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

Hello, everyone, and welcome to Oppenheimer's 36th Annual Life Science Conference. I'm Jay Olson, one of the biotech analysts here at Oppenheimer, and it's a pleasure to welcome you to our discussion with Ionis. And it's an honor to introduce Brett Monia, the CEO, and the timing is perfect as the FDA has just accepted the sNDA filing for olezarsen to treat sHTG with a priority review, which is a really nice surprise this morning. And with that, thank you so much for joining us here today on a busy day. Brett, I'll turn it over to you.

Great. Thank you, Jay. It's a pleasure to be here. And yes, we're thrilled that we received yesterday the acceptance of our supplemental NDA for olezarsen sHTG prior to review status with a PDUFA date of June 30. So that sets us up really, really well. We're ready to launch in June -- at the end of June, early July, and we can talk a lot about that. So I have a few slides. I'll go through these quickly, and then we could open it up for Q&A. How does that sound? So again, it's a pleasure to be here at the Oppenheimer Annual Health Conference. Forward-looking statements, I recommend for you to look at the right time. So Ionis is very well positioned today for continued success. We've had a great deal of success in 2025. And it was one of our -- it was definitely a pivotal year, a transformational year for the company as we've really became a fully integrated commercial stage biotechnology company, something we've been seeking to do for the last 5, 6 years since I moved into the CEO role, and we achieved that. We had our first 2 independent launches last year and both are off to a very good start. TRYNGOLZA for FCS and DAWNZERA for HAE prophylaxis. We have great technology, great science that's fueling a robust innovative pipeline that's continuing to deliver success from mid-stage to late stage. The clinical results successes we've had over the last few years have been quite remarkable. Phase III -- positive Phase III results, FDA approvals, and successful launches and same can be said for the mid-stage pipeline. And as I said, the commercial launches, the initial independent commercial launches are off to a very good start. And all this is setting us up very nicely for accelerating revenue growth, positive cash flow and to achieve our objective to be cash flow breakeven by 2028 and then revenue growth there -- positive revenue growth there to follow. As a reminder, we are highly focused at Ionis. We're working in areas where the unmet need is the greatest, working in areas where our technology -- our technologies work most effectively and where we have a very strong track record of success. And those 2 areas are in cardiometabolic diseases as well as in neurological diseases. And we're developing treatments in these areas for both rare and highly prevalent common disease areas. As I said, we're building on a lot of really strong momentum that we -- based on the successes we've had in 2025 and even in 2024, and that's setting us up for an even more eventful, more exciting transformation set of transformational events in 2026 and beyond. Over the last couple of 2.5 years or so, we've had 6 positive Phase III readouts, 4 approved medicines. You can read them those medicines there. And as I already mentioned, 2 of those medicines are now independently launched successfully by Ionis, setting us up for a great deal of success. And we've established one of the most exciting innovative pipelines in the industry. Today, we have 11 medicines in late-stage development, many of which are set up to read out Phase III readouts this year, which we'll get into in a moment. So based on the pipeline success, based on the positive readouts, we're set up for a steady cadence of product approvals and launches over the next just through 2028 or actually through 2027. This is all based on the success we've already had with recent approvals, WAINUA for ATTR polyneuropathy, TRYNGOLZA for FCS, DAWNZERA for HAE. This year, we're expecting 3 product approvals and launches. Olezarsen in sHTG, as already mentioned, we received priority review with a PDUFA date of June 30 of this year. Zilganersen for a devastating neurodegenerative disease called Alexander disease. Zilganersen is expected -- we expect to achieve approval and launch later in the second half of this year. And bepirovirsen from our partner pipeline for chronic HBV, we announced the first week of January with our partner, GSK, really, really positive results, data demonstrating clinically meaningful functional cures in chronic HBV. And actually, GSK is working to rapidly bring this submissions to regulatory agencies, and they expect to have approval and launch in more than one market by the end of this year. And based on -- and assuming positive Phase III readouts in additional programs