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

Good morning, and welcome to Ionis Conference Call to discuss Olezarsen CORE and CORE2 top line data. 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 off the call. Please begin.

Thank you, Ludy, and thank you to everyone who has joined us today as we discuss the groundbreaking top line results from the landmark CORE and CORE2 studies of olezarsen in people with sHTG. Please be sure to visit the Investors section of the Ionis website to see the press release Ionis issued earlier this morning, along with the slides accompanying today's webcast. Full data from the Phase III Essence Study of olezarsen in people with moderate HTG were also presented over the weekend at the 2025 ESC Congress. The presentation from the ESC Congress is also available on our website. With me on the call today are Brett Monia, Chief Executive Officer, who will provide opening remarks. Sam Tsimikas, Senior Vice President, Global Cardiovascular Development, who will discuss the significant unmet need associated with sHTG and then review the top line CORE and CORE2 study results. Kyle Jenne, Chief Global Product Strategy Officer, will discuss our go-to-market approach to achieving launch success of olezarsen for sHTG, assuming approval. And after Brett's brief conclusion, we'll open up the call for your questions. Before passing the call to Brett, I would like to remind you that our discussion today will contain forward-looking statements based on our current expectations and beliefs. Such 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, and thank you, everybody, for joining us this morning. We are thrilled to be here today to report highly positive top line results from the Phase III CORE and CORE2 studies of olezarsen in people with severe hypertriglyceridemia, sHTG. In these pivotal studies, olezarsen met its primary endpoint, demonstrating a highly statistically significant and clinically meaningful mean reductions in placebo-adjusted fasting triglycerides at 6 months. Olezarsen also significantly and substantially reduced acute pancreatitis events, making it the first and only treatment to achieve this positive outcome in people with sHTG. And importantly, olezarsen also demonstrated favorable safety and tolerability across the 2 studies. We believe these unprecedented results position olezarsen to meet the substantial unmet needs of people with sHTG, a patient population in great need for more effective triglyceride-lowering treatments to reduce the risk of potentially fatal acute pancreatitis. These results come at a time of extraordinary progress at Ionis. In January, we launched our first Ionis-owned commercial medicine, olezarsen, under the brand name TRYNGOLZA. As the first and only FDA-approved treatment for familial chylomicronemia syndrome or FCS, the TRYNGOLZA approval was a pivotal moment for patients. The launch is off to an excellent start, driven in large part by TRYNGOLZA'S strong profile that is meeting the needs of people with FCS. The TRYNGOLZA launch was also a pivotal moment for Ionis representing the beginning of a new era as a fully integrated commercial stage biotechnology company. And just over a week ago, we announced the FDA approval of Ionis' second commercial medicine, DAWNZERA, the first and only RNA-targeted HAE prophylactic for patients 12 years and older in the U.S. Within days of approval, we began receiving prescriptions and shipping product to patients, and we are pleased with the excitement that DAWNZERA is already generating within the HAE community. With the positive CORE and CORE2 results now in hand, we have the opportunity to build on our success with FCS and commercialize Ionis' first medicine for a prevalent patient population. Following today's top line results, we look forward to presenting the full data from CORE and CORE2 at a medical congress later this year. And by year's end, we plan to submit our supplemental NDA for olezarsen for the sHTG indication followed by additional regulatory filings outside the U.S. expected next year. As you'll hear from Kyle, our commercial teams are actively preparing to launch olezarsen for the treatment of sHTG in the U.S. in the second half of next year. With a substantial first-mover advantage in sHTG together with today's top line results, we are confident that olezarsen can meet the needs of the large sHTG population and fully realizes -- and fully realize its blockbuster market potential. Before I turn the call over to Sam, I'd like to take this opportunity to thank all those who contributed to the exciting top line results we're reporting today, including the patients, families and clinicians who participated in the olezarsen Phase III ESSENCE, CORE and CORE2 studies. I also want to acknowledge our team at Ionis, whose unwavering dedication to patients in the olezarsen program enabled the highly positive outcome that we're reporting today. With that, I'll pass the call over to Sam to walk through our olezarsen sourcing clinical program and the positive top line results. Sam?

