Great. Thanks very much, everybody. It's a very topical time to have a CNS-focused discussion with Ionis, given some tau data this morning and the tofersen AdCom. You know, maybe I can kick it off. We've got Eric and Holly here who are very in-depth on all this stuff, and you've both been at Ionis for a while. As we sort of sit here today, I know you have a lot of different programs. What are the one to two things that are getting you most excited within your CNS pipeline today? Yeah, maybe we can start with that.
Yeah, sure. Well, thanks for having us on, Paul. We really appreciate it and love to talk about neurology as you well know. So I guess the things that would be especially topical would be three things. Tofersen, obviously. We just had an AdCom where we got unanimous support for the drugs in an accelerated approval-type pathway, and a really nice discussion on the risk benefit profile of the drug, and we can talk about that later.
So we think the drug is doing some good for patients and look forward to the PDUFA date. Then we kind of count eplontersen in peripheral neuropathy as a neurology drug. It's a peripheral drug, not a central drug, but certainly it's a neurology indication.
We just had top-line data from the 66 week trial of that drug in polyneuropathy, which largely mirrored the 35 week, and we're filing worldwide based on that 66 week data, in addition to the late this year PDUFA date that we have in the U.S. on that drug. That's at the top of our minds.
MAPT, I think is a great drug that we can talk about in this call, had really exciting data that's released today that's being presented at ADPD, and Holly can fill you in all the details there. We really think that's typical of the type of drugs that we're making right now for the neurology indications, in addition to tau being a fantastic target in AD that we think is uniquely amenable to exploration with antisense oligos. Lots of other stuff going on in our pipeline, obviously, and we can get to that, but those are kind of three things that are at the top of our mind this week anyway.
Okay. Excellent. Well, congrats on Tofersen and the positive outcome. I guess, as you think about the readthroughs to your pipelines more broadly, maybe even specifically the utility of neurofilament for other diseases that you're pursuing, how do you think about that?
Yeah. I mean, you can see where the agency was going and what they were thinking. We, you know, It might have been 10 years ago, we started talking about neurofilament and what its utility was and whether it's a good biomarker for neurodegeneration and in what instances. Disease-associated biomarkers are fantastic for the development of drugs.
They help the drug developer, and they help you see if your drug's doing what it's intended. We're, we're very happy with the views on using biomarkers to assist in neurogenerative drug development. It's a, it's a hard area to be in, right?
One thing we've learned with some of this is you treat longer and treat earlier in these diseases where neurons are dying. Having a good biomarker really aids you in figuring out whether your drug is working. You know, since we first started to think about neurofilament, I think a lot of the science has filled in where neurofilament light in, especially motor neuron diseases, really seems to be a pretty good biomarker.
I think it'd be very, very helpful for us. If, if, you know, to the extent that the agency is willing to consider that for regulatory approval of accelerated pathways, I think that help gets drugs to patients faster who have really severe needs and no therapies, especially no disease modifying therapies. I think Tofersen fits that bill.
Yeah. Yeah. Okay. You have a couple other efforts in ALS. Is this something where now neurofilament becomes a key thing to watch, you know, for your FUS program or anything else there?
Well, we're certainly watching it. I think others are too. It makes sense. You know, I think that, you know, while the data, because of the length of the VALOR trial, it isn't stat sig in any way, and it missed its endpoints.
We think that the LTE open-label extension data really shows that the drug made a difference in the late start analysis. You start to think, well, we lowered our target, we lowered neurofilament. It does look like it's giving a benefit to these patients. You can start to build the case that in ALS, if you lower neurofilament, you're probably doing a good thing, I guess the opposite can then thought to be true.
I guess I would use an example, I'm sure you're going to ask about it, of the C9orf72 program where we looked at we tested a hypothesis that you can lower the dipeptides from the expanded repeat transcript. We didn't see any effect on neurofilament.
As a result, made a decision not to continue that drug. There's a negative example, but it's an example where we were able to use our technology to reasonably rapidly test an obvious hypothesis to test in C9-driven ALS. Unfortunately, it didn't look like it was working.
Yeah.
There, another example where we use neurofilament to answer a question quicker than if we would have gone to a phase III outcome trial, for example.
How extract relatable do you think that is to other neurological diseases? you know, I guess, look, the other side of this, right, could be the, you know, we saw these neurofilament elevations in the phase II in Huntington's and the phase III was a disappointment, right? I mean, do you feel like now you can look at NFL across pretty much any neurodegenerative disease and, you know, start to have a more cost-efficient way to get to either proof of concept or a no-go decision?
