Ionis Pharmaceuticals at UBS Virtual CNS Day: Neurology Pipeline Insights

On Monday, 17 March 2025, Ionis Pharmaceuticals (NASDAQ: IONS) participated in the UBS Virtual CNS Day 2025, presenting a strategic overview of its neurology pipeline. The discussion, led by UBS analyst Ellie Merall, highlighted both promising developments and ongoing challenges. Ionis emphasized its focus on rare neurological diseases, with updates on programs for Alexander’s disease, Angelman syndrome, and Alzheimer’s. The company remains optimistic about its clinical trial designs and commercial strategies, despite facing a competitive landscape.

Key Takeaways

• Ionis is advancing its neurology pipeline, with key programs for Alexander’s disease, Angelman syndrome, and Alzheimer’s.
• The company reported an 84% quarter-over-quarter growth in sales for WAYNEUWA, capturing 40% of new patients in the TTR polyneuropathy space.
• Ionis anticipates data readouts for Alexander’s disease later this year and the MAPT program next year.
• The Angelman syndrome program is moving to a Phase 3 trial, aiming for a broad patient inclusion.

Financial Results

• WAYNEUWA saw a $42 million increase in sales from Q3 to Q4, marking an 84% growth.
• The program captured approximately 40% of new-to-treatment patients in the TTR polyneuropathy space.

Operational Updates

• Alexander’s Disease: Data readout expected in the second half of the year. Focus on faster diagnosis and patient identification.
• Angelman Syndrome: Phase 3 study to start in the first half of the year, with plans to complete enrollment next year.
• MAPT Program: Fully enrolled Phase 2 study with a data readout expected next year.

Future Outlook

• Alexander’s Disease: Collaboration with patient advocacy organizations and development of CMEs for faster diagnosis.
• Angelman Syndrome: Aims for a broad label in Phase 3 and plans to open a zero-to-two open-label program.
• SHTG Program: Phase 3 data readout expected later this year, focusing on the drug’s effect on acute pancreatitis.

Q&A Highlights

• Alexander’s Disease: Market size estimated at 300-700 patients in the US.
• Angelman Syndrome: Prevalence estimated at one in twelve thousand to one in twenty thousand.
• MAPT Program: Potential combination therapy with beta antibodies, with Biogen fully licensing the program.

For more detailed insights, readers are encouraged to refer to the full transcript below.

Full transcript - UBS Virtual CNS Day 2025:

Ellie Merall, UBS Analyst, UBS: Hi, guys. I’m Ellie Merall. Thank you, for joining, the UBS Virtual CNS Day. Very excited to have Aionis Pharmaceuticals, here with us today for a fireside chat. Joining us from Ionis is, Holly, Kordowitz, sorry if I butchered your name, SVP of Neurology Research and, Wade Walk, SVP, Investor Relations.

I know we just have twenty five minutes, so I’ll jump right in. Maybe just high level, can you provide kind of an overview of, some of the programs in the neuro space that you have and the timelines, and then we can jump into specific programs.

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah. So in our neurology program, we have a a number of exciting things going on right now. We have, first of all, our Alexander’s program is reading out later this year. This is a pivotal program. We also have our MAPT program, which is reading out next year.

It’s a phase two study there. And then, of course, we have our Angelman program. And there, we’re getting our phase three study up and running in the first half of this year. So those are the main things that we’re focused on in neuro right now.

Ellie Merall, UBS Analyst, UBS: Great. Maybe starting with Alexander’s, you know, with the data expected in the second half, can you talk a bit about the biology here and, you know, how that translates into, you know, the data we should be looking to see?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah. Yeah. Happy to. So Alexander’s disease is caused by mutations in GFAP. These are gain of function mutations which lead to accumulation of GFAP in astrocytes and the formation of ROSEN cell fibers.