Thank you, Brett. And hello to everyone with us on the call. Before I begin, I would also like to recognize and thank everyone whose contributions made today's groundbreaking results possible including our colleagues at the TIMI Study Group who collaborated with us on the olezarsen Phase III program. Here is a brief reminder of the study is making up our comprehensive olezarsen Phase III development program, encompassing both severe and moderate hypertriglyceridemia. First are the pivotal CORE and CORE2 studies in people with severe hypertriglyceridemia or sHTG with nearly 1,100 participants across the 2 studies, this is the largest pivotal program ever conducted in this patient population. We also conducted a Phase III ESSENCE study, which enrolled nearly 1,500 participants, primarily of moderate hypertriglyceridemia and elevated cardiovascular risk with the result of the study contributing to the safety database in our sHTG sNDA filing. Over the weekend, the ESSENCE study results were presented at ESC and simultaneously published in the New England Journal of Medicine. In the ESSENCE study, olezarsen demonstrated statistically significant mean reductions in placebo-adjusted fasting triglycerides of 58% and 61% at 6 months with olezarsen 50 and 80 milligrams, respectively. Nearly 90% of olezarsen treated participants achieved normal triglyceride levels of less than 150 milligrams per deciliter. Olezarsen also met all key secondary endpoints, including a significant reduction in the total number of atherogenic lipoproteins as measured by ApoB levels and a nearly 70% mean reduction in remnant cholesterol. Olezarsen demonstrated overall favorable safety and tolerability in the ESSENCE study. Adverse effects during the trial were balanced across the treatment groups as were SAEs and SAEs leading to treatment discontinuation. Injection site reactions, which were generally mild, were the most common adverse event that occurred more frequently with olezarsen compared to placebo. And now I will turn our focus to sHTG and the positive results from the pivotal CORE studies. The CORE and CORE2 studies were designed to evaluate olezarsen in people with sHTG. sHTG is defined by fasting serum triglyceride levels greater than equal to 500 milligrams per deciliter, driven by genetics, diabetes, obesity, metabolic syndrome and lifestyle all of which can impair triglyceride clearance. When triglycerides are elevated above 500, chylomicrons begin to form, at high enough concentrations chylomicrons can become toxic to the pancreas and lead to acute pancreatitis, which is associated with increased mortality, hospitalization, intensive care admission and acute and chronic complications. Current triglyceride lowering treatments, such as fibrates and omega-3 fatty acids offer only modest effectiveness and often fail to reduce triglyceride levels below the threshold for pancreatitis. Moreover, none have shown a proven benefit in lowering the risk of acute pancreatitis in FHCG or any other patient population. This treatment gap strongly suggests the need for more potent and effective drugs. It is particularly critical given the size of the sHTG population with over 3 million people in the U.S. alone. There are estimated to be more than 1 million people who are considered high risk, which includes those with triglycerides above 880 milligrams per deciliter or above 500 milligrams per deciliter plus a prior history of pancreatitis. CORE and CORE2 were designed to address these unmet clinical needs. They are global, randomized, placebo-controlled studies conducted in 1,063 participants with sHTG. Participants were required to be on stable standard of care lipid-lowering therapy throughout the trial. Diet was stabilized during screening and maintained with the support of counseling throughout the treatment period. Participants were randomized one-to-one to receive olezarsen 50 milligrams or 80 milligrams than 2:1 to receive olezarsen or placebo. Participants were also stratified by triglyceride levels greater than or less than 880 milligrams per deciliter and a history of at least 1 episode of acute pancreatitis within 10 years prior to screening. The treatment period was 12 months and the primary efficacy endpoint, the placebo-adjusted mean percent reduction in fasting triglycerides was assessed at 6 months. A key prespecified secondary endpoint was a percent change in adjudicated acute pancreatitis events with pooled olezarsen compared to pool placebo at 12 months. Pancreatitis events were adjudicated by an independent clinical research organization blinded to treatment assignment. Established adjudication criteria were based on the revised Atlanta classification of acute pancreatitis. Additional secondary endpoints included triglyceride reductions at 12 months as well as reductions in APOCIII and a variety of lipid parameters at 6 and 12 months. The primary and secondary endpoints and statistical hierarchy of both CORE and CORE2 and the combined analyses were recently published in the American Heart Journal. Participants who completed the placebo-controlled portion of these studies were eligible to enroll in an open-label extension study, and we are pleased to report that more than 90% of eligible participants elected to enter the ongoing open-label extension, which reflects both the perceived benefit of olezarsen to patients and to physicians as well as a lack of effective therapeutic options for sHTG. Here are the baseline characteristics from CORE and CORE2 as published in the American Heart Journal earlier this year, which highlight the severity of sHTG in the study population. Median baseline triglyceride levels were 836 milligrams per deciliter in CORE and 749 milligrams per deciliter in CORE2 and further reflecting the severity and risk in the study population, the mean baseline fasting triglyceride levels were 1,182 in CORE and 1,023 in CORE2. 47% of the participants in CORE and 37% of the participants in CORE2 had baseline fasting triglyceride levels greater than 880 milligrams per deciliter. 22% participants in CORE and 13% of participants in CORE2 at had at least one event of acute pancreatitis in the 10 years prior to enrollment. All participants were on stable background treatment with at least 1 lipid lowering therapy, including statins, fibrates, omega-3 fatty acid, ezetimibe and a small percentage were on PCSK9 inhibitors. Over 60% of participants were on 2 or more lipid-lowering treatments, underscoring the lack of effective therapies for severely elevated triglycerides. Median baseline LDL cholesterols were relatively low across the 2 studies which reflects aggressive standard of care. A majority of participants have diabetes at baseline, which is common in sHTG. And now to the CORE and CORE2 top line results beginning with the primary efficacy endpoint of triglyceride reduction at 6 months. In CORE, the mean percent change from baseline in fasting triglycerides in the placebo group was a 0.5% reduction. In contrast, a mean 63% reduction was achieved with olezarsen 50 milligrams and 73% reduction with olezarsen 80 milligrams. The placebo-adjusted reductions in fasting triglycerides were 63% with olezarsen 50 milligrams and 72% with olezarsen 80 milligrams. These results were highly statistically significant with p-value less than 0.0001 for each dose. In CORE2, the mean change from baseline in fasting triglycerides in the placebo group was a 14% reduction. In mean, 63% reduction was achieved with olezarsen 50-milligram and 88% reduction with olezarsen 80 milligram. The placebo-adjusted reductions were 49% with olezarsen 50-milligram and 55% with olezarsen 80 milligram. And again, these results were highly statistically significant with P less than 0.0001 for each dose. We now turn our focus to the most clinically relevant secondary endpoint for this sHTG population, the reduction in acute pancreatitis events which were assessed in a comparison of pooled olezarsen to pool placebo across the 2 study. We are extremely pleased to report that olezarsen achieved a highly statistically significant 85% reduction in adjudicated acute pancreatitis events with a p-value of 0.0002. CORE and CORE2 represent the first pivotal program to ever achieve this in an sHTG population. Furthermore, olezarsen's very large treatment effect producing the risk of pancreatitis by 85% in only 1 year of treatment definitely proves the link between elevated triglycerides and acute pancreatitis and sHTG. Olezarsen demonstrated a favorable safety and tolerability profile in CORE and CORE2. Adverse events were generally balanced across treatment groups, but serious adverse events occurred less frequently in the olezarsen-treated participants. Injection site reactions, which were mostly mild, with the most common treatment-emergent adverse event occurring more frequently with olezarsen compared to placebo. So in summary, in the pivotal CORE and CORE2 studies in people with sHTG, treatment with olezarsen resulted in highly statistically significant and clinically meaningful mean reductions of up to 72% in placebo-adjusted fasting triglycerides at 6 months, highly statistically significant reduction in acute pancreatitis event rate and a favorable safety and tolerability profile. We look forward to presenting full data from the CORE and CORE2 studies at a medical congress later this year. We believe that this is an unprecedented and historical achievement in the field of lipidology, where the quest to reduce the risk of acute pancreatitis in sHTG has been ongoing for nearly 50 years. We look forward to providing a new treatment paradigm for patients and caregivers to reduce the risk of acute pancreatitis associated with sHTG. And with that, I'll turn the call over to Kyle.

