With our next company presenter at the B of A Annual Health Care Conference, joined by Ionis Pharmaceuticals and Brett Monia as Chief Executive Officer. My name is Jason Gerberry. I'm one of the SMID Cap biotech analysts here at B of A. Ionis has a lot going on from a pipeline perspective. Brett, maybe I don't know if you want to tee it up at all with some of the near-term updates that you guys plan on having that you're most excited about, and then we'll jump into more specific program-related questions.
Happy to, Jason. Thank you. It's a great pleasure to be here this morning. We've had a great start in 2024. With the late December approval of Wainua for TTR polyneuropathy, we launched at the end of January for that indication, and the launch is off to a really solid start. We also presented a fulsome data set or overview of our phase III results for olezarsen and FCS at ACC last month, and we've now submitted the NDA for olezarsen and FCS. If we receive priority review, we're looking forward to another drug approval in December of this year. We also reported very positive phase III data in January for our prophylactic treatment for hereditary angioedema, donidalorsen. We're looking to submit that NDA in the second half of this year as well.
We have one of the richest pipelines, late-stage pipelines, in the industry with 9 medicines in phase III development for 11 disease indications. I'm pleased to report that all 9 of those programs are moving forward on track. We're looking forward to a steady cadence of phase III readouts for many years to come, including next year when we are expecting at least 3 new phase III readouts. We're preparing to have our first independent commercial launches. The first will be olosarsen for FCS, and then soon to follow with hereditary angioedema. All is going well. As far as readouts looking forward, we're looking forward to Wainua approvals this year in additional ex-U.S. markets outside the U.S., the potential, as I mentioned, approval of olosarsen for FCS later this year.
And then we have several mid-stage pipeline readouts, including our Angelman's program, which is in a first-in-patient study, as well as our geographic atrophy study in the second half of this year. So a lot of success already this year in 2024, and we're set up to build on that momentum with a lot of news, a lot of events coming up.
OK, great. Maybe we'll start with HAE since that's the most seemingly imminent of the programs where there's an update. I guess to me, if there's debates or controversy, it's really around the commercial opportunity. I used to cover Shire, so I remember the conversion of Cinryze was the from Takhzyro to Cinryze, and a step change of improvement used to be IV, used to be androgen. Just thinking about this marketplace, what proportion of it is served by Takhzyro versus, say, androgen? Or is it all about driving a switch off of Takhzyro and, say, the key U.S. market, and then sort of key unmet needs as you see it that pipeline innovators like yourself can address?
Yeah. We're very excited about our HAE prophylactic treatment, donidalorsen. As you indicated today, the prophylactic market in the United States is served largely by Takhzyro, a once every two-week subcu injectable with a syringe and vial that has the potential to go every four weeks, but there's a lot of loss of control of HAE attacks. So the vast majority of patients are every two weeks. It is indeed, in the U.S., because most patients are on Takhzyro, it is a switch market. Outside the U.S., it's really a market that needs to be developed, that needs to be built for the prophylactic treatment. Right now, HAE outside the U.S. is largely addressed with on-demand treatment, which means your attacks start and then you inject yourself subcutaneously with a bradykinin receptor inhibitor to try to quell the attack. It's clearly prophylactic treatment is coming outside the U.S.
But in the U.S., it's a switch market. What we've learned from our market research is consistently that this is a market, prophylactic treatment in the U.S., that there's a need for patients to have better treatment options. Patients are looking for better efficacy. Patients are still getting attacks with HAE. Secondly, patients want better tolerability in the treatments that they take. And thirdly, they want to have more convenience, less frequent dosing, with the advantage that we offer of simple autoinjectors that a patient could administer once every month or once every 2 months is what we're expecting. So we really have the potential to shift the dose frequency algorithm for HAE prophylaxis with donidalorsen.
We're looking forward to sharing a full comprehensive data set from our phase III program at the European Allergy and Immunology Conference in Spain on May 31 this year, in which we'll include our comprehensive review of our phase III data, which we think the reduction in HAE attacks are going to prove to be very competitive. Secondly, the durability of the protection that we're achieving. We showed really durable protection in our phase II open label extension for up to three years now. We're also going to share phase III open label extension, which I think is going to really, really demonstrate excellent durability. And then thirdly, most importantly for the U.S. market, is a comprehensive review of our phase III switch data at the meeting.
