The primary endpoint of the trial is expressive communication. How did you come to that as your primary endpoint as opposed to the Bayley-4 overall?

Yes. So we're very excited about our Angelman's program. We're very excited about our CNS platform overall. As you well know, David, it's the Ionis CNS platform that delivered SPINRAZA, QALSODY for SOD1-ALS and other programs. We have 11 medicines in development today for CNS diseases as rare as forms of ALS as well as big as Alzheimer's disease. And Angelman's is another product from this leading -- industry-leading platform. It's a very unique mechanism. We're actually unmasking the paternal UBE3A gene to produce the protein UBE3A, which is deficient in this disease. This is a highly prevalent rare disease, estimated to be about 100,000 people in major markets with no treatment options available. These individuals live normal lifespans, but really do not move intellectually beyond the capabilities of a 2- to 4-year-old. So very, very severe burden on the health care system and, of course, on families. We shared data at the Angelman's meeting this past July and then again, in November, demonstrating that compared to very strong, well-established natural history data, we showed profound improvements in all endpoints that we looked at that afflict these individuals, including communication, expressive and receptive, cognition, motor function, seizures, sleep patterns, quality of life and so forth, using instruments such as Bayley-4, Vineland, other ones, SAS-CGI, ORCA, consistent across the board. We chose -- we moved in -- clearly, it supported going to Phase III development. We had a very positive end of Phase II meeting with the FDA. We recommended expressive communication as our primary endpoint to your question for several reasons. Number one was that the greatest magnitude of benefit that we demonstrated in our Phase II study was in expressive communication. And that was true for all of the instruments we use, whether it be Bayley-4, Vineland or so on. Second, we saw a dose response. In our Phase II study, we tested a medium dose and a high dose. And it was very nice to see a dose response relationship on expressive communication in our study. And then thirdly, it has been well documented by the Angelman's community that expressive communication, the ability of the individual to communicate with family members and physicians and address issues that are bothering them, things that are working for them to help them with their intellectual improvements, education and so forth, if they can improve one thing, they consistently have said it is the ability to communicate expressively. Those are the reasons why we chose expressive communication as our primary. Bayley-4 overall, looking at all the components of the Bayley-4 scoring instrument is not considered by regulators as a validated instrument. It's really the subcomponents. So it's always a question of which sub-domain would we use. We are going to be looking at other sub-domains in our secondary endpoints such as cognition and so forth, but that is the reason why we chose expressive communication. The Phase III study is moving forward, and we expect to initiate in the first half of next year.

You were using a placebo control and a competing pivotal trial is using a sham control. Could you elaborate on the differences between the 2? And how could it affect each study and what they eventually show?

Yes, I can -- so I can't speak for competitor programs and their views on placebo versus sham. What we know and we all know is that a placebo-controlled randomized Phase III trial is the gold standard for any clinical outcome. It ensures study integrity. And it's the sponsor's job, it's the sponsor's responsibility to ensure that a study was conducted properly, well blinded and with high integrity when you go to the FDA for approval. A placebo-controlled study is definitely the gold standard. Clinical sites, which always have staff shortages, prefer placebo-controlled because if you're conducting a sham-controlled study, it's obvious that the person administering the treatment is unblinded. So you have to have an unblinded treatment staff as well as a blinded treatment staff, which is conducting the assessments in the study and so forth. So it's less of a burden on clinical sites. And there are other advantages to just interpreting the data, having the same exact procedure being conducted in the placebo group versus the treatment group conducted. So the FDA has put out guidelines that they prefer sham control for intrathecal administration of new medicines, unless you can demonstrate safety, right? So that the patient that's exposed to placebo is not being exposed to any greater risk, even though they have no real chance for benefit. We have a long history of administering our treatments for intrathecally for CNS diseases. I mentioned some of the approved products earlier, thousands of patients, the FDA just asked for that data. And once they reviewed all of our data, placebo as well as treatment, they concluded right with us that the proper way to do the study was a placebo-controlled trial. They fully supported it and off we go. So those are the advantages of placebo, and we're pleased to have that as a part of our Phase III design.

