Hi, guys. I'm Ellie Merle. Thank you for joining the UBS Virtual CNS Day. Very excited to have Ionis Pharmaceuticals here with us today for a fireside chat. Joining us from Ionis is Holly Kordasiewicz. Sorry if I butchered your name. SVP of Neurology Research and Wade Walke, SVP Investor Relations. I know we just have 25 minutes, so I'll jump right in. Maybe just high level, can you provide kind of an overview of some of the programs in the neuro space that you have and the timelines? Then we can jump into specific programs.
Yeah. In our neurology program, we have a number of exciting things going on right now. We have, first of all, our Alexander 's program is reading out later this year. This is a pivotal program. We also have our MAPT program, which is reading out next year. It is a Phase II study there. Of course, we have our Angelman program. There we are getting our Phase III study up and running in the first half of this year. Those are the main things that we are focused on in neuro right now.
Great. Maybe starting with Alexander's, you know, with the data expected in the second half, can you talk a bit about the biology here and how that translates into the data we should be looking to see?
Yeah, yeah, happy to. Alexander's disease is caused by mutations in GFAP. These are gain of function mutations, which lead to accumulation of GFAP in astrocytes and the formation of Rosenthal fibers. Once you have that, that leads to damage of the myelin, the sheath covering neurons, and then you have hypomyelination, so loss of myelin. It is a leukodystrophy. Since it is caused by that central GFAP mutation, our target is GFAP. We have beautiful preclinical data because you can make mice and rats that have Alexander's disease by introducing mutant GFAP. You can lower that. You can reverse that hypomyelination. You can have a benefit and a meaningful benefit on the function of the animals.
For our first in human study and our pivotal study, we have a really unique design in that this is an ultra rare disease and we have one study. It is both first in human and it is pivotal. That is what is reading out at the end of this year. There we have a number of different endpoints that we are looking at. This is a complex disease with many different symptoms. Our primary is a 10-meter walk test, but we also have a number of secondaries looking at that constellation of symptoms of the disease. What we are looking at to translate is evidence that we are having an effect on the overall underlying disease.
Looking at trends across all those different measures that they are beneficial. That is because we are going after that central target, and we want that evidence that we are affecting the underlying disease.
I guess how should we think about, I mean, because we haven't seen clinical data yet, or at least we haven't. Maybe you have.
We're still blinded too.
Okay. Like, how do we think about what good data looks like here?
Yeah, that's a great question. What we're looking for, as I mentioned, is those trends across the board. Good data will be trends in different domains showing that we're having that effect on the underlying disease. We, of course, have our primary endpoint, but that's not our only focus. It's also those secondaries as well. We've had discussions with regulators that there will be a lot of regulatory flexibility here given the rareness of the disease in this type of design that we have for our pivotal study.
Awesome. I guess, and then given that this is an ultra rare disease, maybe if you could speak a little bit to sort of the market sizing here and how much market development do you expect, you know, it will take in the U.S. for Alexander's ?
Yeah, so it's about one in a million. We think about 300 to 700 patients. Because it is ultra rare, there's going to be moderate market development. The big thing we're focusing on there is faster diagnosis and patient identification. Really looking at education, we're supporting initiatives to try to be able to identify these patients earlier and diagnose them sooner so that they could get access to treatment, assuming everything works in our pivotal study. What that looks like in terms of development is we're doing CMEs for neurologists on reading Alexander's disease signs and symptoms and MRIs for diagnosis. We're trying to do this in a very efficient way, collaborating with patient advocacy organizations, using Congress presences, using omnichannel to get access to those individuals who might see these patients and get that diagnosis.
What proportion of this, like, 300 to 700 patients in the U.S. are currently diagnosed, if you have a sense?
We don't have a good sense of that. What we do have is, thankfully, there's an ICD-10 code that actually came out for this about 18 months ago. We are getting more and more information on diagnosis and the use of that and identification of patients through that. That has been really nice for this ultra rare disease to have.
I guess just how, like, I know probably some of the work is still in progress, but like, in terms of like the patients that are diagnosed, is the treatment more centralized at, say, academic centers or sort of centers of excellence, or is it more spread out, maybe, you know, going into kind of the community setting?