Thank you, Sam, and good morning, everyone. This is indeed an exciting day. We're thrilled about what these results from the CORE and CORE2 studies of olezarsen could mean for people living with sHTG. As Sam explained, acute pancreatitis is the most serious complication associated with sHTG. Individuals with triglyceride levels around 880 milligrams per deciliter face a fivefold increased risk of a first AP event, and each attack further increases the risk for another attack. Each event can cause lasting pancreatic injury such as necrosis and beta cell dysfunction, often leading to diabetes. AP events can also result in systemic complications such as respiratory, renal and cardiac failure. The mortality rate is also higher compared to other causes of AP reaching as high as 8% per triglyceride induced event. These clinical realities are consistent with commentary we hear from physicians treating people with sHTG. One recent quote from a lipidologist KOL sums this commentary up well. He told us, and I quote, "I regularly see sHTG patients suffer their first AP attack. And after that, their pancreas is absolutely destroyed." With positive data from the CORE and CORE2 studies now in hand, we are confident that olezarsen is uniquely positioned to meet the needs of patients with sHTG and provide physicians with the efficacy they've been seeking in a new, more effective treatment. First, olezarsen demonstrated highly statistically significant and clinically meaningful placebo-adjusted mean reductions of up to 72% in fasting triglycerides. Second, these triglyceride reductions resulted in a highly statistically significant 85% reduction in acute pancreatitis events making olezarsen the first and only treatment to achieve this positive outcome in people with sHTG. Third, olezarsen demonstrated favorable safety and tolerability. And finally, olezarsen has the potential to offer patients the simplicity of monthly self-administration with an auto-injector, which empowers patients to manage their treatment on their own terms without frequent trips to the doctor. We believe olezarsen checks all the boxes for what physicians are looking for and a new treatment for sHTG. As another KOL recently told us "a therapy that meaningfully lowers triglycerides and reduces AP events, something we've never seen before would be a game changer in the treatment of sHTG." There are estimated to be more than 3 million people with sHTG in the U.S., as represented by our pyramid shown on this slide. We plan to focus within this high-risk sHTG patient population at launch which includes patients with triglycerides of greater than 880 milligrams per deciliter or with triglycerides of greater than 500 milligrams per deciliter and a history of acute pancreatitis.. At launch, we plan to prioritize high-risk sHTG treaters in the U.S. made up of cardiologists, endocrinologists and lipidologists. These specialists manage the vast majority of the high-risk sHTG patient population. Our cardiometabolic account specialists will focus on these treaters to deliver the same high-quality experience as we are currently achieving in FCS. Looking further into the future, we see sHTG as a growing market with the opportunity to penetrate deeper into the 3 million plus patient population with triglycerides greater than 500 milligrams per deciliter and with the potential to bring the first APOCIII targeted triglyceride lowering therapy to market that has demonstrated highly statistically significant reductions in acute pancreatitis, we are positioned to scale our commercial capabilities as the market evolves. We have been on quite an exciting journey with olezarsen already, and more important catalysts are still to come. In terms of our next steps, we are planning to present full data from the CORE and CORE2 studies at a medical congress later this year. Following that, we are on track to file our sNDA in the U.S. before the end of the year with additional global filings expected next year. And launch preparations are already underway and moving with urgency as we look to deliver olezarsen to the market for the treatment of sHTG in the second half of next year. In closing, the top line results from our Phase III CORE and CORE2 studies reinforce what we've long believed. Olezarsen has the potential to transform the treatment landscape for people with severe hypertriglyceridemia. By meaningfully lowering triglycerides and reducing the risk of acute pancreatitis, olezarsen directly addresses the urgent clinical needs of people with sHTG. And our launch strategy is designed to realize olezarsen's blockbuster potential by initially focusing on the people with the greatest unmet need. We're excited about what lies ahead and remain deeply committed to bringing olezarsen to the patients in need. And with that, I'll turn the call back over to Brett.

