I think we can go ahead and get started. My name is Ali Bratzel, one of the biotech analysts here at Piper Sandler, and it's my pleasure to introduce our next company, Ionis. Joining us today, we have CEO Brett Monia, and I look forward to a good discussion, so if anyone in the audience has any questions, feel free to just raise your hand, and we'll get your questions asked, but I will go ahead and get us kicked off, so Brett, maybe just kind of an intro question. We all know Ionis has a long history as a leading antisense and ASO company. You're in the process of becoming a fully integrated biopharma company and are kind of at a very important point right now in the company's history. So just walk us through that, your late-stage programs, your commercial programs, and just how you are positioned for value creation.
Thank you, Ali. Good morning, everybody. It's a pleasure to be here and to represent Ionis. Yeah, indeed, Ali. Ionis is on the cusp of a really important, meaningful transformation that is really going to drive tremendous value to all stakeholders, including our shareholders. A few years ago, five years ago almost exactly, we set out on a course to bring Ionis forward to become a fully integrated commercial stage leading biotech company that is to match the excellence we've always had in research and development to build a commercial organization of equal excellence, and we're on the verge of doing that with our upcoming independent launch just in a couple of weeks, olezarsen for familial chylomicronemia syndrome. The first step towards commercialization was a step we took purposefully to do a co-commercialization partnership to build the infrastructure for the organization.
We did that a few years ago to co-commercialize eplontersen for ATTR amyloidosis, starting with polyneuropathy, then cardiomyopathy with AstraZeneca, and that was a great step. That launch is off to a great start, and it set us up very well for our first independent launch, olezarsen, as I mentioned, with a PDUFA date of December 19th. All is going well, and we're ready to launch olezarsen. And following olezarsen for FCS, we're looking at a very highly prevalent disease related to FCS for olezarsen, called severe hypertriglyceridemia, with phase III data next year. Also, our second independent commercial launch is rapidly coming, donidalorsen for hereditary angioedema, great phase III data, and now with a PDUFA date with our NDA accepted of August of next year. And then right behind that is a really robust partnered pipeline and a very robust wholly owned pipeline that continues to go forward very nicely, setting us up for a steady cadence of phase III readouts and commercial launches this year, next year, and for many years to come. So we think that that's going to drive tremendous value for all stakeholders.
Excellent. Maybe starting out on eplontersen, I think we're about a year into the Wainua launch in ATTR polyneuropathy. Can you just talk to learnings or takeaways you have from that experience over the last year, specifically on the self-administration profile? Anything you can extrapolate to the cardiomyopathy indication?
Yeah, yeah. So eplontersen, brand name for hereditary ATTR polyneuropathy is Wainua. And we couldn't be more pleased with the launch. It's off to a great start. We launched in February, so it's a partial year. And we're very proud of the fact that we've met or exceeded all of our key performance indicators for the launch, including patient starts, patients staying on treatment, getting coverage rapidly after prescriptions are set and the drug is prescribed. And everything is going great. We've had quarter-over-quarter growth. And in fact, the last quarter, we've had more than 40% growth in the third quarter over the second quarter. We expect that to continue well into the future. The reason behind that is, first, of course, we know TTR amyloidosis very well. AstraZeneca is an excellent partner that knows Ionis very well. We've been together for many years. The drug profile is excellent.
I mean, remarkable efficacy, very clean safety profile, well tolerated, and to your point, the ability for patients to self-administer using a simple, painless auto-injector, low-volume auto-injector, we believed would resonate well with the patients and the HCPs, and it has. It has really resonated very well. Patients like the independence of being able to self-administer and not have to go see a physician or a clinician to administer the drug. We think that that will also resonate very well in the much larger cardiomyopathy indication, which we're in phase III development with data expected in 2026. The largest phase III study ever conducted in ATTR cardiomyopathy that sets us up for really, really comprehensive data that we think will be highly differentiating.
The ability for patients to self-administer in the much larger patient population and elderly population, we think, will continue to be a big, big differentiator for eplontersen, Wainua, as will the partner, AstraZeneca, who's a real leader in cardiovascular diseases, commercially, heart failure, and we'll be able to reach patients around the globe very rapidly with this unique partnership. So we think there's tremendous read-through to cardiomyopathy.