Well, I'm gonna kick this to Holly in a little bit, but I think that probably the jury's still out on that. We'll have to see. Certainly, you know, I knew you were gonna ask about Huntington too. Huntington is different than ALS in many, many ways in terms of disease complexity and the regions that are affected and the elevations that you see in neurofilament, for example. I think it certainly makes sense that if neurons are dying, you can see some biomarker of that neuronal death and.
Right.
I think we have to be a little cautious about just saying, "Oh, neurofilament is good for all," and using that as a one-size-fits-all.
Yeah.
Holly, what are your thoughts on that one?
No, I completely agree. I think the jury is still out. I think there are going to be instances where it's useful and it works like ALS, but I think there's others where it's not. It's important to remember that ALS neurofilament is pretty elevated, and it's elevated in a way where it stays high and it stays like it's consistently being released.
It's looking like in ALS, it's a marker for constant damage, and that's what we still don't understand in all the other diseases. That data for ALS has just come out in the last three years. This is a huge area of study.
Every natural history study is looking at neurofilament. Now, with the plasma neurofilament that we can look at, the assays are easy. I think in the next couple of years, we'll start to know where the diseases are looking like they're behaving the same as ALS and where they'll not and be able to sort that out.
Yeah. Okay. Makes sense. I want to ask you one more biomarker question before we get more specific on various programs you have, and that is: what do you think right now about MRI? Like, I thought MRI intuitively should be a great biomarker, but then we look at the Aβ antibodies where there's a drug effect, but the MRI is not going in the direction that you would think. Do you feel like MRI is a reasonable tool for proof of concept, or is it just something that we don't really understand yet?
We still don't understand. I mean, it's the same concept. We're understanding it more and more in the natural history, in the context of disease-modifying therapies, it's, as you mentioned, there's examples that go in both directions.
Until we have more disease-modifying therapies, it's something to definitely look at and keep an eye on and continue to build our natural history data. I don't think any one of these is gonna be a perfect translatable across all the different diseases and areas. We really need to understand the natural history of the disease, understand it in the context of disease modification.
Okay. Okay. Makes sense. You brought up eplontersen, which wasn't gonna be my primary topic of discussion because I was thinking, like, too simply that neuroscience is brain, but I guess it's also the peripheral nervous system too. On eplontersen, I think the investor community largely appreciates the dosing profile, the massive improvement in safety over the prior generation.
I feel like those things are taken for granted. The main question I generally get from folks, and I'm sure you do too, is when we see the full data, are we gonna be confident that the efficacy matches, you know, the siRNA product that's out there? What can you say about that in terms of your confidence in the competitiveness of it?
Yeah. Well, we're confident in the product as evidenced by our filing and our intention to file worldwide and our statement on that. Our partner AstraZeneca is confident, as evidenced by their actions. You know, I hear you guys. We've been cautious in releasing data.
You've been very shy here, you know?
Well, it's a competitive space, as everyone keeps reminding us. So we don't want to turn over too many of our cards. We had two things. One is it was an ongoing trial. I'm sure you're going to ask me about a neural program where I'm going to say that we're not releasing data in an ongoing trial because we want to maintain, as best we can, the integrity of the trial.
So that was a key point. It's a competitive space. If you turn over too many cards, your competitors will use that information and learn from your trials. You know, in some regards in this space, we're a little behind what we think is our key competitor.
We're going to use that information as everything is released, we're going to use to guide our thinking about our drugs. You know, we're happy with the drug. We think it's performing great. We know it's engaging its target. We're pleased with the safety.
The 66 week data supports what we learned at 35 weeks. We look forward to sharing all the data at the right time. There's an AAN discussion coming up at the end of April where we've said we're going to have some data. We also publish, right? You know, we publish our data, so it'll all get out there.
Yeah.
We're happy with the drug profile and so is AstraZeneca. Look forward to getting that drug available and have a PDUFA late this year, and hopefully it'll be made available to patients who need better therapy.
Will you be at AAN?
I'm not going.
Ionis is, but we're not personally going.
Okay. Fair enough. It's in Boston, that's why I asked.
We travel too much.
I get it. I get it. Okay, switching gears then. The tau program that you showed some more data on this morning. I feel like this program is extremely under the radar, right? Can you talk about the tau lowering data you've generated?
You know, I think with any ASO, my natural question is just when you have a CSF biomarker, how confident are you that that biomarker is representing what's happening in the key areas of the brain relative to the disease? Maybe you can talk about the data you've generated and kind of your confidence in the overall drug effect as you move forward.
Yeah. I'll start with the target engagement, We've had this debate and discussion before. To us, when you see the target moving in the CSF, you have to assume that that movement is coming from the bulk of the tissue, right?
If you just treated a tiny little area, if you just treated only the spinal cord, which has always been a critique that people have given us that I don't agree with and I think is not well-based in the preclinical data we have. You wouldn't see the CSF protein moving. You have to treat the bulk of the brain to move the biomarker in the CSF.
