Ionis Pharmaceuticals, Inc. ($IONS)

All right. Everyone, welcome to this afternoon session of the first day of the 2026 Global Healthcare Conference here in sunny Miami. I'm happy to welcome everybody to my adopted hometown, as I said earlier. I'm Mani Foroohar, Senior Analyst [ Leerink ] Medicines. Very fortunate to be hosting Brett Monia, the CEO of Ionis Pharmaceuticals. Brett, how are you doing?

Great. It's great to be here, Mani. Happy to be in Miami.

I'm happy to have you. All are welcome. Let's chat a little bit. I know we spoke over breakfast this morning on some of these issues. So it's a little bit repetitive, you'll have to forgive me. But let's dive into where we are on the ongoing TRYNGOLZA launch and the transition to what's going to be an sHTG launch over the course of this year, but involves a little bit of label change, tinkering with pricing, contracting. Like how should we think about the tempo of that price evolution?

Sounds great, great topic. We're excited about the TRYNGOLZA program. Let me hijack that question very briefly and talk...

Hijack away.

A little bit, but I'll get to -- I'll be brief. We're set up for a great year in 2026. There's so many real game-changing events, some of which have already occurred, but we're really set up for a lot of them this year with the priority review for TRYNGOLZA achieved a week or so ago, sets us up really well. And then, of course, we had Phase III positive data with GSK, our partner for chronic HBV this year. And this builds on tremendous momentum from 2025, including our first 2 independent launches which both are off to a great start, including TRYNGOLZA for familial chylomicronemia syndrome. So that's a really short opening that 2025 was a pivotal year for the company. 2026 is set up to be a transformative -- really a transformative year for the company with so many game-changing events. First, FCS. The -- our first independent launch in our history was an incredible success in 2025. We achieved product revenue of $108 million quarter-over-quarter growth, beat all estimates that were out there based on the profile of the treatment, based on our ability to find patients and gain access with payers and so on. Of course, that's just the beginning for TRYNGOLZA. To your point, severe hypertriglyceridemia is coming, and that's not a rare disease like FCS is. sHTG is estimated to affect more than 3 million people in the United States today. There's a high-risk patient population that we can talk about a little bit that are particularly on risk for acute pancreatitis, which can be fatal, which is about 1 million people in the United States today, inadequate treatment options available for this large patient population. The FCS launch continues to go really well as we approach the sHTG launch. As I said before, we have got -- received priority review for sHTG with a PDUFA date of June 30. We're launch-ready. We've been -- we're in the field now preparing for the sHTG launch while we are promoting and doing sales on TRYNGOLZA for FCS. And that's going -- continues to go well. Despite the fact that there's a new competitive entrant into the FCS market, we've seen no meaningful impact on subscriptions for TRYNGOLZA for FCS patients nor on adherence persistence. It continues to go extremely well. Where we have had some impact is on pricing pressure, right? As you would expect, since we're priced at a rare disease, we've been priced at a rare disease since the 1st of January last year, and that has gone extremely well. A competitor has come in with a much, much lower price. We don't fully understand why, but we're receiving some pressure on that. We're managing it effectively. Different payers are requiring different negotiations. Some none, none. They're saying, we'll just wait for the sHTG launch. And we're having discussions with them on what that price could look like for sHTG, and that's giving them a lot of comfort. Others, we are reducing the price. So we're going to have some impact there, but it's only a few months. With the June launch or a July launch, a June PDUFA date, it's not that far along. What is that price going to be? For severe hypertriglyceridemia, we've been doing HCP research, HCP demand research for -- even before we had Phase III data that we announced last year at the American Heart Association. And then following the Phase III data, which was groundbreaking, 85% reduction in acute pancreatitis, 72% reduction in triglycerides on top of standard of care, truly remarkable data and then payer research as well. Based on HCP demand, we increased our peak product sales in the U.S. for more than $2 billion for TRYNGOLZA and sHTG. We announced that in January. That's over -- that's increased from $1 billion plus. That's based on HCP demand. The payer negotiations are going well. And we're -- our focus, of course, is to ensure for the highest price possible to retain as much value as possible while making sure that we do not create roadblocks for prescribers to put in NDCs in place or other restrictions that prevent easy -- relatively easy access for patients to maximize population that get access to TRYNGOLZA for sHTG. We're getting closer to the finish line. We're getting close. We think we're threading the needle very effectively on the ultimate WACC price. And we'll announce that price at approval and launch.

