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

Great. Thanks very much, everybody. It's my pleasure 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, I'm sure everyone knows Wade has had a long tenure at Ionis. And so 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.

Yes, thanks for having us. So it's an exciting time at Ionis for neurology right now. So this first half of the year, the big thing we're doing is getting the trial started for our Angelman program, so the pivotal study. We're getting that for that first half of the year. Then at the end of this year, we have our Alexander's disease program, pivotal study reading out. And then next year, we have our [ tau Phase II ] program reading out. So those are the big upcoming things. In the last year, we've also started 4 new Phase I/II studies in patients for the rest of our neurology franchise. So busy time.

So with Angelman. I guess the -- like 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 derisking for the Phase III trial that you're going to be running?

Yes. So first was just to highlight the prior data. So our HALO study was our first study. And as you mentioned, it was open label. Here, we looked at a number of different endpoints across the domains of the disease. And in all instances, we saw benefit. So it was better across the board, not just in some domains or others. So we saw improvements in cognition, communication, motor domains and with different tests as well. And so there was cross-test validity. We used the CGI, we used the Vineland and we used the Bayley and there's some of the similar domains across the test and there were similarities. So that gives you confidence in the data and the totality of the data is going directionally in the same way. We also -- our first-in-human study was a MAD, so we had multiple dose levels. We had a low dose, a mid-and high dose. The mid and the high performed similarly, but the low dose didn't perform as well. So that always helps. And then we also have -- in terms of moving now into a placebo-controlled trial, we have previous experience in Angelman with the [ AVID ] trial, where we can pull information from there and 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. So we do take that into account. We do recognize that it is something to be aware of and we are considering it.

Yes. Okay. Makes sense. What are the key similarities and differences between your molecule and the Ultragenyx molecule?

Yes. So both of our drugs are antisense oligonucleotides that are targeting the antisense transcript of UBE3A. So in Angelman, UBE3A is lost by targeting the antisense transcript, we're both up regulating UBE3A. That's really where the similarities end. We have different chemistries, and we have different oligonucleotides and that our oligo is using our proven platform. It's the same technology that we use for MAPT or 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. And then 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, patients across mutations. What's the thought process there? And is there any added risk in having a population that's somewhat more heterogeneous?

Yes. So the thought population -- the thought process is that we want to treat the whole population. We also want to help everybody with Angelman syndrome with our therapeutic, and we think mechanistically, it should be able to do that. So there's no reason not to. And then we're confident in our trial design because we have a lot of data to back it up. So we, of course, have the HALO study, which included adults and children. It also included mutation and deletion carriers, and we saw benefit across the board. We also have beautiful natural history data in the Angelman community. They've done a great job getting longitudinal data, both mutation and deletion carriers, adults and children, so we can look at that. and we've used all that information to look at the variability across the population to power our study appropriately with that. And so 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 in the pivotal study, our pivotal cohort, our primary analysis endpoint cohort is a 2- to 17-year-old. So that's a separate cohort from the adults.

Okay. Okay. Makes sense. Anything else you want to add on this program before we talk about tau.

Just another question we hear a lot is timing. So we're looking to start the first half of this year. We then have planning and completing enrollment next year, and then it's a 12-month primary endpoint for the readout.

Yes. Okay. Okay. Great. That would be very exciting. 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 [ affect ]?

Yes. It's a totally different mechanism of action. So here, we're lowering the production of the protein where the antibodies are promoting clearance. And the thing with tau is the tangles that happen in Alzheimer's disease are intracellular. They're not extracellular like a beta. So 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. And we're shopping that protein that's ultimately going to be aggregated and be detrimental from even being produced. And 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. And so we could get reversal of pathological tau. And that's really incredible for a couple of reasons. One, it taught us that if you stop production that you can get reversal. So the brain is able to naturally then clear out that tau. And then two, it also let us know that our oligo distributed throughout the brain because all the regions that we got that had tau pathology, we had clearance. And so that...

Was the magnitude of that clearance variable across areas? Or is it consistent?

It was fairly consistent across areas. And so we put out -- there's a publication that our colleagues at Biogen put out and it has all the details for all the different regions. And you can look at those bar graphs and they're pretty similar. So now there's differences in the baseline amount 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.

Yes. Okay. Okay. What gives you confidence that knocking down tau won't be toxic?

Yes. So that's a really good question. So tau knockout animals are actually fine. So they don't have any issues. And one of the really remarkable things is that you cross the tau knockout animals that don't have any tau from birth, these animals actually protect against A-Beta toxicity. They protect against cytotoxicity from epileptic agents that will cause seizures and even in epilepsy models. So they're -- in the instances that we've cross tau knockouts with disease models, there was a protective effect. It's one of the cool mechanisms that are underlying tau. 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. And then, of course, from all the data that we've generated for our oligo. There's, of course, the preclinical studies, including chronic studies where we lowered tau, and we didn't see any concerning effects in the Phase I/II study. Now don't want to be dismissive, but the totality of the evidence really doesn't flag anything that would be a concern for lowering tau. But of course, we're keeping in 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. And I guess maybe the other question around safety is just around idiosyncratic tox for the algo, 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 the margin here, right? The dose level you're giving compared to other.

