Great. Continuing with the theme of oligos in CNS, it's my pleasure to be moderating a panel with Holly Kordasiewicz, who is the Senior Vice President of the Neurology Group at Ionis, along with Wade Walke, Senior Director, VP of Investor Relations. So, good to see both of you this morning. You know, I think instead of, like, I think most folks are well aware of Ionis' like, overarching efforts and the great success you guys have had in CNS. So I thought what would be interesting would be to maybe just go through program by program. I'm super interested in the Angelman's program, super interested in tau, some of the other ALS targets you're looking at. And so if that works for you, maybe we can just get into it.
Sounds great.
All right. So, starting with Angelman's, do you wanna talk a little bit more on the background of ION 42-- or 582, excuse me? Like I know there was a lot of work pre-clinically, that I talked to Eric about, about really trying to find, like, the right candidate, one with a wide therapeutic index. So, you know, what have you sort of described here pre-clinically before getting to the clinic? And at a basic science level, how does the chemistry and mechanism here compare to the Ultragenyx molecule?
Yeah. So ION582 is designed with our MOE chemistry, with—and with our rigorous screening and optimization process. Now, both molecules, ours as well as the, the 102, are single-stranded oligonucleotides, but there are some key differences. So the, the competing molecules for UBE3A are a different class of chemical that we chose not to use for our CNS applications. And as you mentioned, we took the time during the design and optimization of ION582 to really find the, the best-in-class molecule. The chemistry we're using is the chemistry that we know how to work with. We have extensive experience within the CNS.
For example, ION582 is the same chemistry that has gone through that same rigorous design process, and optimization as our MAPT tau program that we released a lot of data on last year, and we'll talk about later. And also the same chemistry as our two approved CNS drugs, Spinraza and Qalsody. So it's something we have a lot of experience with, and then we've done the work to really find the best molecule. One of the key things that we do is we build those human preclinical animal models that express the full human genes, so that we can really find and tune in those optimal oligonucleotides.
And then also another thing to highlight for this is the preliminary assessment of our early clinical findings with ION582, which we released at FAST last year, are really encouraging, and no safety signal issues were identified. So we think that we have a best-in-class molecule, and that appears to be supported by the preclinical profile and the clinical profile that's starting to emerge.
Okay, great. So as it relates to this upcoming readout, it's an open-label study, right? In, you know, and not dismissing the severity of Angelman's as a disease, but, you know, in open-label trials in neurology, right, you can always have a big sort of placebo effect, depending on the clinical measure. So how are you analyzing these data to understand if there's a real drug effect? You know, what endpoints are you focused on? And, like, I guess, in the population that you're studying, like, how heterogeneous is it? Like, what would be the likelihood of spontaneous improvement? Like, maybe just kind of walk us through your thought process there.
Yeah. So the upcoming readout we have is focused on the MAD portion of the study. We've got 51 patients, so it's a decent size. They do range in age from 2 to 50 years, so there is a wide group of patients. The study includes treatment for 3 months, with a 1-month follow-up after the last dose. So that's the MAD portion. This is our first study in this patient population, so we looked at many different endpoints, both established as well as more exploratory endpoints. We selected measures that are both the gold standard for measuring change in key areas of functioning in Angelman syndrome, including both direct assessment of functioning, subjective clinician measures, and parent reporting and home assessments to try to capture participants in their typical environment.
So we really tried to cover all the different ways that we can look at this disease in these patients and how they're performing. Now, for how to interpret the data, as you mentioned, it's open label, so we need to interpret it very cautiously. Fortunately, there's a fair bit of good natural history data in Angelman syndrome patients, and we're able to compare our treatment data to that. So it's not perfect because it is open label, but there is that nice natural history data that we have. And the Angelman trajectory is fairly stable. They do have some improvements on some of the measures over time, but those are known from the natural history, and so we can compare to that.
Now, for endpoints that we're most interested, this is a safety and PK study, so of course, the main things we're focused on are safety and PK, and then evaluating the totality of the data to begin to design subsequent clinical trials. That's, of course, assuming the data supports continued development.
Okay. Because of the really wide age range, just to drill in deeper here, like, does it make sense to look at this by, like, age cohort or demographic and compare it to, like, subsegments of natural history data? I mean, 2 to 50 is, like, kind of incredible.
Yeah. No, it does, and we actually have separate cohorts for the different age groups.