This is the first study we're doing, the switch study we've done and are continuing to do, is the first time ever a switch study from an existing prophylactic treatment in HAE, which patients were converted over to a new treatment, was actually conducted in a clinical setting. What we're going to be looking for in that study are how well are we protecting patients in the study, how long do patients stay on treatment, do they continue treatment long beyond the study such that they roll into an extension of the study, and what are patients' preferences? Do patients prefer our treatment versus another treatment, and why? We're looking forward to that presentation because it's a litmus test, honestly, of the U.S. market, which is, as I mentioned, a switch market. We think those results are going to be really eye-opening.
Do you think, well, I have a sense of if there's a strong preference to Q8 versus Q4 out of the switch study data. What is your operating assumption regarding sort of where the market would net out with your Q4 versus Q8?
The switch study only includes every 4-week dosing. So patients that enter the study, it's only 4-week dosing. But we will have a considerable amount of data from our phase III study with every 4-week and every 8-week dosing. The way we see we see this, as I mentioned, the ability for patients as a base case to be treated once per month versus once every 2 weeks for the lead prophylactic that's on the market in the U.S. today as a real game changer by itself. The ability for patients to administer treatment every 8 weeks, every 2 months, provides dosing flexibility. And patients are going to have the option to be able to dose themselves every month or every 2 months of dosing. If a patient happens to have an attack with every 2-month dosing, they could always come back to every month, once per month dosing.
We expect that there's going to be a sizable portion of patients that are going to be attack-free. They're going to do just fine on every 2-month dosing. But what this does is it provides dosing flexibility that's not available for patients today with any HAE prophylactic treatment. So we think it's another aspect of the differentiating profile for donidalorsen over existing treatments.
Got it. And as we think about this as a switch market, what are the learnings that are out there that give you confidence that patients are willing to switch? And do you look at oral therapies, the launches of oral therapies, as a good analog for switch dynamics?
I think there's a lot of evidence that patients want better treatment options and are willing to switch. First, the Orladeyo launch is direct evidence that a newly approved medicine, despite the fact that it's HAE prophylaxis, the improvement in HAE attack rate that is seen with Orladeyo was, on an average basis, inferior to that of Takhzyro. Patients were still willing to try it. In fact, that happened quite a bit. Then patients tended to switch back based on our market research because they weren't getting the protection, but they were willing to try it. Secondly, our switch study has enrolled very quickly. It's a sizable study. More than 60 patients on existing prophylactic treatments, whether it be Takhzyro, Orladeyo, or Cinryze, eagerly moved into our study, moved on to donidalorsen.
I'm pleased to say that the vast majority of those patients have stayed on treatment long term. I think we have real evidence there. In addition, the market research and the advisory boards that we've had over the last couple of years really indicates that patients are looking for new options and they're willing to try new options.
OK. Well, maybe shifting gears to Angelman's. I believe you'll have an update for folks mid-year, whatever mid-year means. And then there's an Angelman's medical meeting in July, I believe. So against that backdrop, if you can maybe just the latest in terms of where you are at with that trial, which is open label, and there's a data package handoff to Biogen at some point, if you can maybe just frame where we are, and we'll go from there.
Yep. Angelman syndrome is a neurodevelopmental disease, a rare disease, genetic disease in which there's a very, very significant unmet medical need. This is a reasonably highly prevalent disease within the rare disease category. There are no treatment options available today. We think we have a potential best-in-class molecule for Angelman syndrome. We reported encouraging data at the FAST patient meeting last year in November, which we reported that several indications of clinical benefit, as well as EEG data, were trending in the right direction after only four weeks of treatment. And then all those patients we completed enrollment in the study, and then all those patients have now rolled over into the long-term extension. Some of those patients have now gone beyond a year of treatment. This is a complicated disease, and it's a complicated trial. These patients suffer from a whole host of problems.
