To be moderating this panel on Ionis, where we'll focus on the Ionis neuroscience efforts with Holly, who runs the neuroscience drug development group at Ionis, and Wade, who is Head of IR, who I'm sure everyone knows. Wade's had a long tenure at Ionis. With that, maybe, Holly, I can ask you to just kind of give us a snapshot of the key neuro efforts at Ionis, and then I have some follow-up questions on individual programs. Thank you again for attending. It's always great to talk to you.
Yeah, thanks for having us. It's an exciting time at Ionis for neurology right now. This first half of the year, the big thing we're doing is getting the trial started for our Angelman program, the pivotal study. We're getting that set up first half of the year. At the end of this year, we have our Alexander's disease program pivotal study reading out. Next year, we have our tau Phase II program reading out. Those are the big upcoming things. In the last year, we've also started four new Phase I/ II studies in patients for the rest of our neurology franchise. Busy time.
Great. With Angelman's, you know, I guess the major sort of question, right, is how do we bridge from open label data to a placebo-controlled study, right, which at a high level of neuroscience is never easy. What gives you the confidence that the prior data is truly de-risking for the phase three trial that you're going to be running?
Yeah, so first of all, just to highlight the prior data. Our HALOS study was our first study. As you mentioned, it was open label. Here, we looked at a number of different endpoints across the domains of the disease. In all instances, we saw benefit. It was benefit across the board, not just in some domains or others. We saw improvements in cognition, communication, motor domains, and with different tests as well. There was cross-test validity. We used the CGI, we used the Vineland, and we used the Bayley. There are some of the similar domains across the tests, and there were similarities. That gives you confidence in the data, and the totality of the data is going directionally in the same way. Our first in human study was a MAD. We had multiple dose levels.
We had a low dose, a mid, and a high dose. The mid and the high performed similarly, but the low dose did not perform as well. That always helps. We also have, in terms of moving now into a placebo-controlled trial, previous experience in Angelman with the Ovid trial, where we can pull information from there on what the background placebo effects can be that we expect, and then apply that, of course, when we do our power calculations for our current reveal study. We do take that into account. We do recognize that it is something to be aware of, and we are considering it.
Yeah, OK, makes sense. What are the key similarities and differences between your molecule and the Ultragenyx molecule?
Yeah, so both of our drugs are antisense oligonucleotides that are targeting the antisense transcript of UBE3A. In Angelman, UBE3A is lost by targeting antisense transcript; we're both upregulating UBE3A. That's really where the similarities end. We have different chemistries, and we have different oligonucleotides, and our oligo is using our proven platform. It's the same technology that we use for MAPT, our approved drug, QALSODY, for ALS. We have a lot of experience with these molecules, both in developing them in the CNS, but then also in screening for them and making sure that we can find safe, well-tolerated compounds that engage their targets effectively.
Makes sense. As it relates to the trial population, right, you've gone like somewhat broad, right? I mean, obviously, this is a genetic disease, but you have adults and adolescents. You have patients, you know, across mutations. What's the thought process there? Is there any added risk in having a population that's somewhat more heterogeneous?
Yeah, so the thought process is that we want to treat the whole population. We ultimately want to help everybody with Angelman syndrome with our therapeutic. We think mechanistically it should be able to do that. There is no reason not to. We are confident in our trial design because we have a lot of data to back it up. We, of course, have the HALOS study, which included adults and children. It also included mutation and deletion carriers. We saw benefit across the board. We also have beautiful natural history data in the Angelman community. They have done a great job getting longitudinal data, both mutation and deletion carriers, adults and children. We can look at that. We have used all that information to look at the variability across the population to power our study appropriately with that.
I think that this is going to be our best chance to get the broadest label possible to have that. One important thing to note, though, is even though we are including children and adults in the pivotal study, our pivotal cohort, our primary analysis endpoint cohort, is the 2-17-year-olds. That is a separate cohort from the adults.
OK, OK, makes sense. Anything else you want to add on this program before we talk about tau?