Thanks, Kyle, with positive top line results from the CORE and CORE2 studies in hand now, we've taken a major step forward, not just in advancing olezarsen toward a prevalent second indication, but in transforming care for people living with severe hypertriglyceridemia. These results build on our recent successes with TRYNGOLZA for the treatment of FCS and DAWNZERA for the treatment of HAE and demonstrate the strength of our science, pipeline and strategy to deliver innovative new medicines directly to patients in need. We are thrilled with our recent progress, we're just getting started. In fact, we're on track for a steady cadence of additional new product launches next year, we have the potential to independently launch our first medicine for a neurological disease, zilganersen for the treatment of Alexander disease and to expand TRYNGOLZA'S indication for the treatment of sHTG, of course. Together with TRYNGOLZA and DAWNZERA, our first 4 independent commercial launches have the potential to deliver multibillion dollar revenue. In the next 2 years, we also have the potential for up to 4 key partnered product launches, each positioned to generate substantial additional revenue for Ionis. As we advance toward these and future successes, we are doing so from a position of strength and with a culture of innovation. We're building on this with a proven and expanding drug discovery platform, a focused commercial strategy and a team that has independently launched 2 Ionis drugs this year, deeply committed to achieve continued success well into the future. I look forward to keeping you updated as our progress continues. But for now, we'll open the call up for questions. I'd like to ask the folks online asking questions to limit their questions to 1 question and to focus the questions on the olezarsen program overall. Thank you very much. And operator, we can now take questions.

