Okay. Well, 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. We avoided the snowstorm, which is what we were worried about. Next year, we'll do it in San Diego.
Yeah. Yeah, sounds great.
Lots to talk about. Last year was really, I would say, a breakout year for Ionis. You're our 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 five sets of data coming by the end of this year. Maybe let me turn it over to you. 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. Indeed, 2026 is set up to be a really big year for Ionis, with so many pipeline and commercial events coming. 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?
We successfully did that, as I mentioned, with two 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. Two launches that are off to excellent starts. 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. Looking into this year, so much opportunity at Ionis. Not only are we gonna have an additional full year of launch for DAWNZERA in hereditary angioedema, but we're also looking to two 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 30th just last week for sHTG, a multibillion-dollar blockbuster opportunity that Ionis is leading the way in with a PDUFA date of June 30th, and we're ready to launch. 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.
In addition, on the partnered side of things, we're expecting five positive, or we're expecting five 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)(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 IONIS-FB-LRx for IgA nephropathy. If that's not enough, we're looking to start two new phase III trials, at least two 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 line readouts as well.
Exciting that Ionis really set up for substantial growth in this year.
Great. Thank you, Brett. When you're thinking about the guidance, the guidance for TRYNGOLZA was $820-$825, and that assumed a regular review, now it's a priority review. I know you obviously can't, you know, amend the guidance today. You did also mention that you are expecting Redemplo was launched at $60,000 per year versus $595. 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 are, I imagine, are gonna become a lot more competitive on price. How does that work in the commercial setting?
On the one hand, one would imagine you're not gonna be proactively offering a discount to a payer, but you wanna maximize access, and at the same time, you haven't launched sHTG, so you haven't announced your new price. Maybe strategically help us understand how that works?
Let me start with the guidance, then we'll talk a little bit about pricing and the competitive landscape. 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. You know, our guidance was set on standard review. Obviously, that's gonna 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, 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 priced price that I think is commensurate with G. We're managing that.
You can affect its form as all payers, and we're only a little way 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 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 four patients to prevent a potentially fatal attack after only one 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 while maximizing access of TRYNGOLZA for patients, minimizing NDC blocks and any sort of headwinds for payers are gonna 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.
I think historically, you mentioned $10,000-$20,000. 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. I think there's been, in the past, you've said that $60 might be a little too high in terms of the given the breadth of the label AP. When we talk to clinicians, they're not thinking that they're going to treat necessarily the 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 the sweet spot between $20 and $60, or why not go high and then rebate along the way?
First of all, level set, there's more than three million people in the United States with severe hypertriglyceridemia that we think will qualify, if you will, be eligible for the treatment of TRYNGOLZA. 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. Still, that label will be broad. It'll be 500 milligrams per deciliter and above.
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, potentially debilitating, fatal, first-time acute pancreatitis attack. With respect to the pricing, $10K-$20K is what we announced would be a range on a net price, 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 $60K is a WAC price. Right? 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-$20 range for a net price in the U.S. That's not necessarily where we're gonna 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. Stay tuned for that. We'll certainly have room in there for negotiating with payers, rebating, what have you will, you know, in our final price. In that, you know, that $10-$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?
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, Yaron, is two-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 are 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, I mean rapidly reducing triglycerides in patients with high triglyceride levels. Reducing those through the apoC-III mechanism, in large part occurring through clearance through the liver, right? As we see, as the liver is acclimating to this large bolus of triglycerides being cleared, it's gonna 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 wanna 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. I could also tell you that based on the data we're seeing to date, long-term treatment up to two years now with many patients, we're seeing a, 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, two-year updates data at Medical Congress later this year.
Great. I'm gonna switch to DAWNZERA. By any chance, if anybody has questions, just raise your hand. I'm happy to take them. On DAWNZERA, you published at $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? It sounds like you've said that it's a combination of new switches and also patients moving from, you know, from previous therapies as well. Is it mostly naives, or is it mostly switchers 'cause it's a switch market? When they switch, at what point can they start testing the Q 8 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 chose not to switch our patients that were on clinical trials over to a commercial because we saw the value of long-term treatment with DAWNZERA. This resonates very well with the HCPs, the allergists that treat these patients to seek long-term treatment and to be involved in our, in 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. In addition, we have a free drug program.
A free drug program that allows DAWNZERA to patients to 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. After the first month, they get one dose and we can convert them over. 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. You know, the novel mechanism of action for DAWNZERA as an RNA, 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 wanna do something novel. That has resonated well.
Of course, the product profile has also resonated well. You can administer DAWNZERA every four weeks or every eight weeks of treatment, which is very convenient for patients using a simple auto-injector. The majority of patients, as we expected, that are going on to DAWNZERA are switchers. Switchers primarily from TAKHZYRO. It's the market leader in the field. We're seeing switchers from all current prophylactic treatments for coming on to DAWNZERA. We're also seeing switchers from patients that never had a prophylactic treatment and 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. It's principally the switch market that or the switch patients that we're seeing for coming onto DAWNZERA.
Maybe based on the OASISplus data, what percentage at least in the phase III, were able to successfully go to Q 8 weeks?
Well, on the commercial side?
Maybe from the clinical studies as maybe a corollary for what to expect.