Almost as if you and I had this exact conversation hours ago. So let's dive into a little bit of those competitive dynamics. Looking forward to sHTG, you're going to have a year, perhaps a little year and change of headway before competitor launches. Competitors fairly publicly disclosed their top line WACC price at $60,000. You've given some commentary around net price. So it's a little bit of apples oranges. But let's talk about the size of this patient population and what parts of the sHTG population, starting from those who already have a pancreatitis event, very high 880-plus level of triglycerides 500, et cetera. Like which of those populations do you think are the sweet spot for TRYNGOLZA to launch into? And how does that influence pricing and contracting decisions?

Yes. First, we believe that having first-mover advantage, coupled with the amazing data that I just summarized for you that we presented last year is a big, big advantage there. And we think that we're at least a year, maybe 1.5 years now that we have priority review over competition for sHTG. I also mentioned at the beginning that this population, as defined by triglycerides 500 and above is over 3 million in the United States alone. But to your question, the patients that are in the greatest need, the patients that are going to be prioritized by endocrinologists, cardiologists, lipid specialists, pancreatologists, out of the gate are going to be those that are at the highest risk for acute pancreatitis. Who are those? Those are people that have already had an acute pancreatitis event. Some of them multiple events, and they're losing function of their pancreas because of those multiple events with triglycerides above 500 or those that are above 880, which is a critical threshold of triglycerides that cause persistent chylomicronemia, and that puts them at high risk for an acute pancreatitis event. And docs want to prevent that first attack from happening even if they didn't have a history of AP. As I mentioned, that's about 1 million people alone. Those are going to be the priority for physicians to target out of the gate because those are the ones in the greatest unmet need. We expect our label, though, to be broader than that. It's not just in the high-risk persistent chylomicronemia patient population. Guidelines say already, cardiology and endocrinology guidelines that if you have sHTG by -- as defined by 500 and above triglycerides, you need to treat patients as aggressively as you can to get them below 500. And there's going to be physicians that are going to want to prescribe to label. We expect label to be as an adjunct to diet for patients that have triglycerides above 500 period. So it's a much broader population, and we'll work on that broader -- the broader component of that population in time. But out of the gate, it's that severe high-risk patient population with a history of AP or above 880 that we'll be targeting and that physicians will prioritize as well to get to TRYNGOLZA as quickly as possible.

So let's talk about a debate that's around the same competitive dynamic. How much of a difference is there between your once-monthly form factor and once every 3-month form factor presumptively will enter the market a year later. How meaningful is that? Is there a sub-published to patients, patients for whom there is a huge difference in terms of convenience?

Not in the research we've done, also not in common sense practice, in common sense thinking. Once per month administration is very convenient out of the gate. And we do not believe that there's any evidence that going to every 3 months administration offers any meaningful advantage from a patient convenience standpoint. We are launched in FCS with an auto-injector, right? That means that you do not see the needle visibly, not a prefilled syringe. And that auto-injector has gone -- has resonated really well with the FCS patient population as it has for other launches we've done like WAINUA, for example, for TTR amyloidosis. Once per month is very convenient. What is far more important is the data, right? The data on 85% reduction in acute pancreatitis, 72% reduction in triglycerides, that's a very high bar for anyone to meet. And we believe that at the end of the day, the data is going to drive enthusiasm by practitioners in addition to being first to market and to set this market as we did in FCS, where we led the way. We've created this market opportunity in FCS. We identified the patient population as we did now -- as we're doing now in sHTG. And those are the big advantages is the product profile, which is going to be tough to beat and being first.

So let's talk about another point of differentiation or not, which is the debate around hepatic fat fraction. Obviously, this is one that's been discussed to what extent it's on mechanism, to what extent it may or may not be off mechanism. And what is the clinical significance of an elevated hepatic fat fraction seen in a proportion of patients in the CORE studies?

