Ionis Pharmaceuticals Inc (IONS) May 19, 2026 Conference Transcript

Excellent, everybody. Luca Isi, Senior Biotech Analyst here at RBC Capital Market, and today is our great privilege to have Ionis Pharmaceutical as part of our 2026 Global Health Air Conference. Representative of the company, we have Holly Kordasiewicz, who is the Chief Development Officer. Holly, thanks so much for joining us. How are you doing today?

Great, how are you?

Good, good, good, yeah. We have a list of questions, but maybe before we go into the specifics, it would be fantastic if you could maybe talk a little bit big picture about what progress has the organization made over the last few months, and kind of most importantly, what's ahead here for Ionis.

Yeah, absolutely. So it's been an exciting time. We had our first two independent launches last year with Tringosa and FCS and Don's Era and HAE. We're, of course, planning for two PDUFAs this year for, again, our wholly-owned pipeline. We have Tringosa for SHTG coming up in June, hopefully approval and then launch. And then at the end of the year, we have Zilgenersen for the treatment of Alexander disease, which is our first wholly-owned neurology program that will be launching. Following behind that, we then have five phase three readouts this year. The first is Bepi Beerson. Of course, this was positive. The data is going to be presented later this month at EASL. We then have two cardiovascular outcome trials reporting out later this year. One is CardioTransform for ATTR-CM, and then, of course, Pella Carson, the Horizon Study, looking at LP little a lowering. And then behind that, we have a robust mid-stage pipeline that's advancing, and of course, our partners at Biogen just last week announced the TAO program and that they're going to be advancing. That and to phase three clinical testing. So busy times, but lots of opportunities for continued growth in 2026 and beyond at Ionis.

Got it. Got it. Super helpful. I'm going to start asking you a bunch of questions now that I know you're not going to answer. Anyways, obviously, Tau, the data, you know, fresh off the press, you know, Biogen presented the top line data last week. It sounds like the data is good enough for them to actually pursue a Phase III trial. Just tell us a little bit more about your reaction to that top-line data, and is there any context you can provide in terms of, like, what benefit they have shown in terms of CDR sum-the-boxes or ADAS-COG, and how does that benefit kind of compares to the A-beta antibodies? Like, I think that's some of the questions we're getting from investors, so any context would be much appreciated.

First to start, I'm really excited about this program and this data for the AD patients and community. This is a new mechanism of action. So here we're using an oligonucleotide to lower tau. So we're lowering intracellular tau because we're stopping production of tau. So a new way to go after the disease. In our phase one study, we had robust reductions in CSF tau, which is our pharmacodynamic biomarker, as well as reversal of tau PET. So it was the first time in an AD brain where we actually showed clearance of pathological tau. So that biomarker data in the Celia Phase II study, which Biogen just reported on last week, it replicated. So we have those nice reductions in CSF tau and tau PET. And then it also showed, and this is what it was designed to do, a benefit on cognitive endpoints. And they were unprecedented. It is the first time anyone has shown this with tau. They are in line with what has been shown with amyloid therapies and in some cases exceed it. So very encouraged by the data. It met Biogen's pre-specified endpoints for going into a phase three. So excited that they're advancing that. They have the data that gives them confidence to do that, as well as the data needed to select dose and design that next study.

Got it. Got it. Super helpful. Any context on how placebo has, you know, formed in that trial? You know, obviously we're seeing, especially in small data sets, sometimes, you know, placebo underperform or overperform can, you know, magnify the benefit or underrepresent the benefits. Is there any context for what placebo have shown in that trial?

So fortunately, in the space, we have lots of data on how this should perform in this patient population, and there's nothing in either the biomarker data or the cognition data that says it's not performing as expected.

Got it. Got it. That's super encouraging. What about, you know, the lack of those response, if you will? I mean, obviously, Bajan have mentioned that the cohort that, you know, showed the best cognitive benefit was actually the lowest dose, which is obviously a little counterintuitive. I guess, you know, what's the best way to rationalize that? If I recall it correctly, the lowest dose is also the one that has the smallest N. So could that have been confounding and amplified the benefit, or how should you think about that part?

