Okay, great. Good afternoon, everyone. I'm Ellie Merle, one of the biotech analysts here at Barclays. Very happy to have Ionis here with us today for a fireside chat, but we should call it a beachside chat since we are in Miami. Joining us from Ionis is Brett Monia, Chief Executive Officer. Brett, thank you so much for making the time and joining us today. Before we dive into questions that I know there's a lot of programs to cover and a very catalyst-rich year for you, maybe if you could give us an overview of, you know, the Ionis platform and portfolio and some of the key catalysts for the company over the next 12 to 18 months.
That sounds great. It's great to be here, Ellie. Thanks. You know, let me provide a brief intro on where we are today and where we're headed at Ionis. As I think most people in the audience are aware, we're a genetic medicines company focused on novel treatments targeting RNA for clinical medicine diseases where there's a high unmet need. You know, 2026 is really setting up to be a big year for the company, a transformational year for the company. We have so much coming and that's really built on tremendous momentum that we established last year in 2025.
In 2025, we launched our first two independent medicines, the first ever FDA-approved medicine for Familial chylomicronemia syndrome, FCS, TRYNGOLZA. As our first independent launch in our history, it was a spectacular success. Quarter-over-quarter growth, $108 million in total revenue for the year, beating all estimates. We also had our second independent launch with the August approval of DAWNZERA in hereditary angioedema, a prophylactic treatment for that disease, which really serves patients incredibly well, meeting the needs of patients. That launch too is off to a very good start. We also had several pipeline readouts last year that is gonna really serve us well this year.
The breakthrough, the most notable phase III readout we had was a wholly owned program of the second indication for TRYNGOLZA to follow FCS, which was for severe hypertriglyceridemia, a disease that's not rare, that afflicts millions of people in the United States that are in desperate need for new treatments to substantially lower triglycerides and avoid acute pancreatitis. We shared the full data at the American Heart Association, presented the data, and indeed, this is really set up to be a really big drug for the company, for patients, a blockbuster potential.
Also right around the same time, we announced positive phase III data for a new medicine for the treatment of a neurodegenerative disease called Alexander disease, a rare condition in which there are no effective treatment options that's commonly fatal. We showed highly statistically significant benefit in all endpoints in the study, essentially, including the primary endpoint of motor function. As I said, that momentum just sets us up great for this year. This year, we're looking forward to the approval and launch of TRYNGOLZA for severe hypertriglyceridemia, a blockbuster opportunity, as I mentioned, wholly owned. Just recently, just last week, we received priority review from the FDA recognizing the importance and the unmet need here. We're gonna launch in July.
That's obviously a big event for the company. We're also expecting the Alexander disease drug to be approved this year, and we'll launch that in the fall. From our partnered pipeline, the beat goes on. We're expecting five phase III readouts this year, one of which has already been achieved with our partner GSK for chronic HBV, which was highly positive. We announced that in January with GSK. We're expecting the phase III readouts for eplontersen for ATTR cardiomyopathy, pelacarsen for Lp(a) cardiovascular disease, an IgA nephropathy drug, and another, a second ALS drug. We have one approved already. Great year last year. This year's gonna be even better, and we're off to a fantastic start.
Great. Yeah, definitely. You're probably the company with the most catalysts in my entire coverage. You've a lot going on. Maybe starting with TRYNGOLZA and the commercial trajectory in FCS and, you know, potentially soon sHTG, can you give us more color on kind of the cadence of revenues you expect over the course of the year?
Yeah. It's gonna be really interesting, and very we're very much looking forward to it. It's gonna be a big year for TRYNGOLZA for severe hypertriglyceridemia. As I mentioned in my opening comments, the FCS launch was incredibly strong and quarter-over-quarter growth beating all consensus estimates on total revenue. This is continuing into this year with FCS with the FCS indication as we prepare for sHTG. The demand for TRYNGOLZA continues to ramp up for FCS. Patient stories, physician experiences are so incredibly strong. We're seeing re-authorizations come in over and over again. Patients are staying on drug and we're seeing continued growth demand, patient group demand for TRYNGOLZA and FCS.
Despite the emergence of a competitor that came late last year, we're continuing to see this go really well. You know, we are experiencing some pricing pressure. This is a rare disease drug with a rare disease price, and a competitor came in with a much lower price and for FCS. You know, we're managing that effectively. You know, different payers are requiring different things. All of them recognize the fact that we're just a few months away from launching an sHTG, which is really the key event. When we get to sHTG, when we get to the launch in July, with approval in late June expected, we'll announce price.