Just another question we get a lot is timing. We are looking to start the first half of this year. We then have planning and completing enrollment next year. It is a 12-month primary endpoint for the readout.
Yeah, OK. Great. That'll be very exciting.
Yeah.
Yeah, so maybe let's talk a little bit about tau, right? So you guys have some interesting Phase I/II data. I guess, what about the data you've generated so far do you feel like differentiates this approach from a number of the antibodies that have failed?
Yeah, so it's a totally different mechanism of action. Here, we're lowering the production of the protein where the antibodies are promoting clearance. The thing with tau is the tangles that happen in Alzheimer's disease are intracellular. They're not extracellular like Aβ. The way the antibodies are working is they're grabbing the tangles as they move from cell to cell. They're preventing the progression of the disease throughout the CNS. What we're doing is we're stopping the disease in the cells. We're stopping that protein that's ultimately going to be aggregate and be detrimental from even being produced. What we've shown in our Phase I/II study, and we were the first to ever show this, is that when you stop production of tau, the pathological tau that's already in those 80 patients' brains reverses. We could get reversal of pathological tau.
That is really incredible for a couple of reasons. One, it taught us that if you stop production, you can get reversal. The brain is able to naturally then clear out that tau. Two, it also let us know that our oligo distributed throughout the brain because all regions that we got that had tau pathology, we had clearance. That.
Was the magnitude of that clearance variable across areas, or is it consistent?
It was fairly consistent across areas. We have put out there is a publication that our colleagues at Biogen put out, and it has all the details for all the different regions. You can look at those bar graphs, and they are pretty similar. There are differences in the baseline amounts of pathology, but the amount that changed was pretty similar across the board, granted with the resolution that you can get with the tau path.
Yeah, OK, OK. What gives you confidence that knocking down tau won't be toxic?
Yeah, so that's a really good question. Tau knockout animals are actually fine, so they don't have any issues. One of the really remarkable things is that if you cross the tau knockout animals that don't have any tau from birth, these animals actually protect against Aβ toxicity. They protect against excitotoxicity from epileptic agents that will cause seizures and even in epilepsy models. In the instances of where we've crossed tau knockouts with disease models, there was a protective effect. It's one of the cool mechanisms that are underlying tau. If you also look at the human data, there isn't evidence from the human genetics that loss of function is going to be a challenge.
Of course, from all the data that we've generated for our oligo, there's the preclinical studies, including chronic studies, where we lowered tau and we didn't see any concerning effects in the Phase I/II study. I don't want to be dismissive, but the totality of the evidence really doesn't flag anything that would be of concern for lowering tau. Of course, we're keeping an eye on this with the ongoing trials and as the program progresses.
All right, the clunkiness of muting and unmuting myself just to make sure there's no background noise. I mean, all that makes a lot of sense. You know, and I guess maybe the other question around safety is just around idiosyncratic tox for the oligo, right? I mean, I know you guys have a ton of experience in doing this. It does feel like maybe something idiosyncratic was an issue with the Huntington's program. What can you say about what can you say about the margin here, right, the dose level you're giving compared to other CNS programs?
Yeah, so we've learned a lot about oligos since the Huntington program. One of the things that we learned is that the oligos last a lot longer in the brain than we had originally thought. If you remember, the Huntington program was doing really frequent dosing, even up to monthly dosing. In the tau program, in the Phase I study, we did monthly dosing for the lower dose cohorts. In the higher dose cohorts, we went out to quarterly dosing. Even with just two injections of the tau oligonucleotide, we had nice reductions in CSF tau. Those lasted for six months after dosing. We then put everybody in the LTE. That's the longest we had. Tau levels were still down and still flat at six months.
That gave us confidence going into the phase two study that we're doing two different dose levels, but also quarterly and every six months. The dosing interval is now six months instead of monthly. With six-monthly dosing, and that really infrequent, it's not a lot of drug that's being exposed to these brains to be able to have suppression of tau for long term.
Yeah.
We are seeing that across the board with our programs. We talked about Angelman earlier, and that is going to be quarterly dosed. We really are spreading out those dose intervals, so a lot less drug than some of our original programs.