that are expected this year, that sets us up for additional launches next year, pelacarsen for Lp(a)-driven cardiovascular disease, eplontersen for ATTR cardiomyopathy due to read out in the second half of this year. It's a co-development, co-commercialization partnership with AstraZeneca that we're conducting, sefaxersen for IgA nephropathy. And then more to follow, including our Angelman syndrome program. What this means is that we will have launched 4 products independently by the end of this year and with our -- from our partner pipeline by the end of next year, 4 key partner launches, delivering a steady cadence of new medicines to patients to the market. DAWNZERA was approved on time. We're very proud of this fact. In August of last year as a novel prophylactic treatment for .hereditary angioedema. It is the first and only RNA-targeted medicine for the prevention of HAE attacks in this genetic disease. This is resonating -- the fact the novelty of the mechanism of action is resonating very well with the physicians that treat these patients and manage these patients. There's about 7,000 people with HAE in the United States today. And although there are existing prophylactic treatments on the market today, there's clear dissatisfaction by patients. They want better efficacy. They want better tolerability, they want better convenience. DAWNZERA offers a compelling product profile that really satisfies all 3 of those components. Substantial and durable efficacy, excellent safety and tolerability and the convenience of once per month or once every 2 months self-administration using a simple auto-injector. The early launch is off to a good start. It's a switch market. Patients are primarily a switch market. Patients that are on standard prophylactic treatment today are being switched from those treatments to DAWNZERA, recognizing that it offers what I just took you through, better efficacy, convenience, tolerability. And we're seeing switches from all 3 segments. We're seeing switches from existing prophylactic treatments. We're also seeing DAWNZERA being prescribed for patients that manage their disease using on-demand treatment. They're now trying their first ever prophylactic treatment, which is DAWNZERA. And we're seeing newly diagnosed patients move on to DAWNZERA. Now although it's a slower launch than you might -- than a launch into a disease area where there are no treatment options available because it's a switch market, we're still very, very pleased with everything we're seeing in the launch based on patient demand and enthusiasm as well as HCP. We also got approval in Europe in January, and that launch is now underway with our partner, Otsuka. This is our -- what our cardiometabolic pipeline looks like today, switching gears from HAE into cardiometabolic. We have a rich pipeline of medicines. Our wholly owned pipeline, of course, is anchored by olezarsen for severe hypertriglyceridemia. I also want to point out that we have a follow-on program to olezarsen targeting apoC-III ION775 that entered the clinic early last year, and we demonstrated proof of concept and that supports twice a year, maybe even once per year self-administration. So more durability, more convenience for patients. And we have other programs in our wholly owned pipeline for cardiometabolic diseases, including our first targeted delivery medicine for cardiac myocytes utilizing TfR1 targeting from our wholly owned pipeline. And then our partner pipeline, of course, is robust as well. Eplontersen for ATTR cardiomyopathy pelacarsen for Lp(a) cardiovascular disease, our AGT program with Kardigan and another targeted delivery strategy for the myocardium targeting phospholamban with our partner, AstraZeneca, which is now in Phase I development. So a very rich pipeline in cardiometabolic diseases, and it's going to continue to grow. TRYNGOLZA was our first independent launch, which is the first ever FDA-approved medicine for familial chylomicronemia syndrome, severe genetic disease that afflicts about 3,000 patients in the United States today. These patients suffer from a whole range of comorbidities, but most importantly, a potentially fatal bout of acute pancreatitis. We demonstrated robust efficacy, excellent safety and tolerability reductions in acute pancreatitis and the medicine is administered conveniently using an auto-injector once per month. The launch -- it was a great year for our first year of launch. We saw -- we demonstrated quarter-over-quarter growth for TRYNGOLZA in FCS. A 56% increase in quarter-over-quarter growth from third to fourth quarter in revenue, yielding $108 million in total revenue for the first year of launch, which exceeded all consensus, all estimates that were out there. And of course, the big opportunity for TRYNGOLZA is in the much larger disease indication, severe hypertriglyceridemia. More