[Operator Instructions] Our first question comes from the line of Akash Tewari with Jefferies.

I know your team has talked about net pricing in the kind of 10,000 to 20,000 range. Now that you have this strong absolute trig reduction and AP events, could we see pricing upside versus your guided historical range? And how much does kind of the Medicare Part D redesign affect pricing decisions from here?

Thanks for the question. First, let me start by saying how excited we are about this data that's just been read out for olezarsen in the sHTG patient population, very high unmet need. This is a prevalent population, really complicated dynamics with acute pancreatitis. And this data is really, really so positive, highly statistically significant with reductions in TGs of up to 72%, first and only treatment to significantly reduce AP in people with sHTG. As it relates to the data, now that we have this information, we need to go out and do the work. This is exactly what we were waiting for so that we can go out and talk to HCPs and talk to payers and understand exactly what the value of olezarsen represents to those different stakeholders. When we do that work, we'll announce the price at the approval of the sHTG indication. And as I stated, it will reflect the value of olezarsen in that patient population. So more to come on that. And as it relates to the Medicare Part D redesign, again, out-of-pocket costs are going down in this patient population, making drugs more accessible having patients fill prescriptions more frequently and having patients stay on drug longer. So I think we're going to be in a very positive position as it relates to either commercial or Medicare populations. Thank you.

Your next question comes from the line of Gary Nachman with Raymond James.

And congrats on the great data. So for the AP events, the 85% reduction was a great outcome, can you give us a rough idea of the number of events and how it compares to the FCS study when most of the events occurred during the year? And do you think you'll be able to get this AP reduction on the label for severe high trigs? How important will that be to promoting it?