Yeah, yeah. In the clinical studies, a smaller segment of patients, I think there was about 25% of patients in the randomized trial were on every eight-week dosing versus every four-week dosing. Then when they moved into the open-label extension, if they were well controlled, they had the option to go to every eight-week dosing. We saw a good number of patients that went to every eight-week dosing in the open-label extension, but it wasn't, you know, it wasn't a large percentage. We recommend, although it's not restricted to do this in the label, the label you can start with every four-week dosing or every eight-week dosing, we recommend starting with every four-week dosing.
That makes sense because, although we're seeing 90%+ 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 four-week dosing is faster. We're recommending that patients start with every four-week dosing and then, if they're well controlled, to move into the every eight-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 eight-week dosing, ignoring our recommendations, and they're doing well. That's the recommendation today, but the majority of patients, a vast majority of patients are on every four-week dosing right now on the commercial side.
If patients start Q8 and they're not well controlled, they can dose down to Q4?
They can, yes. They can come back to every four 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 2.5 x 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 and not all-cause mortality?
We're guiding to the second half of this year for the outcome of the CARDIO-TTRansform study. As you said, Yaron, landmark study, largest study by far ever conducted in ATTR cardiomyopathy, which offers a lot of advantages with respect to data generation that we're gonna be getting from this study, which is gonna go really well. The primary endpoint is a composite of cardiovascular mortality and cardiovascular hospitalizations. You know, 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. This is true if you look at all the outcome trials done in this, in this disease indication to date, they're pretty much the same.
The vast majority of patients that experience a mortality event in TTR cardiomyopathy is due to cardiovascular causes, but that was the rationale there.
When we looked at, you know, 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 two components, so almost two kind of studies there. When you look overall, maybe give us a little bit of a sense, 'cause this is more of an add-on to TAF or a stabilizer. At the time of HELIOS-B, stabilizers 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. When you looked at the data with censoring for drop-ins or without, hazard ratio was identical, essentially 0.67 versus 0.68.
Essentially in that study, eplontersen worked very well mono, and the combo didn't seem to do a lot more. Again, it was obviously fairly underpowered. Maybe give us a little bit of a sense when 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. That's based on replicating the data that's out there and the other silencer. 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 gonna be a little bit over that at baseline. We're well-balanced, not egregiously different. We'll have more than 50% of tafamidis at baseline. It's still on par with HELIOS-B.
There'll be more drop-ins over time because, as you said, tafamidis will be standard of care. We think that that bodes really well for us because it is the real-world setting. It is what patients are using today, and we believe that adding a silencer to a stabilizer is gonna create additional benefit for patients. It makes complete sense to do so. They're complementary mechanisms of action. 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 silencer to reach the market bodes really well, lends tremendous confidence for a highly successful outcome for WAINUA in ATTR cardiomyopathy.
Based on the size of the study, we have the opportunity to demonstrate and provide believable, meaningful benefit, evidence of benefit in combination usage, which we think is gonna 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 wanna add another mechanism of action, and if you have the data to support that, it is gonna 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. As far as the imaging studies, we think that's really important too.
We're gonna have data sets that, you know, again, stand alone. We're the only ones with cardiac MRI to measure amyloid load in the heart and related function in the heart. technetium scintigraphy, another way to measure amyloid load in the heart. Are we clearing the amyloid faster? Are we clearing the amyloid, period? Are we doing it faster in combination usage and so on? Is that resulting in better heart function? It's gonna be a rich data set, and we're looking forward to it second half.
The primary endpoint is, as you mentioned, is essentially an all-comers, I think you have a secondary endpoint specifically looking at combo. You elevated that hierarchically in the analysis. Can you talk about that?
Yeah. We're guiding towards having the richest data set and combination usage based on this 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, you know, there's a chance that we can hit stat sig. You never know, right? No one's ever done this before. If in case we do hit stat sig in the subgroup combination usage, we certainly wanna be able to have designated that as a key secondary endpoint to include it in the label and that kind of thing. So we elevated it in our hierarchical statistical plan to a key secondary endpoint.
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, you know, we get a lot of questions all the time. The study passed the two interim analysis, 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% may it's in a higher risk, but, you know, is it possible to still hit that sig if it's even lower?
Maybe just give us a little bit of your thoughts on just a phase III cardiovascular outcomes and what does it mean when you don't pass, when you 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. We're excited about the pelacarsen outcome around midyear this year with our partner, Novartis. Eight 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. 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, you know, 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. 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. That certainly lends additional confidence.
Okay. I know we have about a minute left, so maybe a quick, a final question on Angelman, ION582. You've mentioned now that based on the longer-term, data, you're shifting to the 80-milligram dose. Before, you were 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 gonna be at 80. What led you to move to the higher dose?
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 the study. That was an evaluation after about four to six months of treatment, right? When we looked at the long-term extension of those patients, 40 and 80 milligrams for up to two years now, what we saw was some evidence of a dose response in which the 80 milligram was showing evidence of greater benefit.
Moreover, we saw no safety signals at all that would preclude us from using the high dose to maximize efficacy in the phase III study. To help us simplify the study, to ensure that as many patients 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 in this study moved into an open-label extension, which we increased their dose to 80 milligrams, and they're gonna stay on that in a open-label study. We expect to complete enrollment in our Angelman study this year and to read the phase III data out next year.
Essentially, you'll need to sort of backfill those 40, the patients who on 40 mg?
Yeah. No, 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.