Yeah, it's really at centers for excellence. The experienced treaters for Alexander are at those centers for excellence because they can provide that multidisciplinary, complex symptomatic care that's happening right now for the patients. We actually expect a lot of our treatment decisions and administration to happen at those centers for excellence. That's really where we're going to be, where we are focused on and where we're going to be focused on for the launch. Again, assuming everything goes well in the pivotal.
Great. We are looking forward to seeing that data later this year.
Let's do it.
Maybe turning to Angelman's, maybe can you give us an overview of the biology of the disease, the severity, and, you know, the unmet need, and just how those patients, you know, are currently managed?
Yeah. Angelman syndrome is cause of loss of function by UBE3A. This is an E3 ubiquitin ligase that's really involved in synaptic remodeling. This is a neurodevelopmental disease. Again, our target is we're upregulating that lost gene of UBE3A. These patients, they have normal development, and then they stop hitting milestones. That happens around six to twelve months of age is when they start being visible that they aren't meeting milestones. The patients continue to develop, and they peak at about the neurotypical two to a four-year-old. They have a normal lifespan. You can imagine this is a really severe disease where patients are developed cognitively and with their speech and their motor to about a two to four-year-old, and then they live a normal life.
In terms of how it's managed, there are some treatment options in terms of treating the epilepsy, anti-epileptics with seizures, and some sleep medicines that are given to the individuals with Angelman, but most of it is managed care. Most of it is physical therapy, behavioral therapy, communication, speech therapy, things like that. There really aren't many options for these patients and definitely no disease-modifying options, which is what we're trying to do with ION582.
Can you walk us through what was seen in the Phase II data last year and I guess the natural history work that's been done to sort of put that data in context?
Yeah, so we're really happy. HALOS was our trial. That was our first in human study. This was a MAD design. We had three different dose levels. We looked at those patients over time. We looked at a number of different domains for this disease. We looked at cognition, motor, communication. We used multiple different COAs. We had the Bayley, we had the Vineland, we had the CGI, and we've shared all this data. What we found is that there was benefit across the domains. We had benefit across the domains in a dose-dependent manner, and it was benefit that exceeded that of natural history. One of the really great things about Angelman is even though it's rare, the community has been really fantastic. Way back in 2006, they started natural history studies.
We have lots of longitudinal data in natural history in this disease. We were able to pull out 150 patients from that natural history where we had nice longitudinal data that we could match to our cohort that we had in HALOS and demonstrate that the HALOS effects that we saw in that trial exceeded the natural history.
Great. I guess with the Phase III, you know, beginning soon, I guess, can you walk us through the decision to choose Bayley for with the expressive communication as a primary endpoint? I guess, was this like sort of the FDA steering you towards this domain versus the others, or was there some flexibility?
This was our choice. This was our choice that we proposed to the FDA, and the FDA readily agreed. The rationale that we provided for them is there's a nice stable baseline. These patients, they have no speech or very limited speech. You're at the very bottom of that scale. There's lots of room for improvement, and it's very stable. Over time, it doesn't change, which is what you want in your natural history for an endpoint. It's also the most bothersome symptom for caregivers. They're very clear that if their individuals with Angelman can communicate, that would be a meaningful difference for them, which of course is important to us and regulators. It had the biggest magnitude of effect in our HALOS trial.
Having the biggest magnitude of effect and that stable low baseline, it gives us that nice big delta that we will be looking for in our placebo-controlled trial. Highest probability of success for that. No pushback from FDA, readily accepted, and we're happy that we're moving it forward.
Maybe what are some of the other endpoints of focus or maybe just how the sort of KOLs in the space tend to talk about the various endpoints and the relative importance?
Yep. What we'll be looking at is very similar to what we had in the HALOS study. Of course, we'll be using the Vineland, the CGI, and the ORCA as well. The different COAs that are out there, the different assays that are available. In terms of the KOLs, as you can imagine, they have lots of opinions, and there's lots of different opinions. There's no one focus that they have that we should be zeroing in on. There are pros and cons to all of them. Since we've decided on expressive communication, we haven't heard anything negative about that, only support from that from the KOLs.
Their biggest thing is just to make sure you're looking at the complexity of the disease in our secondary so that we can see which and hopefully all of the domains are having benefits like we were able to show during HALOS and making sure we're capturing that complexity.
Absolutely. You know, in the context of maybe the competitive landscape with Ultragenyx, maybe what are some of kind of the, like, you know, what you view as differentiating features of your program?
