Thanks a lot, everybody. Luca Issi, Senior Biotechnology Analyst here at RBC Capital Markets. Today it's our great privilege to have Ionis Pharmaceuticals as part of our 2026 Global Healthcare Conference 2026. Representing 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. Yeah. We have a list of questions. 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. It's been an exciting time. We had our first two independent launches last year with TRYNGOLZA in FCS in DAWNZERA and HAE. We're of course planning for two PDUFAs this year for, again, our wholly-owned pipeline. We have TRYNGOLZA for SHTG coming up in June, hopefully approval and then launch, and then at the end of the year we have zilganersen for the treatment of Alexander disease, which is our first wholly-owned neurology program that'll be launching. Following behind that, we then have five phase III readouts this year. The first is bepirovirsen, of course, this was positive. The data is gonna be presented later this month at EASL. We then have two cardiovascular outcome trials reporting out later this year. One is CARDIO-TTRansform for ATTR-CM, and then of course pelacarsen, the HORIZON study, looking at Lp(a) lowering.
Behind that we have a robust midstage pipeline that's advancing and of course our partners at Biogen just last week announced the tau program and that they're gonna be advancing that into phase III clinical testing. Busy times, but lots of opportunities for continued growth in 2026 and beyond at Ionis.
Got it. Got it. Super helpful. I'm gonna start asking you a bunch of questions now that I know you're not gonna answer. Anyways, obviously tau data, you know, fresh off the press, you know, Biogen presented it, the top line data last week. Sounds like the data is good enough for them to actually pursue a phase III trial. Just tell us a little bit more about what was your reaction to that top line data, and is there any context you can provide in term of like what benefit they have shown in term of CDR Sum of Boxes or ADAS-Cog, and how does that benefit kind of compares to the Aβ antibodies? Like I think that's some of the questions we're getting from investors. 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 'cause we're stopping production of tau. A new way to go after the disease. In our phase I study, we had robust reductions in CSF tau, which is our pharmacodynamic biomarker, as well as reversal of tau PET. It was the first time in an AD brain where we actually showed clearance of pathological tau. That biomarker data in the CELIA phase II study, which Biogen just reported on last week, it replicated. 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. Very encouraged by the data. It met Biogen's pre-specified endpoints for going into a phase III. 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. Super helpful. Any context on how placebo has, you know-
Yes.
... performed in that trial? You know, obviously we've seen, 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?
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 dose response, if you will? I mean, obviously Biogen 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. Could that have been confounding and amplified the benefit, or how should we think about that part?
I think 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. This isn't unexpected given the doses that were used and the target engagement that we observed, and that'll 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. Maybe just pivoting to severe hypertriglyceridemia. Obviously, the PDUFA date is only six weeks away. How do you feel about it? Are you guys already in labeling discussions with the FDA?
Everything. Yep, everything is progressing as planned. We feel excellent about it. Of course, this is a phase III study where we had beautiful data, efficacy data. Here we had an 85% reduction in AP events in people with high triglycerides. 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 the 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. How should we think about, you know, how that data will be potentially reflected on the label? Do you think that that's gonna 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? Or how should we think about?
No. It is well-tolerated in CORE I and CORE II studies and in the ASCENT study. 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 with TRYNGOLZA. 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 III studies. That rapid clearance of triglycerides, it's gonna end up in the liver.
Another important thing is that we're following these individuals over time from the CORE I and CORE II studies. They were all able to roll into an open label extension where we're continuing to monitor this for over two years. Over time we're seeing stabilization and then trending back towards baseline.
Got it. That's actually helpful. For severe hypertriglyceridemia, how are you thinking about the TAM?
Yeah.
I think obviously there's a lot of patients out there that have severe hypertriglyceridemia. However, when you look at the patients that have severe hypertriglyceridemia and a history of acute pancreatitis, the TAM is so much smaller, maybe like, you know, single -digit types of percentage, when you reflect on the $3 million versus the one that have history of acute pancreatitis. Is this gonna be a primary prevention type of drug where like patients that don't have a history of acute pancreatitis will receive the therapy? You think there's a scenario where the payers will restrict the access to this drug to primarily the patients that have a history of acute pancreatitis? How do we think about this?
No, we've set-
Primary versus secondary prevention?