Once you have that, that then leads to damage of the myelin, the sheath covering neurons, and then you have a hypomyelination, so loss of myelin. So it’s a leukodystrophy. And since it’s caused by that central GFAP mutation, our target is GFAP. So we have beautiful preclinical data because you can make mice and rats that have Alexander’s disease by introducing mutant GFAP. You can lower that.

You can reverse that hypomyelination. You can have a benefit in

Wade Walk, SVP, Investor Relations, Ionis Pharmaceuticals: a a meaningful benefit on

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: the function of the animals. So for our first in human study and our pivotal study, we have a really unique design in that this is an ultra rare disease, and we have one study. So it’s both first in human and it’s pivotal, and that’s what’s reading out at the end of this year. And so there, we have a number of different endpoints that we’re looking at. This is a complex disease with many different symptoms.

Our primary is a 10 meter walk test, but we also have a number of secondaries looking at that constellation of symptoms of the disease. And what we’re looking at to translate is the evidence that we’re having an effect on the overall underlying disease. So looking at trends across all those different measures that they’re beneficial. That’s because we’re going after that central target, and we want that evidence that we’re affecting the underlying disease.

Ellie Merall, UBS Analyst, UBS: So, I guess, how should we think about I mean, because we haven’t seen clinical data yet or at least we haven’t. Maybe you have. Yep.

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: We’re still blinded too.

Ellie Merall, UBS Analyst, UBS: Okay. Like, how do we think about what good data looks like here?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah. So that’s a great question. So what we’re looking for, as I mentioned, is those trends across the board. So good data will be trends in different domains showing that we’re having that effect on the underlying disease. So we, of course, have our primary endpoint, but that’s not our only focus.

It’s also those secondaries as well. And we’ve had discussions with regulators that there’ll be a lot of regulatory flexibility here given the rareness of the disease in this, type of design that we have for our pivotal study.

Wade Walk, SVP, Investor Relations, Ionis Pharmaceuticals: Mhmm.

Ellie Merall, UBS Analyst, UBS: I guess, Evan, given that this is an ultra rare disease, maybe if you could speak a little bit to sort of the the market sizing here and how much market development, do you expect, you know, will take, in the in The US for Alexander’s?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah. So it’s about one in a million. So we think about three hundred to seven hundred patients. And it because it is ultra wide, there’s gonna be moderate market development. The big thing we’re focusing on there is faster diagnosis and patient identification.

So really looking at education. We’re supporting initiatives to try to be able to identify these patients earlier and diagnose them sooner so they could get access to treatment, assuming everything works in our pivotal study. What that looks like in terms of development is we’re CMEs for neurologists. I’m reading Alexander’s disease signs and symptoms and MRIs for diagnosis. And we’re trying to do this in a very efficient way, collaborating with patient advocacy organizations using congress presences, using omnichannel to get access to those individuals who might see these patients and get that diagnosis.

Ellie Merall, UBS Analyst, UBS: What proportion, of this, like, three to seven hundred patients in The US are currently diagnosed, if you have a a sense?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Don’t have a good sense. So we don’t have a good sense of that. But what we do have is, thankfully, there’s an ICD 10 code that actually came out for this about eighteen months ago. And so we’re getting more and more information on diagnosis and the use of that and identification of patients through that. So that’s been really nice for this ultra rare disease to have that.

Yeah.

Ellie Merall, UBS Analyst, UBS: And then I guess just how, like, I I know probably some of the work is still in progress, but, like, are in terms of, like, the patients that are diagnosed, is the treatment more centralized, let’s say academic centers or sort of centers are excellent or or is it more spread out maybe, you know, going into kind of the community setting?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah. It’s really at centers for excellence. So the experienced treaters for Alexander are at those centers for excellence because they can provide that multidisciplinary, complex symptomatic care that’s happening right now for the patients. And we actually expect a lot of our treatment decisions and administration to happen at those centers for excellence. So that’s really where we’re gonna be where we are focused on and where we’re gonna be focused on for the launch.

Again, assuming everything goes well in the pivotal.