Yeah, so I love our drug. It's a well-tolerated drug. It's safe. It's one that is using our proven technology that we are very familiar with, and it's performing exactly how we would expect based on what we knew previously. Because of that, I'm happy with what we're moving forward with. I also like our design as well. Our design is we have for our Phase III study, we're looking at a broad patient population. Because we're not limited, because we don't have any of the safety effects that they've had, we can do ambulatory and non-ambulatory patients. Because our HALOS trial included both mutation and deletion carriers, we have confidence of including both of those in our pivotal cohort, as well as looking in the overall REVEAL study. That's the name of our Phase III trial, that adults as well as children.
We will have that broad patient population in our trial to hopefully give us that broad label that we're looking for to be able to help all the patients with Angelman.
You know, kind of building off of Alexander 's disease, like, how should we think kind of about both the opportunity in terms of like the number of patients with Angelman’s that are currently diagnosed and sort of as an organization, how you would approach the scale-up potentially from, you know, Alexander’s to Angelman’s from a commercial perspective?
Yeah, so it's a great question. There's, of course, many more patients with Angelman than there are with Alexander 's disease, but with Alexander 's disease being first, we can use that to start building the foundation in pediatric neurology so that when we then move into Angelman, which is larger, we can grow quickly. One of the overall strategies that we have for our commercial organization is to look for significant synergies across the organization, and particularly within rare neurology and cardiology. We're going to leverage all the work we do for zilganersen, for then Angelman syndrome. A great example of this is the leadership that we've already built in our current commercial organization has extensive experience building those rare markets.
Even with our TRYNGOLZA, which is also a rare market, which they are building, they will then be able to apply that experience to both Alexander disease and then Angelman.
How should we think about the diagnosis rate of Angelman's today? I mean, it seems like the symptoms are perhaps, you know, pretty clear or at least like prompt sort of a visit to the doctors. How should we think about kind of the size of the prevalence pool and the proportion that are diagnosed currently?
Yeah, so it's one in 12,000 to one in 20,000, we think. So potentially, I mean, 500,000 people worldwide, which is huge. And because of the awareness of Angelman and just the sheer size of it, comparing it to Alexander disease, it's much quicker diagnosis. And then the genetic confirmation comes fairly quickly after that. So there's much more awareness, but there's still work to be done in terms of making sure that all the patients who could potentially benefit are aware of it. There's also really fantastic patient communities out there that we're collaborating with who are bringing this awareness and spreading that information. So I think it's in a good place in terms of people understanding the disease and being aware of it. And then again, with anything that we're doing, once there's a treatment, we expect there to be more awareness and more uptake.
We saw that with SPINRAZA. One final thing to note that we have not touched on yet is for both these indications for Alexander disease as well as for Angelman, the ultimate goal is to get this on newborn screening. If you can get this on newborn screening, then you can get these children treatment very early. When we have talked to parents, this is exactly what they want. When there is diagnosis, they want to be on treatment. Both for our Alexander's program, we have a zero to two open label cohort that we are treating. For our Angelman program, we are opening up a zero to two open label program.
Because our drug has been shown to be safe, we're going to be able to do that so that we can have data on those very young individuals so that as soon as that diagnosis is made, then they can get on therapy. We think all that will help raise awareness and open up the patient community and the patient identification.
How should we think about the timelines here, just like, you know, how you're thinking about how long it will take to enroll and like basically like when from, you know, where we said we could next get an update, whether it's a longer-term data from some of the Phase II study or, you know, say the Phase III data?
We will start the trial the first half of this year. We are on track to do that. We have everything, the protocol set, the regulatory alignment set, and we're just getting the sites up and going. That's going to happen. We are planning to complete enrollment next year, and then it's a 12-month endpoint for the primary endpoint for the REVEAL study. You can kind of do the math from there and figure out where we should land.
All right. 2027-ish. Okay. We're looking forward to seeing that data. MAPT, yes, I'm interesting. Yeah, like early data from the program so far. I guess with data coming next year, I guess maybe can you talk about what you've seen from your initial first in human study and sort of maybe how using an ASO might be different from using an antibody in terms of addressing the tau burden?