Yeah. We've set this program up specifically not to restrict access. There's 3 million patients that have the high triglycerides over 500 mg/dL. 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 mg/dL, which then puts them at severe risk, and then over 500 mg/dL with history of acute pancreatitis, and that's still 1 million patients. That's where we'll be starting. We will get to all those patients then at 500 mg/dL 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. You know, you now obviously have settled to $40,000 as the, your WAC. Your competitor last week came forward with a $45,000 WAC. Again, they have an argument that maybe their drug is dosed less frequently, and they could have some pharmacological properties that are different versus your molecule. Like, what's your take on what was your reaction to Arrowhead actually pricing their drug at $45,000 versus $40,000?
Our approach is entirely data-driven. We first did HCP research. We're using our CORE I and CORE II data. With our phase III data, we took that out to understand demand. Once we understood demand with existing phase III 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. Not limiting the access, but still having a favorable price. That's where we landed on the $40,000 WAC. For our, for the other company, they don't have phase III 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. I think that has been a little bit of a moving part. I think you guys started with $1 billion, then I think at JP Morgan was $2 billion, I should say $1+ billion , then became $2+ billion , and now most recently is $3+ billion .
Yep.
Walk us through like some of the assumptions in your models that got you there.
Yeah.
Is it just simply function of price or there are other variables including, you know, either access or discontinuations?
Yeah.
Walk us through the evolution from $1 billion to $3 billion. That's a big delta.
It is. The first one, it was demand based on the data. The phase III 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 880 mg/dL of four. Only four patients need to be treated in one year to prevent an acute pancreatitis attack, and only 20 patients in that larger population. 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 that doctors are planning on prescribing this for.
Once we got to the $2 billion, then we did the pricing work, and we had initially assumed a lower price. 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, then that's where we increased it from $2 billion to greater than $3 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. This growth isn't unexpected given that we're just learning as we're doing this and generating the data.
Yeah. Yeah. Certainly, you know.
Very.
Conversations with payers and whatnot obviously influence some of these assumptions, so, which, you know, 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. Their trial is, you know, designed slightly different than your trial, a little smaller trial. There's also some differences around randomizations and whatnot. What's your take? Do you think that, you know, Arrowhead has a chance of hitting the, you know, second key secondary endpoint of reduction in acute pancreatitis in a statistical significant fashion?
I think they have a good chance. Data's gonna 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 gonna help, as we just discussed, that this is a new market, it's a growing market. Having more voices out there to help raise awareness is gonna help those patients.
We certainly have seen that movie over and over again.
Yeah.
Wit more players, there's also, you know, often market expansion there.
Yep.
Sometimes it's not about, you know, a market share, but it's more like market expansion.
Absolutely.
If I can pivot to Angelman, which you know is your, you know, bread and butter, if you will. Just talk about big picture of what data have you seen so far. Just remind us about differentiations versus Ultragenyx, and just walk us through what's next here.
Yeah.
Maybe if I can, quickly, I think it comes up in conversations with investors a decent amount, maybe just refresh our memory for why Biogen ultimately decided to pass on-
Yeah.
... that program.
First of all, this is a neurodevelopmental disease, 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 two to a four-year-old, and then they stay that way for the rest of their lives, and they have a normal lifespan. What we've seen in our phase I study, which is our open-label HALO study, it was an improvement across domains and across measures. 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. It's nice in an open label setting to see consistency in the data across different ways of collecting it. 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. With that gave us confidence to go into the phase III study. The phase III 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, that'll read out next year. 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 gonna 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. In total, this is something we want back. We didn't want to negotiate. They wanted to negotiate. It's ours.
Got it. That's super helpful. What's your take on the Ultragenyx approach? I think it's fascinating to me that, you know, they're splitting the alpha, actually between two separate endpoints, right? Obviously they have Bayley's for cognition, and they're spending most of the alpha on the Bayley's for cognition.
Yeah.
They're also spending some of the alpha through, you know, mNIS+7, which is more of a composite endpoint. You obviously have a different approach here because you have a separate primary endpoint. You're using expressive communication as your primary endpoint. Are you potentially considering doing something similar where you split the alpha and you maybe have kind of two shots on goal, or what's your take there?
