IONS - NASDAQ

Good morning, and welcome to Ionis Second Quarter 2025 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead up the call. Please go ahead.

Thanks, Steve. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financials. We believe non- GAAP financial results better represent the economics of our business and how we manage our business. We've also posted slides on our website that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer; Kyle Jenne, Chief Global Product Strategy Officer; Richard Geary, Chief Development Officer; and Beth Hougen, Chief Financial Officer; Eugene Schneider, our Chief Clinical Development Officer; and Eric Swayze, Executive Vice President of Research, will also join us for the Q&A portion of the call. I would like to draw your attention to Slide 3, which contains forward-looking language statement. During this call, we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail. And with that, I'll turn the call over to Brett.

Thanks, Wade. Good morning, everyone, and thank you for joining us on today's call. We have continued to build strong momentum across our business, highlighted by the excellent early commercial performance of our first independent launch Tryngolza, the first and only FDA-approved treatment for familial chyloymicronemia syndrome. Tryngolza exceeded revenue expectations during the second quarter on the market, underscoring its strong therapeutic profile, our well-executed commercial strategy as well as the significant unmet need Tryngolza is addressing. The revenue and commercial performance of Tryngolza to date, along with our confidence in Tryngolza's continued commercial success supports the increase in our financial guidance for 2025 which Beth will cover in more detail shortly. We're also pleased that Tryngolza recently received deposits of CHMP opinion paving a way to bring this transformative therapy to patients. Shifting gears, we anticipate Donidalorsen for erector angioedema or HAE will be our second independent launch by receiving FDA approval next month. Based on the progress of the review, we believe the approval and subsequent launch remains on track. Donidalorsen has the potential to become a preferred prophylactic therapy for many HAE patients with strong efficacy and on safety and tolerability in the pivotal studies, a patient-friendly autoinjector and a convenient dosing schedule of monthly or every other month self administration. We're well positioned to launch Donidalorsen filing approval. Additionally, our Phase III pipeline continues to advance well, with data expected later this year from 2 wholly owned Ionis programs. If positive, these results would support the continued steady cadence of independent launches next year, bringing important new treatments to patients. These include a second indication for Olezarsen in severe hypertriglyceridemia or sHTG, a condition of a large patient population and significant unmet need and