There'll be a step-down in price because we're gonna go from a population that's estimated to be 3,000 in the United States to a population that's estimated to be three million in the United States. It warrants obviously a significant step-down in price. We're working through that right now. We'll announce price. Our job is to maximize value, highest price possible, while ensuring that patients, the maximum number of patients can access TRYNGOLZA without physicians having difficulty in prescribing the drug or payers creating roadblocks for the drug to really maximize the full potential of this blockbuster opportunity. That's going really well. We're managing it effectively, and then there's a lot more to come.
Great. You know, feel free to answer this how you will. I know it's a sensitive topic, but price. There's a lot of conversation among investors around how to think about the sHTG pricing. How has your thinking on price evolved over time, and to what extent are you thinking about how this price decrease will work in practice?
Yeah. I think it was almost two years ago, you know, when we first introduced the opportunity in severe hypertriglyceridemia, an opportunity that was not appreciated by really almost anybody. We were making the case that this is a big opportunity, a big unmet need. Of course, everybody recognizes that now. One of the questions we continued to get was price. How are you gonna price it if when you go from FCS? You know, we did some back-of-the-envelope estimations, large patient population, and what we put out there at that time was $10,000-$20,000 price in net. Very important that that's a net price for sHTG. That was before we had data.
That was before we did, you know, really extensive market research, HCP demand research, payer research, and so on. Now that we have the phase III data, you know, groundbreaking results, we've been able to go and do more informative HCP demand research and payer research. We're coming to the conclusion there. We'll announce a WAC price. We're gonna move away from net price, you know, announcements and disclosures. We're gonna focus on a WAC price, and we'll announce that, as I said before, when we launch the drug this summer. Again, we're threading that needle. Maximize price while maximizing the ability for physicians to prescribe without a hassle, and payers to not provide roadblocks and access.
Mm-hmm. The sHTG population is very large. How are you thinking about the initial focus population for the launch and, you know, what you're expecting, frankly, from the initial cadence of the sHTG launch?
As I mentioned, 3+ million people with severe hypertriglyceridemia, that's defined as triglycerides 500 mg per dL and above. Normal triglycerides are below 150 mg. These patients suffer from many issues. Most importantly is the risk of a potentially fatal acute pancreatitis attack. If it's not fatal, it tends to lead to additional AP attacks, which cause eventually pancreatic failure if they continue. High unmet need. We showed an 85% reduction in acute pancreatitis attacks in our phase III study, unprecedented. Number needed to treat to prevent an AP attack in the highest-risk population was four patients. Treat four patients, you'll prevent one potentially fatal AP attack. Really remarkable results. Out of the gate, that's the population we're gonna focus on, is that highest-risk patient population.
That's based on what we're hearing also from the physicians, the cardiologists, the endocrinologists, the lipid specialists that manage these patients. First out of the gate are gonna be those patients that have had a history of acute pancreatitis or have such high triglycerides that they're gonna have an AP attack sooner or later. We want to prevent that first attack from happening. That's typically above 880 mg per dL . That's the high-risk population that's estimated to be about 600,000-700,000 patients in the United States. When you add to that patients with other comorbidities, they may not have had an AP attack. They have sHTG, but they have cardiovascular disease or diabetes. That rounds up to about a million in the United States.
That's the focus for us out of the gate. As far as revenue guidance and those sorts of things, you know, we're gonna be going from a rare disease price to a specialty price out of the gate. There's gonna be some impact initially on revenue out of the gate as we make up for volume in this indication, which will start to really take hold in the second half of this year and then really accelerate next year. We estimate $2+ billion in peak product sales in the United States alone. We're very confident we're going to achieve that based on the profile of TRYNGOLZA for sHTG, based on the fact.
Based on what we've experienced with FCS, which has been highly positive for this medicine, based on the HCP demand, what we're hearing from, and based on the awareness. Everybody in the cardiology, endocrinology community is aware of TRYNGOLZA, and they just can't wait to get to be able to treat their patients, sHTG patients with TRYNGOLZA. It'll dip a little bit in revenue and as we begin to get to that acceleration phase when we really increase volume.
Dipping prior to the launch because we should see price decreases even before the approval in sHTG?
Well, we're getting some price pressure, as I mentioned before, in FCS.
Mm-hmm
Between now and the late June PDUFA date, which we're managing effectively. We'll have a step down to the sHTG price at launch.
Mm-hmm.
It'll be a slow drop in revenue, but then we're expecting in second half of the year for it to pick up.
Yeah. Certainly a very exciting opportunity, and could be a major growth driver for you. We look forward to seeing that launch. Turning to some of the major clinical readouts this year. You have a lot of them. Maybe starting with CARDIO-TTRansform, I guess what's the latest on your expectations for what good data would look like? You know, your thinking on how the patient population, whether it's the patients on baseline tafamidis or other factors in terms of the severity of the disease might compare to other trials in the space.
