Good morning and welcome to Ionis C onference Call to discuss Olezarsen CORE and CORE 2 topline 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, Ludi. Thank you to everyone who has joined us today as we discuss the groundbreaking topline results from the landmark CORE and CORE 2 studies of Olezarsen in people with sHTG. Please be sure to visit the Investor 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 topline CORE and CORE2 study results, and Kyle Jenne, Chief Global Product Strategy Officer, who will discuss our go-to-market approach to achieving launch success with Olezarsen for sHTG, assuming approval. 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. 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 Topline 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 highly statistically significant and clinically meaningful mean reductions in placebo-adjusted fasting triglycerides at six 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. Importantly, Olezarsen also demonstrated favorable safety and tolerability across the two 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 Pharmaceuticals, representing the beginning of a new era as a fully integrated commercial-stage biotechnology company. Just over a week ago, we announced the FDA approval of Ionis Pharmaceuticals' 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.
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 Pharmaceuticals' first medicine for a prevalent patient population. Following today's topline results, we look forward to presenting the full data from CORE and CORE2 at a medical congress later this year. 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 topline results, we are confident that Olezarsen can meet the needs of the large sHTG population 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 topline 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 and 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 clinical program and the Positive Topline Results. Sam?
Thank you, Brett. 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 studies 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 two 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 with moderate hypertriglyceridemia and elevated cardiovascular risk, with the results of the study contributing to the safety database in our sHTG s NDA 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 six months, with Olezarsen 50 mg and 80 mg, respectively. Nearly 90% of Olezarsen-treated participants achieved normal triglyceride levels of less than 150 mg /dL . 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.
I will now 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 or equal to 500 mg/dL, driven by genetics, diabetes, obesity, metabolic syndrome, and lifestyle, all of which can impair triglyceride clearance. When triglycerides are elevated above 500 mg, 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 sHTG 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 at high risk, which includes those with triglycerides above 880 mg/dL or above 500 mg/dL, 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 mg or 80 mg, then two to one to receive Olezarsen or placebo. Participants were also stratified by triglyceride levels greater than or less than 880 mg/dL and a history of at least one 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 six months. A key pre-specified secondary endpoint was the percent change in adjudicated acute pancreatitis events with pooled Olezarsen compared to pooled 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 apoC-III 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. 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 mg/dL in CORE and 749 mg/dL in CORE2 . 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 mg/dL. 22% of participants in CORE and 13% of participants in CORE2 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 one lipid-lowering therapy, including statins, fibrates, omega-3 fatty acids, ezetimibe, and a small percentage were on PCSK9 inhibitors. Over 60% of participants were on two or more lipid-lowering treatments, underscoring the lack of effective therapies for severely elevated triglycerides.
Median baseline LDL cholesterols were relatively low across the two studies, which reflects aggressive standard of care. The majority of participants had diabetes at baseline, which is common in sHTG. Now, to the CORE and CORE2 topline results, beginning with the primary efficacy endpoint of triglyceride reduction at six 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 mg and 73% reduction with Olezarsen 80 mg. The placebo-adjusted reductions in fasting triglycerides were 63% with Olezarsen 50 mg and 72% with Olezarsen 80 mg. 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.
A mean 63% reduction was achieved with Olezarsen 50 mg and 88% reduction with Olezarsen 80 mg. The placebo-adjusted reductions were 49% with Olezarsen 50 mg and 55% with Olezarsen 80 mg. 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 pooled placebo across the two studies. 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, reducing the risk of pancreatitis by 85% in only one year of treatment, definitely proves the link between elevated triglycerides and acute pancreatitis in 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, were the most common treatment-emergent adverse event occurring more frequently with Olezarsen compared to placebo. 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 six months, a 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. I will 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 mg/dL face a five-fold increased risk of a first AP event. Each attack further increases their 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.
Finally, Olezarsen has the potential to offer patients the simplicity of monthly self-administration with an autoinjector, 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 in 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 mg/dL or with triglycerides of greater than 500 mg/dL 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 familial chylomicronemia syndrome. 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 mg/dL. With the potential to bring the first apoC-III-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 s NDA in the U.S. before the end of the year, with additional global filings expected next year. 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 topline 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.
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. With that, I'll turn the call back over to Brett.
Thanks, Kyle. With Positive Topline 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, but 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 four independent commercial launches have the potential to deliver multibillion-dollar revenue. In the next two years, we also have the potential for up to four 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 two 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. 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 one question and to focus the questions on the Olezarsen program overall. Thank you very much. Operator, we can now take questions.
Thank you, ladies and gentlemen. We will now begin the question and answer session. To ask a question, you may press star followed by the number one on your telephone keypad. To withdraw your question, please press star two. With that, our first question comes from the line of Akash Tiwari with Jefferies. Please go ahead.
Hey, thanks so much. I know your team has talked about net pricing in the kind of $10,000 - $20,000 range. Now that you have this strong absolute trig reduction and AP event, could we see pricing upside versus your guided historical range? How much does the Medicare Part D redesign affect pricing decisions from here? Thanks so much.
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. This data is really, really so positive, highly statistically significant with reductions in TGs of up to 72%. First in all, a 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.
As I stated, it'll reflect the value of Olezarsen in that patient population. More to come on that. 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 drugs longer. I think we're going to be in a very positive position as it relates to either commercial or Medicare populations. Thank you.
Thanks, Akash. Next question, please.
Your next question comes from the line of Gary Nachman with Raymond James. Please go ahead.
Thanks, and congrats on the great data. 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 compared to the FCS study and when most of the events occurred during the year? 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? Thank you.