Thank you, Brett. With our first independent launch now well underway and a second launch right around the corner, our commercial team is executing on our strategy to capitalize on these significant growth opportunities. Tryngolza reported $19 million in net product sales for the second quarter, reflecting a threefold increase in revenues quarter-over-quarter. In the second quarter, Tryngolza continued to build launch momentum. This was a result of several factors, including effective patient identification efforts, a strong product profile, favorable payer dynamics and overwhelmingly positive HCP reported experience. Our patient identification initiatives are paying off. The breadth and depth of unique physicians prescribing Tryngolza continues to grow and meet prescribe the therapy to 2 or more patients underscoring the positive experience of both clinicians and patients. This demand also expands a broad mix of specialties with cardiologists and endocrinologists representing roughly 50% and 30% of prescribers, respectively, and lipidologists and internal medicine providers making up the balance. Overall, physician feedback remains highly favorable with significant benefits have remained favorable. To date, the coverage mix for patients entering goals is approximately 60% commercial and 40% government. Importantly, patients whether clinically diagnosed or genetically confirmed have gained access. Patients have obtained coverage through a growing number of formal policies or via the medical exception process. This highlights both the urgent unmet need and payers' willingness to support access even before formal policies are in place. Additionally, over 90% of patients have paid $0 out-of-pocket since launch and time lines for patients obtaining the medicine are consistently beating our aggressive internal benchmarks. Nearly all patients have opted into our Ionis Every Step Support program, a testament to the value the program is providing. We established the Ionis Every Step Support program to ensure a positive patient experience by providing disease and nutrition education, auto injector training and reimbursement support among other offerings. For health care providers, the program provides helpful support from insurance authorizations and coverage coordination to reauthorizations and refills. Proud of Tryngolza's early momentum in to focus on our patient finding efforts and HCP education. Our customer-facing team has reached over 3,000 physicians and over 30,000 HCPs have been targeted through our omnichannel capabilities, both intended to further increase awareness of FCS, expand patient identification and educate on the potential benefits of Tryngolza treatment. Backed by an experienced and high-performing team, we are well positioned to continue to take advantage of our first mover position to bring Tryngolza to patients in need and keep them on treatment. Just in FCS, we are advancing toward a potential blockbuster opportunity in severe hypertriglyceridemia with Olezarsen. SHTG represents a large patient population, many of whom struggle to manage their triglyceride levels with current treatments. In the U.S. alone, more than 1 million people have high-risk sHTG and includes individuals with triglyceride levels above 880 or above 500 with a history of acute pancreatitis. With a significant first-mover advantage, we believe Olezarsen is well positioned to address the unmet needs of patients with severe hypertriglyceridemia. Our commercial team is making excellent progress as we prepare for a potential launch next year. Donidalorsen, our second independent launch has the potential to transform the treatment paradigm for individuals with HAE as the first and only RNA-targeted prophylactic medicine. More than 20,000 people in the U.S. and in Europe are estimated to have HAE with approximately 7,000 people in the U.S. alone. Most patients are currently on prophylactic treatment. However, many HAE patients remain unsatisfied with up to 20% of patients switching therapies each year in search of a more effective and convenient option, highlighting a need for new treatments with enhanced profiles. We believe Donidalorsen is uniquely positioned to meet this demand. The Donidalorsen clinical data have shown durable efficacy and favorable safety and tolerability profile with a patient- friendly monthly or every other month self-administration with an auto-injector. Importantly, as we prepare to bring Donidalorsen to market, we are applying the same disciplined and innovative approach that has made the Tryngolza launch a success. We have deployed our field team who are educating and anticipated approval of Donidalorsen and are energized to successfully execute the launch. Meanwhile, our market access team is actively engaging with payers and our -- continues to lay the essential groundwork to ensure a smooth and successful launch. Our experience and scalable commercial organization is already delivering excellent results, so the early success seen with the launch of Tryngolza and FCS. As we build on this momentum, we remain focused on maximizing Tryngolza's full potential while preparing to successfully execute teaches by the end of next year, including Donidalorsen in the coming weeks, enabling Ionis to reach more people in need with our medicines. With that, I'll now turn it over to Richard.

Thank you, Kyle. We are making excellent progress across our pipeline, positioning Ionis to deliver on our mission of bringing transformational medicines for years to come. Let me start with the recent updates from our wholly owned pipeline. As a reminder, Donidalorsen is currently under regulatory review in both the U.S. and EU, with submission supported by its robust clinical data. We remain confident in the August 21 PDUFA date based on the engagement we've had with the FDA at this stage in the process. Pending approval, we look forward to making this potential best-in-class prophylactic treatment available to people living with HAE. Beyond its approved use in FCS, Olezarsen is also being evaluated for the treatment of severe hypertriglyceridemia or sHTG, with 3 separate Phase III studies supporting our planned sNDA filing, assuming positive data. Line results from the ESSENCE study which will help satisfy the regulatory safety requirements for the broad HTG population. ESSENCE primarily enrolled patients with triglyceride levels between 150 and 500 milligrams per deciliter, a level of dry glycerides that is generally not associated with high risk for acute pancreatitis. In contrast, the CORE and CORE2 studies exclusively enrolled sHTG patients. Participants in these studies had triglycerides that were greater than 500-milligram per deciliter with approximately 43% of the participants across both studies with triglycerides greater than 880-milligram per deciliter at baseline triglycerides at this level for acute pancreatitis. The ESSENCE study met its primary end point showing statistically significant placebo-adjusted mean reductions in triglyceride levels of 61% and 58% at 6 months with the 80- and 50-milligram monthly dosing, respectively. The vast majority of participants thus reaching the normal range. Also had all key secondary endpoints stated a favorable safety and tolerability profile. The results from this study were recently accepted as a hotline session at the ESC Congress 2025, and we look forward to sharing additional details from the study then. The Phase I, these studies remain on track with top line results expected in September. We believe this indication representable to adequately manage their triglycerides with current therapies. Physician feedback continues to highlight strong, underscoring the potential value of Olezarsen in this population. Importantly, this feedback indicates that physicians understand that lowering triglycerides will reduce the risk of acute pancreatitis and that they would prescribe Olezarsen, if approved, based solely on its ability to substantially lower triglycerides. Although the CORE and CORE2 studies were not designed as AP outcome studies, we are seeing acute pancreatitis events on a blinded basis. As a result, we expect to have accumulated more combined pancreatitis events for CORE and CORE2 than we had in the FCS balance study. This gives us confidence we could have sufficient data to observe at least a favorable