Ellie Merall, UBS Analyst, UBS: Okay. Great. Well, we’re, we’re looking forward to to seeing that data later this year.

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: That’s it.

Ellie Merall, UBS Analyst, UBS: Maybe turning to Angel Mims, maybe can you give us an overview of the biology of the disease, the severity, and, you know, the unmet need, and just how those patients, you know, are currently managed?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah. So Angelman syndrome is cause of loss of function by UB3A. This is an E3 ubiquitin ligase that’s really involved in Syndapse remodeling. So this is a neurodevelopmental disease. And again, our target is we’re up regulating that lost gene of UB3A.

These patients, they have normal development and then they stop hitting milestones. And that happens around six to twelve months of age is when they start being visible that they aren’t meeting milestones. And then the patients continue to develop, and they peak at about the neurotypical two to a four year old. But then they have a normal lifespan. So you can imagine this is a really severe disease where patients are developed cognitively and with their speech and their motor to about a two to four year old, and then they live a normal life.

And in terms of how it’s managed, this is there is some treatment options in terms of treating the epilepsy, antiepileptics with with seizures, and some sleep medicines that are given to the individuals with Angelman, but most of it is managed care. And most of it is physical therapy, behavioral therapy, communication, speech therapy, things like that. And so there really aren’t many options for these patients and definitely no disease modifying options, which is what we’re trying to do with I’m five eighty two.

Ellie Merall, UBS Analyst, UBS: And can you walk us through what was seen in the phase two data last year and I guess the the natural history work that’s been done to sort of put that data in context?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah. So we’re really happy. So HALOS was our trial. That was our first in human study. This was a MAD design.

So we had three different dose levels And we looked at those patients over time. We looked at a number of different domains for this disease. We looked at cognition, motor, communication. We used multiple different COAs. So we had the Bayley.

We had the Vineland. We had the, CGI, and we shared all this data. And what we found is that there was benefit across the domains. So we had benefit across the domains in a dose dependent manner, and it was a benefit that exceeded that of natural history. So one of the really great things about Angelman is even though it’s rare, the community has been really fantastic.

And way back in 02/2006, they started natural history studies. So we have lots of longitudinal data and natural history in this disease. So we were able to pull out a 50 patients from that natural history where we had nice longitudinal data that we could match to our cohort that we had in halos and demonstrate that the halos effects that we saw in that trial exceeded the natural history.

Ellie Merall, UBS Analyst, UBS: Alright. Great. And I guess with the phase three, you know, beginning soon, I guess, can you walk us through the decision to choose Bayley four with the expressive communication as a primary endpoint? I guess, was this, like, sort of the FDA steering you towards this domain versus the others or was there some flexibility?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: This was our choice. So, this was our choice that we proposed to the FDA and the FDA readily agreed. The rationale that we provided for them is there’s a nice stable baseline. So, these patients, they have no speech or very limited speech. So you’re at the very bottom of that scale.

So there’s lots of room for improvement and it’s very stable. So over time, it doesn’t change, which is what you want in your natural history for an endpoint. It’s also the most bothersome symptom for caregivers. They’re very clear that if their individuals with Angelman can communicate, that would be a meaningful difference for them, which of course is important to us and regulators. And then it had the biggest magnitude of effect in our HALOS trial.

So having the biggest magnitude of effect in that stable low baseline, it gives us that nice big delta that we will be looking for in our placebo controlled trial. So highest probability of success for that. So no pushback from FDA readily accepted and and we’re happy that we’re moving it forward. Mhmm.

Ellie Merall, UBS Analyst, UBS: And maybe what are some of the other endpoints of focus or maybe just how the sort of KOLs in the space tend to talk about the various endpoints and the relative importance?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yep. So the, what we’ll be looking at is very similar to what we had in the HALO study. Of course, we’ll be using the Vineland, the CGI, and the ORCA as well. So the different COVIDs that are out there, the different assays that are available. In terms of the KOLs, as you can imagine, they have lots of opinions, and there’s lots of different opinions.