ATTR cardiomyopathy is a growth market. You know, we've estimated 500,000 patients plus that have ATTR cardiomyopathy, heart failure, due to a buildup of TTR in the cardiac tissue. We don't really know what the prevalence is. This is clearly a growth market. There are several treatments out there today. There are two classes, stabilizers and one silencer that's on the market will be the second silencer, assuming positive phase III data in the second half of this year. A quick reminder for everybody that this same medicine is already approved in many geographies around the globe, including the United States, for the hereditary form of polyneuropathy. That launch is going very well.
The demand is very high and continues to grow in patient demand quarter-over-quarter, doing very well. I think that speaks to the profile of the drug. It's a really effective and well-tolerated medicine. For cardiomyopathy, we have the largest study ever conducted in ATTR cardiomyopathy. We were pleased with the results of the first silencer that read out at phase III in TTR cardiomyopathy, and how well the launch has gone because that bodes really well for us. Because we have the same mechanism of action, very similar profile, it's virtually identical reductions in TTR in this population. It greatly de-risks the outcome of our phase III study.
Based on the size of the study and the design of the study, we're gonna have several aspects of data that could be highly differentiating. Most notable, you highlighted the combination data, right? Tafamidis is the standard of care for TTR cardiomyopathy today in the United States. You know, there's been some usage of silencers, a silencer plus stabilizers out there. There's clearly going to be, and there has been more recently pushback, particularly by payers, to combine these data because they're expensive drugs, right? There's no data. There's absolutely zero data supporting combination usage will create added benefit to patients. Everybody progresses on stabilizers. They're breakthrough treatments. No mistake about it. Everybody's progressing and many patients progress rapidly, quickly.
Adding another mechanism of action like a silencer to a stabilizer could really add benefit, but there's no data. All previous studies were vastly underpowered. We have the potential to generate data for the first time that can show potentially if the mechanisms are indeed additive, we need to learn that. First time to really provide convincing evidence that combination adds greater benefit to patients with TTR cardiomyopathy, a high unmet need. Our peak product sales for eplontersen when we get to this market, we've announced it with our co-development, co-commercialization partner, AstraZeneca, to be $5+ billion , $5 billion range. That's based on replicating the previous silencer, if you will.
Having added data like combination data or other subgroup data, which we are in a good position based on the size of our study, is just upside to that peak product sales revenue that have been projected. In addition, patients have the ability with our medicine to self-administer, which is unique, right? It does not have to be administered by a healthcare provider. Ours will be the only silencer that can be administered by a patient themselves in the United States. That too is resonating incredibly well in the neuropathy, polyneuropathy launch. We think that that will be amplified in the cardiomyopathy launch.
Great. That's helpful. What are your latest expectations in thinking about whether you will reach statistical significance on the combination?
Well, that's a high bar. What we think will be a big win is if we can provide data that is, you know, that appears clinically meaningful and believable by HCPs that my patient's progressing, but they're getting some benefit from a stabilizer. Show me the data, and we, of course, publish it and so on, that patients are gonna do better. I'm gonna fight for this. I'm gonna advocate for this combination usage. Of course, once tafamidis goes generic, then the headwinds on using combination data, if there's data out there to support it or combination usage, if the data is out there to support it, will be easier to justify. With that said, that's our hope.
Again, assuming the mechanisms are additive, we have to prove that. If we hit statistical significance, then that's a grand slam, if you will, right out of the gate. You know, we're not necessarily, of course, powered for that. We're powered for our primary endpoint. Secondary endpoints, you don't typically are powered for. However, in case we underestimate the effect size of combination versus monotherapy in our study, we did make the decision to elevate the secondary endpoint on combination usage as a pre-specified secondary endpoint. We will have it in our hierarchical statistical analysis plan just in case. Our guidance is, you know, we're looking to see if we can just have believable, really meaningful data showing strong trends favoring combination usage.
Interesting. Well, certainly a large and growing market, so we look forward to seeing that data. Another major cardiovascular readout coming this year, Lp(a), massive population. How are you thinking about what would be clinically meaningful from a relative risk reduction here? Like, if we see something like 15%, is that clinically meaningful, and how are you thinking about that readout?
Clinically, clinical meaningfulness is always hinged on the unmet need, right?
Mm-hmm.