I think so. So all doses showed a benefit. That's the important point, is all doses showed a benefit, and there's overlapping of all of that data. And so this isn't unexpected, given the doses that were used and the target engagement that we observed. And that will all become clear once the totality of the data is presented at AAIC in July.

Yeah, right. I guess we stay tuned for that data that is obviously upcoming. I mean, maybe just pivoting to severe hot triglyceridemia, obviously the PDUFA date is only six weeks away. How do you feel about it? Are you guys already in labor discussions with the FDA?

Everything is progressing as planned. We feel excellent about it. Of course, this is a phase-through study where we had beautiful data, efficacy data. Here we had an 85% reduction in AP events in people with high triglycerides. And so that we also received breakthrough therapy designation based on that data. And that gives us a lot of confidence going into the discussions with regulators. Everything is on track for that PDUFA date on June 30th.

Got it. Got it. That's actually helpful. I think when you look at that data set, there's maybe a little bit of a worsening in liver fat, and again, it's, you know, the magnitude of the increase in liver fat is relatively modest, but how do you think about, you know, how that data will be potentially reflected on the label? Do you think that that's going to only be in the, you know, adverse sessions of the label? Could there be something more? Could this be like a REMS or a black box warning? How do you think about that?

No, so it's well tolerated in core one and core two studies and in the essence study. So we do not expect any monitoring or anything like that. This is, to be clear, this isn't a safety signal. This is a biomarker signal that does not correlate with any sequelae or any other safety signals or biomarkers. This is information that has been shared broadly with HCPs. They have no concerns about this, given, of course, the benefit profile that we see. And so taken together, this is not of a concern. This is on mechanism. This isn't unexpected, given that we are drastically lowering triglycerides over 70% in the phase 3 studies. That rapid clearance of triglycerides, it's going to end up in the liver. Another important thing is that we're following these individuals over time from the Core 1 and Core 2 studies. They were all able to roll into an open-label extension where we're continuing to monitor this for over two years. And over time, we're seeing stabilization and then trending back towards baseline.

Got it. Got it. That's actually helpful. For severe hyperglyceridemia, how are you thinking about the TAM? Because I think there are a lot of patients out there that have severe hyperglyceridemia. However, when you look at the patients that have severe hyperglyceridemia and a history of acute pancreatitis, the TAM is so much smaller. Maybe like, you know, single digits type of percentage when you reflect on the three millions versus the one that have a history of acute pancreatitis. So is this going to be it? Or primary prevention type of drug, like patients that don't have a hysterical pancreatitis will receive the therapy? Or do you think there's a scenario where the payers will restrict the access to this drug to primarily the patients that have a hysterical pancreatitis? How do we think about primary versus secondary prevention?

Yeah, so we've set this program up specifically not to restrict access. So there's 3 million patients that have the high triglycerides, over 500. Within that 1 million patients, we consider at high risk, and those are the original patients that we'll be focusing on. These are everybody over 880, which then puts them at severe risk, and then over 500 with history of acute pancreatitis, and that's still a million patients. So that's where we'll be starting, but we will get to all those patients then at 500 and above that do have risk of acute pancreatitis.

Got it, got it, got it, that's helpful. Maybe pricing. It feels like your thinking around pricing has evolved over time. And, you know, you now obviously have settled to $40,000 as your WAC. However, your competitor last week came forward with $45,000 WAC. And again, I think they have an argument that maybe their drug is those less frequently, and they could have some pharmacological properties that are different versus your molecule. What's your take on what was your reaction to Arrowhead actually pricing their drug at $45,000 versus $40,000?

So our approach is entirely data-driven. So we first did HCP research. We're using our core one and core two data. So with our phase three data, we took that out to understand demand. Once we understood demand with existing phase three data in hand, we then were able to talk to payers and work out the pricing implications based on that as well to find a price that would get us the broadest access to the most individuals. So not limiting the access, but still having a favorable price. And then that's where we learned it on the $40,000 WAC. And so for our, for the other company, they don't have phase three data yet. They don't have information in SHTG. And so we did a data driven approach.