It's a neurodevelopmental disease. As I said, they suffer from intellectual, cognitive challenges, communication challenges, both receptive and proactive, fine motor, gross motor function problems, seizures, sleep problems, all kinds of issues related to the disease. Our phase I and II study is designed to capture as much data of any study ever done in this patient population. We're looking at children, we're looking at adolescents, and we're looking at adults. And we're looking at various measures such as Bayley-4 or CGI or Vineland that are different ways of addressing these different aspects of this disease. It's an open label study. To make this study even more complicated, we don't have a placebo group. But what we have is great natural history data that we're going to be relying on. And what we're looking for are indications that certain aspects of these diseases are improving in a meaningful manner.
What we're hoping to see is that we can see commonalities between Bayley-4, CGI, Vineland, and other measures of aspect, which will lend greater confidence that what we're seeing is real, even though it's a noncontrolled study. Of course, what we'll be comparing to is the natural history data. Our objective is to gather together enough data and have the confidence that would move us into a pivotal study as the next step of the development of this program.
So we don't need to get into the technicalities here. But target knockdown is difficult to measure, and you won't be able to measure it in the foreseeable next 6 months. So as we think about observing other antisense oligonucleotides that have been explored clinically in this space, I mean, this is very much a very directional positive analysis that we're conducting here with these therapeutics. Do you feel each ASO is kind of constructed individually and uniquely, or would you expect if one works, others should have effect as well? Just maybe what's the read across from competitor updates kind of directionally?
So for those that are new to this, this is a loss of function disease from the maternal UBE3A gene. What we're doing is unsilencing the paternal gene to upregulate a protein called UBE3 to basically replace the protein that's deficient in this disease. There are two antisense oligonucleotide programs in development relatively at the same stage. They're both utilizing the same mechanism of action. Our platform, our chemical platform, we have a great deal of experience with. It's the same chemical platform as Spinraza, a blockbuster for SMA, as Qalsody, a breakthrough for SOD1-ALS, and the rest of our rich 11 medicines in development from our CNS program. So we have a validated platform, a platform that we have a great deal of safety and efficacy experience with. As for other programs that read through to what we will see, we're really focused on our trial.
We don't think that there's going to be much read through. It'll be very interesting, however, to be able to determine when our study does read out whether or not the areas of improvement that we're seeing in our study are similar to what other programs are showing, because that would lend even more confidence that what we're seeing is real. Again, both studies are uncontrolled, so there's no placebo group. So anything we can get to garner more and more confidence will be helpful.
OK. And so I guess just to summarize, as you go into this HALOS study update, Vineland, Bayley, and EEG probably have the richest amount of natural history. And those should be maybe the three endpoints to focus in on the most? Or I don't know if you would push back and say it's more nuanced and we need to consider other factors.
I would say Bayley-4 is the most important and the subdomains within Bayley-4. I would view CGI and Vineland as more supportive because the Bayley-4 is a physician-administered measure of performance. Others are patient-reported or family member-reported outcomes. They can be more subjective and more subject to false readings. The subdomains within Bayley-4, I think, is what's really going to be most important, and also breaking that down to how are those subdomains performing in the children, in the adolescents, and in the adults. All that, I mean, we purposely cast the widest possible net for our phase II study so that it can inform our design of a potential phase III trial going forward.
We could probably spend the next hour talking about the regulatory path. But maybe just at a high level, have you interacted with FDA on Angelman's? And as we think about pathway forward, I don't know, do you feel optimistic that it's a manageable pathway forward from a development standpoint?
Well, with the caveat that we haven't completed review of the data yet, if we do go forward to a pivotal study, the next step will be FDA regulatory advice and end of phase II meeting to set us up for a pivotal study to come. So we have not had formal discussions with the FDA about what a phase III trial designs. It's premature. We haven't submitted our data yet or anything like that. We haven't reviewed our data in totality yet. But that would be the next step. And it's a data support. So I'm confident that the FDA will be able to negotiate a reasonable path forward with the FDA. They've been very supportive of Ionis. They've been very supportive of our platform for neurological diseases. And they understand the unmet need.
With this trial that's ongoing, is there an independent data safety monitoring? Are they looking at things like lower extremity weakness and sort of the update that we would get to better understand that aspect of it? And is it a class effect? Is it something that maybe is molecule specific?
Yes, there is. There's a safety oversight committee that meets regularly. We haven't had any significant safety concerns or issues in this study. Everything is moving forward very, very smoothly.
