Ionis Pharmaceuticals, Inc. (IONS) Earnings Call Transcript & Summary

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 tofersen AdCom, and maybe I can kick it off. We've got Eric and Holly here, who are very in depth on all this stuff and you both have 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 1 to 2 things that are getting you most excited within your CNS pipeline today? Yes, maybe we can start with that.

Yes, sure. Well, thanks for having us on, Paul. We really appreciate it. We love to talk about neurology as you well know. So I guess the things that would be especially topical would be 3 things: tofersen, Obviously, we just had an AdCom, where we got unanimous support for the drugs in an accelerated approval type pathway and really nice discussion on the risk benefit profile of the drug, and we can talk about that later. And 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. And we just had top line data from the 66-week trial of that drug in polyneuropathy, which partially mirrored at the 35-week, and we're filing worldwide based on 66-week data in addition to the late this year PDUFA date that we have in the U.S. on that drug. So that's at the top of our minds. And then MAPT, I think, is a great drug that we can talk about on this call. Had really exciting data that's released today that's being presented at AD/PD and Holly can fill you in all the details there. And we really think that's typical 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, we can get to that. But those are kind of 3 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 read-through to your pipelines more broadly and maybe even specifically the utility of neurofilament for other diseases that you're pursuing, how do you think about that?

Yes. I mean, certainly, you can see where the agency was going and what they were thinking. We've been -- 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. And obviously, disease-associated biomarkers are fantastic for the development of drugs. They help the drug developer and they help you see if your drug is doing what it's intended. So we're very happy with the views on using biomarkers to assist in neurogenerative drug development. 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. So having a good biomarker really aids you in figuring out whether your drug is working. And since we first started to think about neurofilament, I think a lot of the science has filled in where neurofilament light and especially lower neuron diseases really seems to be a pretty good biomarker site. So I think it would be very, very helpful for us. And to the extent that the agency is willing to consider that for regulatory approval of accelerated pathways, I think that help get drugs to patients faster, who have really severe needs and no therapies, especially no disease-modifying therapies. And I think tofersen fits that bill.

Yes. Yes, okay. You have a couple of other efforts in ALS. Is this something where now neurofilament becomes a key thing to watch for your FUS program or anything else there?

Well, we're certainly watching it and I think others are, too, so it makes sense. I think that while the data, because of the length of the VALOR trial, it isn't stat sig in any way that 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]. And so then you start to think, well, we lowered our target, we lowered neurofilament. It does look like it's getting a benefit to these patients. And so you can start to build the case that if you lower neurofilament, you're probably doing a good thing. And I guess the opposite can then thought to be true. And 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. And we didn't see any effect on neurofilament and as a result, made a decision not to continue that drug. So there's -- it'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. So 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 extrapolatable do you think that is to other neurological diseases? I guess, look, the other side of this, right, could be we saw these neurofilament elevations in the Phase II in Huntington's and the Phase III is a disappointment, right? I mean, do you feel like now you can look at NFL across pretty much any neurodegenerative disease and to have a more cost-efficient way to get to either proof of concept or a no-go decision?

Well, I'm going to kick this to Holly a little bit, but I think that probably the jury is still out on that and we'd have to see. Certainly, I know you're going to ask about Huntington, too. Huntington is different than ALS in many, many ways in terms of disease complexity and the reasons that are affected and the elevations that you see in neurofilament for example. So I think it certainly makes sense that if neurons are dying, you can see some biomarker of that neuronal death. But 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." 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. And 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. So it's looking like in ALS -- a marker for constant damage. And that's what we still don't understand in all the other diseases. And that data for ALS has just come out in the last 3 years, so 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. So 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 be able to sort that out.

Yes, 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 A-beta 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, but then in the context of disease-modifying therapies, it's -- as you mentioned, there's examples that go in both directions. And so until we have more disease-modifying therapies, it's something you definitely look at and keep an eye on and continue to build our natural history data, but we still need to -- I don't think any one of these is going to be a perfect translatable across all the different diseases in areas we really need to understand the natural history of the disease and then understand in the context of disease modification.

