Ionis at Needham Conference: Strategic Growth and Future Prospects

On Monday, 07 April 2025, Ionis Pharmaceuticals (NASDAQ: IONS) presented at the 24th Annual Needham Virtual Healthcare Conference, outlining its strategic initiatives and future prospects. The company highlighted its transition into a fully integrated commercial biotech, emphasizing both opportunities and challenges in its pipeline. Despite recent stock fluctuations, Ionis remains confident in its commercial strategies and partnerships.

Key Takeaways

• Ionis is launching TRINGOZA for FCS, marking its first independent commercial launch.
• The company is optimistic about its pipeline, including olezarsen for SHTG and donidalorsen for HAE.
• Ionis plans to expand its sales force and leverage synergies between FCS and SHTG.
• Partnerships with AstraZeneca and Novartis are crucial for the development of eplontersen and pelicarsen, respectively.
• The Angelman syndrome program presents a significant commercial opportunity due to high unmet needs.

Financial Results

• TRINGOZA for FCS: Launch progressing well, marking Ionis's first independent commercial endeavor.
• WAYNUA for ATTR Polyneuropathy: Achieved $40 million in Q4 sales, with expectations of multi-billion dollar peak sales in partnership with AstraZeneca. The product captured over 50% of US growth in polyneuropathy sales from Q3 to Q4.
• Donidalorsen for HAE: The global market exceeds $3 billion, with peak sales estimates for donidalorsen north of $500 million.
• Pelicarsen: Partnered with Novartis, expecting multi-billion dollar peak sales and eligible for over $1.2 billion in payments.

Operational Updates

• FCS Launch: Products were in the channel by year-end, with patients on the drug before the end of last year.
• SHTG Program: Phase 3 data for CORE and CORE-two expected in the second half of the year, with over 1,000 patients enrolled.
• WAYNUA Launch: Focus on newly diagnosed patients and broadening community use.
• Donidalorsen: PDUFA date set for August this year.
• Pelicarsen: Phase 3 data expected in the first half of 2026.
• Angelman Syndrome: Phase 3 trial planned to start this year, with continued enrollment next year.

Future Outlook

• Olezarsen (SHTG): Aims for higher triglyceride reductions and anticipates a first-mover advantage in the SHTG market.
• WAYNUA (Cardiomyopathy): Targets a $15 billion to $20 billion market, with AstraZeneca estimating sales north of $5 billion globally.
• Donidalorsen (HAE): Expects every four to eight-week dosing to be a key differentiator.
• Pelicarsen (Lp(a) lowering): Confident in achieving a 20% risk reduction in the overall patient population.
• Angelman Syndrome: Developing a disease-modifying treatment, with a significant unmet need.

Q&A Highlights

• Olezarsen Regulatory Approval: Only needs to hit the primary endpoint of triglyceride lowering for potential approval.
• Olezarsen Pricing Strategy: Aims for a $10,000 to $20,000 range for SHTG, lower than FCS pricing.
• WAYNUA Market Penetration: Focus on underserved global markets with potential for significant growth.
• Donidalorsen Commercial Execution: Plans to build a dedicated field force for HAE, leveraging synergies for market access.

For a detailed review of Ionis's strategic plans and future prospects, refer to the full transcript below.

Full transcript - 24th Annual Needham Virtual Healthcare Conference:

Joey Stringer, Bio Tech Analyst, Needham and Company: Good afternoon, everyone. Thank you for joining the twenty fourth Annual Needham Healthcare Conference. My name is Joey Stringer, and I'm one of the Bio Tech analysts at Needham and Company. It's my pleasure to introduce our next presenting company, Ionis Pharmaceuticals. Joining us today from Ionis is Head of Investor Relations, Wade Walk Eric Swayze, Executive Vice President of Research and Kyle Ginny, the Chief Global Product Strategy Officer.

For those of you joining us on the webcast, if you would like to ask a question, please do so at any time. You can submit a question using the chat box at the bottom of your screen. With that, we'll get started. Wade, Eric, and Kyle, thank you so much for joining us today.