Yes. Let me level set for everybody, make sure we're all on the same page from the get-go. So what we saw was a small but dose-dependent increase in liver fat triglycerides in the liver of patients in our Phase III CORE and CORE 2 studies in sHTG, small but statistically significant, but small. We are 100% confident this is an on-target effect. Think about what we're doing here biologically, folks. We are very acutely, in other words, relatively fast and substantially reducing circulating triglycerides from the blood. And the clearance of those triglycerides is happening through 2 mechanisms. One is breakdown through lipoprotein lipase. The other is clearing through the liver, right? And the liver does -- when you look at the magnitude of triglycerides reductions we're achieving, the liver is doing a pretty darn good job of clearing that out without a substantial increase in liver fat, but there's some. We've also saw it with a competitor -- a competitor program with an siRNA where they showed in Phase II dose-dependent increase in liver fat. Same thing. It's on -- we believe this is on target and makes complete sense. With that said, we also went into this -- when we looked at the data, we also believe that this would be -- that the liver would be able to adapt to this, have an adaptive response. And once they got through that initial bolus of triglycerides that are cleared effectively, it would get around to the rest of the triglycerides in time. That's exactly what we're seeing in the long-term extension data. In 2 years out now, we have a sizable number of patients that are now -- have reached 2 years. We're continuing to monitor by MRI, and we're seeing return to baseline in patients. So we're going to publish and present that data later this year. But what's most important, that's important. But again, it's not an adverse event. It's not a toxicity. It's an observation because there is no correlation with clinical sequelae. There's no correlation with ALT elevations. There's no toxicity correlations at all. It's an observation. And we're seeing it return to baseline with time. So we look forward to sharing that data probably in the second half of this year.

Great. Let's move to commercial opportunity and just wrap up this topic. You've talked about in the U.S. alone, $2 billion-plus opportunity for you guys in this indication, obviously, a sizable population. Give us a quick overview of the status of this indication for you guys, OUS and your economics that you draw in from there?

Yes. So we have -- our business model today, it will evolve, but today is to focus on our independent launches in the United States market -- U.S. market and then to partner ex U.S. for the time being. There will be a time, not too far down the road, probably where we will emerge from the U.S. market. But today, we have partners for commercialization of TRYNGOLZA and DAWNZERA. For TRYNGOLZA, for FCS, we are now launched, approved and launched in Europe. Our partner is Sobi, and they're preparing for a launch in the broader we'll call sHTG population. Economics to Ionis is royalties in the mid-20% range or so. But what Sobi is doing is very thoughtful when it comes to pricing ex U.S. that will support pricing ex U.S. and addressing the patient population with the greatest unmet need is that they're focusing entirely on patients that have triglycerides 880 and above. Whether or not they have a history of AP, they're focused on that patient population, which instead of multiple millions of people is more in the 700,000 to 800,000 patient population range, which will allow them to command a higher price because it's the most severe patient population out there. Sobi has said that ex U.S., this is a greater than $1 billion product opportunity in Europe alone. So we have a good partner. I should also mention that our first-generation molecule, I'll call it that, WAYLIVRA, which is approved in Europe for FCS, Sobi is our partner. So they know this space well. They've done a great job with WAYLIVRA. And the first patients that have come on to TRYNGOLZA in the FCS launch are switches from WAYLIVRA over to TRYNGOLZA. And they're doing a great job finding new patients as well.

So let's pivot off of this end market over to another partnered program in TTR, obviously, cardio transform long time coming, critical data set for you guys. Talk to me about how you see the combo with tafamidis opportunity now? What -- what a positive static benefit on top of tafamidis would mean for your commercial opportunity in the U.S. and EU in cardio transform?