Yes. So we've learned a lot about oligo since the Huntington program. And one of the things that we learned is that the oligo last a lot longer in the brain than we had originally thought. So 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 cohort, we went up to quarterly dosing. And so even with just 2 injections of tau oligonucleotide, we had nice reductions in CSF tau, and those lasted for 6 months after dosing. We then put everybody in the LTE. So that's the longest we had, and there was -- tau levels were still down and still flat at 6 months. So that gave us confidence going into the Phase II study that we're doing 2 different dose levels also quarterly in every 6 months. So the dosing interval is now 6 months instead of monthly. And with 6-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. And we're seeing that across the board with our programs. So we talked about Angelman earlier, and that's going to be quarterly dosed. And so we really are spreading out those intervals. So a lot less drug than some of our original programs.

Yes, yes, yes. Okay. Great. And then in the Phase Ib, there was some efforts by Biogen to try to contextualize some of the cognitive data. And 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 I don't want to read too much into it. So with that out there, it was 36 patients and 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, a large placebo cohort where they were able to match the individual patients based on demographics. So they had a matched placebo cohort that was an external placebo that be compared to our BIIB080 data. And the reason they had to do that is our Phase I/II study, as I mentioned, we did 3 months of dosing with 6 months of recovery, but then everybody went via the LTE. So all of our later time points, everybody had drug on board. So they did an analysis at week 100 and then they were able to show that based on that external comparator that there was a benefit in favor of BIIB080 on the cognitive end points, including the CDR sum of boxes, which is the endpoint that they'll be using in the Phase II study. So very promising directionally. The magnitude was lovely, bigger than some of the early A-Beta trials, but post-hoc analysis external control, only 36 patients.

Yes. Makes sense. How do you think about the right population to intervene or with the tau mechanism versus the amyloid mechanism?

Yes. So there's a lot of discussion about that. And I think that's what we're going to learn a lot from the ongoing Phase II study. So right now, the current trial is focusing in on million cognitive impairment and mild dementia, so going early on in the disease. And the question will be is this more amenable to later disease intervention than some of the amyloid therapies. And you would expect that mechanistically because tau seems to be downstream of A-Beta and tau correlates better with cognitive decline over time than A-Beta. So 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. But that said, for our current trial, we are focusing on those earlier patient populations because that is where we still expect to have the biggest effect.

Yes. Yes. Okay. 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, and we're 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. And so there's a lot of potential here if this mechanism plays out.

Yes. yes. Okay. Great. what program do you want to talk about next?

Alpha-synuclein?

Yes. Okay. 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, but maybe I'll let you kind of take it away to start.

Yes. So that's exactly why I thought it was a good segue from tau. So 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 antibody have tried to catch this protein as it transported between neurons and spreads throughout the brain, but there's a fair bit of data that shows it's probably not completely exposed as it's moving between these neurons. And so that's 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. So if you lower endogenous alpha-synuclein and you introduced virals into the brains of animals that cause alpha-synuclein misfolding, spreading and cell death, you can prevent that, and you can even reverse it once that pathology is already established. Just to be clear, you can't reverse the cell death, obviously, but you can reverse the pathology. So a 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. And so our first in-human program that we're doing right now is a Phase I/II. This will read out at the end of this year as well is an MSA and that's a really interesting population has synucleinopathy caused by aggregation of synuclein just like Parkinson's disease. But here, it's a younger population, and it's a much more rapidly progressing population.

Is this a genetic -- 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. So it's typically diagnosed clinically. But what they found is that if you look at CSF synuclein, you can actually show and diagnose patients based on the aggregation capabilities on their CSF synuclein. So they use an assay, it's an amp prion assay, where it's very similar to the assay RT-QuIC that's used in prion disease, where you use the CSF and you say, can you then seed that and can you seed degradation? If you can seed aggregation, then it tells you have aggregate in the CSF. And in this case, it's synuclein aggregates. So 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. So it's an exciting evolution that's just happened in the last couple of years, and then it can identify these younger, faster progressing patients that we're focusing on for our first in human study.

Yes. Okay. 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. And what can you point to there as [ that ]?

Yes. Yes, you're totally right. There is a gradient from cord. So cord to cortex is similar. It's about a 1:1 from cord to frontal cortex. But then as you go into the deeper brain structures, there's less. And so it does require more drug, and you do get a lot of suppression in the cortical regions to target the deeper brain structures. But for synuclein, we think that, that's fine. So synuclein we don't have concerns about lowering synuclein. We haven't seen anything preclinically to give us concerns about lowering that. So dosing so that you can target those deeper brain structures is absolutely possible. And the data that supports that is all the nonhuman primate data that we published over the years, including for synuclein and then also with [ MalA ] and other molecules as well.