Okay.
You can look at the data-
Okay
... that way. But then there's also, there's natural history data across all those different age groups as well.
Okay, okay. Got it. And so you've talked about this, like, EEG biomarker, delta power. And not to dismiss its relevance in Angelman's, 'cause I wanna hear, like, more context about that. But, like, I feel like delta power, gamma power, I don't know, just being someone who covers a lot of different stuff in CNS-
Yeah
... like, I've heard people speak to these EEG biomarkers and tell me, with conviction, that they mean, like, really, really different things, right? So, like, why is delta power a relevant biomarker in Angelman's, and how well established is it that it actually correlates with, you know, the severity of phenotype or, or something?
Yeah. And there, there's good data in this space. So real quick, so in Angelman syndrome patients, they tend to have an increase in slow-wave delta and a decrease in faster theta. So to kind of give you a reference, delta is what's typically found in the healthy brain when someone's asleep.... And so that's what the Angelman brain is looking like. So it's giving you a read on, on brain function in a patient, and it's something that you can do longitudinal. So that's the sort of thing that drug developers get really excited about. So we've assessed EEG and natural history studies in Angelman syndrome patients, and the delta power predicted the Bayley cognitive scores, once you control for age and genotype pretty well.
We shared at FAST last year that the EEG, we saw a reduction in slow-wave delta and an increase in faster frequency theta when compared baseline one month after the last dose in that MAD portion, part one of the study. So it is, it is something that we see in Angelman. It's a readout for brain activity, and it is something that we, we saw move in the MAD. So, it, it's an interesting marker, and this is an encouraging early biomarker. But to put it into context, it suggests that our ASO is engaging the target and having an effect on the disease biology. But at least for me, that- that's about all it, it's telling us.
Right.
Which is, I shouldn't diminish that either, that those are good things.
Yeah, yeah, yeah. No, for sure. Are there ways like... So, Angelman is very, in, like, the genetic level, right? Like you have, like you have, I guess, like, for lack... I don't know. Tell me if this is the wrong word, right? But, like, silencing of the paternal gene.
Yeah.
you know, I know we use silencing in a different context when we talk about oligos, right? But, like-
Yeah.
Do we, do we understand how to measure the degree to which you're reversing this and the degree to which you're getting this to wild type levels?
Yeah, so that's a great question. So our partners at Biogen, they've developed an assay to look at UBE3A in the CSF. So that's a way to look at a pharmacodynamic biomarker. There's also the EEG that has been correlated, and correlated in the EEG, compared, as I mentioned, to the Bayley. So you can use that. So there are indirect measures to give you an idea of how this is performing. But it's not... With anything in the CNS, it's difficult to say, "Yes, this is an exact one-to-one, and this is exactly how things are moving with those biomarkers," 'cause they all are indirect biomarkers.
Okay. So just to kind of round it out on this upcoming readout, it sounds like we're gonna get. Is it fair to say that we're gonna get, like, a number of different endpoints, data cuts, like, some somewhat comprehensive way to kinda contextualize this, assuming the underlying view here is that you're gonna move forward? Is that fair?
Yes. We haven't decided exactly everything, but it's really the MAD portion of the study, a whole bunch of clinical endpoints, as well as the biomarkers that we've discussed, that we've been assessing.
Okay. Okay. On the endpoint side, so I was talking with Priya from Biogen about this yesterday, too, and it'd be great to also get your perspective. But I mean, there's been like there's clearly differing views from companies in this space on what the right registrational endpoint is and whether the current endpoints are well suited and sensitive enough. You know, it sounds like your and Biogen's view is that you can work with what's already established. Is that right? And I guess, like, why is that?
Yeah, so this is... Yes, so that is correct, and based on our previous experience working to develop disease-modifying therapies in pediatric indications, this isn't the first time we've done that, and that we've done it with Biogen. So we do expect that we're gonna need to have a controlled study with a clinical meaningful clinical outcome measure. Now, exactly what that clinical outcome measure is, is gonna be determined from the data that we're generating now and then, of course, discussions with regulators and KOLs. So it's important to note that we have generated a lot of data in that open label, in that MAD portion, as I mentioned. We're looking at a lot of different endpoints, including the gold standards, but other more exploratory things that could be interesting. We also have an ongoing long-term extension.
So that was originally one year, and we've recently extended that for two more years. So that's gonna give us a lot more experience with these endpoints and a lot more longitudinal data to help us plan those subsequent studies.