than 3 million people suffer from severe hypertriglyceridemia, which is defined as triglycerides 500 and above. Normal triglycerides are below 150. More than 3 million people with above 500, but more than 1 million people, about 1 million people or so with what we call high-risk severe hypertriglyceridemia, patients that have a history of AP, pancreatitis or above 880, which really puts them at risk for acute pancreatitis or other comorbidities. What we demonstrated at the American Heart Association in our presentation last year was highly statistically significant, clinically meaningful reductions of up to 72% reductions in triglycerides on top of standard of care in this patient population and highly statistically significant reduction in acute pancreatitis attacks. -- unprecedented, never been demonstrated before in this patient population, the reductions in AP that we shown in this study. Same administration as for FCS, very convenient and well accepted. And as we just touched on already, we were notified yesterday that we -- our sNDA for sHTG was accepted with priority review and PDUFA date of June 30. Recent -- early this year, we -- based on HCP demand research that we conducted, we increased our peak product sales for TRYNGOLZA and sHTG from more than $1 billion to more than $2 billion for this opportunity. And then now shifting gears quickly to neurology, our other main therapeutic area. We have, of course, a proven platform in neurology, having conceived, discovered and developed medicines such as SPINRAZA for SMA, QALSODY for SOD1-ALS, WAINUA for ATTR polyneuropathy. Today, we have 12 medicines in clinical development, 6 wholly owned, including Zilganersen for Alexander disease and our Angelman syndrome medicine, which is in Phase III development and from our partner pipeline as well, including our tau program in Alzheimer's disease with Biogen, , tominersen for Huntington's disease in Phase II development with Roche. And very importantly, a medicine that was discovered here at Ionis and licensed to Biogen as a follow-on to SPINRAZA, salanersen, which supports once per year intrathecal dosing, which will initiate Phase III development very shortly. Two products I'll highlight from our wholly owned pipeline that are very important. Zilganersen for the treatment of a fatal -- typically fatal leukodystrophy, neurodegenerative disease called Alexander disease. We reported positive Phase III data in September of last year. And we've now submitted our NDA for Zilganersen. That data included disease-modifying benefit never been shown in this patient population before. The NDA is now submitted, and we're expecting to launch in the second half of this year, and we've initiated now an expanded access program for this disease indication. This is important not only for patients, not only because it will potentially -- we expect it will provide meaningful revenue for Ionis, but also it represents Ionis' first of what we expect to be many independent launches in the neurology space. And then there's Obudanersen for the treatment of Angelman syndrome, which is now in Phase III development. This is, again, a rare disease, much larger than for Alexander's disease, more than 100,000 people in major geographies with Alexander disease. This is a neurodevelopmental disease, not a neurodegenerative disease. We've been granted breakthrough therapy designation based on our Phase I/II data, and we expect to complete enrollment in the Phase 3 REVEAL study this year with data expected next year. So we're not only delivering on the pipeline, we're delivering financially, and we're very well positioned to continue to drive substantial value through revenue generation and achieve our objective of cash flow breakeven by 2028. And what we're seeing just from the products over the next couple of years that we expect to be launched or have been launched over the last couple of years, more than $4 billion in potential annual peak product revenue from our Ionis-owned medicines that we launch ourselves. Based on royalties, more than $2 billion from partnered medicines exceeding more than $6 billion in revenue. So a very bright future for the company financially. And I think I'll wrap up -- I think I'm wrapping up here. As I mentioned, 2025 was a breakthrough year for the company and 2026 is set up to be another breakthrough year for the company. We're expecting 5 Phase 3 data readouts this year. One of already -- one positive readout has already happened, as I mentioned, at bepirovirsen for chronic HBV, but pelacarsen, eplontersen and the others, resulting in 4 NDA submissions, 3 product launches, 2 of which are independent and multiple Phase II data readouts, including our tau program with Biogen, which is expected around midyear this year. So I think that's my last slide, Jay, and I'll just now hand it off to you for questions.