Thank you, Richard. I'm pleased to report that for the second time this year, we are significantly raising our 2025 financial guidance. This time driven by strong revenue performance to date, including the early launch success of Tryngolza and an improved outlook for the year. In the second quarter, we earned revenue of $452 million, a twofold increase year-over-year and $584 million for the first 6 months of 2025, an increase of nearly 70% versus prior year. The strong second quarter revenue we earned also enabled us to generate $154 million in non-GAAP net income for the quarter. As you heard from Kyle, the early Tryngolza launch continues to perform $3 million in product sales, representing a threefold increase over the first quarter. Royalty revenues increased by approximately 10% to $70 million in the second quarter, anchored by meaningful contributions from both SPINRA

Another period of strong execution and momentum for Ionis. The continued excellent performance of Tryngolza highlight the strength of our commercial execution and the value of our innovative science and addressing serious unmet needs. As we prepare for the potential approval and launch of Donidalorsen, the deep and advancing Phase III pipeline, we are well positioned to deliver a steady cadence of independent and partnered launches over the next few years. These upcoming milestones reflect the significant progress we're making towards delivering additional transformative medicines to people with serious diseases and building a sustainable, high- growth company. Before I conclude, I'd like to provide 2 additional announcements. On October 7, we will be hosting an Innovation Day in New York City to highlight our pipeline, our drug discovery capabilities and will provide additional insights into our ongoing and upcoming independent launches. We'll provide additional information as they get closer for what we believe will be a highly informative event. Additionally, we are eager in the CORE in CORE2 Phase III studies in HCG. Given that we expect to report the results of both studies at one time in September, we will be initiating a quiet period starting to more, July 31. Our quiet period will be lifted upon data announcement and with that, we'll now open it up for questions.

[Operator Instructions] Our first question comes from Gary Nachman with Raymond James.

Congrats on the strong quarter. So first, just talk a bit more about how the Tryngolza FCS launch is going in terms of finding these new patients and getting them through the reimbursement process and on drug. So what gives you confidence we'll see that strong sequential growth in the back half of the year based on the fiscal year guidance of $75 million to $80 million. So for us a little bit more on that. And then on the upcoming sHTG readout in September just what level of trig lowering are you expecting to see? What are you powered to see? And what do you believe will be considered clinically meaningful in these patients that physicians want to say? And it sounds like you're still confident there'll be enough pancreatitis events across both studies to show a positive trend. Do you think physicians need to see that to use it for severe high trigs bearing in the physician community on that?

Thanks, Gary. Kyle, would you start with the FCS launch? What we expect in the second half of the year?

Thanks, Gary. So as we communicated, we're really off to an encouraging start, again, with the FCS launch in Tryngolza for the first half of the year. the $19 million in Q2 and a threefold increase over the previous quarter really demonstrates the early momentum that we're very proud of. The product profile, first of all, is playing through very effectively. The reductions in and APOCIII, reductions in triglycerides, improvements in acute pancreatitis or reduction in risk of acute pancreatitis and reductions in hospitalizations, I mean all of these things stack up very, very favorably in terms of the receptivity for Tryngolza and the FCS population. In addition to that, a very strong commercial strategy, as I referenced, our customer-facing team has over 3,000 physicians that they're interacting with currently. Our marketing and our omnichannel capabilities were reaching greater than 30,000 HCPs right now with that education. And then you also asked about reimbursement, access is going extremely well, either clinically diagnosed or genetically confirmed patients are going through the process and getting reimbursement very quickly. Patient out-of-pocket expenses, greater than 90% of those patients are paying $0 out of pocket. So overall, what we're seeing is very strong execution from a very strong program. In terms of the second half, the real focus is on additional patient identification and continuing to get those patients diagnosed. And through the activities of our commercial team, be it customer-facing and/or our omnichannel and marketing capabilities we expect that to continue, but to continue to identify these upwards of 3,000 patients that potentially have FCS is going to some work, and we expect that we'll continue that growth throughout the rest of the year.