There’s no one focus that they have that we should be zeroing in on. There’s pros and cons to all of them. Since we decided on expressive communication, we haven’t heard anything negative about that, only support from that from the KOLs. Their biggest thing is just to make sure you’re looking at the complexity of the disease in our secondary so that we can see which and hopefully all of the domains are having benefits like we were able to show during halos and making sure we’re we’re capturing that complexity.

Ellie Merall, UBS Analyst, UBS: Okay. Absolutely. And, you know, in the context of maybe the competitive landscape with Ultra Ultragenyx, maybe what are some of kind of the, like, you know, what you view as differentiating features of your program?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah. So I love our drug. It’s a well tolerated drug. It’s safe. It’s one that is using our proven technology that we are very familiar with, and it’s performing exactly how we would expect based on what we knew previously.

And so because of that, I’m happy with what we’re we’re moving forward with. I also like our design as well. So our design is we have for our phase three study. We’re looking at a broad patient population. Because we’re not limited, because we don’t have any of the the safety effects that they’ve had, we can do ambulatory and non ambulatory patients.

Because our HALOS trial included both mutation and deletion carriers, we have confidence of including both of those in our pivotal cohort as well as looking in the overall REVEAL study, that’s the name of our our phase three trial, that adults as well as children. And so we’ll have that broad patient population in our trial to hopefully give us that broad label that we’re looking for to be able to help all the patients with Angelman. Mhmm.

Ellie Merall, UBS Analyst, UBS: And, you know, kind of building off of, Alexander’s disease, like, how should we think kind of about both the opportunity in terms of, like, the number of patients with Angelman’s that are currently diagnosed and sort of as an organization, how you would approach, the scale up, potentially from, you know, Alexander’s to Angelman’s from a commercial perspective?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah. So it’s a great question. So there’s, of course, many more patients with Angelman than there are with Alexander’s disease. But with Alexander’s disease being first, we can use that to start building the foundation in pediatric neurology so that when we then move into Angel Mickens, which is larger, we can grow quickly. One of the overall strategies that we have for our commercial organization is to look for significant synergies across the organization, and particularly within rare neurology and cardiology.

So we’re gonna leverage all the work we do for Zogonersen, for that Angelman syndrome. And a a great example of this is the leadership that we’ve already built in our current, commercial organization has extensive experience building those rare markets. And even with our Trangolza, which is also a rare market, which they’re building, they’ll then be able to apply that experiments to both Alexander’s disease and then, Angelman.

Ellie Merall, UBS Analyst, UBS: Okay. How should we think about the diagnosis rate of Angelman’s today? I mean, it seems like the symptoms are perhaps, you know, pretty clear or at least, like, prompt sort of a visit to the doctors. But how should we think about kind of the size of the prevalence pool and the proportion that are diagnosed currently?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah. So it’s one in twelve thousand or one in twenty thousand, we think. So potentially, I mean, half a million people worldwide, which is huge. And because of the awareness of Angelman and just the sheer size of it comparing it to Alexander disease, it’s much quicker diagnosis. And then the genetic confirmation comes fairly quickly after that.

So there’s much more awareness, but there’s still work to be done in terms of, making sure that all the patients who could potentially benefit are aware of it. There’s also really fantastic patient communities out there that we’re collaborating with who are, bringing this awareness and spreading that information. So I think it’s in a, it’s in a good place in terms of people understanding the disease and being aware of it. And then again, with anything that that we’re doing, once there’s a treatment, we expect there to be more awareness and more uptake. And we saw that with SPINRAZA.

And one final thing to note that we haven’t touched on yet is for both these indications for Alexander’s disease as well as for Angelman is the ultimate goal is to get this on newborn screening. And if you can get this on newborn screening, then you can get these these children treatment very early. And when we’ve talked to parents, this is exactly what they want. When there’s diagnosis, they wanna be on treatment. So both for our Alexander’s program, we have a zero to two open label cohort that we’re treating.

