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

Good morning, everybody, and thank you for joining us for the 46th Annual TD Cowen Healthcare Conference. I'm Yaron Werber from the biotech team, and it's really a great pleasure to moderate the next fireside chat with Brett Monia, Chief Executive Officer of Ionis. Brett, good to see you.

Good to see you. Yaron, I forgot how cold it gets in Boston.

It's about to get to 60, I believe, in a few days, but we avoided the snowstorm, which is what we were worried about. Next year, we'll do it in San Diego.

Yes. Sounds great...

So lots to talk about. Last year was really, I would say, a breakout year for Ionis. You are a topic for this year. So we're actually thinking this is going to be the breakout year since there's so much going on with almost 5 sets of data coming by the end of this year. So maybe let me turn it over to you, maybe as you think about the business, what are the critical deliverables for you and things that you're mostly focused on?

Thanks, Yaron. Good morning, everybody. Thanks for being here. So indeed, 2026 is set up to be a really big year for Ionis with so many pipeline and commercial events coming. And of course, what makes this year so transformational for Ionis and there's so much opportunity to get involved with Ionis this year still. We're building on tremendous momentum that we created in 2025, right? 2025 was also a very big year for the company, really a transformational year as well in that we achieved our vision to becoming a successful fully integrated commercial stage biotechnology company, evolving from a company that was really focused on R&D for decades, right? And we successfully did that, as I mentioned, with 2 independent launches, TRYNGOLZA for familial chylomicronemia syndrome, FCS, a full year of TRYNGOLZA for FCS, the first approved FDA medicine for FCS, a severe debilitating genetic disease and DAWNZERA for HAE prophylaxis, 2 launches that are off to excellent, excellent starts. And we had multiple really important meaningful clinical trial Phase III readouts last year, too, that sets us up in part for a very successful 2026. So looking into this year, so much opportunity at Ionis. Not only are we going to have an additional -- a full year launch for DAWNZERA in hereditary angioedema, -- but we're also looking to 2 additional independent FDA approvals and launches this year. TRYNGOLZA, going from a rare disease indication, FCS to a highly prevalent disease indication, severe hypertriglyceridemia. We achieved -- we received priority review acceptance with a PDUFA date of June 30 just last week for sHTG, a multibillion-dollar blockbuster opportunity. The Ionis is leading the way in with a PDUFA date of June 30, and we're ready to launch. And then in addition, we are looking at our first Ionis wholly owned neurology launch for a disease indication called Alexander disease, where we reported highly positive Phase III data last year. This represents the first of many anticipated neurology launches coming that are wholly owned by Ionis for years to come. And then in addition, on the partner side of things, we're expecting 5 positive -- or we're expecting 5 Phase III readouts from our partnered pipeline this year. One already is in the books and it's highly successful for bepirovirsen for chronic HBV with our partner, GSK. Two, cardiovascular outcome trials, pelacarsen for Lp(a) driven cardiovascular disease and eplontersen, our co-development co-commercialization partnership with AstraZeneca for ATTR cardiomyopathy. We have an ALS drug targeting a genetic cause of ALS and sefaxersen for IgA nephropathy. And if that's not enough, we're looking to start 2 new Phase III trials, at least 2 this year. Salanersen, a follow-on to SPINRAZA for spinal muscular atrophy that supports once per year intrathecal dosing and then sapablursen for polycythemia several readouts as well. So exciting Ionis really set up for substantial growth in this year.

Brett, when you're thinking about the guidance, the guidance for TRYNGOLZA was $820 million to $825 million, and that assumed a regular review, but now it's a priority review. I know you obviously can't amend the guidance today. As you -- you did also mention that you are expecting Redemplo was launched at $60,000 per year, so versus $595,000. And you are expecting that there will be a step down potentially in revenues and then a step up on the heels of a launch in sHTG, just as you, I imagine, are going to become a lot more competitive on price. How does that work in the commercial setting? Because on the one hand, one would imagine you're not going to be proactively offering a discount payer, but you want to maximize access. And at the same time, you haven't launched sHTG, so you haven't announced your new price. So kind of how -- maybe strategically, help us understand how that works.