Yes. Okay. 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?

Yes. So we're working through that now. We're working out all those details at this point. It's still early.

Yes. Okay. Okay. But I guess like -- yes, I mean maybe I don't want to ask you to front run it, right? But like some people have tried to do like even frontline studies where you're looking at like time to levodopa like that -- like is that -- like do you have...

Everything is being discussed, and I don't want to get ahead of my clinical colleagues.

Okay. Okay. Okay. All right.

We'll have much more solid plan by the time we get to the end of the year, and we have the data from the first study reading out.

Yes. Okay. 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.

Yes. And 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.

Yes. Let's talk about that. I mean, I think -- maybe just talk about like the mechanistic rationale. And you said it's ultra rare. Like how rare are we talking relative to things something like SOD1?

One in a million, so 300 to 700 patients in the U.S., so very rare.

Okay. Okay. Yes, go ahead.

Yes. So because of this, so this is -- 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. So there's hypomyelination. So you lose those sheets that cover the neurons that allows for conduction. So it's a leukodystrophy. It's a very devastating disease. It's ultimately fatal. It affects broadly, as you can imagine, the CMS, given that it's a demyelinating disease. And in the preclinical models, because we're going after the gene that the disease, you can have a really robust effects. We can even restore myelination by stopping the damage that's happening from these astrocytes expressing too much GFAP and then have functional benefits in the animal models [ with that ] intervention early or late. And so with that really robust preclinical data, we went into the clinical testing. Now this clinical study is a really unique design. And it's a unique design in that it's our first in-human study, and it's our pivotal study. So given that it's ultra rare, we want to be very efficient. So we're doing a single study, just over 50 patients that potentially could be registrational. So it's exciting from that point of view and that you could potentially help this patient population with a registrational study in a very efficient manner. But it's also a bit challenging because then we're now going into a pivotal readout, and we have no human data that we can point to at this point because it's all one single study in all blinded.

Yes. Yes. Yes. Okay. Interesting. Great. The one last thing I want to talk to you about Holly is delivery. And just -- there's been a lot of buzz with the transparent approaches and which we haven't seen it yet with an oligo, but I think it's coming. You guys have your Bicycle collaboration, but where are you there? And I guess for Ionis, right, I mean I feel like you guys are paving the way in testing so many of the targets with the IT dosing. I think it would be tough to see you guys like prove some of this stuff out and then have someone come out with something that's like a conjugate that's IV. So what are you doing there to kind of make sure you're still at the forefront of these technologies as everything evolves?

Yes, absolutely. So first, I'll just hit on Bicycle real quick and what we're doing with that, and then I'll get into the BBB delivery, if that works. So Bicycle, overall, just so everybody is aware. So we have exclusive access to Bicycle's proprietary macrocyclic peptide, the Bicycles, for transparent and oligonucleotide. So we're using those in 3 different ways for targeting cardiac muscle, skeletal muscle and then also for BBB delivery. So our most advanced program is targeting cardiac muscle, that's in clinical development right now. And so we're derisking the Bicycle from that perspective. And these are really lovely molecules because they allow for -- because they're so small. So for example, if you 100 mgs of oligo to a Bicycle, it's only 130 megs of total drugs. 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 subcu, which is really exciting in terms of convenience and delivery. And so because of that, we're advancing it for cardiac muscle. We're also exploring it for skeletal muscle, but then it's also very exciting for BBB. So BBB delivery, we're focusing on transferrin right now. We have 2 different approaches. One is Bicycle, but we also have a relationship with Vect-Horus, which is their nanobody technology. And we're looking at that as well for BBB delivery. The Vect-Horus is a little bit more advanced. But Bicycle is also really exciting because of that subcu element that I mentioned. And so we're evaluating that as well. And 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 follow molecules and things like using this BBB technology to be able to not just do IV, but even to do subcu for some of these patients.

Yes. Yes. Okay. Great. 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.

Yes. So the higher dosing is looking great. Biogen has released that data and that information that has all been filed. And so now we're waiting for outcomes from that, and that will be coming through at the end of this year.

Okay. what -- like what are the key points that would give us -- make us optimistic that like a higher dose should be additive on [ efficacy ]?

Yes. So what they're seeing in the higher dose for me, I think the most compelling data is that you're seeing an improvement on neurofilament and 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. And then this improved it even further and so that further improvement, which I think really compelling for me as a scientist.

Yes, Absolutely. I look at the SPINRAZA NFL data from years ago looked really compelling, and it was one of the examples we would point to people and there was the question of is this just an MS biomarker? Is it more probably extrapolatable? All right. Great. Well, 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.

Okay. Okay. 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 in 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. And so I think as we continue to focus, you'll see more and more advancement in these areas that we think we're excited. We've pioneered the field of already targeted CNS diseases, and I think we're going to continue to do that.

All right. Great. Congrats on all the progress. Thanks for taking the time.

Yes. Thanks.

All right. See you soon.