Thanks, Gary. So we've been saying now for nearly 2 years that based on the size of the study and how the CORE and CORE2 studies were enrolling what our mean triglyceride levels were, median triglyceride levels were that we expected to have more AP events in CORE and CORE2 combined than we had in the FCS balance Phase III study. And that absolutely happened. So very, very, very much as expected. We're going to present the detail on all the numbers at the medical congress later this year, as Sam and Kyle highlighted earlier, including the numbers of AP events in total in the different groups and in the CORE and the CORE2 studies separately and so forth. We're very pleased with the results in acute pancreatitis, but we're going to have to leave that there for now. With respect to timing in the placebo group, the events that I could tell you that if you look at the Kaplan-Meier curves in the balance, FCS Phase III study, we're -- the time course looks similar to what we saw in BALANCE in FCS. And as you recall, we started seeing AP events in the placebo group in the BALANCE study very early on and that study has reported in the New England Journal of Medicine. Label to be determined. We -- that -- we're just getting started here. We've been preparing the NDA certainly, we think that we will push for the AP data in the label. But I want to remind you, Gary, that the AP data is already in the label. This is a label that will expand using through a supplemental NDA. We have AP in the label for FCS. We hope to have AP in the label for sHTG as well. But that's topic of discussion with the FDA. As far as being able to market the AP data, we are planning to publish the data and Kyle, that will essentially allow us to market AP data. Is that correct?

That's correct. Yes. Our medical affairs teams will obviously use that data as well as our sales teams if the product is approved. And again, I just think this is tremendous data. These are landmark studies and to be able to demonstrate the correlation between olezarsen reductions in TGs and reductions in acute pancreatitis, I think, is very significant here.

And your next question comes from the line of Yanan Zhu with Wells Fargo.

Great. Congrats on the very strong data from CORE and CORE2. So I was just wondering in terms of additional color from the acute pancreatitis endpoint, do you have any -- at this point, any data on the baseline triglyceride levels in those patients who had attacks. And also, any color on whether olezarsen is effective in preventing first-time attacks, given that I expect most of the tax will be from recurrence of patients with prior histories. And any color on the first attack will be very helpful. I think Kyle mentioned a physician talked about how devastating the first attack is and potentially that will have a big implication on addressable market for the -- for people with -- have no attacks.

Thanks, Yanan. Again, we're going to present all the details on the AP data. I'm going to ask Sam to maybe provide a little bit more color on this, but recognize again that the specifics on the relationship of triglycerides with AP and first time versus second recurrent AP events will be shared at the -- at a medical congress this year -- later this year. But Sam, have at it, maybe you can provide a little bit more color at this point.

Yes. I think it's well known that the relationship of pancreatitis to TG is linear, particularly after 500 milligrams per deciliter. So that's a sort of thing that I think we've seen in the other trials that we worked on and certainly in this trial, your question about the differences in the triglyceride levels, that was not part of our top line data. So we will get that for you later, but we can't tell you right now what the differences were in the triglyceride levels. So -- but we've also seen, obviously, the patients that have had a prior attack have the highest event rate but new events also for -- in patients without prior attack. And we'll provide that information also, but we've seen AP on both groups that were just mentioned.

Your next question comes from the line of Gena Wang with Barclays.

I also want to add my congress on such impressive data. So quickly, I think regarding the dose, in FCS, you did have approved the 80-milligram dose. Now with this, you do have a very impressive data from both 50-milligram and 80-milligram doses. Any thoughts when moving forward, what will be the dose? Will we stick with 80-milligram doses? Or could there be a possibility have the flexibility of dose -- both doses? And then a very quick question regarding the sales force, Kyle, can you add some color on potential, how much more sales you need to add and related cost associated in preparation of launch second half next year?

Why don't you start with that, Kyle.