Thanks, Kyle. Gary, the triglyceride lowering that we're expecting in sHTG is probably going to be similar to what we saw in ESSENCE. Where we saw 58% to 62% reduction based on the dose 50 year versus 80 milligrams. And what we know based on extensive work we've done with the lipid specialists or the cardiologists or the endocrinologists that manage these patients what they're looking for are any substantial reductions in triglycerides on top of the treatments they're already giving their patients quite omega-3, fatty acids or fibrates. So they're already recognized that these patients need to be treated, and they're not getting much triglycerides lowering to the existing treatments, so they want something to produce a substantial lowering of triglycerides. Anything north of 50% is a big win in this patient population on top of standard of care and that is what we expect. With respect to AP events and what we're hearing from physicians, we're hearing exactly what I just said, is that substantially lower that these patients are in harm's way for acute pancreatitis that can be fatal and we need to lower their triglycerides substantially to get them out that way. They don't need to see the AP advance. However, with that said, although the CORE and CORE2 studies were not the AP outcome studies, we are seeing, as Richard mentioned in his formal remarks, we are seeing on a blinded basis, acute pancreatitis events. And we expect to have more accumulated AP events in the combined CORE and CORE2 study than we had in the FCS BALANCE study. This gives us confidence we could have sufficient data to observe at least a favorable trend in Olezarsen's impact on AP within these studies, and we look forward to discussing more when we read out the data in September.

Okay. Great. And then just 1 quick 1 on doni with the PDUFA coming up on August 21. Just you're in labeling discussions. So how you feel relative to your expectations, if you think the switch data will make it on there if it will be once every month and once every other month dosing, that option will be available for patients. And it sounds like you're ready to launch basically right after approval. So just confirm everything is in place for that?

I'll start. This is Richard. We're definitely on track for the PDUFA date on August 21, everything that we've been discussing with FDA indicates that, that date is on track. And then I can't speak to the launch, although everything looks to be in place, and we're excited about it. I think your other question in regard to what we get in the label is a matter of negotiation, it always is. And so we work with the agency. That's certainly been our position, let's get that in there, but we don't need it in the label because it is published. And now that we have a publication and it's related to the work that was done in the clinical trials, we have an opportunity to promote on that.

Kyle, maybe you could touch on the launch preparations.

In terms of launch readiness, we're building on the synergies from our FCS capabilities. Our medical affairs teams have been out interacting with allergists and immunologists treating HAE. Our sales team is now in place, market access abilities. So everything is ready to go in terms of launch readiness. As Richard was describing the program from a regulatory standpoint, the overall totality of the data here for Donidalorsen is very, very strong from an efficacy standpoint, in terms of the durability and control of attacks, the tolerability using the easy-to-use, self-administered auto-injector by the patient and convenience. Here, we have a program with the longest dosing interval available or potentially that will be available for patients living with HAE. The Switch study is going to be helpful. This is in United States. The majority of patients are on a prophylactic treatment today. And what we were able to demonstrate is that, number one, patients are willing to switch. Number two, they can do so safely and move over to Donidalorsen, they can have an additional reduction of upwards of 62% improvement from baseline on an existing and 84% of the patients said that they preferred Donidalorsen over the existing treatment that they were on once they were switched. So the totality of the data combined with the timing of the launch year upcoming, hopefully, on August 21, we'll be ready to go.

The next question is from the line of Yanan

Great. Congrats on a very strong quarter. Perhaps a first question about CORE and CORE2. So I think I heard in the prepared remarks that the cumulative AP rate on a blended basis is now above what you saw in FCS. So I just want to confirm. It seems like in the BALANCE study, you had 13 events and just wanted to get a sense of in the CORE and CORE2 was across 1,000-plus patients. Are we thinking about the rate above that? And could you also give us a sense that based on the CORE, CORE2 patient profile, what is the expected AT rate in untreated population like that so that we can help us prepare for the data and the AP data? And I've a follow-up on the FCS and sHTG launch dynamic.