Eight-10 million people today have cardiovascular disease, often fatal myocardial infarctions, strokes, due to an independent risk factor, Lp(a), high levels of Lp(a). You're at high risk for cardiovascular disease. It's a big unmet need because no other treatments effectively lower Lp(a) to get them out of harm's way for an event, right? We're in the phase III study. We did the phase II. We licensed the drug to Novartis. The HORIZON phase III study will read out in the second half of this year, maybe by midyear. You know, we're expecting 80%+ reductions of TTR, of Lp(a), that gets the vast majority of patients into the normal range of Lp(a), getting them out of harm's way, we hope.
First to market by a significant length of time if the study is approved. A groundbreaking study in cardiovascular medicine. The study is powered, designed to achieve a 20% relative risk reduction in the overall population, 25% relative risk reduction in a slightly sicker patient population based on slightly higher Lp(a) levels in this study. That's all been published now, the demographics for this study. Your question, what's clinically meaningful? 10%, 15% is gonna be a big deal. The unmet need is enormous. There's no other treatment. Physicians are seeing patients that have had one, two cardiovascular events sometimes in their 20s, 30s, 40s of age because of this independent risk factor.
Any statistically significant reduction, statistically significant benefit on the primary outcome is gonna be important, and it's gonna be meaningful for HCPs who are trying to manage these patients, and they have no weapons. They have no ability to manage Lp(a) CVD. It's powered for 20%. Show me stat sig, and I think we have a real breakthrough in cardiology.
Mm-hmm. Yeah. Definitely exciting. Really look forward to seeing that data. Turning to your tau program with Biogen, I guess, what are your expectations for data this year, and what would give you confidence to move forward?
Yeah. You know, our two therapeutic areas of priority for Ionis are in cardiology, cardiometabolic diseases. We just talked a lot about that, and then in neurology. A platform that has delivered Spinraza for SMA, QALSODY for SOD1 ALS. Our zilganersen program, positive phase III data in Alexander disease that I mentioned in my opening. Next up is the phase II data for tau. You know, tau is considered to be one of the most relevant targets for dementias, Alzheimer's disease. The problem is that approaches like antibody approaches have not been able to target intracellularly produced tau, only extracellular, mopping up the extracellular.
We know that tau intracellular causes a severe neurodegenerative disease as well as extracellular, and by blocking production, we're gonna address both of those for the first time. In fact, we already did. Two years ago or so, we reported results phase I, two in patients with AD, where we showed not only substantial reductions in tau and CSF, we showed reversal of tau pathology by PET imaging, neurofibrillary tangles, reversal with evidence of improved cognition in that study. That's exactly what the phase II study that's gonna read out midyear this year. The study is called CELIA, a large phase II study with the primary endpoint of being CD Sum of Boxes, which is, you know, the cognition primary endpoint in the study.
We're looking at two dose levels. We're looking at dose intervals, three months or six months in intrathecal dosing. It'll be the first validation of a tau targeting approach blocking production in the neurology field. You asked expectations. I expect the study to be positive based on the phase I two data where we've already generated evidence of reversal of pathology and some evidence of improved cognition.
Great. Turning to Angelman, you know, not readout from you this year, but a readout from Ultragenyx, which I think a lot of investors view as a meaningful read-through to your program. How are you thinking about the size of the opportunity in Angelman, and what gives you confidence that some of the phase II data that you've seen or that Ultragenyx has seen could translate into a successful phase III study?
There's about 100,000 people living with this severe neurodevelopmental disease, Angelman syndrome. This is a rare disease. There are no effective treatments available for this disease. We and two other sponsors have reported positive early clinical data. Same mechanism of different drugs, but utilizing the same mechanism of action to address the root cause of the disease. Strong evidence of benefit in open label studies compared to natural history data. We have the fortune of the natural history data, and Angelman's is really strong. People have been working on this for years, so we have really good baselines to compare to, but it's still open label. With that said, we have a proven platform in neurology.
We know how to discover neurology drugs very effectively, and our phase I/2 data compared to natural history is very, very strong. We've seen in evidence of benefit across all symptoms, whether it be communication, cognition, motor function, just whatever instrument you use, Bayley-4, CGI, ORCA, others, we're seeing very consistent benefit. We're seeing now in long-term extension data that we reported last year, patients that are rolled over into the OLE from that study continued benefit in endpoints. You know, the first readout is gonna be the second half of this year. We're very much looking forward to it. You know, we believe in our medicine. We believe in our trial design, and we don't believe. You know, we believe that our drug, it's called Obudanersen, it really has strong potential to make a meaningful difference for the Angelman's community.
Great. Well, I know we're at time, but exciting year ahead and certainly a very large pipeline, so exciting things to come. Appreciate you making the time.
Thank you, Ellie. It was a pleasure.