Yeah, so I love this program. I mean, I love most of our programs, but this one I'm particularly fond of. That's because in Alzheimer's disease, there's two pathologies, of course. There's Aβ plaques, and then there's the tau tangles. The tau tangles are intracellular. What we're doing is we're stopping the production of tau. Before any pathology forms, you stop tau from being made. Antibody approaches after tau are only going for extracellular tau. You have to catch it when it's moving from neuron to neuron. Once it gets in that neuron, then the antibodies aren't going to do anything. Here we stop the production within a neuron. We've shown in preclinical models, if you stop the production within a neuron, you actually reverse existing tau. The exciting data from our first in human study is there's tau PET.
We can look at tau pathology longitudinally in man. We were able to show that with treatment, we did the oligonucleotide that stopped tau. We looked at 100 weeks. We looked at baseline, then we looked at that 100-week time point at tau pathology, and we actually reversed tau pathology. That is really important. We did not just stop production. We reversed existing pathology. By stopping tau production, the body, the brain, the aged Alzheimer's brain is actually able to clear that existing tau pathology and then prevent more pathology from happening. That was really exciting. That is, since it is so central to disease, could potentially be a really important treatment for Alzheimer's disease. I think that is where a lot of the excitement and the buzz is coming from for this one.
Yeah, no, it's exciting data. Maybe can you tell us a little bit more about the design of the Phase II and, you know, I guess what data we should be, you know, looking for next year?
Yeah, of course. The Phase II study is looking at different dosing regimens. We are doing both a quarterly as well as a six-month dosing regimen. From our first in human study, we also saw that the oligonucleotide lasted a really long time in man. We could spread out the dosing interval. That means treatments, if that works, just twice a year to potentially be therapeutically beneficial in Alzheimer's disease. We are looking at an endpoint, which is a clinical endpoint. We are looking at the CDR sum of boxes, and that is at 76 weeks of placebo-controlled treatment. It is just over a 300-patient trial. I think we ended up in the 370 range, about there when we were finally enrolled. As we have been mentioning, that reads out next year. It is fully enrolled, and we are just waiting for the data now.
Exciting. What's clinically meaningful in terms of like the difference on CDR sum of boxes? Or yes, are we still looking at that like 30% or so range? Or yeah, how should we be thinking about that?
Yeah, so you're referencing in what's happened with Aβ. I think on par with Aβ will make a lot of sense. Because of our mechanism of action, the Aβ antibodies, they do have a small effect, but it is a meaningful effect. I think that's been clear in what we've seen being approved in that space. It comes along with ARIA. I think that's where a lot of the hesitation around the antibodies are, that safety. Because of our mechanism of action of lowering tau, we shouldn't have that safety effect. There's no evidence of ARIA and no prediction of that from our mechanism of action. The other exciting thing for tau is that the tau pathology correlates best with cognitive decline. There is the benefit of more.
It would be great if we saw more, but I wouldn't set that expectation. If we're on par with the Aβ antibodies, because these are two different mechanisms, you could envision using them together. Using them together could then be additive or even synergistic based on the mechanisms. That would be the next question.
What would the, I guess, next steps be? Would it be to run a Phase III monotherapy, but then also study a combination? I guess, have you looked at like your plans with sort of combination in Phase II?
That's in discussion right now, but absolutely a Phase III. I think it's going to depend on the data, but Phase III monotherapy and then what else we do in parallel will be dependent on the data and the state of all the other therapies on the market and how they're doing and how they can be used. Of course, this is partnered with Biogen. They will fully license this program, so they'll be making all the final decisions on that.
I guess given the like potentially like better safety, I guess what really is the bar from an efficacy perspective? Like I guess what would be the lowest improvement that you could see on, say, CDR sum of boxes and still want to move forward into Phase III given the biology safety?
Biogen hasn't given out those numbers, but I'd be happy with anything on par with the Aβ antibodies.
Great. Like how would this work in practice? Is it sort of, you know, almost like oncology where, you know, patients would get multiple agents?
Yeah, so that's what I think. I think that's where we're going. We could be blown away by tau and it could be just amazing and that it could be all you need. It could be the hypothesis that tau is downstream of Aβ is right and this is going to capture everything. I think Alzheimer's is a multifactorial disease. There are multiple things going on. To fully treat the disease and all the patients that have it with those different underlying pathologies, we're going to need multiple shots on goal and potentially multiple therapies in individual patients. That's just my personal view of the science and what's going on.