Okay, okay. Makes sense. So you brought up eplontersen, which wasn't going to 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. So 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 going to be confident that the efficacy matches the sRNA product that's out there? What can you say about that in terms of your confidence and the competitiveness of it?

Yes. Well, we're confident in the product as evidenced by our filing and our intention to file worldwide in our statement on that. Our partner, AZ, is confident as evidenced by their actions. And I hear you guys. We've been...

Yes, you've been very shy here.

Well, it's a competitive space as everyone keeps reminding us. And so we don't want to turn over too many of our cards. And we had 2 good things. One is it was an ongoing trial. And I'm sure you're going to ask 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. And it's a competitive space, and if you turn over too many cards, your competitors will use that information and learn from your trials. And in some regards in the space, we're a little behind what we think is our key competitor. We're going to use that information to -- everything is released, we're going to guide our thinking about our drug. So 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. And so we look forward to sharing all the data at the right time, and there's an AAN discussion coming up at the end of April, where we've said we're going to have some data. And we also publish, right? We publish our data so we'd longing out there. And we're happy with the drug profile and so is AZ. So look forward to getting that drug available and have a PDUFA late this year and hopefully it will be made available to patients who need a new 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? And I think with any IT 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? So maybe you can talk about the data you've generated and kind of your confidence in the overall drug effect as you move forward.

Yes. I'll start with the target engagement and we've had this debate and discussion before. To us, when you see the target moving in the CSF, you have to assume that the target is coming, 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 on the preclinical data we have, then you wouldn't see the CSF protein moving. You have to treat the bulk of the brain to move the biomarker and the CSF. And so 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. And 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 with people pushing us on it. And we think that some of the data presented at AD/PD will finally -- hopefully, it will help turn some of those skeptics around because there's a nice picture, and I'll definitely comment on the data.

Yes. So this is an exciting new bit of data, is the tau pat. And so the tau pat obviously, is looking at tau in the brain area. And in all the regions that had tau pathology, there's actually a reversal of pathology. So the tau pathology is going away and these patients that are getting although in the brain. And so 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. And 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 pat if you kind of compare to what we're seeing on amyloid pat?

This is reversal. Amyloid pat only slows it. We actually take tau pathology that's there at the baseline and it goes away.

Don't you see -- you see it in amyloid pat, too, right? You can get patients to pat...

So A-beta, yes. So A-beta can -- the tau with the A-beta antibodies. So the tau with A-beta antibody...

Yes, right. It's about 25%. Yes, yes, yes. Okay, okay. That's pretty cool. Can I ask you a totally crazy question? Why not just file for accelerated approval? How better track disease progression than amyloid? Amyloid has a certain endpoint.

Yes. So we need more patients.

You need more safety data, but like could that actually be a conversation at some point with this drug?

Yes. Well, as you know, this is a Biogen partner program, so I'll direct you to ask Biogen that question. 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 want to get some clinical data to support the tau hypothesis. So just -- 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. And 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. And so 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. And so 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. And so 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.

Yes. Okay, okay. Makes sense. On the safety side for that program, what's made you comfortable with knocking down all forms of tau, given it's important as a structural -- 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. It's not embryonically lethal.

No...

You're confusing with Huntington's...

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, and you can actually cross the tau knockouts with the A-beta models and the AD models and it's protective. It's even protective if you take a tau knockout and you hit it with agents to cause excitotoxicity, you see production as well. And so the tau knockout actually provides benefit in disease contacts. And that's full knockout. That had provided benefits to but full knockout even more.

Okay. I like that you guys just shook your heads for a second.

Well, it's -- we're dealing with this a long time, too, because the name is a microtubule-associated protein and every minute we think you knock it down, it makes all your microtubules fall apart. But that's not what happens. And there's lots of microtubule-associated proteins and lots of complex structure there. And I think this is a function of the name of the protein, if it was named some random [Indiscernible] people wouldn't be so freaked out about it.