Okay. Great. Thank you so much, Brett. And congrats again on the priority review. Maybe that's a good place to start, and it looks like this is really going to be a transformational year for Ionis with your 5 registrational studies reading out, one of them already positive. And now you get the priority review with a potential midyear launch for olezarsen in sHTG. Can you just talk about your commercial readiness? I know you said that you -- yesterday during your quarterly update, you mentioned that you'd be ready to launch at any time. And now that we know it's potentially going to be midyear. Just talk about some of the planning that's been done and the resources that you plan to have in place for launch.

Yes. The ability to be already out there in FCS in this patient community that is patients that are suffering from severely elevated triglycerides is a big advantage for us, right? So we're already out there. Our presence is well recognized in the HCP community and in the patient community. The efficacy, the safety, the tolerability, the availability of our team and patient support programs and so on has resonated extremely well in this community. I guess what I'm getting at is that we built our reputation as a leader in the triglyceride space, if you will. And that's resonating really well with treaters who not only treat FCS patients, but they also treat sHTG patients and they're asking when can I get my sHTG patients on this medicine. Of course, they have to wait until we get the label expanded to include sHTG. But my point is that the enthusiasm that we've built based on the positive outcomes and experiences with FCS is going to go really well for us in sHTG and building our reputation. We've been assuming a priority review just to make sure we are prepared for launch since last year. And we've now hired -- and we actually have recently earlier this year, hired our full field team to support the anticipated summer launch, early July launch for TRYNGOLZA in sHTG, that's about 200 or so field team representatives. They, of course, are focused on helping with the FCS launch, identification of patients, but also in educating on severe hypertriglyceridemia, what to look out for and those kinds of things build further strengthening our reputation. Our medical affairs team has been out there also for quite some time in preparing the field for TRYNGOLZA and educating on severe hypertriglyceridemia, again, establishing further strengthening our leadership there. Commercial supply is in place. We're in a good position. We're in good shape for the initial launch from a supply standpoint. So that's all taken care of. It's important to recognize that this is our first launch in a highly prevalent disease indication, FCS and HAE, of course, rare disease indications. And we're well prepared from a supply standpoint.

Okay. Great. And then I guess, just based on your leadership in the management of elevated triglycerides and your experience in FCS launch, how are you thinking about your launch strategy in sHTG? Will you initially focus on a certain segment of patients like those with a history of acute pancreatitis? Or how are you thinking about going out at launch for sHTG?

Yes. There -- we've been thinking about this for quite some time and receiving a great deal of feedback from the endocrinologists, the cardiologists, the lipid specialists, pancreatologists that manage these patients on who they would treat most urgently. And not surprisingly, although there's more than 3 million people estimated in the United States with sHTG, there's the more at-risk patient population that have already had a history or that have a history of acute pancreatitis. The patients that have triglycerides above 500 with AP history or patients that have triglycerides above 880 with or without a history of AP. Once you're above 880, there's really an inflection in the risk of potentially fatal acute pancreatitis attack. These are -- based on the HCP demand research that we have conducted and investigations, other types of investigations we've done, this is clearly the priority out of the gate. These are the patients that physicians feel are at the greatest risk and they want to treat. There's about 1 million, as I said, those patients in the U.S. Also patients, you can also lump in there patients that have high triglycerides above 500 that have other comorbidities versus history of cardiovascular disease or history of diabetes or have diabetes, for example. This is the high-risk patient population that we're going to focus on initially because that's -- those are the ones that physicians are going to treat most urgently. There's also patients that don't have a history of AP that are about 500 to 880. We expect some of those patients to be for TRYNGOLZA to be prescribed for as well, but that's not going to be the focus initially. Eventually, we expect to expand to that milder population, if you will, but that's not the focus as the initial focus.

Okay. Understood. And then I apologize for asking you this question because I know that the news is brand new. This morning, but a lot of investors ask about the impact on your revenue guidance. I know there's a lot of moving parts there, but any preliminary thoughts you could share with us there? Or is that more of a stay tuned type of thing?

It's going to be more of a stay tuned thing, Jay, but I'll confirm what we said in our earnings call yesterday is that everything we presented yesterday on guidance was assuming a standard review. And what we also said was that if we receive priority review, that, of course, gets us into the sHTG market much faster, 4 months faster. And therefore, it will affect our guidance, and it will improve our guidance. And we're going to share our revision or changes to our guidance at our end of Q1 earnings call coming up. And we'll also be able to -- it will also allow us to provide product level revenue guidance at that time for TRYNGOLZA and DAWNZERA.