Now let's jump to WAINUA. WAINUA was launched in polyneuropathy, ATTR polyneuropathy. And tell us about how that launch is going, how the drug is being used in naive patients versus switches from another commercial -- other commercial options out there and what you think is driving that?

Yes. We're very pleased with the early launch of WAINUA for hereditary TTR polyneuropathy. WAINUA is the same chemical platform as olezarsen, donidalorsen, pelacarsen, which are all -- I've commented on some, and they're all in Phase III development. It was approved in December of last year. It was launched at the end of January this year. So it's -- what we have now is a partial year of launch metrics for WAINUA in hATTR polyneuropathy. We're thrilled with the -- with how the launch is going. We've achieved and/or exceeded all of our key performance factors for this study, numbers of patients, sales, we've demonstrated quarter-over-quarter growth. In fact, the last quarter, more than 40% increase in sales over the second quarter of this year. We're laser-focused on getting WAINUA to patients that are newly diagnosed or not on treatment for whatever reason today. It's estimated that there are about 50,000 people with hATTR polyneuropathy in major markets. More than 80% of those patients are not on treatment today for whatever reason. So that's where the unmet need is. That's where the market opportunity is. That's where we're focused on. The majority -- the vast majority of patients that are coming to WAINUA are very pleased with it. They're staying on WAINUA and they're new to treatment. And because that has been our strategy to identify those patients, to get the word out using all kinds of methodologies to identify patients. These patients are often misdiagnosed with other forms of diabetic -- or other forms of polyneuropathy such as diabetes and so on, CMT. We're getting the diagnosis done. We're getting coverage occurring fast after diagnosis, and they're getting on drug and they're staying on drug. We're also seeing some switches. We welcome those, of course. We're seeing switches from -- on treatments -- all available treatments on the market today for TTR polyneuropathy. And we're pleased that patients are wanting to go on to WAINUA, and HCPs are putting them on WAINUA even though they're on other treatments. So the launch is off to a great start. And we also -- I wanted to point out that we also have a positive CHMP opinion for WAINUA in Europe, and we're potentially expecting approval by year-end.

Now we jump over the cardiomyopathy side of things. There's WAINUA's profile itself, its trial. Then there's the dynamic of TTR silencers versus stabilizers. How do you think that things ultimately will shake out between the 2 different mechanisms or mode of action themselves, the silencers versus stabilizers? And how do you think WAINUA will ultimately fit in?

Yes. TTR cardiomyopathy is a highly prevalent disease. It's estimated to be upwards of 500,000 people. Current treatment is tafamidis, a stabilizer. It's effective, but patients continue to progress and eventually, they progress to death due to heart failure. So there's a need for more effective treatments. We believe, as does our co-partner, AstraZeneca, that WAINUA will ultimately be the treatment of choice for TTR amyloidosis, neuropathy, cardiomyopathy based on its overall efficacy profile, based on the ability to self-administer using a simple at-home using a simple auto-injector. The partnership between Ionis and AstraZeneca is vast globally. There are additional reasons why we think WAINUA will be the treatment of choice, and the polyneuropathy launch is off to a great start, helping to support that conclusion. Ultimately, when the silencers get to the market, like WAINUA and others, we believe that many patients, maybe most patients are going to prefer -- and HCPs are going to prefer a silencer mechanism over a stabilizer mechanism as first line, maybe not all, but certainly a lot of them will. And that's just based on the data, but also based on the sentiment that blocking the production of a toxic protein would be more effective than stabilizing an existing toxic protein that's in the circulation. We also believe that there will be combination usage if you have data to support combination usage. And our Phase III study, as the largest study ever conducted in this population, will generate the most robust combination data of any study conducted to date. And thirdly, as I mentioned, patients are progressing on stabilizers today. So there'll be a large opportunity there for patients that progress to move on to a silencer. So we think that all those opportunities will be available for the silencers, and we think that silencers do very well once they reach the market.