Turning to maybe the commercial side in polyneuropathy, sort of what's the latest in what you're seeing in terms of the uptake of WAINUA and in particular if there's certain like segments where you're seeing more uptake versus less and, you know, how that's going?
Yeah, I'll handle that one. We’re really pleased with the performance of WAINUA in 2024. We saw really good growth. If you look at the last quarter growth, so Q3 to Q4, you know, we saw a $42 million increase in sales. That’s an 84% growth quarter-over-quarter with $19 million in increase over the previous quarter. It’s interesting because if you look at the total combined TTR sales with our competitors’ drugs and our drug, I think it was like $39 million in increase. Ours was more than half of that. Pretty impressive performance for three quarters of the way into the launch for this drug. We estimate that we’re capturing about 40% or so of patients new to treatment in the TTR space for polyneuropathy. For us, we see that as a good sign.
We continue to see that kind of growth going forward into 2025. You know, what we're hearing is that, you know, we're getting some switches. We're getting some combo treatment. Our focus from the beginning has been on patients who are new to treatment because, you know, about 80% of the patients out there are not diagnosed and on treatment, right? We have a great partner with AstraZeneca who is able to, you know, have the commercial resources to get out into the communities, into the community centers and try and identify these patients and get them on treatment. The majority of our patients coming on treatment are patients new to treatment. Not saying that, you know, we're still seeing good uptake in centers of excellence as well. Obviously, that's where you also find a lot of these patients.
We're hearing that patients really appreciate the profile of WAINUA, whether they're new or whether they're switching. They like the convenience of being able to administer the drug themselves anytime they want at home. The auto injector is very convenient for them to use. They like the profile of the drug as far as the quality of life improvements that they're seeing. The safety and efficacy is on par with what they're expecting. All of those things combined, I think, are good signs for the continued growth of WAINUA this year and next.
You guys have had some interesting commentary in that you're seeing combination use commercially. Any color that you can sort of give there, like the proportion or, you know, mix that you're seeing with combination use?
I wish I could, but we can't give those kind of details out right now. I don't think AZ would be happy with me if we did. It is encouraging to know that, you know, this is a deadly disease. Just like with cancer, if there are two different drugs with two different mechanisms attacking a disease like this, there is a desire to use those drugs to try and get the maximum benefit for patients. You've got patients who are diagnosed with cardiomyopathy on tafamidis, for example, patients who are diagnosed with polyneuropathy getting WAINUA. You've got two drugs, two different mechanisms of action treating these patients. It's certainly something that I think physicians and patients would like to be able to do when possible, especially if patients are seeing two different symptoms or they're progressing in their symptoms.
Absolutely. Last question, just sHTG. A lot of investor focus on this readout later this year. We know that you can lower triglycerides. I guess, how do we think about what's clinically meaningful when it comes to acute pancreatitis?
Sure. I mean, the treatments that are out there right now, especially in patients with very high triglycerides, don't really have much of an impact in lowering triglycerides, right? You may get patients who get, you know, 10-20% reduction in triglycerides. If you're starting out at 600 or 800 or 900, a 10-20% decrease in triglycerides isn't going to move the needle much for you, right? You know, given the fact that we've seen, you know, anywhere from 50-80% reduction in triglycerides, depending on the patient population and the study that we're looking at, I'd say we're pretty encouraged with the potential of olezarsen to be able to lower triglycerides in patients with severely elevated triglycerides. We've certainly seen it in FCS patients. We'll see it later this year with our sHTG Phase III studies.
You know, I think, you know, seeing a substantial decrease in triglycerides is the bar for our Phase III studies. Now, beyond that, we're also looking at, you know, the major problem with having very high triglycerides is that you have risk for acute pancreatitis. You know, one of our key secondary endpoints is looking at, you know, what kind of effect do we have on acute pancreatitis? We've engineered the Phase III studies. There are two. There is a pivotal and a confirmatory pivotal that are reading out at about the same time. We're going to be able to do a meta-analysis combining both of those studies to be able to look at the effect of the drug on acute pancreatitis. That is one of the key measures as well that we'll be looking at.
Interesting. Great. Holly, Wade, thank you so much for making the time and sharing all the insights today. We look forward to all the data readouts.
Thanks. We're excited.
Thanks. Bye.