Yanan, so you said the rate is higher. It's about the rate, the rate is lower, of course, in HCG. I think that's what you knew that. What we're talking about is the accumulated number of AP events in the CORE and CORE2 studies combined. And I can confirm that there'll be more events in CORE, CORE2 combined FCS BALANCE study. As far as what we think the AP, I mean, we don't really know what the AP rate is -- this study will be the first actually really definitively provide information on what the AP event rate is in sHTG. Is that right, Eugene?

Yes, absolutely right. There's no outcome data can inform us. We're early awaiting the CORE and CORE2 readout.

Got it. Got it Yes, yes. And on the FCS launch and potentially the later launch of sHTG. Congrats on a very strong second quarter of launch in FCS. It feels like the opportunity in FCS is actually pretty sizable given this momentum. Can you talk about is this opportunity relative to your anticipation? Is it bigger or in line? And more importantly, as we think about you going into SHTG with a much reduction in the pricing presumably across the board for both indications. Any strategy to protect the FCS opportunity in terms of timing of launch and also any way to manage the pricing change? That would be super helpful.

Yes. Let me first talk about the FCS population that you described. I still believe that it's representative up to 3,000 potential patients. It's still early innings. The majority of these patients still are not diagnosed. Obviously, several hundred patients have either participated in a clinical trial or we're waiting for a medication because they had been previously diagnosed and needed a treatment. First mover advantage here is very important, not only in FCS but also sHTG. So our work for the first half of this year was to convert our clinical trial patients, which we did effectively to help those patients that were previously identified with FCS to go on to treatment. And then to continue to expand our patient identification efforts, we've been spending a lot of time on that, as I referenced in terms of reaching greater than 3,000 HCPs with our sales team and reaching greater than 30,000 HCPs through our education related to our marketing and our omnichannel efforts. So we're continuing to educate. The time that we're spending on FCS specifically is with physicians that are treating SHTG patients. And so what we're doing is having conversations around the implications of high triglycerides and how these patients present and ultimately looking for a phenotype of an FCS patient in order to either clinically diagnose them or get a genetic confirmation of their disease. So that work is ongoing, and that's what we'll need to do through the second half of this year. We provided the guidance of $75 million to $80 million this year, which represents not only the patients that we've converted already in the first half, but the ongoing efforts that we believe will be successful with through the second half of this year. So I believe that the FCS population is in line up to 3,000 that we've represented up to this point. As it relates to sHTG, this is a much broader patient population, obviously, in the treating physician population is much more significant. Greater than 1 million patients have high-risk sHTG, which is inclusive, obviously, of patients over 500 with a history of AP or patients over 880 milligrams per deciliter. So there's a lot of effort already around education in this population and working to identify these potential patients within these practices as we go out and have these interactions. As it relates to the pricing dynamic, we're still working through that. There's more work for us to understand in terms of the data, which we are still waiting for. And then we'll work obviously with the payer community to understand the budget impact of the patient population, their interpretation of the data. and obviously, the value that, that represents to patients. So that's the work that we will do going into next year. And ultimately, we will announce price upon the approval of the SHTG pending positive outcome there.

Congrats on the quarter again.

The next question is from the line of Steven Idoff from TD Securities.

This is Stephen Ido on for Yaron Werber. Congrats again on fantastic quarter. One more on Doni and on competition specifically. It looks like TAKH