Got it. OK. Maybe we can jump to APOC3, which was a recent update that you had for your FCS program. And I believe you've got phase III data for the larger SHTG indication. That'll be first half next year?
Yeah, mid-year next year. So yeah, we're really excited. As I mentioned in my opening, we reported a lot of new data, all the data from our Phase III FCS trial at ACC. We also published in the New England Journal of Medicine simultaneously. And we're looking forward to a potential approval for FCS by the end of the year if we get priority review. That's a rare disease. That's a rare genetic disease. The much larger unmet need, the more prevalent disease, is SHTG, severely elevated triglycerides in a non-genetic patient population. The prevalence of this disease is in the millions in the United States. There are no effective treatments for severely elevated triglycerides. Both FCS patients and SHTG patients, although one's genetic and one's non-genetic, suffer from the same thing: severe risk of acute pancreatitis that can be fatal.
If it's not fatal, it typically lands them in an ICU for a week or longer. Once you have one event, you have more events: abdominal pain, cognitive problems, and so on. In our FCS study, we showed a substantial reduction not only in triglycerides but also in acute pancreatitis that we think is going to potentially read through to SHTG. We're certainly going to be expecting substantial reductions in triglycerides, which is what endocrinologists and cardiologists are looking for. We also feel more confident than ever, based on our FCS data, that we're also going to see a substantial reduction in acute pancreatitis. One other thing, in our FCS study, we also saw nearly a 90% reduction in hospitalizations in the treatment group versus the placebo group, which is very important for payers, of course. That was not all due to reductions in acute pancreatitis.
In fact, the majority of the hospitalizations in the placebo group were not due to acute pancreatitis. They were due to severe abdominal pain, not feeling well, and those sorts of things. So we expect to not only have a best-in-class molecule, we expect to be first to market by several years versus any competition that we see behind us.
Got it. So for SHTG, I'm a little bit struck by how limited characterization there is of the pancreatitis event rate in that population. I think there's been a couple of studies that have been done. Event rates are somewhere in the single-digit territory. I know that you've commented about hopefully being able to pool your phase III study data to show at least a trend on pancreatitis. So just curious, as you ran those trials, what is your understanding of that event rate? How important is it to have some benefit on trend if you're to realize, I think, that being a peak $1 billion-plus revenue opportunity?
Yeah. In our FCS trial, we weren't expecting, and nobody was expecting to have statistically significant reductions in acute pancreatitis. And we did. The event rate for AP in FCS or SHTG is not well understood. Yes, there are publications that project certain rates. But it's really the clinical trials, like ours, that are ongoing that are really going to inform on what the true event rate is in using the placebo groups for that data. The event rate in the FCS placebo group was much higher than what we expected. We had something like 15-16 events out of around 20-25 patients in the placebo group alone, which is a much higher event rate than what people had projected at the time.
In our SHTG trial, we expect the event rate to be somewhat less than in FCS because these patients, although they have severely elevated triglycerides, it's on an average a bit lower than FCS. However, we're going to be looking at around 1,000 patients versus 60, 70 in our FCS study. So we're going to have a much greater pool to collect AP events in that patient population. I could also tell you that we are seeing AP events in our SHTG phase III trial in a blinded manner. And virtually every AP event in our FCS trial was in the placebo group. So if that translates to SHTG, we're going to be in really good shape. How important is it? Physicians that treat patients with severely elevated triglycerides, in which triglycerides are above a threshold that is around 880 or so, are already convinced that patients need treatment.
They've got to get their triglycerides down. They've got to get them out of harm's way for AP and all the other problems that I mentioned. Triglyceride lowering will be enough to target that initial crop of patients that sets us up for a blockbuster potential opportunity. Having acute pancreatitis trends or statistically significant will add a lot of value on top of that for treaters that are in the moderately aggressive treatment group. That's market development. Having that data will be very important to expand the market beyond what we see for triglyceride lowering by itself. We will look at both the pivotal study and the supportive pivotal study, CORE and CORE2. As you said, we also have the option to be able to pool them together to add power to achieve potential statistical significance in AP reduction.