Yeah, OK, great. In the Phase I b, there were some efforts by Biogen to try to contextualize some of the cognitive data. I know it's like a small sample, but do you want to talk a little bit about that?
I will, but I'll first start with all the caveats. It was a post-hoc analysis. And it's a very small sample size, so don't want to read too much into it. With that out there, it was 36 patients. What Biogen did is they had placebo data from a previous trial that they had done. It was one of their tau antibody trials that hadn't moved forward, but they had the placebo, large placebo cohort, where they were able to match the individual patients based on demographics. They had a matched placebo cohort that was an external placebo that they compared to our BIIB080 data. The reason that they had to do that is our Phase I/II study, as I mentioned, we did three months of dosing with six months of recovery, but then everybody went via the LTE.
All of our later time points, everybody had drug on board. They did an analysis at week 100. They were able to show that based on that external comparator, there was a benefit in favor of BIIB080 on the cognitive endpoints, including the CDR sum of boxes, which is the endpoint that they'll be using in the phase two study. Very promising directionally. The magnitude was lovely, bigger than some of the early Aβ trials, but post-hoc analysis, external control, only 36 patients.
Yeah, makes sense. How do you think about the right population to intervene for with the tau mechanism versus the amyloid mechanism?
Yeah, so there's a lot of discussion about that. I think that's what we're going to learn a lot from the ongoing phase two study. Right now, the current trial is focusing in on mild cognitive impairment and mild dementia, going early on in the disease. The question will be, is this more amenable to later disease intervention than some of the amyloid therapies? You would expect that mechanistically because tau seems to be downstream of Aβ. Tau correlates better with cognitive decline over time than Aβ. You could imagine that tau, you could intervene even at later stages of disease and have a benefit, especially if this reversal that we saw in the Phase I shows up.
That said, for our current trials, we are focusing on those earlier patient populations because that is where we still expect to have the biggest effect.
Yeah, yeah, OK, great. I mean, I'm excited to see these data. Is there anything else you'd want to add, Holly?
No, just that the study reads out next year. We are also very excited to see the data for this program because a tau oligonucleotide has the potential to affect a lot of people, not just in Alzheimer's disease, but other tauopathies. There is a lot of potential here if this mechanism plays out.
Yeah, yeah, yeah. OK, great. What program would you want to talk about next?
Alpha-synuclein?
Yeah, OK, let's do it. I mean, I think there's a lot of analogs between synuclein and tau as it relates to just where the target is, the issue with antibodies. Maybe I'll let you kind of take it away to start.
Yeah, so that's exactly why I thought it was a good segue from tau. Alpha-synuclein is another program where we have an oligonucleotide where we're lowering the production of the protein. Again, this is an intracellular protein. The antibodies have tried to catch this protein as it transported between neurons and spreads throughout the brain. There is a fair bit of data that shows it's probably not completely exposed as it's moving between these neurons. That is why the antibodies might not be the best mechanism for this. We're lowering, just like with tau, we saw in preclinical models, you could reverse existing pathology by stopping production, and the brain could clear it. The same thing is true for alpha-synuclein. If you lower endogenous alpha-synuclein and you introduce fibrils into the brains of animals that cause alpha-synuclein misfolding, spreading, and cell death, you can prevent that.
You can even reverse it once that pathology is already established. Just to be clear, you cannot reverse the cell death, obviously, but you can reverse the pathology. Very similar mechanism to tau. The difference is that when you have synuclein pathology, instead of having Alzheimer's disease, you have Parkinson's disease and other synucleinopathies. Our first in human program that we are doing right now is a Phase I/II. This will read out at the end of this year as well, is in MSA. That is a really interesting population because it is a synucleinopathy caused by aggregation of synuclein, just like Parkinson's disease. Here, it is a younger population, and it is a much more rapidly progressing population.
Interesting.
Yeah, and so we.
Is it a genetic population?