Along that line of thinking, there's been a lot of interest, debate, on the ATTR cardiomyopathy market, how it's going to evolve as new stabilizer and silencer therapies come to market. The question is, how do you expect the treatment paradigm to look when eplontersen is launching in cardiomyopathy? And how does this affect your positioning of the drug? Help us understand the thinking around the launch environment.
We're really looking forward to the phase III readout from the CARDIO-TTRansform study for ATTR cardiomyopathy. And we think eplontersen is going to be a very significant player once it reaches the market for some of the reasons I already touched on. And to highlight, one of the main points is the fact that we have the largest study by far ever conducted in this patient population, which is positioned to generate the deepest data and most comprehensive data set, not only the primary endpoint of cardiovascular hospitalizations and mortality, but subgroups, combination data, monotherapy mortality data, time to event, imaging studies that we have ongoing, and so forth. Really, really setting us up well. We and our partner at AstraZeneca strongly believe that eplontersen will be a treatment of choice for many, many patients with TTR amyloidosis as frontline treatment.
There's a strong belief that silencers are the mechanism of choice when it comes to treating this disease relative to stabilizers. Stabilizers will certainly have a very important role, continuous and continuing going forward, but silencers will be a very important player in this very large market opportunity. In addition, we all know that stabilizers do not stop or reverse the disease today. All patients on stabilizers progress. And the first choice will be then to put those patients that progress on silencers to help correct the progression of the disease. And then thirdly is combination. Combination of a silencer with a stabilizer makes complete sense mechanistically. And if you have data to support the usage of combination treatment between a silencer and a stabilizer, we strongly believe that cardiologists will advocate for combination usage. Patients will want combination usage if they feel it's going to help them have a more effective treatment, and as I said, we are well positioned to have the most robust data set for combination usage based on the size of our study and the design of our study, so we think that the silencer class, in particular eplontersen, is well positioned for frontline treatment, second line treatment for patients that progress, as well as for combination usage.
Excellent. So now shifting to olezarsen. This is obviously a cart, it's going to be a cart before the horse question since we're awaiting the lezarsen PDUFA in FCS and the SHTG data next year. But can you just talk or help us understand the FCS and then the SHTG launch progression and strategy and what that might look like?
Yeah, absolutely. So let's just level set. olezarsen is a novel, highly innovative treatment for patients suffering from diseases related to severely elevated triglycerides, a lipid. There are no effective treatments today to manage severely elevated triglycerides. People with severely elevated triglycerides suffer from all kinds of problems: body pain, brain fog, cognitive defects, but most importantly, a risk of potentially fatal acute pancreatitis. We are developing olezarsen for severe hypertriglyceridemia for two patient populations. First, a rare genetic population called FCS, familial chylomicronemia syndrome, a genetic disease, a rare genetic disease in which there are no treatment options available today in the United States. And then for the much larger indication, millions of people suffering with non-genetic severe hypertriglyceridemia. Again, no effective treatments today. We had really exciting, robust phase III data that we reported earlier this year in FCS.
We submitted for our NDA, got priority review, and we have a PDUFA date just in a few days, a couple of weeks, December 19th. And as I said earlier, this represents our first independent commercial launch. We're excited about it. The phase III data not only showed substantial reductions in triglycerides that were really unparalleled for treatment compared to existing treatments today, but we also demonstrated a substantial reduction in acute pancreatitis events. The first time ever someone has actually demonstrated pharmacologically that lowering triglycerides will lower the risk of acute pancreatitis. We also lowered hospitalizations by more than 90%, and the drug was very well tolerated. So we're ready to go for that launch. For severe hypertriglyceridemia, the much larger indication, we are looking forward to phase III data in the second half of next year with a potential launch in 2026. So stay tuned for that. Right now, we're laser focused on FCS and getting that launch going. And we think we have several advantages, most importantly that we're first to market. We're going to create this market. We're going to mold this market. And patients are waiting for a treatment like olezarsen.
Excellent. Another cardiovascular asset with data next year, pelacarsen. Can you just talk to your confidence and with partner Novartis on your phase III readouts next year and really how you envision the Lp(a) competitive landscape evolving? It'd be great to get some color there.