Yes. So very much looking forward to the Phase III data in cardiomyopathy in the second half of this year. Just as a reminder to everybody, we are approved for the hereditary TTR polyneuropathy indication already. And that launch continued -- the patient demand for WAINUA for polyneuropathy continues to be very, very strong, very encouraging. But we're only indicated for one -- we only have one indication now. It's the hereditary polyneuropathy. We're looking forward to get into the cardiomyopathy indication, which is well north of 500,000 patients or so. Our CARDIO-TTRansform Phase III study is the largest study ever conducted in TTR cardiomyopathy, and it's not even close. It's more than double the size of the next largest study conducted. There's one -- AMVUTTRA is approved, silencer, the first silencer for this indication is doing well. We're very pleased about that because we believe it bodes extremely well for our drug, eplontersen brand name WAINUA, based on sheerly on the fact that our product profile shows as good, if not better TTR lowering, excellent safety and convenience as a once-per month treatment that patients can self-administer at home and not rely on a health care provider to administer the drug like our competitor. We believe that the results of the first silencer actually greatly derisk the outcome of our study for the primary endpoint, which is what we're powered for. Getting into the secondary endpoints to your question about combination usage. Today, we know that the one silencer that's out there today is being used to some extent with stabilizers, a combination approach. We believe that the 2 mechanisms will be complementary and offer greater efficacy. However, there are headwinds on that because there's no data. There's absolutely no data showing added benefit of a combination usage. So as these branded molecules are out there with branded pricing, it creates payer pushback, if you will. We believe that, that can all change with data. If you have data that delivers believable and meaningful evidence of benefit in combination usage that HCPs will advocate because we know that all patients are continuing to progress on stabilizers. These are not treatments that are reversing disease or halting the progression. These patients are still progressing. They want added benefit and complementary mechanisms has the potential to offer that. We believe that we're set up to offer that data, to generate that data, which can go very well, which will resonate very well with HCPs and payers, if you can show them the data that covering 2 medicines will halt the disease or show added benefit versus either agent alone. We're not guiding towards stat sig. It's a secondary endpoint, but we are hedging our bets, if you will, that we could have really nice data in combination based on the size of our study. So we did elevate the secondary endpoint of combination to a key secondary endpoint. So it is part of a hierarchical statistical analysis plan in case we do hit it next year. Nevertheless, we will have the strongest data whether we hit stat sig or not in this study.

Let's pivot over as we have a couple of other studies talk about a partner study targeting Lp(a) with Novartis. It's been delayed a couple of times due to event rate. Admittedly, also Amgen has also seen delays. This has been something that's happened across the space. Talk about what you're expecting from the horizon based upon your conversations with your partner and how you think about the commercial opportunity at any particular level of event reduction, given the debate is, are we talking 15, 20, 18, et cetera? There's a lot of nuance on Wall Street.

Yes, there aren't a lot of independent cardiovascular risk factors left that aren't addressed by treatments today. Lp(a) is one of the last ones. We know that 8 million to 10 million people suffer from cardiovascular disease due to excessively high levels of Lp(a) causes atherosclerosis, strokes, heart attacks and is not effectively addressed with other agents that are out there today, PCSK-9, statins, anything that's out there today. What we're doing is targeting Lp(a) with pelacarsen, first mover advantage, at least 1.5 years ahead now with the delay you just referred to by a competitor program that's closest to get market first. Big market opportunity. The study is powered to achieve a 20% to 25% relative risk reduction. and based on several assumptions, but that's what the study was powered based on based on the Lp(a) lowering that we're achieving, which is greater than 80% in the study. And that's obviously a multibillion-dollar blockbuster opportunity with attractive economics to Ionis, Novartis running that study. The study has been delayed. As you mentioned, the competitor program was delayed, too, simply because -- I mean, as far as we could tell, we were blinded to the data, but it's just that the events are taking longer to accumulate to support the powering assumptions for this study than was originally projected. And a lot of assumptions go into that rate when you do something for the first time, an outcome trial for the first time. The other contributor to the slower event rate is the fact that these patients' other risk factors are extremely well controlled. Their LDL-cholesterol is normal. Their diabetes is controlled, their hypertension is controlled. This is a pure play on Lp(a) CBD, which is good for the drug, because that's what we're doing. We're lowering Lp(a). We're normalizing it in this study. Is this a big market opportunity if we don't hit 20%, if we hit 15%, 12%? This is still a big market opportunity even in that situation because the unmet need is so big and there are no effective treatments on the market today.

We've popped around the pipeline a little bit. I do want to move forward to your own wholly owned rare disease assets as well beyond that sort of commercial. I want to touch base on Angelman Syndrome, where your pivotal data is coming somewhat later than your competitor Ultragenyx. Talk about how you're going to be interpreting that data. and how it would read forward to your data and how you think about what its implications, both scientifically and strategically?