Got it. That's helpful. Obviously, the company has guided peak revenues, and I think that has been a little bit of a moving part. I think you guys started with a bill, then I think JP Morgan was two bill, I should say one bill plus, then became two bill plus, and now most recently is three bill plus. Walk us through, like, some of the assumptions in your model that got you there. Is it just simply functional price, or there are other variables, including, you know, either access or discontinuations, or walk us through the evolution from one bill to three bill. That's a big delta.

So the first one, it was demand based on the data. So the phase three data was excellent. We had an 85% reduction in acute pancreatitis events. This leads to a number needed to treat in one year in the high risk group, the over 80 of four. So only four patients need to be treated in one year to prevent an acute pancreatitis attack and only 20 patients in that larger population. So with that really remarkable efficacy data, we then took that out and did the demand research. And it was the initial demand research that led us from that $1 billion to the $2 billion. And just the sheer number of patients the doctors are planning on prescribing this for. Then once we got to the $2 billion, then we did the pricing work. And we had initially assumed a lower price. And then once we had done that work in hand to make sure that we weren't restricting access to the broader patient population, that we would still be able to get the drug to everybody that we need to get it to. And that's where we increased it from two to greater than three billion.

Super clear.

Just to say it, this is a population that didn't exist before we had this drug in the way that we're now thinking about it. So this growth isn't unexpected, given that we're just learning as we're doing this and generating the data.

Yeah, and certainly conversations with payers and whatnot obviously influence some of these assumptions, which makes total sense to me. Maybe, again, going back to your competitor, I think investors are on the edge of their seats waiting for the Shasta 3 and Shasta 4 data. Again, their trial is designed slightly different than your trial, a little smaller trial. There's also some differences around randomization and whatnot. What's your take? Do you think that Arrowhead has a chance of hitting the key secondary point of reduction in acute pancreatitis in a statistical significant fashion?

I think they have a good chance. Data's going to be really hard to beat. It's a high number, but I think they have a good chance at it, and that's actually favorable in that having two people out or two companies out on the market is only going to help, as we just discussed, that this is a new market, it's a growing market, and so having more voices out there to help raise awareness is going to help those patients.

And we certainly have seen that movie over and over again with more players. There's also, you know, often market expansion there. So sometimes it's not about, you know, a market share, but it's more like market expansion. So maybe if I can pivot to Angelman, which, you know, it's your, you know, bread and butter, if you will, just talk about big picture of what data have you seen so far? Maybe just remind us about differentiations versus ultragenics and maybe just walk us through what's next here. Maybe if I can, quickly, if it comes up in conversations with investors a decent amount, maybe just refresh our memory for why Biogen ultimately decided to pass on that program.

So first of all, this is a neurodevelopmental disease. So this is not a degenerative disease like some of our other CNS programs where we see decline. These are individuals who they develop cognitively to about the age of a 2 to a 4-year-old, and then they stay that way for the rest of their lives, and they have a normal lifespan. So what we've seen in our phase one study, which is our open label HALO study, it was an improvement across domains and across measures. So these individuals have motor communication, cognition, dysfunction, and across the board, we saw benefits across all those various domains, as you would expect if you were restarting neurodevelopment, which is the mechanism that we think will be happening by targeting the underlying cause of the disease. We also saw this across measures that were physician-administered, physician-reported, and parent-reported. So it's nice in an open-label setting to see consistency in the data across different ways of collecting it. So we have a benefit across these different domains, a restarting of development that appears to be happening in individuals that really just have stable development once they hit that peak at about two- to four-year-old neurotypical development. And so with that, that gave us confidence to go into the phase three study. The phase three study is enrolling right now. We plan to complete enrollment for that this year. It's a one-year primary endpoint in the reveal study, and so then that'll read out next year. And then in terms of Biogen and why they passed, there was risk in the endpoint. They wanted to de-risk that. They wanted more information. We did not want to. Give any more time. This is a program that we very much wanted back. We wanted to build our neurology portfolio. We had pivoted as a company from just an R&D company to an R&D who was going to then take things through commercialization. We saw this as a really attractive fit, as you can imagine, with Alexander disease, which is launching later this year, assuming approval. And so, in total, this is something we want back. We didn't want to negotiate. They wanted to negotiate, and so it's ours.