Yes, I'd be happy to talk about that. This is -- I think what we know in this marketplace and what's come through very clear is that patients on existing prophylactic treatments are not completely satisfied and that they would be willing to switch to a new therapy. A recent Harris Poll said that greater than 90% of patients actually would look to switch to an improved therapy. And I think you're seeing that play out with the newly approved treatment already, and we would expect to see the same from Donidalorsen. The profile overall with Donidalorsen is very strong, as I mentioned, not only the efficacy data but also the ability for patients to self administer. As you pointed out, this therapy is going to be potentially prescribed every 4 weeks or every 8 weeks depending upon how patients present and how stable they are with their disease. So that is, again, another key differentiator here. And then finally, I'll just mention the switch study. I mean what we have demonstrated is that patients are willing to switch. When they do so, they can do so safely. They have the potential to improve the control of their disease. And ultimately, when they've ended up on Donidalorsen, they preferred it. over the treatment that they were on. So I believe from a competitive point, we're in really good shape, and we've got a great team. We've hired a sales organization that has experience in the allergy and immunology space, many of whom have direct HAE experience for many years and they know the treating physicians, and they've got not only existing relationships, but they understand how to competitively sell. So we're really excited about the upcoming launch potentially with the approval on August 21.

The next question is from the line of Mike Ulz with Morgan Stanley.

Congratulations on the strong quarter as well. Maybe just a question on the Phase III sHTG core data. Previously, you suggested data 3Q, you're narrowing that a little bit to September. I guess first question, just any -- what's the rationale there? Or anything behind that? And then secondly, last quarter, do you suggest that AP data might not be available in the top line release? I guess just maybe give us a sense of what level of AP data you plan to share in the top line release in September?

Sure, Mike. So the -- just refining the time line to September from the second half of the year is just blocking and tackling. Getting the studies completed database locked, they've cleaned and all that. So we just felt it was appropriate to provide more specificity on the exact timing. So nothing significant behind there, except operational in conducting studies. We will provide a statement on AP in our top line press release. Our primary endpoint, again, is triglyceride lowering. We will provide top line information on triglycerides as well as safety -- overall safety, and we'll provide a statement on AP. What's also, I think even more important is that we will provide and present the full data set at a medical congress in the second half of this year. And we look to publish the data in the second half of this year as well.

The next question is from the line of Andy Chen from Wolfe.

Brandon on for Andy. On Wainua polyneuropathy, where do you think those patients are coming from? Do you think that they are -- you're winning new -- winning new to brand share or stealing patients from Alnylam ? If you can provide any quantitative splits on those details, that would be great.

I'd be happy to talk about that, Brandon. Thanks. This is Kyle again. First, I'll just say, Wainua continues to perform very well. From demand, the polyneuropathy market is a growth market. The majority of these patients are not diagnosed yet, and that's exactly where Astra

The next question is from the line of Gena Wang from Barclays.

Also congrats on a very strong quarter. So I have 2 questions regarding Tryngolza. When I look at the guidance, $75 million to $80 million, even if we use $80 million seems every quarter's 3Q for only $75 million growth. So maybe give us a little bit more color. Are you -- is the guidance too conservative? Or is there reason that why the new patient add-on was slow down compared to 2Q over 1Q. So that's the first question. And the second, I don't know if you can comment. I think should the total cumulative events for quarter 1 and quarter 2 will be more than 13%. So giving certainly different disease and the price history of AP in the 2 studies -- so maybe like how much more? Are we talking about the total AP events still in the teens? Or could that be in 20s.

Thanks, Gena. Beth, do you want to touch on the $75 million to $80 million guidance?

Yes. Actually, I think I'll just pass that to Kyle because that's in his hat. He's responsible for that.

So I think what's most important here is the way that we progress throughout the launch, right? As I referenced, we converted the clinical trial patients, we've been working very effectively with patients that were identified prior to the approval in order to get those patients formally diagnosed and put on to treatment. So you had a number of patients that were identified. So where we're at right now at the launch is really looking for newly identified and newly diagnosed patients, right, in order to penetrate deeper into that up to 3,000 FCS patient population that we believe exists in the U.S. So that takes some time. It takes a lot of education and it takes a lot of conversations. And then it also takes a little bit of time for physicians to get potential patients into the practice in order to be either clinically or genetically confirmed with their condition. So we've done a nice job throughout the first half of the year. We expect to continue to identify these patients, but it just might take us a little bit of time because of the complexity of the rare disease that we're dealing with in being first to market and having a great product with positive physician and patient experience is helping us to increase that patient identification over time.