It's not genetic, but there has been some really amazing efforts in the community in the last couple of years where they found a biomarker. It's typically diagnosed clinically. What they found is that if you look at CSF synuclein, you can actually show and diagnose patients based on the aggregation capabilities of their CSF synuclein. They use an assay. It's an Amprion assay where it's very similar to the assay RT-QuIC that's used in Creutzfeldt-Jakob disease, where you use the CSF and you say, can you then seed that? Can you seed aggregation? If you can seed aggregation, then it tells you you have aggregates in the CSF. In this case, it's synuclein aggregates.
By looking at these synuclein aggregates, they can now confirm fairly well if somebody has MSA or somebody has Parkinson's and then diagnose even pretty early some of those MSA patients. It is an exciting evolution that has just happened in the last couple of years. It can identify these younger, faster progressing patients that we are focusing on for our first in human study.
Yeah, OK. I mean, I guess the one question I have is just like for Parkinson's, right, you really got to access the deep brain. Is that, can you actually get the same level of target engagement there with an IT oligo? My impression was that some of your biodistribution data looks best in the cortex or the spinal cord. What can you point to there as evidence?
Yep, yep, yep, you're totally right. There is a gradient from cord. Cord to cortex is similar. It's about a one-to-one from cord to frontal cortex. As you go into the deeper brain structures, there's less. It does require more drug. You do get a lot of suppression in the cortical regions to target the deeper brain structures. For synuclein, we think that that's fine. Synuclein, we don't have concerns about lowering synuclein. We haven't seen anything preclinically to give us concerns about lowering that. Dosing so that you can target those deeper brain structures is absolutely possible.
OK.
The data that supports that is all the non-human primate data that we've published over the years, including for synuclein and then also with MALAT1 and other molecules as well.
Yeah, OK. I guess for Parkinson's, right, I mean, the other challenge with just running disease-modifying trials in general has been around the pace of patient progression. How do you think about actual clinical proof of concept in this population?
Yeah, we are working through that now. We are working out all those details at this point. It is still early.
Yeah, OK, OK. I guess like yeah, I mean, maybe I don't want to ask you to front-run it, right? Some people have tried to do even frontline studies where you're looking at time to levodopa. Is that.
Yeah.
Do you know if you?
Everything is being discussed, and I don't want to get ahead of my clinical colleagues.
OK, all right.
We'll have more solid plans by the time we get to the end of the year and we have the data from the first study reading out.
Yeah, OK, all right, that makes sense. What's next, Holly? I'll leave it to you. I like that you're picking topics in order. It gives everybody the vibes of what you're most excited about.
Yeah, so then just timing-wise, there's the Alexander's disease program at the end of this year. That's a pivotal study readout. That's an ultra-rare program. So that's one we can chat about.
Yeah, let's talk about that. I mean, I think maybe just talk about the mechanistic rationale. You said it's ultra-rare. How rare are we talking relative to something like SOD1?
One in a million, so 300-700 patients in the U.S., so very rare.
Wow, OK.
Yeah.
OK.
And.
Yeah, go ahead.
Yep, so because of this, this is a disease that's caused by mutations in GFAP. You have mutations in GFAP, which is an astrocyte protein. It leads to increases in GFAP and aggregation of GFAP, which then leads to the astrocytes causing demyelination. There is hypomyelination. You lose those sheaths that cover the neurons that allows for conduction. It is a leukodystrophy. It is a very devastating disease. It is ultimately fatal. It affects broadly, as you can imagine, the CNS, given that it is a demyelinating disease. In the preclinical models, because we are going after the gene that causes the disease, you can have really robust effects. We can even restore myelination by stopping the damage that is happening from these astrocytes expressing too much GFAP and then have functional benefits in the animal models with intervention early or late.
With that really robust preclinical data, we went into the clinical testing. Now, this clinical study is a really unique design. It is a unique design in that it is our first in human study, and it is our pivotal study. Given that it is ultra-rare, we wanted to be very efficient. We are doing a single study with just over 50 patients that potentially could be registrational. It is exciting from that point of view in that you could potentially help this patient population with a registrational study in a very efficient manner. It is also a bit challenging because we are now going into a pivotal readout, and we have no human data that we can point to at this point because it is all one single study and all blinded.