So let me start with the guidance, and then I'll talk a little bit about pricing and the competitive landscape. So we put out our guidance for the 2026 year last year at our earnings call, and that was based, as you said, Yaron, on standard review for TRYNGOLZA olezarsen for severe hypertriglyceridemia. A day later within hours actually of our press release and our earnings call, we received acceptance of our supplemental NDA with the FDA for sHTG with priority review. So our guidance was set on standard review. Obviously, that's going to have an impact on our guidance, and we're looking forward to providing updated guidance at our Q1 earnings call this spring. You can expect that we will increase our revenue guidance. We will reduce our net operating loss at that time, and we'll also provide product level revenue guidance on TRYNGOLZA and DAWNZERA for the year. With respect to competitive landscape, pricing and so on, so let me just say flat out right from the beginning that with the entrance of a new competitor in the FCS space late last year, we've seen no impact, no meaningful impact at all on the demand for olezarsen for the loss of patients that were previously on olezarsen or the feedback we're getting from HCPs and so on. Obviously, we're getting some pushback from some on pricing because our price and they price that we think is commensurate with -- we're managing that. It's performed all payers, and we're only a little away from the sHTG approval in June and the launch. We're in good shape there. With respect to pricing on sHTG, I'm really happy with where we are today. We're the only one -- we're the only company that actually has Phase III data to utilize for meaningful product level discussions with payers, right? We have remarkable Phase III data on triglyceride lowering on top of standard of care, more than 70% reductions in triglyceride lowering in severe hypertriglyceridemia, 85% reduction in acute pancreatitis attacks, number needed to treat to prevent an acute pancreatitis in the severe population of 4 patients to prevent a potentially fatal attack after only 1 year. That is resonating incredibly well with the patient community. Our job, our mission is to thread that needle to maximize price to preserve as much value for TRYNGOLZA as possible while minimizing -- maximizing access of TRYNGOLZA for patients, minimizing NDC blocks and any sort of headwinds that payers are going to provide if we price too high. I like where we are today. The research is going very well, and we're looking forward to announcing price upon approval.

So I think historically, you mentioned $10,000 to $20,000. And I think now you're talking about $20,000 net -- and it sounds like you're getting more and more comfortable again. Redemplo was at $60,000. I think there's been -- in the past, you've said that $60,000 might be a little too high in terms of the -- given the breadth of the label in A. And when we talk to clinicians, they are not thinking that they're going to treat necessarily only the high-risk patients at all, but they're really looking at it as a broad utilization for the product. I know you can't say a lot about pricing, but is a sweet spot between $20,000 and $60,000 -- or why not go high and then rebate along the way?

So first of all, level set, there's more than 3 million people in the United States with severe hypertriglyceridemia that we think will qualify, if you will, be eligible for the treatment of TRYNGOLZA. Now of course, those at highest risk for acute pancreatitis that can be fatal and is debilitating and can lead to additional AP attacks will be the priority for Ionis, will be the priority for HCPs out of the gate. But still, that label will be broad. It will be 500 milligrams per deciliter and above. And we do expect, in addition to those at the greatest risk for acute pancreatitis attacks that -- and in accordance with the guidelines that are published that people with triglycerides above 500 will still -- some of those will still have access and will be prescribed TRYNGOLZA to manage sHTG to potentially debilitating fatal first-time acute pancreatitis attack. With respect to the pricing, $10,000 to $20,000 is what we announced would be a range on a net price for TRYNGOLZA before we even had data, right? That was providing some guidance to because we were getting a lot of questions about that. The competitor that you referred to on $60,000 is a WACC price, right? So we're comparing apples and oranges here, right? Since we had the data that we presented at AHA last year, we've been guiding towards the high end of that $10,000 to $20,000 range for a net price in the U.S. That's not necessarily where we're going to land. We're doing the research, as I mentioned before. And we, again, believe that we're in the best position to optimize the price to maximize patient access while maximizing value, maximizing price for Ionis and all stakeholders. So stay tuned for that. We'll certainly have room in there for negotiating with payers, rebating, what have you will, in our final price. But that 10 to 20 was set, and that's a net price that was set quite some time ago.

The first year data came out late last year. At what point can we expect the second year data from the study from core?