Yes. Thanks, Kyle. And on your second question, Gena, we're not going to go more than that. I mean, in this call today, we confirmed that we will see more AP events in the quarter or 2 studies combined, and we saw in FCS balance when we confirmed that we will make a statement summarizing to some extent, top line summary of AP findings in CORE and CORE2. We're not going to go further than how many more AP events we see. We look forward to sharing the data in September.

Next question is on the line of Luca Issi from RBC.

Well, great. Congrats on the great quarter here. Maybe, Brett, if I can circle back on one statement you made earlier, the physicians appreciate that triglyceride they're the bad guys, so to speak, and they don't need to see stats on acute pancreatitis. Is that a U.S. comment? Or do you think that is applicable also to the rest of the world I guess, in a scenario where you don't show static or strong trend on AP. How should we think about the uptake of this drug outside the United States? And then I know I'm probably pushing my luck here, but you mentioned you'll have a statement on AP in the press release will that be a qualitative statement or a quantitative statement?

We're not going to go more than that, Luca, on what we're going to say. We're going to -- we will speak to our findings in CORE and CORE2 on AP in our top line press release and share for the full data set at a medical congress this year. So just going to hold off on that one. Your first question is very -- is an important question. because really what you're getting is payer dynamics outside of the U.S. That's really -- Kyle will address that. But I can tell you that in the U.S. and I have spent a lot of time with the specialists over the last 2 years who treat sHTG patients. They do not -- they are convinced that they need to get patients on the most effective triglyceride lowering agents possible if they're sHTG patients because they are convinced they know that their patients are in harm's way for acute pancreatitis. In fact, they're already treating them. They're treating them with everything they have, whether it be fibrates or omega-3s, they're just not effective. So they're looking for something on top of standard of care. As a reminder, our CORE and CORE2 studies are on top of standard of care. -- that to get their triglycerides down. And that's true for payers in the United States, too. outside the U.S., let maybe focus on Europe, it's more complex, right?

It is. From a regulatory standpoint, though, obviously, triglyceride lowering is going to be sufficient for a label in the EU and that filing is there. And we've obviously positive CHMP opinion and optimistic about the outcome and where that goes in terms of the approval. So from a payer and reimbursement dynamic standpoint in the European countries, for example, it's really about the breadth of the population that you're ultimately going to be able to treat. Who to treat and why to treat those patients, right, is the key thing here in order to demonstrate outcomes in the patient population. One thing that's very positive already is if we are able to secure an indication in Europe is we've got FCS. FCS already has AP data. It already has very strong hospitalization data and so we've got information to be able to substantiate pricing and reimbursement from an FCS standpoint. We also have a very strong partner in Sobi many years, and they've navigated pricing and reimbursement very successfully in the FCS population already across numerous countries across Europe. And I think we're very optimistic that we'll be able to continue that success with the program like Tryngolza. So then the question becomes sHTG if you have a potential label expansion and what do you need to show there. Outcomes in AP are obviously going to be important for the broad population but could you potentially look at a different population, a little bit more narrow than anybody over 500, for example, patients that are at high-risk sHTG such as patients over 880 patients with 500 in the history of AP or potentially patients with other comorbidities. So there are a lot of dynamics and things to think through there. And pending the data, obviously, we'll work through putting that body of evidence together and supporting Sobi in their pricing and reimbursement efforts across each country as they go to launch.

The next question is from the line of David Lebowitz from Citi.

Given the strong early ramp of Tryngolza and FCS. Are you -- how are you thinking about the pricing change that would inevitably happen when it gets approved for severe hyper triglycerides. Is it just going to be a pretty prompt drop or are you going to try to find some way to observe the revenues while you're dropping the price and ramping up?

Yes. Thanks, David. So our pricing work is ongoing. We've got more work to do there. What we've communicated up to this point is in a disease that has 3 million to 4 million patients. Typically, the U.S. payers are accepting of a price somewhere in the $10,000 to $20,000 price range. However, when we're looking at sHTG specifically, and the data that Olezarsen can potentially have in the sHTG population, we'd like to go back to the payers and do more testing and understand exactly where this price point could land based on the value to patients and the value to the payers. So there's more work to do. In terms of the execution of that, the FCS population ultimately will be consumed within the sHTG population. So it will become anybody over 500 would be within the sHTG population. So there is a question around how do you execute that and the pricing dynamics? And do you bring the price down. I think regardless of what the decision is there, if we do it immediately or if it's done over time, what we do know is that the sHTG population is quite substantial. And I think what we believe is that we'll be able to maintain enough patient population to be able to continue the revenues that we're producing at the time of an sHTG potential approval.