Yeah. Great. All right, that's an exciting one. I wanted to briefly switch gears and talk about the ulefnersen.
Mm-hmm.
Is that right?
Yeah, you did.
Okay. All right, thank you. I just like calling these things by their target. For everyone listening, the FUS program. So we actually have... I think it's, it's probably not under the radar at all in your world, but on the Wall Street world, it is a little bit under the radar in terms of clinical evidence for this FUS target. So maybe you can talk about that and talk about this sort of program and, and where things are progressing.
Yeah. So FUS-ALS is like SOD1-ALS, and SOD1-ALS, which is the target of our recently approved drug, Qalsody, is a dominantly inherited form of ALS. Now, in FUS-ALS, it's caused by mutations in the FUS gene. So like SOD1, our target is very central to disease in these patients. So the goal is that by going after that target central to disease, we'll be able to have a significant disease-modifying effect for FUS patients. And this program has an interesting backstory, in that it was originally an early access program that was treating an oligonucleotide in patients, and in those patients, there was observed benefits. So some patients looked like they were stabilizing, and then there was also been reported a decrease in neurofilament in those patients as well.
In the ALS world, if you see a decrease in neurofilament, like we saw for our SOD1 program, that's really good evidence that suggests you're modifying the underlying disease. And so-
How substantial of a decrease are we talking on NfL? Like-
It's pretty similar to what we saw in SOD1, with a similar slope in the EAP patients.
Okay, got it. Okay. Okay. Sorry. I didn't mean-
Yeah.
Yeah.
No, no, no, of course.
Okay.
So that's why that's what gives us the excitement for this program, that we have the target central to disease, and we understand ALS 'cause of our Qalsody experience, so then this should be hopefully a successful trial.
Yeah. Okay, that's great. And, yeah, so what's the design of that study? When, when are we getting the readout?
... Yeah, so the readout for that is in 2026, and this is a phase III study. It's a single study, so first in human and registrational. So this allows us to get through clinical testing into patients as efficiently as possible. One of the key learnings from tofersen was that you need to wait a bit to see a difference between placebo and treatment if you're using a disease-modifying therapy in ALS. So the study was originally designed with a 6-month placebo control, but we've extended that out to 18 months, and that's really based on the, the Qalsody learnings. And so then the idea is that can give us meaningful clinical endpoints looking at the ALSFRS.
Yeah. Okay. And maybe a silly question, but how and why did this get carved out of the Biogen agreement?
So the way the Biogen agreement works is they get an option on any of our neurology programs, and it's at an early stage of research that they get that option, and there's financial implications for it. So they get to decide at that point, if they want the program or if they don't. We make a lot more things than Biogen can advance. We have a very prolific R&D organization, and so a lot of things Biogen chooses not to take forward for business, strategic, different reasons, and this was one of them.
Yeah. Okay, got it. How would you characterize the prevalence of FUS versus SOD1?
Yeah. This is the third most common inherited form of ALS. It's about 25% the incidence of SOD1, so it's ultra-rare.
Ultra-
A few hundred patients in the U.S. and Europe.
Okay. Okay, okay, got it. All right, great. Exciting one. So we have that in 2026. You know, in the meantime, I think the other wholly owned neurology program that you've talked about a decent amount is in Alexander disease. Can you give us the download there, and your confidence in GFAP as a target?
Yeah, of course. So again, with GFAP, we're going right to the heart of the disease. Here, the mutations are on GFAP. They cause a dominantly inherited fatal Alexander disease, and these GFAP mutations lead to a loss of myelin. Those are the sheaths that cover neurons. And then that causes a bunch of neurological symptoms, including motor, speech difficulties, cognitive decline, and seizures. It's an interesting disease and target because the underlying mechanism is that loss of myelin, but it's potentially repairable. So in preclinical models, suppression of GFAP with our oligos leads to a reversal of those myelin deficits and improvement in symptoms. So the preclinical models are strong because they mimic the disease. The big question now is, will this benefit translate to patients?
So for our GFAP program, like FUS, we've designed a single clinical study with 50 patients, and it's registrational. So we want to move this therapeutic as quickly as and efficiently as we can through clinical development. But that also means that we don't have any clinical data on this yet, and so that's what's gonna read out next year.