Yes. We launched our Phase III study called REVEAL in Angelman Syndrome using Obudanersen, that's the generic name now, ION582 previously. And the enrollment is going very well. We're going to complete enrollment this summer in our Phase III study. We reported Phase I/II data a year or 2 ago, about 1.5 years ago, showing really strong evidence that we were improving outcome in patients with Angelman Syndrome across the measurements we've made using whatever instrument we made, Bayley-4, SAS-CGI, ORCA instruments on communication, motor function, cognition compared to a very strong natural history data. So that led us to make the decision to move into Phase III development. And we're going to have data next year for that program. This is over 100,000 people in the United States with this rare disease with no effective treatment options available. We're very much looking forward to -- the competitor you mentioned who's going to have Phase III data in the second half of this year, and Mani, we're rooting for them. We want to see that be a good outcome in the study because we know we have a great drug, and we have a proven platform in CNS diseases, platform that is delivered SPINRAZA and QALSODY and our tau program, many more. But they are using a different chemistry than we're using. They're using a much lower dose than what we're using. Our dose is 5, sixfold higher. It's the highest dose that we tested in our Phase I/II study that showed the greatest benefit. So -- but we don't know why they're using a lower dose. Our data indicates equal potency in preclinical models. So we'll see. But we'll see what happens there. Obviously, plenty of room. There's other advantages that we have with respect to dosing and that kind of thing. But at the end of the day, this is a big market opportunity, and we're looking forward to their data in the second half of this year. And moreover, we're looking forward to our data next year.

So we've walked through the pipeline, wholly owned assets, partnered assets. I want to look out a little further to the future. There's a lot of debate around how -- not to say commoditized, but how competitive oligo therapy has gotten. We've seen with the patents that yourselves and Alnylam built the [indiscernible] business as it is now, but this sub-industry on the back of. Many of them expired. The backbone chemistries are developed are fairly well known. And there are many companies everywhere from San Diego, Boston, China, Hong Kong, et cetera, moving assets in the clinic, especially for liver-targeted RNAi. Talk about how you think about that increase in competitive intensity, how you stay ahead of that and what your strategy is to address what is going to be a more crowded pipeline space, especially in the liver?

Yes. What a difference a decade makes. Yes, it's -- as the lead pioneer in the space of oligonucleotide therapeutics, we're very proud of the fact how this has really taken hold and is producing such incredibly groundbreaking meaningful new medicines for the community. For liver targeting, it has become somewhat commoditized. We're seeing a lot of other companies come in who really have no experience in oligonucleotide therapeutics, but it's relatively straightforward to develop an siRNA for a liver target, to your point. And we're seeing them come in unable to really beat efficacy or potency, but they're really focused on durability, less frequent dosing, right? What we have done to counter that at Ionis is for any program that's under our control or any partner we can convince, we have follow-on molecules that are doing the same thing, right? We have a TRYNGOLZA follow-on that's in Phase II development now that supports 9-month dosing, once a year dosing. We're doing the same thing for our other wholly owned drugs and for some of our partnered programs. Where the real different -- so we're going to protect that in that way. But where we are also -- we are differentiating and extending our leadership is in innovation, right? We believe that we have the best platforms to expand, say, in CNS diseases using new blood-brain barrier penetrating technologies to allow us to target CNS diseases where we lead using subcutaneous administration, low-volume subcutaneous administration infrequently every couple of months or so, at least, maybe less frequent. Muscle targeting. We have our first novel ligand, the Bicycle ligand targeting cardiac myocytes in the Phase I development now using siRNA coupled to a bicycle going after a genetically validated target with our partner, AstraZeneca. And we have a second one coming that's wholly owned by Ionis that will be in the clinic possibly by the end of this year, maybe early next year. So it's all about innovation, Mani. It's -- you got to -- people are going to copy well you make sure you stay ahead of them and you become in your first to market and you continue to innovate to open up new opportunities. I think we're well on our way to lead -- continuing to lead in oligonucleotide therapeutics.

Great. And with that, I think we're out of time. And a pleasure to have you and looking forward to the conversation soon.

Great being here. Looking forward too. Thanks, Mani.