So next year, there will be pivotal data from another cardiovascular program, pelacarsen, LP(a). How should we frame our expectations for what we'll see there? It's an outcomes trial, so the results will be fairly definitive in what it achieves. What should we expect to see? And what are Novartis' -- your partner, Novartis' plans in that area?

Yes. We're proud of the fact that we're leading the way in several landmark trials. Our olezarsen first time, our CARDIO-TTRansform study, the size of that for eplontersen is a big study. Pelacarsen for Lp(a)-driven cardiovascular disease is one of the biggest events in biotech next year. The Phase III study is coming out next year. Novartis has reaffirmed that recently. And this is a big unmet need. 8 million to 10 million people today are estimated to suffer from cardiovascular disease due to the overproduction of an independent risk factor called lipoprotein(a). Diet and exercise has no impact on this endpoint nor does statins or available treatments today. We showed in a Phase II study that in patients with cardiovascular disease due to high Lp(a), we were able to normalize their Lp(a) levels, more than 98% of the patients we're able to normalize. And based on that, Novartis licensed the program and conducted a cardiovascular outcome trial. It's more than 8,000 people, had been conducted nearly 4 years now with data next year. An enormous unmet need. The primary endpoint is time to first event, cardiovascular hospitalization or/and mortality. And so we're looking for a meaningful substantial improvement in cardiovascular risk reduction in the Phase III study, which is coming out next year. So this could be a real game-changer, first-to-market opportunity and very attractive economics to Ionis. Novartis is obviously running the study.

Now how easy is it going to be to actually show an outcomes benefit just given we don't necessarily have a lot of direct data to show how the lowering of Lp(a) ultimately contributes to cardiac benefit? It just seems to be generally accepted that it might, but we don't really have any definitive evidence.

We do not have definitive pharmacological evidence, that's for sure. There are no good animal models of Lp(a)-driven cardiovascular disease. That's because most species do not express Lp(a). It's really humans and I think it's baboons that express Lp(a). So you can't prove it preclinically. The epidemiology is very strong. It's clear that once you exceed a certain threshold for Lp(a), your risk for CBD, independent of LDL cholesterol, hypertension or other risk factors, goes up substantially. And the higher it is, the greater the risk for cardiovascular disease mortality or hospitalizations and so on. So this will be needed to be proven. And we -- our Phase III HORIZON study with Novartis is going to be the first proof that whether or not lowering Lp(a) will actually drive benefit in this patient population. So the epidemiology is strong. The mechanism is understood on why Lp(a) is believed to cause cardiovascular disease. But next year will be the first proof of whether or not lowering it will actually provide benefit.

And to wind things up, obviously, the technology antisense, Ionis is a pioneer in that area. It's ahead in the chemistry that's evolved over the years as a way to deliver greater payload and essentially overall lower volumes and with less frequent administrations to reduce tolerability issues that were more apparent early on. What's the next step?

Opening up new disease areas or opening up new ways to deliver our drugs more efficiently. Olezarsen, donidalorsen, WAINUA, pelacarsen are real products of some breakthroughs in chemistry we've made over the last 5 years or so, and they're delivering. We now have new chemistries coming forward that will reach development next year to penetrate and overcome the blood-brain barrier for CNS diseases as an example. So moving away from intrathecal delivery or delivering our drugs intrathecally but less frequently, like annually or semiannually or delivering them intravenously or subcutaneously. So overcoming the BBB for CNS diseases, opening up new tissues using medicinal chemistry such as skeletal muscle for neuromuscular diseases and cardiac muscle tissue for heart failure indications. All that is in the works and all that is coming forward rapidly, and we'll be moving into development shortly.

Got it. Thank you very much for your time.

Thank you, David. It was a pleasure.