Yeah. You know, we're very proud of the fact that we are leading the way in many ways in addressing two of the biggest unmet needs in cardiovascular diseases today: TTR cardiomyopathy and now Lp(a) driven cardiovascular disease. Lp(a) is an independent risk factor for CVD and probably the one major independent risk factor that is untreatable today, effectively treatable today with any treatment that's out there today. So it's different than hypertension. It's different than LDL cholesterol and so on. Lp(a) is, as I said, our independent risk factor that if it's produced from the liver at levels that are too high, you're at high risk for cardiovascular disease, heart attack, and stroke that can affect people in their 20s, 30s, 40s, and older. There are no effective treatments to lower Lp(a) and get it in the normal range. It's genetically determined.
We developed years ago pelacarsen to lower and normalize Lp(a) in exactly this patient population. In phase II development, we were able to show patients that had cardiovascular disease with high Lp(a). We were able to normalize essentially 100% of the patients' Lp(a) levels in that phase II study, which was 12 months, 300 patients or so with great tolerability. Actually, 98.6% of the patients were normalized in that study. Based on that data, our partner, Novartis, licensed the program and launched the HORIZON phase III study with more than 8,000 patients in a cardiovascular outcome trial. This study has fully enrolled last year and has been going on now for nearly four years. This is a landmark study with data expected next year from Novartis. This is a disease that has an immense unmet need with eight to 10 million people around the globe considered to have Lp(a)-driven cardiovascular disease with no effective treatment. So we're very much looking forward to the results of the HORIZON study next year.
Great. I guess I want to keep an eye on time and get to donidalorsen in HAE, where you mentioned you have a PDUFA date coming up next August 21st. So talking to investors, there's a lot of focus or concern maybe about the crowdedness of the treatment landscape here in HAE for approved and developmental therapies. Can you just talk to that? Where do you see donidalorsen fitting in? And just any good analogs from the HAE space or other spaces that you think might apply here?
Yes. Prophylactic treatment of hereditary angioedema, a severe rare genetic disease, is a bit crowded in the United States, but we're not concerned. We think donidalorsen has the therapeutic profile that patients are looking for. Today, there are really effectively two treatments available in the United States for prophy of HAE, Takhzyro, which is a sub-Q injectable that's administered every couple of weeks, sometimes every four weeks, but mostly every two weeks, and then Orladeyo, which is an oral drug. Both of these drugs are not meeting the needs of patients based on all kinds of surveys that have been conducted to date and based on real-world data, which you see patients switching from drug to drug because they're unsatisfied. Donidalorsen addresses the three key categories that patients are looking to improve. One is efficacy.
The efficacy that donidalorsen has showed in reduction of HAE attacks is unparalleled. That's based on phase II data, phase III data, and open label extension data. Second, donidalorsen appears to be the best tolerated drug of any drug that's on the market today. Simple self-administration or using an auto-injector is very well tolerated, just like Wainua, olezarsen, donidalorsen, or pelacarsen, very well tolerated with essentially no meaningful side effects, and then thirdly, the convenience that patients are looking for d onidalorsen is positioned to allow patients to administer either once per month by themselves or once every two months. The two-month data, once every two-month data, and compared to every one-month data, looks equally good when we look at long-term data, reducing HAE attacks in the 90% plus range, so we think we have a very competitive product.
And we've actually validated that belief, conducting a switch study. In a switch study, in the switch study that we came up with, the only independently prospective study conducted this way in HAE, we actually invited patients on existing commercially available treatments that are taking HAE prophylaxis to come on to donidalorsen in a clinical trial. First, we were pleased that we were able to enroll the study very quickly, showing that patients are looking for better treatment options. So it's not as sticky as people think. Second, we were pleased that patients stayed on donidalorsen long term. They continue to stay on today. Now that the study is completed, we've enrolled them into an expanded access program. Thirdly, we were pleased that we were able to improve their HAE attack rates by more than 60% compared to their baseline value.
So we improved the efficacy compared to what they were experiencing previously. And then fourthly, we were able to protect the patients and not have any lapses in efficacy when they were weaning off one treatment and coming on to Donidalorsen. So we were able to manage that very effectively. And then lastly, a survey, an independent survey conducted with patients. They were asked, which is their preferred treatment? More than 80% of patients said that they preferred Donidalorsen over their previous treatment for the same reasons I just highlighted: efficacy, tolerability, and convenience. So yeah, it'll be different than olezarsen. It'll be different than pelacarsen in that those are brand new markets we're going into. This is a switch market in the United States, but we think we have the profile to provide a very important, very effective, and very well-desired treatment for patients with HAE.