And then for our Angelman program, we’re opening up a zero to two open label program. And because our drug has been shown to be safe, we’re gonna be able to do that so that we can have data on those very young individuals so that as soon as that diagnosis is made, then they can get on therapy. So we think all that’ll help raise awareness and open up the patient community and the the patient identification.

Ellie Merall, UBS Analyst, UBS: How should we think about the timelines here? Just, like, you know, how you’re thinking about how long it will take to enroll and, like, basically, like, when from, you know, where we fit we could next get an update whether it’s a longer term data, from some of the phase two study, or, you know, say, the phase three data.

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: So we will start the trial the first half of this year. We are on track to do that. We have everything, the protocol set, the regulatory alignment set, and we’re just getting the sites up and going. So that’s gonna happen. And then we planning to complete enrollment next year, and then it’s a twelve month endpoint.

So for the primary endpoint for the reveal study. So you can kinda do the math from there and figure out where we should land.

Ellie Merall, UBS Analyst, UBS: Mhmm. Alright. So twenty twenty seven ish. Okay. Well, we’re looking forward to seeing that data.

MAPT, yes. Interesting. Yeah, like, early data from the program so far. And I guess with data coming next year, I guess, maybe can you talk about what you’ve seen from your initial first in human study, and sort of maybe how using an ASO might be different from using an antibody, in terms of addressing the tau burden.

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah. So I love this program. I mean, I love most of our programs. But this one, I’m particularly fond of. And that’s because in Alzheimer’s disease, there’s two pathologies, of course.

There’s e beta plaques, and then there’s the tau tangles. The tau tangles are intracellular. And what we’re doing is we’re stopping the production of tau. So before any pathology forms, you stop tau from being being made. And antibody approaches after tau are only going for cellular tau.

So you have to catch it when it’s moving from neuron to neuron. And once it gets in that neuron, then the antibodies aren’t gonna do anything. So here, we stop the production within a neuron. And we’ve shown in preclinical models, if you stop the production within a neuron, you actually reverse the existing tau. The exciting data from our first in human study is there’s tau PET.

So we can look at tau pathology longitudinally in man. And we were able to show that with treatment, we did the omenucleotide that stopped tau. We looked at a hundred weeks. We looked at baseline, then we looked at that hundred week time point at tau pathology, and we actually reversed tau pathology. So that’s really important.

We didn’t just stop production. We reversed existing pathology. So by stopping tau production, the body, the brain, the aged Alzheimer’s brain is actually able to clear to that existing tau pathology and then prevent more pathology from happening. So that was really exciting. And that is, since it’s so central to disease, could potentially be a really important treatment for Alzheimer’s disease.

I think that’s where a lot of the excitement and the buzz is coming from for this one.

Ellie Merall, UBS Analyst, UBS: Yeah. No. It’s exciting data. Maybe, can you tell us a little bit more about the design of the phase two and, you know, I guess what data we should be, you know, looking for next year?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah, of course. So, the phase two study is looking at different dosing regimens. So, we’re doing both a quarterly as well as a six month dosing regimen. So, from our first in human study, we also saw that the oleglutide lasted a really long time in man, so we could spread out the dosing interval. And so that means treatments, if that works, just twice a year to potentially, be therapeutically beneficial in Alzheimer’s disease.

We’re doing a we are looking at an endpoint, which is a clinical endpoint. We’re looking at the CDR sum of boxes, and that’s at seventy six weeks of placebo controlled treatment. It’s just over a 300 patient trial. I think we ended up in the three seventy range about there when we were finally enrolled. And as we’ve been mentioning, that reads out next year.

So it’s fully enrolled, and we’re just waiting for the data

Ellie Merall, UBS Analyst, UBS: now. Mhmm. Ah, exciting. So what’s clinically meaningful in terms of, like, the difference on CDR sum of boxes? Or, yes, are we still looking at that, like, 30% or so range?