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: Good to see you here. Thanks. Thanks for having us on.

Joey Stringer, Bio Tech Analyst, Needham and Company: Well, we'll start off with ozarsen, your program in for FCS and SHTG. I guess, let's focus on SHTG for now. The Phase three program consists of three separate trials, core, core two are the pivotal ones, and we've got a supportive safety study at Essence. For core and core two data coming second half of this year, it'll be a big readout for you guys and estimates later coming middle of this year. So with that backdrop, I want to focus on SHTG.

It's a much larger indication to look into FCS. But when you learn about the FCS launch so far? How has it been playing out? And then how is it helping set the commercial stage for SHDG?

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: Thanks for the question, Joey. I think, if you don't mind, before we start talking about SHDG, I love people talking about SACG. We think it's a it's a great space for us to be in. But I had to kinda wanna back up just a little bit and set the stage for our illness as a whole and kinda where we're heading.

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: That's the thing.

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: This is this is a big deal for us because with with osparcel and the Trinco launch in FCS, that's our first independent commercial launch and represents really the clinical the the the the first true Ionis only step into us being a fully integrated commercial biotech, and that's why we're talking about SACG, and we think it's a great place to be. So we're pretty excited about that. We think it's, obviously, a good change for Ionis. It's a change in our business model, and we think that it's the right avenue for patients and shareholders as we go forward. And Trin Golza is really just beginning by SHTG and Trin Golza.

We also have a PDUFA date coming up in August for dynecomorrison, which is a potential treatment for hereditary angioedema where we have some great looking phase three data and really fantastic switch data. We have a late stage program in Zilda Nursing for Alexander's disease, which is a rare lithotripsy key for our neurology programs that we envision as wholly owned. Following that is our Angelman syndrome program, which we also tend to commercialize ourselves and and bring it forward for, again, a disease that has no therapy. We're hoping to get enrollment for that completed next year. And these kind of really set the stage, and we'll talk about HHH in a minute for Iowa's wholly owned commercial programs, which we think can return some tremendous value to patients and shareholders.

So then if you want to talk about the FHTG and the commercial phase, that's why we got Kyle on and he can start to

Joey Stringer, Bio Tech Analyst, Needham and Company: talk about that.

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: Yes. Thanks, Eric, and thanks, Joey and team, for joining the call today. I'll just mention briefly, as you asked, about the FTS launch. It's going extremely well. We did a great job of building commercial infrastructure on the efforts of Wei Nua first and our co commercialization effort, but then being ready for our first fully owned launch with Tringles and FCS, which we received approval in at the end of last year.

And the performance is very impressive from the commercial team and the medical affairs group so far. We have products in channel before the end of the year. We had patients on drug before the end of last year, and we are continuing to identify, get patients diagnosed, and to get patients on to both commercial and Medicare drugs. So we're very pleased with how this is going so far in the execution on the plans. As it relates to the synergies that you brought up around FCS and FHTG, there are a number of those.

When you think about the FHTG indication, which is a much larger indication you referenced, we're talking about triglyceride levels of 500 milligrams per deciliter and above. This is two primary and secondary causes. So this includes things like diet and lifestyle and other medical conditions and potentially certain medications that patients are on that create this issue. These patients are at high risk of acute pancreatitis. And the number one goal is to reduce that risk of pancreatitis and its most important reason to treat h t g.

A lot of physicians understand this and they understand the risk. But unfortunately, you know, in today's situation, they've got very few options available to them. And many patients even on standard of care today are unable to get their triglycerides down to the goal due to effective products. So in terms of our infrastructure, as I mentioned in the synergies there, it seems like our market access teams, our operational groups, and the basic foundations, kind of the back office staff for commercialization, there are a lot of synergies there. As it relates to the sales organization, we have a great opportunity.

We've got about 30 people or so in the field today, and we'll have the ability to scale that probably in the range of about 200 people or so as we get to SDG in order to capitalize on the common call points that are out there. The main focus is on endocrinology and cardiology and lipidology. They're the ones that are treating this condition and see these patients. But we also have some other synergies as it relates to our Ionis Every Step program, which is our patient support program. I mentioned the co commercialization of Whenua.