So we continue to publish new data from continuing to evaluate subgroups and so on data throughout the year. You can expect us to be presenting at ESC, AHA. We have presentations coming up at ACC looking at subgroups. The data that I think you might be referring to your own is 2-year data on the accumulation of a small increase in hepatic fat that we presented at American Heart Association last year in our Phase III data. Let me be direct on this data. We are 100% convinced as our experts in the field that we speak to that understand lipid metabolism in cardiovascular patients that this is an on-target effect of substantially and acutely -- acutely, I mean, rapidly reducing triglycerides in patients with high triglyceride levels, reducing those through the APOCIII mechanism in large part, occurring through clearance to the liver, right? So as we see -- as the liver is acclimating to this large bolus of triglycerides being cleared, it's going to take some time to clear the fat from the liver. We saw a small increase, and we're looking forward to presenting updates on new data as we follow these patients long term on what's happening to liver fat over time based on MRI. I want to remind you that this is an observation. It's not a toxicity. There was no clinical sequelae. There was no correlation with ALT elevations. It's just an observation. And I could also tell you that based on the data we're seeing to date, long-term treatment up to 2 years now with many patients, we're seeing -- as we expect, the liver is adapting to the triglycerides in the liver, and we're seeing a return of liver fat to baseline. We're looking forward to presenting that data as well as other data, 2-year updates data at a medical congress later this year.

Great. I'm going to switch to DAWNZERA. By any chance, if anybody has questions, just raise your hand and happy to take them. On DAWNZERA, you published $8 million for the year. It was $1 million was the first partial quarter in Q3, $7 million in Q4. I think we had $5 million or so in our model. Which patients are now using DAWNZERA? Are they -- it sounds like you've said that it's a combination of new switches and also patients moving from previous therapies as well. Is it mostly naive? Or is it mostly switchers because it's a switch market? And when they switch, at what point can they start testing the Q8 weeks?

We're very pleased with the fundamentals that we're seeing for the DAWNZERA launch to date. Remember, we launched DAWNZERA late last year, September of last year. There's other aspects of the launch that are important to remember. We did not -- we chose not to switch our patients that were on clinical trials over to commercial because we saw the value of long-term treatment with DAWNZERA. This is going to be extremely -- this resonates very well with the HCPs, the allergists that treat these patients to see long-term treatment and to be involved in our continuing clinical trials and to preserve those patients from other ongoing trials before we convert them over to commercial, which we will be doing soon. And in addition, we have a free drug program, a free drug program that allows DAWNZERA -- patients have access to DAWNZERA quickly while we're working through payers and reimbursements and those sorts of things so they can get their first dose of DAWNZERA quickly and then convert over to commercial after -- it's a once per month drug. So then after the first month, they get one dose and we can convert them over. So that's also impacting in the short term, the commercialization revenue for DAWNZERA. Like I said, we're very pleased with the demand for DAWNZERA, the enthusiasm. The novel mechanism of action for DAWNZERA as the only RNA-targeted medicine for HAE prophylaxis has really resonated well. Physicians are used to antibodies. They're used to small molecules. They want to use something novel that has resonated well. Of course, the product profile has also resonated well. You can administer DAWNZERA every 4 weeks or every 8 weeks of treatment, which is very convenient for patients using a simple auto-injector. The main -- the majority of patients, as we expected, that are going on to DAWNZERA switches. Switches primarily from Takhzyro. It's the market leader in the field. But we're seeing switches from all current prophylactic treatments in the for coming on to DAWNZERA. We're also seeing switches from patients that never had a prophylactic treatment to manage their disease using on-demand treatment, which was a bit of a surprise for us. We're also seeing some patients that are newly diagnosed as well. But it's principally the switch market that -- or the switch patients that we're seeing for coming on to DAWNZERA.

And maybe based on the OASISplus data, what percentage at least in the Phase III were able to successfully go to Q8 weeks?

Well, on the commercial side?

Maybe from the clinical studies, there's maybe a corollary for what...

Yes, yes, yes. So in the clinical studies, a smaller segment of patients, I think there was about 25% of patients in the randomized trial were on every 8-week dosing versus every 4-week dosing. And then when they moved into the open-label extension, they had the -- if they were well controlled, they had the option to go to every 8-week dosing. And we saw a good number of patients that went to every 8-week dosing in the open-label extension, but it wasn't a large percentage. DAWNZERA is -- we recommend, although it's not restricted to do this in the label, the label you can start with every 4-week dosing or every 8-week dosing. We recommend starting with every 4-week dosing. And that makes sense because although we're seeing 90-plus percent control of HAE attacks for either dosing regimen with long-term treatment, like out to a year in open-label extension, the onset of action for every 4-week dosing is faster. So we're recommending that patients start with every 4-week dosing and then if they're well controlled to move into the every 8-week dosing if they want to do that. We're seeing that. We're also seeing some patients start right out of the gate with every 8-week dosing, ignoring our recommendations and they're doing well. But that's the recommendation today, but the majority of patients -- the vast majority of patients are on every 4-week dosing right now on the commercial side.