Given that this is a switching market, I guess how mission critical is it for your switching data to make it onto the label?
Mission critical might be a little too strong, but we do believe that we have a very good opportunity to have the switch data in the label. And this is why I highlighted a few moments ago that we were able to safely protect patients and not experience any gaps in protection from their HAE attacks by weaning them off of one treatment onto another treatment. That's actually a prospectively thought-out process that we engineered to ensure that patients were well protected. We think that that's a safety issue. That's very important in a switch market in the United States. And therefore, it is important to have that information in the label for prescribers to know how to safely switch patients from one treatment to another. So we feel pretty good it'll be in the label. That's certainly been the case we made in our application, which is now accepted with a PDUFA date of August of next year.
Great. Well, I want to leave a little time at least for the wholly owned neuro franchise, specifically 582 and Angelman. So yeah, I guess our understanding that your partner Biogen kind of ran out of time to exercise their opt-in right for this program. And so you were able to redeem full rights. So as we sit here today, now that you have regulatory clarity in hand, this program is in a good spot, I think, for the company. So can you just walk us through the regulatory interactions you've had? What gives you confidence that you've identified the right phase III trial design and endpoints? And just overall confidence that you can replicate the HALOS data in phase III?
Sure, so we're very proud of the fact that we have established an industry-leading platform to treat CNS diseases. This is a platform that delivered Spinraza, that delivered Qalsody for SOD1-ALS, that delivered the Tau program that has shown proof of concept in phase II in Alzheimer's disease, many more examples. Angelman's is the cornerstone of our wholly owned neurology franchise today. More than 100,000 people in major markets today suffering from this neurodevelopmental disease with no treatment options available. So a big, big unmet need, a big, big opportunity for Ionis. We presented phase II data from the HALOS study earlier this year, which demonstrated pretty convincing evidence that patients were improving across all aspects of their disease, whether it be communication, cognition, motor function, seizures, sleep patterns, quality of life, and so forth. Based on that data, we made the decision to go to phase III.
We presented our phase III plans to the FDA in our end of phase 2 meeting earlier this year. We were pleased, not terribly surprised because of our strong relationship with the neurology division at the FDA, but we were pleased that they accepted all of our proposals for a phase III design, including the size of the study, which is about 200 patients, the fact that we're looking at two dose levels that were studied in the phase 1/2 study in HALOS, 40 milligrams and 80 milligrams quarterly. We're looking at a wide range of age groups and genetics as well, mutations and deletions.
Very importantly, they also approved, agreed to that we will conduct this study as a placebo-controlled study, the gold standard for randomized controlled phase III studies, as opposed to a sham study, which is very important for the integrity of a well-conducted study. So we got everything we wanted from the FDA. We're looking forward. We're getting all of our ducks in a row. We're blocking and tackling. We're looking forward to getting the phase III study initiated in the first half of next year.
Great. And then I think we all know there's another asset in late-stage development from Ultragenyx. So I guess how do you envision 582 being differentiated based on your phase III and your phase 2 experience? And is this or isn't it a so-called winner-take-all market?
It's not a winner-take-all market. I don't like to. I prefer not to comment on other people's programs, other companies' programs. I'll just say this. I'll just emphasize what I already said. ION582, our program for Angelman's, has demonstrated robust data in phase II that we have seen nothing better than the data we have. And ION582 emerged from a company that's highly experienced in developing CNS-related treatments. We've conceived, discovered, and developed Spinraza. We conceived and discovered Qalsody. We have a lot of experience in this. And the platform is the same platform, the chemical platform that we're using for Angelman's. It's the same chemical platform that we've used for Spinraza, Qalsody, and the rest of our CNS pipeline. So it's validated. We feel very good about that. We also feel very good about our experience in developing CNS drugs. We think that that plays very well for Ionis to be highly successful, assuming positive phase III data in Angelman’s, as we’ve been successful for these other disease indications.
Excellent. I think with that, we're at time. But thank you for stopping by the Piper Sandler Conference. Great discussion.
Thank you, Ali. It was a pleasure.