Yeah, yeah, yeah, OK, interesting. Great. The one last thing I want to talk to you about, Holly, is delivery. There has been a lot of buzz with the transferrin approaches, which we have not seen yet with an oligo, but I think it is coming. You guys have your bicycle collaboration. Where are you there? I guess for Ionis, right, I mean, I feel like you guys are paving the way and testing so many of these targets with IT dosing. I think it would be tough to see you guys prove some of this stuff out and then have someone come out with something that is like a conjugate that is IV. What are you doing there to kind of make sure you are still on the forefront of these technologies as everything evolves?
Yeah, absolutely. First, I'll just hit on Bicycle real quick and what we're doing with that. Then I'll get into the BBB delivery, if that works. Bicycle overall, just so everybody's aware, we have exclusive access to Bicycles for proprietary macrocyclic peptides, the Bicycles, for transferrin and oligonucleotides. We're using those in three different ways for targeting cardiac muscle, skeletal muscle, and also for BBB delivery. Our most advanced program is targeting cardiac muscle. That's in clinical development right now. We're de-risking the Bicycle from that perspective. These are really lovely molecules because they allow for, because they're so small. For example, if you have 100 mg of oligo and you add a Bicycle, it's only 130 mg of total drug. It's very small. They're smaller than an oligo.
Because of that, you can do formulations and things like auto injectors for at-home use and subQ, which is really exciting in terms of convenience and delivery. Because of that, we're advancing it for cardiac muscle. We're also exploring it for skeletal muscle. It is also very exciting for BBB. For BBB delivery, we're focusing on transferrin right now. We have two different approaches. One is Bicycle, but we also have a relationship with Vect-Horus, which is their nanobody technology. We're looking at that as well for BBB delivery. The Vect-Horus is a little bit more advanced. Bicycle is also really exciting because of that subQ element that I mentioned. We're evaluating that as well. Our intention is not to validate these targets and then walk away from those patients.
Our intention is to validate these targets and then continue to make better and better molecules and following molecules and things like using this BBB technology to be able to not just do IV, but even to do subQ for some of these patients.
Yeah, yeah, OK, great. Hey, I had one question come in, and that was just asking for an update on the efforts with SPINRAZA and the additional development efforts, like higher dosing, things like that.
Yeah, so the higher dosing is looking great. Biogen has released that data and that information that has all been filed. Now we're waiting for outcomes from that. That will be coming through at the end of this year.
OK, what are the key points that would make us optimistic that a higher dose should be added on Africa?
Yeah, so what they're seeing from the higher dose, for me, I think the most compelling data is that you're seeing an improvement on neurofilament. So you're changing the underlying disease. So you're having a bigger effect on the underlying disease. And ultimately, for all these neurodegenerative diseases, that's what we need to be doing, stopping that process as much as possible.
Wasn't there already some data for the current dosing regimen that showed normalization of neurofilament?
Not normalization, but improvement. That improved it even further. That further improvement, yeah.
OK, OK.
Which I think is really compelling for me as a scientist.
Yeah, no, totally. I mean, look, the SPINRAZA -NfL data from years ago looked really compelling. It was one of the examples we would point to to people when there was the question of, is this just an MS biomarker? Is it more broadly extrapolatable? All right, great. This was an awesome discussion, as always. Anything else you'd like to add before we wrap up?
I think we hit on all of it.
OK, OK, Wade, anything you want to chime in with?
I'd just say it's pretty exciting, the advancements we're doing in the CNS space. It's clearly a focus of ours. We've continued over the last several years to focus our efforts and our pipeline in neuro and cardiovascular disease. I think you've seen that with our pipeline focus and also some of the BD deals we've done over the last couple of years. I think as we continue to focus, you'll see more and more advancement in these areas that we think are very exciting. We've pioneered the field of RNA-targeted CNS diseases. I think we're going to continue to do that.
All right, great. Congrats on all the progress. Thanks for taking the time.
Thanks.
All right, see you soon.