OK. Well, maybe in the last 5 minutes, cardiomyopathy is very topical with a competitor data readout in June or July, HELIOS-B. And you've framed it as a very important piece of information that will dictate sort of when you choose to unblind your data in the interim versus the final analysis in 2026. So maybe just set the expectations in terms of the toggles there. How that information can inform Door A versus going through Door B with the longer wait to flip the data card.
Our cardiomyopathy trial is a landmark study. This is for TTR cardiomyopathy, by far the largest study ever conducted in TTR cardiomyopathy. It is so because of the demographics that have shifted, that has changed the earlier diagnosis for TTR cardiomyopathy, which didn't exist. That patient population was much sicker when tafamidis was developed in phase III development. We upsized our study to ensure that we have the proper powering for a successful outcome. Our primary endpoint is CV hospitalizations and CV mortality. That's what we're powered for. We think we have the right trial design to hit on that, as well as potentially our subgroups with and without on top of tafamidis or as a monotherapy. Our base case is to read this study out to its full completion, 140 weeks of treatment for more than 1,400 patients in around mid-2026.
However, we have the ability to read out early in next year, as early as next year, based on a couple of things. One is our blinded event rates. As we continue to collect and monitor our blinded events, once we get into that range that supports the powering assumptions that the study was originally designed based on, we're going to be there. And our events are tracking well in this study. Secondly, we're very much looking forward to the first silencer readout in TTR cardiomyopathy in an outcome trial. That, of course, can inform on all kinds of things, whether the effect size for a silencer is much greater than what we anticipated or not. And we can make adjustments on timing of the readout for our trial based on both the event rates as well as anything we see externally.
So it sounds like the base case is that monotherapy will hit for HELIOS-B. There's less confidence, I think, broadly that the all-comer endpoint hits, right? So thus, the only way that you read out earlier is if there's an unequivocal success with HELIOS-B. At that point, why would you wait any longer if you see clear effect with the silencers, both in a monotherapy and an all-comer basis? Is that sort of a directional, and obviously, this is non-binding. You can choose to do whatever you want. But sitting here today, as you think about it.
Yeah. We haven't laid out specifics on what scenario would lead to what timing for our readout. As I mentioned, our base case is a full 140 weeks, which is mid-2026. This isn't a sprint to the finish line. This is a very large unmet medical need, high prevalence, a very large market opportunity. And we're committed to having the richest data set of any TTR treatment for TTR cardiomyopathy that's out there today and that's coming. The readouts from competitive programs are going to be nuanced. It's really going to be hard to say. I can think of a million different scenarios that can lead to several different outcomes. But suffice it to say that if we're convinced that we can obtain data that's of the same quality as the full 140-week readout by reading out early, we'll certainly want to get to the market as soon as possible.
OK. And then maybe just we only have 40 seconds or so left here. But thinking about the rollout of Wainua for polyneuropathy and the value of self-administered subcutaneous, where are you seeing that play early on? And how does that inform sort of broader, longer-term preference for subcut versus IV options?
We're really pleased with the Wainua launch so far. It's early days. We only reported on a partial quarter, really just February and March for the first quarter. But we're off to a great start. We're hitting all of our pre-planned metrics for successful launch, our KPIs. Going into this whole thing, we felt that the ability for patients to self-administer by themselves at home or wherever they are using a simple low-volume autoinjector was going to be a very significant advantage for this patient population, and not just for polyneuropathy, but then also to translate to cardiomyopathy as well. We're seeing that play out. We're seeing a lot of uptake, a lot of interest in the self-administration profile. The neuropathy market is a market in which more than 80% of patients are not on treatment today globally, including the United States.
So we're really focused on getting those patients, getting market development, getting to newly diagnosed patients. Of course, we welcome switches too. We're seeing some switches from existing treatments for polyneuropathy today. We're pleased about that. We think that'll continue. But what we're really focused on is the newly diagnosed patients. We believe that Wainua is positioned well. Its efficacy, its self-administration profile, the design of our Phase III cardiomyopathy trial, and having a co-commercialization partner like AstraZeneca, which is globally present, positions Wainua to be the treatment of choice for TTR amyloidosis going forward.
Great. Well, we're out of time. But thank you so much for joining us, Brett.
Thank you, Jason. It was a pleasure.
All right.