Okay. Okay. And again, from a prevalence perspective, how does this sort of stack up using the ALS story as a benchmark?
More than SOD, so a few hundred-
More than SOD.
Yes.
Okay. Okay, okay, great. And clinical endpoints there?
Clinical endpoints, so this is because it is a complex disease, the main thing that we're looking at is the walk test.
Yeah.
But we also have a whole, a whole slew of other endpoints that we're, we're looking at. So it's the 10-meter walk test and change from baseline, and we're doing that at week 61, is the main one. And then we also have subsequent ones looking at most bothersome symptom, and then global impression of severity and another... different endpoints that we can use to help support, depending on what the data looks like.
Gotcha. Okay. Okay. So from a strategic perspective, maybe this is a good question for Wade. You know, these are two wholly owned rare neuro programs, certainly a different call point than what we're talking about with, say, olezarsen or donidalorsen. You know, are these things that you actually would take to market and launch independently, or would you try to kinda re-partner them or renegotiate with Biogen or consider other sort of strategic alternatives?
You know, this is one of our key pillars. We look at programs in cardiovascular disease and CNS as programs that we want to own more of and commercialize ourselves. So in the case of CNS diseases, we're looking at several of these rare diseases, which on their own, you know, don't look like a lot of revenue generation coming in. But when you bucket them all together using a similar sales force, similar commercial infrastructure, given the number of opportunities that we have and the probability of success of the chemistry and the technology that we're using, these actually look attractive, bundled together.
And when you can do clinical trials that are like the Alexander study and the FUS study, where you can do a pretty rapid single study to get to registration, the cost of development is also lower. So, you know, overall, bundling these together and commercializing them ourselves looks fairly attractive.
Yeah. Okay. Okay. Very good. Can we talk about tau briefly?
Mm-hmm.
So, I really like this program, and I definitely appreciate the important difference between trying to access tau with an antibody versus an oligo. I guess, do you wanna talk about the target engagement data you generated and your level of confidence that you're not just kind of reducing tau proximal to where you're injecting the drug, but you're actually reducing it in the key areas of the brain?
Yeah. So for ASO distribution, and that's distribution from an intrathecal injection up the neuraxis into the brain, which is where we need to get for many of these diseases. We've been working in the CNS with this type of delivery for a while now, so we have a wealth of preclinical data, as well as autopsy data from patients who very generously donated their brains after they were treated with oligo, but ultimately succumbed to their disease. And that data demonstrates that our ASO is delivered intrathecally to target all brain regions. Now, that data is great, but for our tau program, we have something even better. And that's because here is tau PET, and we can use tau PET to visualize tau burden throughout a patient's brain. And you can do this with imaging longitudinal over time.
You can see how tau burden changes with disease progression, and then we can also see how it changes with our treatment. So we were fortunate enough that this came out, and we were able to include tau PET for some patients in our first-in-human study with our MAPT tau oligo. Here we were able to look at baseline and see where in a patient's brain they had tau pathology, and then look again after treatment. We did this after the 100-week long-term extension and in the patients, and importantly, also in all brain regions that had tau burden, we actually saw tau reverse. We cleared tau by stopping the production, and that was true in every region that had tau pathology at baseline. This, of course, is great for the patient's brain.
We're getting rid of tau, but it's also a great piece of data for the technology 'cause it shows that we're able to target tau in all those regions and areas that are a problem in an Alzheimer's disease patient brain.
Awesome. And, I'm sure the question you regularly get on this one that we've tried to interrogate ourselves is, can we be comfortable that knocking down tau will be safe? And, you know, if you're just to read about tau on any sort of basic scientific website, it's always referred to as, like, an integral cellular structural protein, and, look, if that's all real, the idea of eradicating that is scary. So what gives you the comfort that this is ultimately gonna be okay?
Yeah. So there's actually a whole bunch of literature on this. So first of all, to date, we have no on-target concerns from the clinical data, and that's, of course, the most relevant data. But before we even started, the preclinical data is actually very supportive of tau lowering. So you mentioned it; it has a name that sounds scary, and it has some things, but if you actually look at the data, there isn't data that says we shouldn't be doing this. So multiple groups have actually made full tau knockout animals, so with zero tau at all, and it's important to note that for an oligo, we never get to zero, but if you have zero, these animals are normal.
And in fact, if you cross a full tau knockout or an animal with 50% tau levels, so one allele removed, you cross that with an A-beta model, you actually protect against A-beta-driven toxicity. The animals do better. So zero tau is protective in A-beta models.