We've always felt like when we saw target engagement that we were treating the cortical regions just like the spinal cord, just like we see in monkeys and just like we see in rodents. I get that it's been hard to convince some of the skeptics that that's been happening, but that's what we've always thought was happening.
I've been beating that drum for years and years and years when people have been pushing us on it. We think that, you know, some of the data presented at ADPD will finally, hopefully will help turn some of those skeptics around because there's a nice picture, and I'll definitely comment on the data.
Yeah. This is an exciting new bit of data, is the tau PET. The tau PET obviously is looking at tau in the brain areas. In all the regions that had tau pathology, there's actually reversal of pathology. The tau pathology is going away in these patients that are getting oligo in the brain.
Now we have that image, that data, and we're not just relying on CSF, and we can see in the CNS with an oligo in active patients that we have that. We've always had some autopsy data from patients who have very generously donated their brains and allowed us to do autopsy on ASO-treated patients over the years. That has always been consistent with what Eric has said in the preclinical models, that we get drug into that central compartment, but now having it in an active patient trial is pretty exciting.
How big was the change in tau PET if you kinda compare to what we're seeing on amyloid PET?
This is reversal. Amyloid PET only slows it. We actually take tau pathology that's there at the baseline, and it goes away.
You see that amyloid PET too, right? You can get patients to PET negative.
You see A β.
Aβ, yeah. Aβ can reverse.
Got it.
The tau with the Aβ antibodies.
Yeah. Right. It's about 45%.
Slows tau progression.
Yeah, yeah. Yeah. Yeah, yeah. Okay. Okay. That's pretty cool. Can I ask you a totally crazy question?
Yeah.
Why not just file for accelerated approval? Tau better tracks disease progression than amyloid. Amyloid is a surrogate endpoint.
Yeah. We need more patients.
You need more safety data. Like, could that actually be a conversation at some point with this drug?
Yeah. Well, as you know, this is a Biogen partnered program, so I'll direct you to ask Biogen that question. You know, I think Biogen is doing a good experiment with the phase IIb, Again, it's a neurodegenerative disease.
You need to treat early, you need to treat long, and we wanna get some clinical data to support the tau hypothesis. Just, you know, this drug, I really think, and we've been saying this for years too, is the first drug that can truly test the tau hypothesis in AD.
Yep. Yep.
Because we're affecting tau throughout the brain, we're affecting tau inside the cell, and now we know we're affecting tau pathology in ways that the tau antibodies just haven't been able to do, which is why they're really not seriously in development anymore. I think this drug is set up to test the tau hypothesis, and you really need to test it and look for benefits on clinical outcomes in patients before we start talking about other things.
Yeah.
I think Biogen is doing that experiment, and they are clearly enthused about this drug. You've seen some of their statements, and it's got the attention of their new boss. We think it's a cool program. We've always thought it was a cool program, and we're really excited our partner agrees and is doing a good experiment.
Yeah. Okay. Okay. Makes sense. On the safety side for that program, what's made you comfortable with knocking down all forms of tau, given its importance as a structural protein and I think I always look to this, I don't know if you guys think this is a relevant data point, but I think the knockout is embryonically lethal, which always. It's not?
No.
Okay. It's not embryonically lethal.
No.
All right.
Yeah.
You're confusing it with Huntington.
No, I'm not confusing with Huntington's. I know Huntington's is. I thought this was too. It's really not?
No, it's not. No. You can actually cross the tau knockouts with the Aβ models and the AD models, and it's protective.
Okay.
It's even protective if you take a tau knockout and you hit it with agents to cause excitotoxicity, you see protection as well. The tau knockout actually provides benefit in disease contexts, and that's full knockout. The het provides benefits too, but full knockout even more.
Okay. I like that you guys just reciprocally shook your heads a second ago.
We've been dealing with this a long time too because the name is a microtubule-associated protein, and everybody who thinks you knock it down thinks all your microtubules fall apart. That's not what happens. There's lots of microtubule-associated proteins and lots of complex structure there. I think this is a function of the name of the protein. If it was named some random orf, people wouldn't be so freaked out about it.
Yeah. Okay. All right. I'm gonna ask you an Angelman's question, but it's not gonna be like some interim data question. It's really just, you know, from this study, whenever it reads out, right? Maybe it's next year 'cause, you know, you and Biogen want to have all the full data and not bias it. Do you feel like this study can truly be a clinical proof of concept study where you can actually see clinical benefit effects in kids, or is it really just more of a study around safety and target engagement?
It's a first in human, so you're always gonna get us to say first that it's a safety and as best as we can measure target. I mean, first it's a safety study, and we always look for other things, are we engaging the target, and we always look for exploratory endpoints that we think will give us a read on what if the drug's doing what we want it to do clinically. It's not powered for that.