We have the lead in that with AstraZeneca, and we've been able to build a really strong and capable team around our patient services group.

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: And these are a group

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: of nurse case managers that are actually Ionis employees. They're able to offer a full suite of services, kind of a white glove service for for these physicians and patients. For patients, we're able to do disease state, diet education, nutrition education, and and also, obviously, patient support around the injection training and also reimbursement support if needed. On the physician side, we're able to do things like streamline prescribing process, support the insurance authorizations and things, new coverage assistance and things. So in terms of synergies, I think in terms of the market itself and what we're seeing in the market and also in terms of our capability and commercial infrastructure, a lot of commonalities here and a lot of good things happening.

Joey Stringer, Bio Tech Analyst, Needham and Company: The And with next How big of a deal is AP for patients and payers?

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: Yes. Eric, I'll take this one as well and talk through this a little bit. But first, we're really looking forward to learning more about the benefit that oligarsen can bring to patients with SHTG as we report on both CORE and CORE-two data in the second half of this year. So it's coming up here fairly quickly. The CORE and CORE II studies are powered for the primary endpoint, which is percent triglyceride reduction from baseline compared to placebo at six months.

However, the positive thing that we've got going right now is we've got the results that we saw in the FCF balance study. This gives us great confidence in terms of potential to see a benefit in AP and core and core two, be it in trends and or statistical significance. So it's important to note as well in this category that there are already established guidelines in both endocrinology and cardiology in place for SHG and treating physicians firmly believe that reducing triglycerides as much as possible that you need to reduce triglycerides as much as possible because of the severely elevated triglycerides and the risk again of pancreatitis.

Joey Stringer, Bio Tech Analyst, Needham and Company: So in '4 and 02/02,

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: we've enrolled over a thousand patients in these two studies. Baseline triglycerides were eight thirty six milligrams per deciliter in core and seven forty nine in core two. And in the combined study, we've got about forty percent to fifty percent of the patients, excuse me, the study participants at greater than eight eighty milligrams per deciliter. So the study is designed and really the baseline demographics from these Phase three studies, it really increases our confidence in terms of the potential to generate robust data in these patient populations. Unlike SCS, patients that have FHTG, they've got functional levels of LPL, which means they've actually got greater ability to metabolize triglycerides than people with FCS who don't have LPL activity.

So what we believe that we can reasonably expect are higher levels of triglyceride reductions in SHTG. And we also expect a little bit of a lower rate of AP just because of the greater impact of triglyceride lowering that the most larger size of the study represents. So we've got a study size that's about 10 times the size of study size that was in FCS. And that gives us some confidence that we can actually see benefit on AP and SHGG patients, but we'll wait and see how the data reads out, obviously. But these patients are at risk of AP.

We know that the need is to bring these patients down and get them to goal. That's to prevent the initial AP attack from ever happening if patients haven't had one before or reduce the risk of a second or third attack, which actually increases exponentially after you've had your first attack. So we believe AP trends can be beneficial to payers in The US specifically, but we don't think we need that to achieve statistical significance in order to get reimbursement and access to the drug based on our market research and the time that we've set with payers thus far.

Joey Stringer, Bio Tech Analyst, Needham and Company: Do you have to hit the primary endpoint of both core and core two for regulatory approval? How do you think regulators will view a successful outcome?

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: Yes. So as I mentioned a minute ago, we're really well powered in each of these studies to hit the primary endpoint, which is triglyceride lowering. Both studies enrolled considerably more patients than we needed for our powering assumptions. So, you know, TG lowering is important because the medical guidelines that I was referencing just a few seconds ago, Things are in place right now. We've been able to demonstrate in FCS that patients with TG lowering results and reductions in AT events as well.

So we've got that already. But from a regulatory standpoint, we'll just need to hit the primary endpoint and demonstrate triglyceride lowering in order to potentially get the product approved.

Joey Stringer, Bio Tech Analyst, Needham and Company: Got it. And from a statistical analysis plan for the Q4 Phase III trials, What's the can you walk us through that on the primary endpoint and the AP secondary endpoint? Touch on a little bit before.