Got it. Got it. That's super helpful. What's your take on the ultragenics approach? I think it's fascinating to me that they're splitting the alpha, actually, between two separate endpoints, right? So obviously, they have Baylis-4 cognition, and they're spending most of the alpha on the Baylis-4 cognition, but they're also spending some of the alpha to MDRI, which is more of a composite endpoint. You obviously have a different approach here because you have a separate primary endpoint using expressive communication as your primary endpoint. Are you potentially considering doing something similar where you split the health line, you maybe have kind of two shots on goal, or what's your take there?

So we'll see the data. So right now, we are focusing on our primary endpoint, which is expressive communication. This is the number one thing that is most important for caregivers. There was a listening session last year where the parents overwhelmingly said, I want my child to be able to tell me when something is wrong, to tell me what they want. These individuals, most of them are nonverbal. So as you can imagine, it's very difficult for the families. So that's the main thing that they care about. It was also the thing that we saw the greatest effect on earliest, and it had the most stable natural history, so the most stable baseline. So it gives you the biggest delta for an effect in a phase three study. And so with that, we have confidence that we have a meaningful endpoint. It's also clinical meaningfulness. The expressive communication is if someone is communicating, they're going to score higher on it. So it has inherent meaningfulness in that. It's very different than some of the other endpoints, which are building blocks. How do you judge the clinical meaningfulness of building blocks? where clinical meaningfulness of communication is implicit. And so that taken together, we're happy with where we're at. But of course, we'll see the data. We'll see the data. This is one of the benefits of coming second, is that we can see that readout and then adjust based on data as necessary.

Can you expand and adjust the necessary? Like, I mean, I guess what you're primarily focused on is to see the data from ultrogenics. Sounds like their data is coming late this summer. So, like, what are you primarily focused on? And do you have optionality in your protocol to amend the protocol and maybe make the protocol, make your trial either longer or bigger? Like, walk us through some of the moving parts there and how you're thinking of potentially adjusting your trial based on their data.

So the placebo effect. So nobody knows the placebo effect in Angelman syndrome at this later time point. There has been shorter studies, but there haven't been one year long studies with these clinical endpoints in Angelman. So that's the number one thing to look at, because all the data generated to date is open label. And so seeing that will be very meaningful. And then, of course, how the different responses are. Now, if they don't have a robust response, that's not surprising, given that they're using a very low dose, but we will pay attention to that as well. And then in terms of adjusting, things like RSAP can be easily adjusted.

Gotcha. And especially because they're going to probably read out at a time where your trial is not fully enrolled yet. Would that be fair assumptions at this point or not necessarily?

No, not necessarily. We're not giving out any of those kind of details.

But you're saying that your trial will be fully enrolled second half of this year? We haven't given those details this year. This year, okay. Okay, that's helpful. Maybe one last question on Angelman. Maybe just remind us the commercial opportunity here. Should a trial ultimately work? How many patients are out there? Maybe, I know it's preliminary at this point, but just any commentary at high level or how you think about pricing? Yeah.

So this is a, there's 100,000 individuals, we think, in the U.S. in major markets, and this is a rare neurological disease. So we expect it to be similar to previous, to other rare programs that we have, assuming positive phase three data and efficacy.

Spinraza type of pricing, or too early to comment in this point?

Too early to comment within that rare neural range.