And if patients start Q8 and they're not well controlled, they can dose down to Q8 to Q4?

They can, yes. They can come back to every 4-week dosing if they experience an attack, for example.

Okay. Maybe let's move to WAINUA with CARDIO-TTRansform. We're expecting that data, I think you've said in second half. I believe the 35 months would end around May. So we're thinking it's Q3. That's kind of our words. I think not yours, obviously. The study is at 1,438 patients, so -- almost 2.5x bigger than HELIOS-B. HELIOS-B looked at all-cause mortality. You're looking at cardiovascular mortality and frequency of recurrent CV events. Maybe just on that primary, why was that done in that all-cause mortality?

We're guiding to the second half of this year for the outcome of the CARDIO-TTRansform study. As you said, your own landmark study, largest study by far ever conducted in ATTR cardiomyopathy, which offers a lot of advantages with respect to data, data generation that we're going to be getting from this study, which is going to go really well. The primary endpoint is a composite of cardiovascular mortality and cardiovascular hospitalizations. We chose cardiovascular mortality because we believe it's the purest measure of cardiovascular benefit versus all-cause mortality, obviously. At the end of the day, honestly, Yaron, and this is true if you look at all the outcome trials done in this disease indication to date, they're pretty much the same. The vast, vast, vast majority of patients that experience a mortality event in TTR cardiomyopathy is due to cardiovascular causes. But that was the rationale there.

And when we looked at your study overall, because the study is so much bigger, part of it is you have a cardiac MRI sub-study and there's actually 2 components, so almost 2 kind of studies there. But when you look overall, maybe give us a little bit of a sense because this is more of an add-on to TAF or a stabilizer. At the time of HELIOS-B, stabilizer weren't quite standard of care. So they did have 22% of patients had tafamidis drop-ins. 395 patients in HELIOS-B had AMVUTTRA monotherapy. And when you looked at the data with sensoring for drop-ins or without hazard ratio was identical essentially, 0.67 versus 0.68, so essentially, in that study, AMVUTTRA worked very well mono and the combo didn't seem to do a lot more. But again, it was obviously fairly underpowered. Maybe give us a little bit of a sense in your study, just given the size, what can we expect? And where can it really shine in terms of data?

Our peak market sales for revenue for WAINUA is expected to be $5 billion plus. That's us and our partner, AstraZeneca said that. And that's based on replicating the other silence, the data that's out there in the other silence. Everything else is upside. Everything else is upside in this market opportunity for Ionis based on additional data that we'll be able to generate based on the size of the study, the powering of subgroups and so on. The HELIOS-B data, as I recall, had baseline tafamidis usage nearly 50%, not quite 50%. We're going to be a little bit over that at baseline. We're going to -- we're well balanced, not egregiously different. We'll have more than 50% of tafamidis at baseline, but it's still on par with HELIOS-B. And there'll be more drop-ins over time because, as you said, tafamidis will be standard of care. But we think that, that bodes really well for us because it is the real-world setting. It is what is being -- patients are using today. And we believe that adding silencer to a stabilizer is going to add -- is going to create additional benefit for patients. It makes complete sense to do so. They are complementary mechanisms of action. But previous studies were vastly underpowered to show any evidence of benefit. We think, obviously, the study -- the data that was generated previously with the first silent to reach the market bodes really well, lends tremendous confidence for a highly successful outcome for WAINUA in ATTR cardiomyopathy. But then based on the size of the study, we're going to -- we have the opportunity to demonstrate and provide believable, meaningful benefit -- evidence of benefit in combination usage, which we think is going to bode really well for combination usage. Remember, all patients eventually progress on stabilizers, right? There's a need to either switch patients or to combine them. Patients are getting some benefit, but they're progressing, you want to add another mechanism of action. And if you have the data to support that, it is going to go really well with HCPs, with payers and so on. We're well positioned to have the best data, the only data -- meaningful data in combination usage when we get there. And as far as the imaging studies, we think that's really important, too. We're going to have data sets that, again, stand-alone, only -- we're the only ones with cardiac MRI to measure amyloid load in the heart and related function in the heart. And technetium scintigraphy, another way to measure amyloid load in the heart. Are we clearing the amyloid faster or are we clearing the amyloid period? Are we doing it faster in combination usage and so on? Is that resulting in better heart function. So it's going to be a rich data set, and we're looking forward to it in the second half.

So the primary endpoint, as you mentioned, is essentially in all comers. But I think you have a secondary endpoint, specifically looking at combo. Can you -- and you elevated that in hierarchically in the analysis. Can you talk about that?