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: I can take that if you want. So on core and core two, we've we've published fairly recently in the American Heart Journal, some of the study design and hiring assumptions and baseline characteristics of patient population. So you can look online at the American Personal website and pull that paper. So, basically, we've, you know, we've we've we've got the power assumption in the study to show, you know, with fewer patients than we actually enrolled, but we're able to get 90% powering to hit a 60% reduction in triglycerides or greater in the patient population in both core and two, which and and since we over enrolled in both studies, we're we're we're we're empowered to do that in in both studies. And so we're we're pretty confident that the studies are designed appropriately, and and we've got and we've already mentioned that the baseline characteristics indicate that we have a pretty severe patient population with only fifty percent of the patients in each study having triglycerides above 80.

So they're they're they're, you know, they're they're they're pretty severe. They have pretty high triglycerides. And once you get above 80, your chance for acute pancreatitis increases in exponential manner. So so we think it's a good population to have enrolled, and so I think we have the right study design.

Joey Stringer, Bio Tech Analyst, Needham and Company: And sort of businesses before, but are the patients stratified including core core two one current levels?

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: They are. So you stratified them above eight eight eighty or above and below eight eighty, and we have a secondary analysis that looks like triglyceride lowering in those two different populations. Okay. Got it.

Joey Stringer, Bio Tech Analyst, Needham and Company: What are your updated thoughts on pricing strategy for the larger SHTG indication? What are reasonable comps to think about on price?

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: Yeah. So, you know, we priced FCS, you know, as an ultra orphan or ultra rare disease. So we're we're close to $600,000 annually on the FCS population, which has about three thousand patients in The US. So for the FHCG population, we're talking about potentially addressing, you know, one to three million patients. So we'll need to bring the price down, obviously, to to probably specialty pricing.

So a 10 to $20,000 range is kind of directionally where we're headed. We've got a lot more work to do. We also need to see how the the core and core two studies read out, see what data we have to differentiate the profile of the drug and working payers on that. But that range of 10,000 to $20,000 is kind of directionally hopefully helpful for you guys.

Joey Stringer, Bio Tech Analyst, Needham and Company: Yes. The SHTG market, do you think that's a winner take all market? Or what product profile will ultimately win majority market share?

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: Yes, that's a great question. First, we are super excited that we've got first mover advantage in this market. Currently available products, unfortunately, just aren't significant enough in terms of triglyceride lowering to help physicians and patients get the goal and to to come out of harm's way of having acute pancreatitis or, you know, other events, essentially. So first mover advantage here, we've got about an eleven month advantage in FCS that we're capitalizing on now. We've had about a two year advantage in FHTG.

So I think first mover advantage is a good part to this. The other thing I'll just mention is the product profile for olezarsen or Strangolza is is very, very strong. We've got substantial and sustained reductions in APOC3. We've got substantial and sustained reductions in triglycerides. We've got the acute pancreatitis data in the label for FCS today, which is, you know, a supportive evidence as to why these these patients need to be treated.

We've got a strong safety profile. We've got the ability to self administer with an auto injector similar to what we have with Inua. But very strong data and evidence, and we're anticipating the same from core and core two as those studies read out. And then the final thing I'll mention is we've got a really strong commercial team and medical affairs group. We have very strong talent that's joined the organization with with numerous years of experience, and they know how to build a commercial team and launch execution.

And they really know how to make a difference for these patients and physicians. So I'm really encouraged by the commercialization efforts as well.

Joey Stringer, Bio Tech Analyst, Needham and Company: Got it. And speaking of I knew obviously approved in December of twenty twenty three, had posted solid $40,000,000 in the fourth quarter 'twenty four sales. Can you talk about some of the launch metrics and how these are trending in the first full year launch?

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: Yes. We have been so pleased really with the launch in polyneuropathy, and we're really excited that we're on track as well for the data in cardiomyopathy in the second half of twenty twenty six, which is obviously a much larger indication and the ability to serve two indications. AstraZeneca has already provided peak sales potential in the multibillion dollar range for WAYNUA. We've got very attractive royalties on this program up to the mid 20% range in US and the mid teens ex US. So it's gonna translate into substantial royalty revenue for Ionis.