We'll see the data. 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 non-verbal, so as you can imagine, it's very difficult for the families. 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. It gives you the biggest delta for an effect in a phase III study. 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 gonna score higher on it. It has inherent meaningfulness in that. That'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. 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.
Gotcha. Can you expand on adjust as necessary? Like, I mean, I guess what are you primarily focused on is to see the data from Ultragenyx. Sounds like their data's coming late this summer. Like, what are you primarily focused on, and do you have optionality in your protocol to amend the protocol and maybe make your trial either longer or bigger?
Yeah.
Walk us through kind of some of the moving parts there and how you're thinking of potentially adjusting your trial based on their data.
The main thing that we're looking at from them is the placebo effect. 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. That's the number one thing to look at, 'cause all the data generated to date is open label. 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. In terms of adjusting, things like our SAP can be easily adjusted.
Gotcha. Especially because they're gonna probably read out at the 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-
Can change.
Yeah. You're saying that your trial will be fully enrolled second half of this year. Is that?
We haven't given those details.
Got this.
This year.
This year. Okay. Okay. Okay, that's helpful. Maybe one last question on Angelman. Just remind us the commercial opportunity here, you know, 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're thinking about pricing.
Yeah. There's 100,000 individuals we think in the U.S. and major markets, and this is a rare neurological disease, so we expect it to be similar to other rare programs that we have, assuming positive phase III data and efficacy.
SPINRAZA- type of pricing or too early to comment in this?
Too early to comment. Within that rare neural range.
Okay, that's helpful. You mentioned CARDIO-TTRansform. 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. You know, there's a lot more patients on tafamidis at baseline. There's more patients on SGLT2 at baseline and whatnot. 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 3 x the number of patients that Alnylam had on HELIOS-B on tafamidis at baseline. I think it's 819.
Yep.
Where they only had 259 patients tafamidis. Like, is 819 patient tafamidis baseline a large enough sample size that you think you can actually hit the stats as add-on to tafamidis?
Yeah. That is not the expectation. It is not powered for statistical significance on the secondaries. We did release the study design recently, and as you can see, it's sixth in the hierarchy, so it is in the secondary hierarchy, but it is sixth, so everything else would have to hit to get there. 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 tafamidis than there were in the total previous studies, and this will give us information about how it's behaving. The expectation for the study is on par with what the previous silencer data has looked like, and then anything with tafamidis is gonna be on top of that and upside.
Gotcha. Gotcha. Okay. That's helpful. You mentioned earlier Lp(a). It's probably one of the biggest catalysts in medicine in 2026.
Yeah.
M aybe Lp(a) is gonna be the next cholesterol, who knows? I think you powered a trial to show a 20%-25% benefit depending on, you know, what subpopulations you're looking at. 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. Maybe instead of 20%-25% relative risk reduction, this could be more like in the 10% or 15% relative risk reduction. Should that be the case, do you think that that would still be a commercially viable product?
Yeah. Nobody knows what the relative risk reduction is gonna 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? We'll find that when the trial reads out. The question on is 10%-15 enough? Yes, that's really from research and talking to KOLs and getting feedback from the community on what they would need to see to treat. The answer is that 10%-15%. That's where that shift is coming from. It's really based on the fact that with the human genetics, this is very clear that this is an independent risk factor.
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(a). 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. Got it. That's actually helpful. That's actually helpful. Maybe just pivoting to the other PDUFA day 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 the, you know, medical need. 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. Like, how do we feel about probability of approval at this point?
We hit that 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. 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. 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, there's motor, there's cognition, there's across-the-board effects that these families are dealing with and these individuals.
You hear parents talk about it, the kids gain a new developmental skill, then they lose it because the disease progresses, they work so hard to get something, then they lose it. What we've shown in the data is a stabilization, 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. Then we also have in the secondaries, they all favored zilganersen in that targeting of the underlying disease is providing that broad benefit for the individuals. With that, I'm totally very excited about this program and to get this to patients. We have an EAP open. It's enrolling very well.
Lots of enthusiasm for it, continue to try to get this to as many folks as possible.
Got it. Got it. Have a lot more questions, but no more time.
Thanks.
I appreciate the time. Thanks everyone for joining. We'll talk soon. Thanks again.
Yep. Of course.