Yes. So we're guiding towards having the richest data set in combination usage based on the powering of our study, based on the size of our study and the percentage of patients with combination usage versus monotherapy in our study to be believable, meaningful when the study results. However, there's a chance that we can hit statsig. You never know, right? No one's ever done this before. So to -- in case we do hit statsig in the subgroup, combination usage, we certainly want to be able to have designated that as a key secondary endpoint to include it in the label, that kind of thing. So we elevated in our hierarchical statistical plan to a key secondary endpoint.

Okay. Let's maybe stay in cardio and move to pelacarsen. I think Novartis now said to expect data in the second half of the year from the HORIZON study. I think some of the comments suggested to people that it's sort of middle-ish, maybe the second half part of the middle of the year regardless, that's kind of what we're looking at. We get a lot of questions all the time. The study passed the 2 interim analysis. So we get a lot of questions, does that mean that the treatment effect might be smaller now that you're looking at the final analysis? Does it mean that it was powered for 20% in the overall and 25% MACE in higher risk, but is it possible to still hit statsig if it's even lower? Maybe just give us a little bit of your thoughts on just the Phase III cardiovascular outcomes? And what does it mean when you don't pass don't stop early in the interims? And what can or can we not glean on the final data?

We get a lot of questions, too. So we're excited about the pelacarsen outcome around midyear this year with our partner, Novartis. 8 million to 10 million people worldwide suffer from this independent cardiovascular risk factor. That means no impact -- no contribution of LDL cholesterol, hypertension, diabetes. This is a pure play on Lp(a), CVD. And if you have high levels of Lp(a), you need to get it lower to get them out of harm's way. The design paper has been published. The study is designed with a powering of 20% relative risk reduction in the overall population and in the higher-risk patient population with higher Lp(a), it's a 25% relative risk reduction in the study. I'll speak for Novartis because what they've said is that the delay in the readout for the study has -- in their view, has no impact on probability of success in the study. It's truly just simply in our view and their view that doing something for the first time, the first study to determine the outcome of a novel risk factor for the first time, which was based on a set of assumptions on epidemiology or other medicines that lower Lp(a) to some small extent while they're lowering other risk factors like LDL those powering assumptions are probably off a little bit. And it's just taken a little bit longer to accumulate the necessary number of events to support the powering of the study, first time through the gate. Those assumptions are probably off a little bit. With that said, 993 events are expected to be achieved that supports the readout this year, midyear this year. And Novartis remains very confident in the outcome of the study. Two interim analyses, as you mentioned, both of those were positive interim analyses in which the oversight committee recommended to management to continue the study as planned, and that certainly lends additional confidence.

Okay. I know we have about a minute left. So maybe a quick final question on Angelman 582. You've mentioned now that based on the longer-term data, you're shifting to the 80-milligram dose before you're testing 40 and 80 -- does that mean patients who started on 40, do they stay on 40? Or do they shift to 80? I assume all new patients are going to be at 80. And what led you to move to the higher dose?

So when we first designed the Phase III study, we designed it based on the Phase I/II study, the Phase III study is called REVEAL, which we evaluated in the Phase I/II study, 40 milligrams and 80 milligrams, and both showed a really believable clinically meaningful evidence of benefit versus natural history in this study. That was an evaluation after about 4 to 6 months of treatment, right? When we looked at the long-term extension of those patients, 40 and 80 milligrams for up to 2 years now, what we saw was some evidence of a dose response in which the 80-milligram was showing evidence of greater benefit. But moreover, we saw no safety signals at all that would preclude us from using the high dose to maximize efficacy in the long -- in the Phase III study. And to help us simplify the study to ensure that as many patients are possible -- as possible are receiving the most efficacious dose, no safety concerns, we decided to just focus on the 80 milligram versus placebo in the study. The patients that were on 40 milligrams that were already randomized into the study moved into an open-label extension, which we increased their dose to 80 milligrams, and they're going to stay on that in an open-label study. We expect to complete enrollment in our Angelman study this year and to read the Phase III data out next year.

So essentially, you'll need to sort of backfill those -- the patients on 40 mg?

Yes. Enrollment is going very well in the study. There was only a relatively small number of patients that were randomized to the 40s to make up for in our enrollment for the Phase III.

Well, terrific. I think we're at time. Brett, good to see you. Thanks so much for joining. Appreciate it.

Thank you, Yaron. It was a pleasure.