As it relates to when you as you were asking about, we've seen a lot of momentum last year throughout the year to serve the polyneuropathy indication specifically. We captured just over 50% of the total U. S. Growth in polyneuropathy product sales from Q3 to Q4. New to brand share is over 40% now.

So we are competing very, very effectively in this space. So it's great to see sequential growth throughout the year. We've got strong demand, as you mentioned, in the fourth quarter with sales nearly doubling compared to the third quarter. Population continues to be strong, not only in the centers of excellence, but we are now starting to see other broadening years in the community setting for this patient population. And the main focus on this launch is is newly diagnosed patients.

We really are looking at naive patients and to get new to new to newly diagnosed patients started on whenua. That's where AstraZeneca's focus is. So we are seeing some switches. We are seeing some patients that are used in combination with some of the stabilizers that are out there. So really the focus is on growing this untapped market right now and getting Waynua to be the the product of choice.

The reason that we were seeing physicians use this product as as a first line treatment of polyneuropathy is a couple of things. First, quality of life improvements. We're seeing the polyneuropathy be controlled and well controlled month over month. The second thing is the profile with the ability to self administer with the auto injector. This, again, allows a lot of flexibility for patients to manage and control their own disease.

And then the third thing is around access. Both in the commercial and the Medicare setting, the majority of patients have a $0 out of pocket expense for whenua. So it's very affordable for these patients to have access to. So, you know, we're really encouraged that the profile is playing out very positively. We're seeing the growth that I just explained and the profile overall of the drug is competing very effectively in the market.

Joey Stringer, Bio Tech Analyst, Needham and Company: Yes. And switching to cardiomyopathy. Big picture Platin on the market. How big do you think the total market is in cardiomyopathy, just given what we know about standard sales and some Pfizer commentary that you know, the drug only has 20% market penetration.

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: Yeah. The the market is definitely underserved across the globe. I think when when Pfizer originally was launching spamidase in this space, it said it was about a hundred thousand central patients, I think. The estimates that we're hearing now are probably three hundred to five hundred thousand patients potentially in cardiomyopathy. And I think as you see more drugs come to market and more companies enter this case, I think you're gonna continue to see the growth of this market.

But, you know, I think, ultimately, this is a this is north of 15,000,000,000. We're hearing somewhere between 15 to $20,000,000,000 in terms of the size of the market. But, again, you know, what we're trying to do is use Ionis' deep knowledge in the ATTR space combined with AstraZeneca's significant commercial reach globally where they can get to markets very fast and be able to get to these untapped markets over time and and see a way to up, you know, exception and ultimately become the treatment of choice for these patients all over the globe.

Joey Stringer, Bio Tech Analyst, Needham and Company: Cardiomyopathy phase is competitive. Obviously, there are two approved oral drugs, stabilizers, silencer recently approved. So I guess, big picture, how do you view this market? Or how do you see this market playing out given the competitive dynamics around those three competitors? Also thinking about the potential for the payment of LOE in 2028 and any other factors that we consider to play into your long term outlook?

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: Yes. I think you're already seeing this with the new drug approved in the fourth quarter of last year, for example, that there is definitely an additional need for different therapies and different treatments in this case, not only from the stabilizer class, but obviously from the silencer class as well. We are really looking forward to seeing the data from our landmark study in the second half of twenty twenty six. Right? Just as a reminder, we've got the cardio transform study, which is the largest and the most comprehensive study in the ATTR Centimeters space to date.

It's designed to deliver just a robust data set in a very broad population of patients, including those that are on or naive to stabilizers. You know, that represents the dynamic and the evolving space that you were just referencing. But, you know, we expect, again, as I was talking about the profile of that front person earlier, the efficacy and safety, the monthly self administration, the expertise that we have combined with AstraZeneca's reach and obviously cardiovascular leadership all over the globe that we believe this can be a treatment of choice for HDR patients. Again, I mentioned the market size, you know, at $15,000,000 plus, you're gonna see multiple treatments that we believe can do very well in this category. And we believe that efalanterson is gonna be one of those that performs very, very well with estimates north of $5,000,000,000 globally according to AstraZeneca.