Or yeah. How should we be thinking about that?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah. So you’re referencing in what’s happened with a beta. So I think on par with a beta is will make a lot of sense. So because of our mechanism of action, the a beta antibodies, they do have a small effect, but it is a meaningful effect. And I think that’s been clear in what we’ve seen being approved in that space.

And but it comes along with ARIA. And I think that’s where a lot of the hesitation around the antibodies are, that safety. Because of our mechanism of action of lowering tau, we shouldn’t have that safety effect. So there’s no evidence of ARIA and no prediction of that from our mechanism of action. The other exciting thing for tau is that the tau pathology correlates best with cognitive decline.

So there is the benefit of more. And so it would be great if we saw more, but I wouldn’t set that expectation. Because if we’re on par with the a beta antibodies, because these are two different mechanisms, you could envision using them together. And using them together could then be additive or even synergistic based on the mechanisms. And so then that would be the next question.

Ellie Merall, UBS Analyst, UBS: So what would the, I guess, next steps be? Would it be to run a phase three monotherapy, but then also study a combination? I guess, have you looked at com like, your plans with sort of combination in phase two?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Or anything? Well, that’s in discussion right now, but absolutely a phase three. And I think it’s gonna depend on the data, but phase three monotherapy and then what else we do in parallel will be dependent on the data and the state of all the other therapies, on the market and how they’re doing and how they can be used. And that’s of course, this is partnered with Biogen. They will fully license this program, so they’ll be making all the final decisions on that.

Ellie Merall, UBS Analyst, UBS: Mhmm. I guess, given the, like, potentially, like, better safety, I guess, what really is the bar from an efficacy perspective? Like, I guess, what would be the lowest improvement that you could see on, say, CD or suboxone and still wanna move forward in into phase three given the biology and safety?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: So Biogen hasn’t given out those numbers, but I’d be happy with anything on par with the a beta antibodies.

Ellie Merall, UBS Analyst, UBS: Great. And, like, how would this work in practice? Is it sort of, you know, almost like oncology where, you know, patients would get multiple agents?

Holly Kordowitz, SVP of Neurology Research, Ionis Pharmaceuticals: Yeah. So that’s what I think. That I think that’s where we’re going. So we could be blown away by tau, and it could be just amazing, and that it could be all you need. And it could be the hypothesis that tau is downstream of a beta is right, and this is gonna capture everything.

But I think Alzheimer’s is a multifactorial disease. There’s multiple things going on. So to fully treat the disease and all the patients that have it with those different underlying pathologies, we’re gonna need multiple multiple shots on goal and potentially multiple therapies in individual patients. But that’s just my my personal view of the science and what’s going on.

Ellie Merall, UBS Analyst, UBS: Turning to maybe the commercial side in polyneuropathy, sort of what’s the latest in what you’re seeing in terms of the uptake of WAYNEUWA, and in particular, if there’s certain, like, segments where you’re seeing more uptake versus less and how that’s going?

Wade Walk, SVP, Investor Relations, Ionis Pharmaceuticals: Yeah. I’ll handle that one. So we’re really pleased with the performance of Waynewa in 2024. We saw really good growth. And if you look at the last quarter growth, so Q3 to Q4, we saw $42,000,000 increase in sales and that’s 84% growth quarter over quarter with $19,000,000 in increase over the previous quarter.

And it’s interesting because if you look at the total combined TTR sales with our competitors drugs and our drug, I think it was like $39,000,000 in increase and ours was more than half of that. So pretty impressive performance for three quarters of the way into the launch for this drug. We estimate that we’re capturing about forty percent or so of patients new to treatment in the TTR space for plein neuropathy. And so that’s for us, we we see that as a good sign and we we we continue to see that kind of growth going forward into 2025. You know, what we’re hearing is that, you know, we’re we’re getting some switches, we’re getting some combo treatment, but our focus from the beginning has been on patients who are new to treatment because, you know, about eighty percent of the patients, out there are not diagnosed on treatment.