The next question is from the line of Jay Olson from Oppenheimer.

Congrats on the quarter, and thank you for providing this update. Now that you have the early successful launch experience with Tryngolza and you have several other launches that you're planning in the near term. How does that impact your thinking about your earlier stage pipeline and deciding between out-licensing earlier-stage assets versus retaining full ownership and launching them independently? And then as a follow-up, can you discuss any plans to build out your ex U.S. infrastructure for any future global product launches in the long term?

Thank you, Jay. We have an abundance of riches when it comes to our late-stage pipeline, our wholly owned pipeline, our partner pipeline, it's a nice combination there and our first independent launch is off to a really good start, and we're expecting Donidalorsen to be equally successful as well as sHTG coming up next year. With that said, our research organization is incredibly innovative and prolific. We have to continue to bring in potentially transformational medicines continuously into the early-stage pipeline and bring them to Phase III development in due course. Our focus remains, as we set out 5 years ago, 5.5 years ago, to do is to prioritize the wholly owned pipeline. We'll continue to do so, and we will focus on cardiology and cardio metabolic diseases as well as neurology. We will always have room for exceptions like hereditary angioedema, we have such an excellent looking drug like Donidalorsen, but those will be our focus. Those areas will be our focus. And it will be the priority. With that said, we still need to ensure that we live within our means. We have -- our resources are limited. We are committed to achieving positive cash flow in the next few years. And although we will prioritize our wholly owned pipeline early stage through Phase III development, there will always be assets that either are outside of our means or outside of our priority areas where we will make decisions to partner. A lot of interest in partnering with Ionis these days. Our platform is delivering over and over again. A great example of that is the transaction that we did earlier this year for Polycythemia vera with Ono, $280 million upfront. And we did that because it's outside of our areas of focus. Hematology is not a focused area for us. So you'll see us continue to partner, but that's not our priority. Our priority is our wholly owned pipeline early to late stage and our launches. With respect to outside the U.S., I'd like to just put that 1 on pause. We're thrilled with the early launch of Tryngolza, and we're looking forward to Donidalorsen and sHTG launches in the U.S. And we'll know when it's fine to emerge from the U.S. and maybe start building external or ex U.S. commercial infrastructure. But now is not in time to be distracting to that. We need to get these launches right. We're committed to get these launches right, and we'll do so. With that said, we, of course, as internally on when and what that asset might be that we emerge from the U.S. market with but we're in the early inning of those discussions.

Super helpful. Congrats again on the launch.

The next question is on the line of Akash Tewari from Jefferies.

This is Aki on for Akash Tewari. So in the BALANCE study, it looks like there was a kind of leaked through towards the end of the study in the 80-milligram arm in a patient who did have triglycerides lowered on the drug whereas placebo events seem to cluster earlier on in the first half of the study. I understand it's really small in here, but how do you have ESSENCE some sense of how blinded events are tracking in CORE 1 and 2 how confident are you that this kind of variability won't be a swing factor on AP powering in CORE 1 and 2?

I'll start and then Eugene, please jump in. We're doing everything we can to power -- to increase the power for AP in our study possible. AP analysis will be combined CORE and CORE2. And will be at the 12-month time point. That's correct, right, Eugene? So although the primary endpoint for triglycerides is 6 months. The AP secondary endpoint will be in 12 months and with CORE and CORE2 combined. So we'll have the -- what we're trying to do is maximize time and maximize patient numbers.

The Maximal Power will be achieved by combining CORE and CORE2 and ensuring that the end is much larger than 2 separate.

Our last question comes from Debjit Chattopadhyay from Guggenheim Partners.

I'm just wondering if the second interim analysis in the LPA Horizon study has happened already, and I believe this was after 745 events?

Yes, it has, and there are no more interim analyses planned for the pelacarsen HORI