Joey Stringer, Bio Tech Analyst, Needham and Company: Yes. And you guys mentioned that there is efloxacin Phase III cardiomyopathy trial. Can you just briefly outline trial design there and highlight some of key design elements that you think gives you confidence that you're going to that you have the right approach here, number one, and the results set you up for long term success in this space?

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: Yeah. I mean, as Scott alluded to, it's it's the largest study by far in the state. So it's more than twice as big as as other studies. We made that decision a while ago to increase the size of the study when it became apparent from the actually, that the doctor that that patients were were doing a little better with cardiomyopathy and was severely affected as, for example, with the TEPANDAS trial. So as we all lose, so as a result, we we think we have the ability to deliver a really robust data set in a lot of patients and and this with patients both on monotherapy and also patients that are already on stabilizers such as tafamidis.

We've got a lot of a lot of patients in the trial in in both situations. Primary endpoint is a composite outcome of cardiovascular mortality and frequency of recurrent events at week one forty. So we think it's a pretty good trial that can generate a lot of data, including on subgroups of those on stabilizers and naive stabilizers and which kind of represent how patient get treated in the real world we think. And they also built in some nice, in my view, nice cardiac imaging substudy. There's an MRI substudy and a scintigraphy substudy, which we think will get additional value of data generated about potential benefits of fostering in patients with cardiomyopathy.

And we think it's a it's a very nice program. It gives us a great data set, and we'll if it's successful, we'll set us up in AstraZeneca to front of doctor patients.

Joey Stringer, Bio Tech Analyst, Needham and Company: Got it. Great. Well, helpful discussion on and the CTR study. So I want to switch to Donnieveloresen for ECE. Obviously, PDUFA coming up in August of this year.

So I'll put a market size question. There are multiple prophylactic therapies that are approved, TEKZYRO or Liday LAGARDA. Can you outline what the current prophylactic market size is in terms of number of patients and sales?

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: Yes. I'll just I'll start with the global market. This is north of $3,000,000,000 for HAE treatments globally. There are about twenty thousand patients in The U. S.

And Europe today that are diagnosed with HAE. The prophylactic market obviously continues to grow in The United States, which is primarily a switch market, right? Because the majority of these patients, upwards of probably seventy percent of these HAE patients in The U. S. Are on a prophylactic treatment today.

Outside The U. S, it looks a little bit different. The prophylactic treatment is gaining ground, but it's more of a growth story. It's a marketplace to be developed. Our estimates for gonadalorsen will be with peak sales north of 500,000,000 As I mentioned, it's going to be a switch market.

So it's going to take a little bit of time to transition these patients from their current therapies that they're on today and for physicians and patients to gain experience with Donnie DeLorson. But, you know, we'll we will go after newly diagnosed or naive patients as well as added switch patients. But the the policy the patients from US, obviously, will be switch patients. I think what we know about these patients in The US is that many of them are unsatisfied with their current treatments. They're unsatisfied for really three different reasons.

Either it's not effective enough and they're having to take through attacks and they're not well controlled. They are not tolerating their treatment very well because some of these treatments have very large bolus injections. You have to take them very frequently, which is the third thing. The convenience factor of having to administer this on a on a every two week basis or if you're on an oral having to do this every single day. But Donnie Deloreson, I think, has an opportunity to to bring something different for these patients, not only really strong efficacy and control as we've published, but also tolerability in terms of the ability to self administer with the auto injector.

And then also the convenience. We're shifting out the dosing regimen from every every two weeks, which is a standard today on the injectables to every four weeks or potentially every eight weeks with this treatment. So we believe, you know, we're going to be able to compete effectively and we've got some unique data sets and reasons why in terms of the product profile itself.