Okay. Makes sense. We'll look forward to that. So maybe just shifting gears for a moment to DAWNZERA. I know you talked a lot about the different switching dynamics that are taking place in HAE. And it seems like the dosing frequency is a big advantage for DAWNZERA. So just curious if you're planning to develop a follow-on program that could have even less frequent dosing for HAE.

We certainly have the capabilities. We've proven that with our olezarsen follow-on, as I touched on earlier. We have a wealth of experience, not just in novel medicinal chemistry approaches for antisense oligonucleotides, but also siRNA technology too and the screening know-how and medicinal chemistry and so on. And using Ionis chemistry, we have -- our first si to enter the clinic was our olezarsen follow-on, which clearly easily supports biannual dosing and it's probably based on the durability we're seeing, it could support up to a year, once per year dosing. And we replicated that not in the clinic, but certainly preclinically yet, maybe we'll get into the clinic soon for pelacarsen follow-on, same profile as the olezarsen follow-on. We're certainly tuned into the competitive landscape in HAE. It's hard to beat the efficacy of the new treatments, the new prophylactic treatments DAWNZERA for HAE prophylaxis. So it's all about durability, less frequent dosing convenience. We have the capability to do that. We're working on it, but we haven't stated any specific guidance to when and if and when you'll see something move towards the clinic. But we certainly -- it's on our radar, and we have the capability to do it.

Okay. Understood. We will look forward to that. And maybe if I could just squeeze in one last question. I know that neuroscience is another area of leadership for Ionis. So I wanted to make sure that we got some color on your neuroscience portfolio and looking forward to the potential launch of ailganersen, can you just talk about the synergies that you can capture from zilganersen and apply to Obudanersen in your neurology portfolio? Are those both going to be global launches? And I guess, how should we expect that portfolio to evolve?

Yes. Congratulations on the pronunciation for Obudanersen. Some people struggle with that. Good job. So yes, Alexander's disease, is -- we're very proud of the work we've done in this space. We've worked with the families, the patient community for Alexander's disease for quite some time, several years now. We were -- it was a risky study. It was a very novel study. We went directly to Phase III development. We thought we had the right drug, the right target and the right design to be successful, and we were highly statistically disease-modifying impact on the primary endpoint and several secondary endpoints. And has been really well received by the community. It represents, as I mentioned before, our first independent launch in neurology. Of course, we have a long history in neurology, right? We are the ones that conceived, discovered and move forward QALSODY for SOD1-ALS, the first disease-modifying treatment for ALS, any cause of ALS and SPINRAZA. Alexander disease is -- gets the Ionis presence, the direct presence working directly with HCP, working directly with the patients because we're the ones delivering the medicine directly to those communities. And that is important in its own right for that medicine, but it also sets us up really well for our Angelman's program, which will read out next year for a much larger rare disease indication. It builds up our reputation for other programs like in prion disease, which we have a Phase II study that's ongoing that will read out next year and other programs in the space of dementia and neurodegenerative and neurodevelopmental diseases. The -- as far as the access globally, we will ensure that our medicines that we take forward independently are available for patients globally to the best of our ability. With that said, we -- our business model remains today as it was when we went on this journey to become fully integrated when we initiated our journey to become fully integrated to focus on the U.S. market for commercialization to find partners or distributors outside the U.S. to distribute our medicines more globally. As we did with HAE for Otsuka, Sobi for TRYNGOLZA. And Alexander disease, we'll partner ex U.S. as well to find -- to make sure that medicine is available. There's a lot of interest from partner -- potential partners. We'll get a partnership done before we launch for OUS availability. And then as we continue to develop our plans, we will -- we need to think through when is the right time for Ionis to begin to emerge out of the U.S. market or I should say, expand from the U.S. market to other geographies. It could be the Angelman's program. It could be some other program that follows out of that in the neurology space. So stay tuned for that. But for Zilga, we'll have a partner secured for OUS commercialization before we launch.

Okay. Sounds great. You've got a lot of options and really looking forward to what's playing out to be a transformational year at Ionis. So congrats on all the progress. And thank you again, Brett, for making time for us today. Really a pleasure to catch up with you.

It was a pleasure, Jay. Great catching up with you, too.

Thank you. Thanks, everybody.

Take care.