Yeah.
You can also take tau knockouts and tau heterozygotes, and they're protected against other excitotoxicity insults, like chemically induced or genetically induced seizures or brain injuries. So even though it has a name, at least in the preclinical models, there isn't data that supports that this should be an issue, and we haven't seen anything from our clinical work, though, of course, we'll continue to keep an eye on that.
Yeah. Okay. So in the meantime, that's in a larger phase IIb now, is that right?
Yeah, that's exactly right.
Okay. Okay. No, no timing guidance there yet on that data?
Scheduled to complete in 2027.
Okay, okay. So still a ways away, but exciting. Okay.
Yeah.
Maybe lastly, where is Ionis with kind of the next-gen delivery stuff, right? And, you know, I mean, we can talk about CNS, but, like, even specifically in muscle, you guys had some really cool DM1 HSA-LR data, like three or four R&D days ago. What happened there? And, you know, as that space heats up, you know, with Dyne, Avidity, and others, you know, is that something you see yourselves participating in?
Yeah. So DM1 and DMD are absolutely on our radar and remain areas of interest for us. The data from the ongoing clinical programs you mentioned are very supportive for the targets. And as I think most folks know, we have a relationship with Bicycle to use their small peptide-based ligands. And we've demonstrated that these are excellent at improving targeting of RNA therapeutics for both cardiac and skeletal muscle. And in fact, much of our early validation work that we did with our Bicycle technology, including data in both mice and non-human primates, was done using DMPK, which was the original target that we were pursuing for DM1. We are advancing our first Bicycle delivered therapeutic into the clinic for our cardiology franchise, targeting cardiac muscle with a Bicycle siRNA.
I should note that Bicycle works great with oligos, and it also works fantastic with siRNAs, too. We think that we have... The Bicycle technology has the potential to be best in class, and we're exploring the application of this technology to not only the cardiac muscle, which is our first foray with it, but also into skeletal muscle programs and the obvious targets in the neuromuscular space.
Okay. Why, like, why haven't you moved more aggressively in the muscle space here?
We're just taking the time to make sure that we have the right molecules, and if we do move forward, that we have best-in-class molecules.
Okay. Okay. And is this something that Biogen, like, has the rights to or has already, like, technically opted into because they did DM1 with you before? Or how does that work?
Well, with DM1, I think they had an option for DM1, and I'm not sure that they decided to move forward with it. So I'm not 100% sure if they still have an option to take it forward. But on other ones, they do have an option for-
Okay
- muscular targets.
Okay. Okay, okay. Got it. All right. Any other thoughts on just kind of CNS delivery stuff, like transferrin, and if this is something you could kind of work on, too?
Yeah. So I think the next frontier for CNS delivery strategies is crossing the BBB. So we're pursuing crossing the BBB with multiple... And that's the blood-brain barrier. So when you deliver oligo systemically, they don't get into the brain. We have multiple different receptor targeting strategies to do this. We focused in on TfR1 as our first pursuit in this space, and I already mentioned Bicycle, and that's with TfR delivery. And the muscle data is looking great, but now we're applying that to the BBB. And one of the benefits of Bicycle is that they're really small peptide ligands, and their small size give them advantages over other modalities 'cause it reduces the total amount of drug required, so which is more convenient for patients and also beneficial for manufacturing. And we in Bicycle have demonstrated that TfR1-targeting Bicycles can cross the BBB.
There's a lot of work still to do. It's really early, but it's encouraging. We've also expanded our ligand toolbox with a recent relationship with Vect-Horus. So Vect-Horus has their VECTrans system, and both Ionis and Vect-Horus have generated compelling preclinical data with that modality for crossing the BBB, and we'll be sharing that shortly at an upcoming meeting. So it's a really exciting new area, in my opinion, and delivery of RNA therapeutics for central indications via systemic deliveries is really that next delivery frontier.
All right. Excellent. Well, we covered a lot. So next up, looking forward to Angelman's data. That sounds pretty cool.
Yeah, us too.
Okay. All right. Well, thank you both. I appreciate it. Thanks for putting up the Stifel mug, Wade. That's awesome.
Yeah. Yeah. I thought it'd be nice.
Thank you. Yeah, it's a great touch. All right. Sounds good. Have a good rest of your day.
You too.