Joey Stringer, Bio Tech Analyst, Needham and Company: HIV is a rare disease that kind of sits outside of Ionis' current commercial focus on CV metabolic and CNS programs. So what gives you the confidence that you can execute commercially in this indication?

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: Yes. So I'll start with the fact that the performance in the simple trials were so strong, right, to carry this program forward and for us to pursue the marketplace. We we had to have a convention product that we believed in, and we have exactly that, as I just mentioned. You know, the data around the advocacy and the tolerability and convenience, the switch data that we've generated, demonstrating that if patients move from one of this one of the existing prophylactic treatments over to Donnie DeVorsen, that they do better when they do switch and that they prefer Donnie DeVorsen once they're on it. When we started to see that data, thinking about our synergies that we do have, you know, we talked about the synergies between FCS and SHGG earlier.

When you think about the synergies in the back office, we think about our patient support program and and and also things like market access, etcetera. This is a program that we can layer into our our commercial portfolio and do really well with north of 500,000,000 as I referenced, but also be able to have those other synergies. Where we'll have to build is on the the field force size. Right? So we'll we will have a stand alone field force dedicated to HAE.

But being in this class of medication, how profitable this segment is, we believe we can compete effectively and that it will be a valuable return for Ionis to be able to stay on this market, take this program forward.

Joey Stringer, Bio Tech Analyst, Needham and Company: Great. The telemedicine program partnered Can you briefly walk us through the economics to Ionis?

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: I'll take that one. So we're really excited about telecarcin. It's a medicine we discovered. It targets risk factor, cardiovascular risk factor called Lp. And that's one that Novartis has currently in Phase three study that's on track to read out in the first half of next year.

So this is one where we've got with with Novartis. Novartis has estimated that there's gonna be peak sales in that multi billion dollar range. The estimate that gives us a royalty that is in the mid teens to low 20% range. And we're also eligible to receive more than 1,200,000,000.0 in payments for Policarson under our agreements with Novartis and also with Royalty Pharma on this program. So our next milestone payment.

For this is to be a $50,000,000 milestone payment on NDA acceptance.

Joey Stringer, Bio Tech Analyst, Needham and Company: Great. That's very helpful, Wade. Novartis in late January that the top line data for the Phase III CD outcomes trial for pelicarcen, it was shifted from second half of twenty twenty five to the first half of twenty twenty six based on the event rate. So I guess how should we view the potential impact to that shift on the trial outcome?

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: Yes. You bet. So it is an event based study. So the only thing that's changed is the estimates when we achieved the events needed for the power assumptions, and there was a paper published last week on the design and baseline characteristics of the study. They indicated that it was powered at 90% power to achieve about an 8080% or 28 risk reduction or hazard ratio.

So that's 20% risk reduction in the overall patient population. And so the the extension of the readout timing doesn't affect current assumptions or probability of success. It just meant that the initial estimate for the timing for that reaching those events was off a little bit. So there's still we and our very very confident that the study design is is is appropriate for the hiring. And if you look at the baseline characteristics, it gives us also comments because the the median l p level a level is a 86 deciliter, well above the the risk threshold of of 50.

And even above the higher risk threshold of ninety mgs per deciliter, which is one of the subgroup analysis that we're looking at in the study. So about about eighty percent or so of patients are above ninety milligrams per deciliter, so in the in the higher risk subpopulation. So looking at the baseline characteristics, the study population, and the safety design gives us confidence that the study, you know, can give us robust data on whether or not lowering, you know, having substantial lowering of belts away can reduce the risk of cardiovascular events.

Joey Stringer, Bio Tech Analyst, Needham and Company: Anything else going on the stats plan for the phase three? You touched on that a little bit, but mine is saying the trial is looking at CD risk reduction from your endpoint for both 70 plus and then the 90 plus take per deciliter. Can you explain the significance of each analysis? And I guess, how do you see how do you think these will be viewed by regulators? And what would this mean from a commercial opportunity perspective?

Sure.

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: So the the the first endpoint is, you know, in in the total population, which is patients who have up to the weight greater than seventy minutes per deciliter.

Kyle Ginny, Chief Global Product Strategy Officer, Ionis Pharmaceuticals: Yep.