Yeah.
It's technically a safety study, but of course, we'll look for other things.
What would you?
Just to clarify, we're not planning on having any data this year, so we've been guiding that.
Yeah, I know. I think Wade told me that when I saw him for coffee a few weeks ago. Okay. This study, can you just talk about the design and like the dose levels, duration of treatment, things like that?
Yeah. We haven't shared all those details, but I can tell you what we have shared. It's a one to two open-label study. It's two parts. We have a 13-week MAD arm, then we go into a 49-week long-term extension period.
A variable follow-up like Eric mentioned, the main endpoints are all around safety. We are looking at other things as well that are interesting in Angelman's and neuronal development, but we haven't discussed exactly what those endpoints are. We don't plan to, just given how competitive the space is.
Yeah. Okay. Okay. Maybe next year. All right. My word's not yours. Fair enough.
Not, not this year.
Okay. I mean, I have a list of questions here, and you have so many programs in CNS, but I would love to turn it over to you. Like, what else would you like to highlight that you think is underappreciated in the investor community? I think tau is something really interesting to talk about, and I'm glad we did.
Yeah. Hopefully, the new data will start to get that program some note. We think it's a great drug program and a great space. We've been trying to explain that we think that is the profile, the target engagement that we're having is the profile of the drugs we're making across our platform. you know, you've done Angelman. That's a, that's a very cool program.
Obviously high visibility because of some of the noise that's been made in the space. We think we have a great drug. I know you're a Huntington guy from past. We are happy that Roche is looking at a phase II in HD with tominersen. It's a new trial with a different, you know, an earlier stage patient population.
Roche is doing a great job trying to bring something to Huntington patients who have nothing. You mentioned FUS and then ALS. There's another horrible unmet need in ALS that's a genetically defined patient population, and we have a later stage trial in that.
We have our Alexander disease program, which Holly and I like a lot, which is, you know, an earlier stage program, but one that we intend to own. You know, under the hood, there's a lot of them haven't hit our pipeline yet, but our we really envision our neurology portfolio growing in the near future and becoming a real key pillar of our new commercial Ionis' own franchise.
There's a lot of things that the neuro drug discovery team is working on that are in the more rare type disease space that we think will fit well with an Ionis portfolio. We'll start to grow that pipeline, and it'll start to show up, and we'll have more things to talk about in the next two years as those things fill in the pipeline. Maybe Holly can comment on some other underappreciated gems that are also in the Biogen partnership thing that I think anyone paying attention to.
Hey, Holly, can I ask you about just where you guys are with muscle? That's a space that's gotten a lot of buzz.
Yeah. Do you want to get on with it?
Yeah. Just briefly before that. Well, we're enthusiastic with our Bicycle technology, and where we're using the bicyclic peptides from Bicycle. Just had a Novartis deal announced yesterday. Really nice technology. Targets transferrin receptor.
We have the ability to use that very broadly, and we have some nice data that we can target the muscle with those programs. We're, we're looking to bring some programs forward. Our first one will probably be an siRNA with a cardiac target. So it won't be a neuromuscular target, but it'll probably be a cardiac target. We look to get that into preclinical development very shortly.
Holly, what else did you want to highlight?
Yeah, just the Parkinson's programs that we have partnered. One of them is alpha-synuclein. This is really similar to tau in that it's a proteinaceous aggregates again, and in the preclinical models, there again, we see reversal of existing aggregates in disease. The ability to, if tau is now doing this in man, could alpha-synuclein have the same effects? I think that could be the next really exciting big program coming through.
There's lots of synucleinopathies even beyond Parkinson's disease. I mean, alpha-synuclein is the protein that's in all the aggregates in PD and is in the Lewy bodies. It stands to reason that if you can clear alpha-synuclein, you could make a difference in that space, too. I think that's completely flown under the radar, and I think that our drug will do the same thing that it did in the tau program, which is lower the protein and remove those aggregates.
Where is that program today?
Phase I/II.
Is that partnered or wholly owned?
It's Biogen program.
Part Biogen program, alpha-synuclein ASO in phase I/II .
Yeah. It's kind of where the tau program has been.
Yeah.
It's a little earlier, but it's in the phase I/II, first in human, where we're looking at target engagement and biomarkers.
Okay. Are there good ways to measure synuclein? Is there a PET tracer?
There is. It's not nearly as good as the tau tracer, but there is. There's also, of course, the CSF biomarkers as well.
Yeah. Okay. Okay, great. Thank you. This was super fun, as always, and interesting. A lot of good stuff to talk about.
Great.
All right. I think we're out of time.
Thank you.
Thanks so much.
Good chatting with you.
Look forward to talking again soon. Thanks, everyone, for joining.