Right? So so we’ve got a great partner with AstraZeneca who is able to, you know, have the commercial resources to get out into the communities, into the community centers, and and try and identify these patients and get them on treatment. So, you know, the majority of our patients coming on treatment are patients new to treatment. Not saying that, you know, we’re still seeing good uptake and centers of excellence as well. Obviously, that’s where you also find a lot of these patients.

And we’re hearing that patients really appreciate the profile of Waynewa, whether they’re new or whether they’re switching. They like the convenience of being able to administer the drug themselves anytime they want at home. That the auto the auto injector is very convenient for them to use that they, they like the profile of the drug as far as the quality of life improvements that they’re seeing, in in in the the safety and efficacy is is on par with what they’re expecting. So all of those things combined, I see I think are are good signs for the continued growth of weighing new up this year and next.

Ellie Merall, UBS Analyst, UBS: You guys have had some interesting commentary on that you’re seeing combination use commercially. Any color that you can sort of give there, like, a proportion or, you know, mix that’s what you’re seeing with with combination use?

Wade Walk, SVP, Investor Relations, Ionis Pharmaceuticals: I wish I could, but we we can’t give those kind of details out right now. I don’t think AZ would be happy with me if we did. And, but but but it is encouraging to know that, you know, this is this is a, you know, a deadly disease. And just like with cancer, if there are mechanism two different drugs with two different mechanisms, attacking a disease like this, there is desire to use those drugs to try and get the maximum benefit for patients. So you’ve got patients who are diagnosed with cardiomyopathy on tafamidis, for example, patients who are diagnosed with polyneuropathy, getting RENUA.

And so you’ve got two drugs, two different mechanisms of action in treating these patients. It’s certainly something that I think physicians and patients would like like to be able to do when when possible, especially if patients are are seeing two different symptoms or they’re progressing in in in their symptoms.

Ellie Merall, UBS Analyst, UBS: Absolutely. And last question, just SHTG, a lot of investor focus on this readout later this year. We know that you can lower triglycerides. I guess, how do we think about what’s clinically meaningful when it comes to acute pancreatitis?

Wade Walk, SVP, Investor Relations, Ionis Pharmaceuticals: Sure. So I mean, the the treatments that are out there right now, especially in patients with very high triglycerides, don’t really have much of an impact in lowering triglycerides. Right? So you may get, patients who get, you know, 10 to 20% reduction in triglycerides. And if you’re starting out at 600 or 800 or 900, a 10 or 20% decrease in triglycerides isn’t gonna move the needle much for you.

Right? And so, you know, given the fact that we’ve seen, you know, you know, anywhere from 50 to 80% reduction in triglycerides depending on the patient population and the study that we’re looking at, I’d say we’re pretty encouraged with the potential of olsarsin to be able to lower triglycerides in patients with severely elevated triglycerides. We’ve certainly seen our MCS patients. We’ll see it later this year with our SHTG Phase three studies. And so I think, you know, seeing a substantial decrease in triglycerides is is the bar for our Phase three studies.

Now beyond that, we’re also looking at, you know, the the the major problem with having very high triglycerides is that you have risk for acute pancreatitis. And so, you know, one of our key secondary endpoints is looking at, you know, what kind of effect do we have on acute pancreatitis and we’ve engineered the Phase three studies. There’s two. There’s a pivotal and a confirmatory pivotal that are reading out at about the same time. And we’re gonna be able to do a meta analysis combining both of those studies to be able to look at the effect of the drug on acute pancreatitis.

So that’s one of the key measures as well that we’ll be looking at.

Ellie Merall, UBS Analyst, UBS: Interesting. Well, great. Holly, Wade, thank you so much for making the time, and sharing all the insights today. And, we look forward to all the data we have.

Wade Walk, SVP, Investor Relations, Ionis Pharmaceuticals: Thanks. We’re excited.

Ellie Merall, UBS Analyst, UBS: Thanks. Bye.

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