Yes. So our current sales organization is able to address thousands of the highest treaters of sHTG today. And the sales force has been deployed for quite some time, and we're doing a fantastic job with the TRYNGOLZA launch and finding FCS patients and getting those patients on to TRYNGOLZA. When we get to sHTG, those same targets that we're calling on today will also be treaters of this sHTG patient population. However, there are thousands more treaters that are out there that we'll need to reach. So we will scale our sales organization accordingly to the number of targets that we need to get out in front of. We will be focused in the specialist area, so cardiology, endocrinology and lipidology and we'll be able to size a team to get to tens of thousands of HCPs to educate on sHTG, get the information out about olezarsen and obviously, the positive data that we are sharing today and be able to drive the uptake in the sHTG population.

And your first question, Gena, indeed, both doses look very impressive, and there's no reason why we wouldn't -- couldn't file for both doses for approval with the FDA. But we're still working through the data and aside from the data, we also need to think through our commercial strategy to maximize success on the sHTG market. So we're working through that. So stay tuned, and we'll have more to share with that down the road.

And your next question comes from the line of Jessica Fye with JPMorgan.

Congrats on strong results. So among the 3 groups of high-risk sHTG patients that you're going to be targeting between those with prior AP in triglycerides north of 500, those who are north of 880 and those who are north of 500 with comorbidities, which in your view kind of represents the low-hanging fruit here?

I think what we hear from physicians on a regular basis is all 3 of those groups are very significant, and they've been very challenged at managing these patients effectively. They only have fibrates and fish oils today. Many of these patients are on 1 or both of those. And they are unfortunately not able to get their triglycerides down low enough to get them out of harm's way for AP. An HCP that has seen a patient with acute pancreatitis never wants to have another patient that has acute pancreatitis. They are very, very concerned about the way that these patients present. It's very hard to treat. These patients can stay in the hospital for an average of 17 days for their AP event. It's very costly to payers. So those with a prior history of AP are definitely at the top of the list. But anyone that's above 880 is also a very, very strong candidate for this product because of the risk of AP and how devastating that can be.

Your next question comes from the line of Jason Gerberry with Bank of America.

I've got another AP question. So were patients in the placebo arm who had AP events hospitalized. And the reason I ask is there's competitor commentary around CORE adjudicating AP as abdominal pain versus perhaps a stricter guideline-driven definition of AP. So I just wonder if you can offer any color around that. And then specifically with payers, is there any aspect of how you demonstrate an AP reduction that matters with payers and ability to preserve some of this TRYNGOLZA-level pricing because there are a lot of interesting scenarios in terms of perhaps how you leverage this data with payers in a more, I guess, orphan indication here, but I imagine you're going after the larger TAM and so there's a tension there. But any color you can just provide about what payers really care about in terms of how you show that AP benefit.

Yes. Sam, can you briefly walk us through the strict criteria we utilized for assessing the AP events in the studies?

Sure, sure. Yes. So we use an independent adjudication committee and that has set the criteria for what's considered pancreatitis and that usually the modified ATLANTA criteria. And so that is in the charter that's been published before. They've been doing it for 10 years. They have a lots of experience with it. The committee they use to do that is pancreatitis specialists. So Ionis did not set the criteria. This is set independently by that committee. And so the ATLANTA criteria is the classical criteria for doing that. However, these patients sometimes don't get all the classical tests if they've had prior events. And because of that, there's some other modifications of that criteria in that charter. The bottom line is the vast majority of these cases are documented cases. So for example, in the BALANCE study, which has come up to your question before, 12 out of the 13 of those cases were documented by the ATLANTA criteria. And that's the same criteria we use now, and it's the same kind of trend we're seeing. So there's no doubt that these are real pancreatitis cases. The question is what level of evidence is in that. And so -- in terms of hospitalizations, yes, many of them are hospitalized. In fact, in the BALANCE study, we have evidence that there's a massive reduction in the days of hospitalization. I don't have that in the top line data to give you an exact number, but a lot of these patients are hospitalized because they're very ill from the side effect.

And just to add to that, Jason, documented is the strictest criteria for determining acute pancreatitis. More than 90% of the patients CORE, CORE2 combined were documented.