Okay, okay, that's helpful. You mentioned cardio transform. I think a lot of people are obviously eager to see that data. I think you presented recently the baseline characteristics. I think you highlighted that, you know, this is much more of a contemporaneous population. So, like, you know, there's a lot more patients on the families at baseline, there's more patients on STGLT2 at baseline and whatnot. So, just, you know, maybe just remind us how you design your trial and at the end of the day, how confident are you? I believe you now have three times the number of patients that alnylum had on Helios B on tefamacid baseline. I think it's 819, but we only had 259 patients tefamacid baseline. Is 819 patients tefamacid baseline a large enough sample size that you think you can actually hit the stats as add-on to tefamacid?

Yeah, so that is not the expectation. So it is not powered for statistical significance on the secondaries. We did release the study design recently, and as you can see, it's six in the hierarchy. So it is in the secondary hierarchy, but it is six. So everything else would have to hit to get there. And so we are encouraged, though, by the size of the study. We intentionally designed this as a very large study. As you mentioned, we have more folks on tefaminis than there were in the total previous studies. And this will give us information about how it's behaving. So the expectation for the study is on par with what the previous silencer data has looked like, and then anything with tefamidus is going to be on top of that and upside.

Gotcha, gotcha. Okay, that's helpful. You mentioned earlier L-Pilloway. It's probably one of the biggest callists in medicine in 2026. Maybe alcohol is going to be the next cholesterol. Who knows? However, I think you powered a trial to show a 20% to 25% benefit, depending on what subpopulations you're looking at. However, it feels to me that some of the recent commentary from Novartis kind of implies that maybe the benefit could be a little more modest. So maybe instead of 20% to 25% relative risk reduction, this could be more like under 10% or 15% relative risk reduction. Should that be the case, do you think that that would still be a commercially viable product?

Yeah. So nobody knows what the relative risk reduction is going to be. That's the trial that we're doing right now. This is another first for IONIS where we're asking for the first time, if you lower the largest untreated risk factor in cardiovascular disease, what kind of benefit can you have? And so we'll find that when the trial reads out. The question on is 10 to 15 enough? Yes. And that's really from research and talking to KOLs and getting feedback from the community on what they would need to see to treat. And the answer is that 10 to 15 percent. So that's where that shift is coming from. And it's really based on the fact that with the human genetics, this is very clear that this is an independent risk factor. So you can control everything else, you can get the LDL down extremely low, and you still have this risk that's coming from the LP little a. So because there's nothing to treat it, because this is a on mechanism, directly on target treatment, that they would then do that.

Got it. That's actually helpful. That's actually helpful. Maybe just pivoting to the other PDUFA data that you have upcoming, Alexander disease, appreciate small indication, but maybe just talk about what would an approval for the community, which would be obviously huge given, you know, my medical need. And then, I mean, how confident are you in approval? Again, technically, I believe the p-value was 0.0412, so relatively close to the 0.05 kind of magic number. So, like, how do we feel about probability of approval at this point?

We hit STAT-SIG on a primary endpoint that's clinically meaningful for patients in an ultra-rare patient population. So, very excited about that. We got breakthrough therapy designation because of that. So, confident going into this that there's a path forward and a very clear one and straightforward one, given that we have that beautiful data. And what this means for the community is an excellent question. And most important, the outpouring from the community has been just overwhelming when we announced this data. They have nothing. This is a progressive neurodegenerative disease that affects children, that affects adults. It is almost always ultimately fatal. It affects most systems. And so there's motor, there's cognition, there's across-the-board effects that these families are dealing with and these individuals. You hear the parents talk about it, and the kids gain a new developmental skill, and then they lose it because the disease progresses. And so they work so hard to get something, and then they lose it. And what we've shown in the data is a stabilization, and then if you have that stabilization in the motor endpoint, which is the primary endpoint, that once they make those gains, they can keep them. And then we also have in the secondaries, they all favored zildanursin, so that targeting of the underlying disease is providing that broad benefit for the individuals. So with that, I'm totally very excited about this program and to get this to patients. We have an EAP open. Enrolling very well, lots of enthusiasm for it, and so continue to try to get this to as many folks as possible.

Got it. Got it. I have a lot more questions, but one more time. Thanks to all. I appreciate the time. Thanks, everyone, for joining, and we'll talk soon. Thanks again.

Yeah, of course.