Yes, okay. All right. I'm going to ask you an Angelman's question, but it's not going to be like some interim data question. It's really just from this study, whenever it reads out, right? Maybe it's next year because 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?

Well, it's a first in human so you're always going to get us to say, first, it's the 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 is doing what we wanted to do clinically. So it's not powered for that. And it's technically a safety study, but of course, we'll look for other things. And when you're in -- just to clarify, we're not planning on having any data this year. So we've been guiding that.

Yes, I know. I think Wayne told me that when I saw him for coffee a few weeks ago. So okay. So this study, can you just talk about the design and like the dose levels, duration treatment, things like that?

Yes. So we haven't shared all those details, but I can tell you what we have shared. So we -- it's a 1,2 open-label study. It's 2 parts. We have a [13-week MAGE, arm] and then we go into a 49-week long-term extension period and then variable follow-up where in, like Eric mentioned, the main endpoints are all around safety. We are looking at other things as well that are interesting in Angelman's in their own development, but we haven't discussed exactly what those endpoints are. And we don't plan to just, given how competitive the space is.

Yes. Okay, okay. So maybe next year? All right. My words, not yours.

Not this year.

Okay. What else would you -- 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. I'm glad we did.

Yes. Hopefully, the new data will start to get that program somehow. We think it's a great drug program and a great space. And 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. There's -- you've got Angelman, 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. So we are happy that Roche is looking at a Phase II in HD with tominersen. It's a new trial with a different -- an earlier-stage patient population, but Roche is doing a great job trying to bring something to Huntington patients who have nothing. You mentioned FUS in 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 I like a lot, which is an earlier stage program, but one that we intend to own. And under the hood, there's -- a lot of them haven't hit our pipeline yet, but we really envision our neurology portfolio growing in the near future and becoming a real key pillar of our new commercial Ionis owned 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 the Ionis portfolio. And we'll start to grow that pipeline. It will start to show up and we'll have more things to talk about in the next couple of years as those things still in the pipeline. Maybe Holly can comment on some other underappreciated gems that are also in the Biogen partnership thing -- pay the attention to...

Holly, can I ask you about just where you guys are with muscle? That's a space that's gotten a lot of buzz.

Yes. Do you want to...

Yes. Just briefly before that, so -- well, we're enthusiastic with our Bicycle technology. And where we're using the [bicyclic peptides] from Bicycle and Novartis deal that was announced yesterday. Really nice technology. Targets transparent 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. And so 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 at a neuromuscular target, but it will probably be a cardiac target, and we look to get that into preclinical development very shortly.

And Holly, what else did you want to highlight?

Yes, just the Parkinson's programs that we have partnered. So one of them is alpha-synuclein. This is really similar to tau and that is a proteinaceous aggregates again. And in the preclinical model there, again, we see a reversal of existing aggregates in disease. And so the ability to -- if tau is now doing this in [Indiscernible], could alpha-synuclein have the same effect. And so I think that could be the next really exciting big program coming through.

And there are lots of significant pathies beyond Parkinson's disease. And alpha-synuclein is the protein that in all the aggregates in PD and is in the Lewy bodies. And so it stands to reason that if you can clear alpha-synuclein you can 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 a Biogen program.

Biogen program, alpha-synuclein ASO and Phase I/II.

So it's kind of where the tau program has been. So it's a little earlier, but it's in the Phase I/II first-in-human where we're looking at target engagement biomarkers.

Okay. And are there good ways to measure synucleins? Is there PET tracer?

There is. And then it's not nearly as good as the tau tracer, but there is. And then there's also, of course, the CSF biomarkers as well.

Yes. Okay, okay. Great. Well, thank you. This was super fun as always, and interesting. A lot of good stuff to talk about.

All right.

I think we're out of time. Thanks so much. Look forward to talking again soon. Thanks, everyone, for joining.