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: And that's, again, 90% power to to see a 20% risk reduction in the subgroup that's greater than 90 from that from the study. We also have a primary endpoint there that looks at CD risk reduction that's powered to give us twenty five percent risk reduction at at at 90% powering. So, you know, it's pretty pretty good pretty good opportunity to hit that one as well. So if if if if we hit either one, it's a positive study, basically. I would say, you know, if only hit it in the greater than 90 mix per deciliter, that would probably limit the label to seeing, you know, a you know, two patients greater than 90.

Although, you never know with, you know, there's no treatment for high L2a exactly where where that will end up in in in labeling. That's that's part of the discussion. But that could be a potential outcome if if we only hit it in the greater than 90.

Joey Stringer, Bio Tech Analyst, Needham and Company: Got it. Lastly, I want to briefly touch on Angelman syndrome, how they view the program there. Can you briefly outline the unmet need here and what what is the commercial opportunity in Angelman syndrome?

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: Sure. I'll I'll start and drop and jump on the course opportunity if I mangle it. But it's a Angelman syndrome is is a rare disease, but it's pretty rare disease. We in research, of, it has a, like, type of opportunity. And it has huge unmet medical need.

It's a debilitating neurodevelopmental disease where the patients really never ever develop beyond the very young cognitive age. There there it's a tremendous burden on families and caregivers. And they're desperately in need of disease modifying treatments, and that's what we set out to develop and what we think we have. So our drug raises the levels of u d e three a protein, which is what's deficient in the disease. We've shown that preclinically, and we've shown that in our Phase one two Halo study where we demonstrated consistent and painful improvements relative to natural history on a whole bunch of functional areas.

More than ninety percent of patients showed clinically clinically meaningful improvements relative to natural history and overall Angelman syndrome measure of past called past AGI. We also look at specific measures in terms of communication, cognition, and motor function on things like and the daily core, which will be used for primary on our phase three study, which we plan to get started first half of this year and hopefully continue enrollment next year. Here, we have a cognitive a a communication endpoint for the primary on on the 34 scale. And we think it's a a great opportunity with patients who who who really need the needs of therapy.

Joey Stringer, Bio Tech Analyst, Needham and Company: What do you think differentiates Ionis' approach and program in Angelman relative to some of the competitors out there?

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: Well, I'll I'll start with the with the drugs. You can use a, what what I'll call a validated chemical class. It's the same type of molecule that led to SPINRAZA and CALSADI, the same type of molecule that is currently high stage study run by Biogen with the MAPT, tau lowering drug two eighty, which we have nice data on that has always target broadly in the CMS. You can see it with PET imaging. The class has a proven safety record, consistent and validated dosing ranges.

So we kind of know how to dose. We know the safety. We know the durability, which I really think helps us design our trials. We benchmark our drugs against everything out there in a in a model that predicts human performance, like human gene in a mouse, and we think it's the best way to do this. So we're very, very happy with the activity and duration and and profile of our drug.

As far as the phase three trial, we have a placebo controlled approach for our study, which we think is the gold standard to evaluate safety and efficacy in clinical trials. It also helps simplify the burden on the site a bit because you just need one team to measure the drug. And, you know, back to the molecule, we don't have to seems like he's a tilt table. We haven't filled administer corticosteroids. We haven't allowed.

So we check the profile of our drug in the way it's administered. We think it is it's consistent with the way we've done all of our intrathecal drugs based on our vast experience in the space, and we think the molecule class is is is right for this patient population. And we're clearly running out of time because our lights are not moving around enough. That's the timer. No.

Joey Stringer, Bio Tech Analyst, Needham and Company: We're we're we're we are up on time. So it's just some timing. But thank you, Wade, Kyle and Eric for participating. It was a very helpful discussion.

Eric Swayze, Executive Vice President of Research, Ionis Pharmaceuticals: Thanks for having us, Doug.

Joey Stringer, Bio Tech Analyst, Needham and Company: Thanks, everyone. Thanks joining on the webcast. Everyone have a good day and a good rest of the conference.

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