Thanks, Gary. You know we've been saying now for nearly two 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 balanced Phase III study. That absolutely happened. Very, very, very much as expected. We're going to present the detail on all the numbers at a 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 balanced FCS Phase III study, the time course looks similar to what we saw in balanced and FCS. As you recall, we started seeing AP events in the placebo group in the balanced study very early on in that study, as reported in the New England Journal of Medicine. Label to be determined. We're just getting started here in 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 it through a supplemental NDA. We have AP in the label for FCS. We hope to have AP in the label for sHTG as well.
That's a 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. Isn't 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. I just think this is tremendous data. These are landmark studies. To be able to demonstrate the correlation between Olezarsen reductions in TGs and reductions in acute pancreatitis, I think, is very significant here.
All right. Thank you. Your next question comes from the line of Yanan Zhu with Wells Fargo. Please go ahead.
Oh, great. Thanks for taking our question and congrats on the very strong data from CORE and CORE2. 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? Also, any color on whether Olezarsen is effective in preventing first-time attacks, given that I expect most of the attacks will be from recurrence of patients with prior histories? 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 people who have no attacks. Thanks.
Thanks, Yanan. We are 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 a medical congress later this year. Sam, have at it. Maybe you can provide a little bit more color at this point.
I think it's well known that the relationship of pancreatitis and triglycerides is linear, particularly after 500 mg/dL. That's the 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 topline data. We'll be able to get that for you later, but we can't tell you right now what the differences were in the triglyceride levels. We've also seen, obviously, the patients who have had a prior attack have the highest event rate. New events also occur in patients without a prior attack. We'll be able to provide that information also, but we've seen acute pancreatitis in both groups that were just mentioned.
Thanks, Yanan.
Our next question comes from the line of Gena Wang with Barclays. Please go ahead.
Thank you for taking my questions. I also want to add my congrats on such impressive data. Quickly, I think regarding the dose, you know in FCS , you did have approved the 80 mg dose. Now, with this, you do have very impressive data from both 50 mg and 80 mg doses. Any thoughts when moving forward? What will be the dose? Will we stick with 80 mg doses, or could that be a possibility to have a flexibility of both doses? A very quick question regarding the sales force. Kyle, can you add some color on potential, you know how much more sales you need to add and related cost associated in preparation of launch second half next year?
You start with that, Kyle.
Yeah, so our current sales organization is able to address thousands of the highest treaters of sHTG today. 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 onto 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. 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.
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're sharing today, and be able to drive the uptake in the sHTG population.
Your first question, Gena, indeed, both doses look very impressive, and there's no reason why we couldn't file for both doses for approval with the FDA . You know we're still working through the data. Aside from the data, we also need to think through our commercial strategy to maximize success on the sHTG market. We're working through that. Stay tuned, and we'll have more to share with that down the road.
Thank you. Your next question comes from the line of Jessica Fye with JP Morgan. Please go ahead.
Good morning and congrats on strong results. Among the three groups of high-risk sHTG patients that you're going to be targeting, between those with prior acute pancreatitis and triglycerides north of 500 mg, those who are north of 880 mg, and those who are north of 500 mg 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 three 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 one or both of those, and they're 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. Those with a prior history of AP are definitely at the top of the list.
Anyone that's above 880 mg is also a very, very strong candidate for this product because of the risk of AP and how devastating that can be.
Thank you. Your next question comes from the line of Jason Gerberry with Bank of America. Please go ahead.
Hey, guys. Good morning. Thanks for taking my questions. I've got another AP question. Were patients in the placebo arm who had AP events hospitalized? 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. I'm wondering if you can offer any color around that. 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? 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. I imagine you're going after the larger TAM, and there's a tension there. Any color you can just provide about what payers really care about in terms of how you show that AP benefit. Thanks.
Yeah, Sam, can you briefly walk us through the strict criteria we utilize for assessing the AP events in the studies?
Sure, sure. Yeah. We use an independent adjudication committee, and that has set the criteria for what's considered pancreatitis, and that uses the modified Atlanta criteria. That is in the charter that's been published before. They've been doing it for 10 years. They have lots of experience with it. The committee they use to do that is pancreatitis specialists. Ionis did not set the criteria. This is set independently by that committee. 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. 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.
For example, in the balanced study, which has come up to your question before, 12 out of the 13 of those cases were documented by the Atlanta criteria. That's the same criteria we use now, and that's the same kind of trend we're seeing. There's no doubt that these are real pancreatitis cases. The question is, you know what level of evidence is in that. In terms of hospitalizations, yes, many of them are hospitalized. In fact, in the balanced study, we have evidence that there's a massive reduction in the date of hospitalization. I don't have that in the topline data to give you an exact number, but a lot of these patients are hospitalized because they're very ill from this side effect.
Just to add to that, Jason, documented is the strictest criteria for determining acute pancreatitis. More than 90% of the patients who are CORE2 combined were documented.
Thank you. Your next question comes, go ahead.
Yeah, I was going to address the question on payers, Jason. Thanks for asking that and the value of the data that we've just read out on the topline. What we know in the FCS population is obviously the payers appreciate and understand the value of Tryngolza in the FCS population and the correlation to acute pancreatitis, which is currently in the label. We've also been able to demonstrate reductions in visits and reductions in hospitalizations. What I believe when we get out and are able to test this sHTG data with CORE and CORE2 is payers will see similar value based on the strength of this data. To be able to reduce triglycerides up to 72%, reduce acute pancreatitis 85%, we'll be able to correlate that to costs and associated value for the payers.
We will price accordingly and announce that price at the approval of the sHTG indication.
All right. Thank you. Your next question comes from the line of Luca Issi with RBC Capital. Please go ahead.
Oh, great. Thanks so much for taking my question and congrats on the very strong data here. Maybe one more for you, Kyle. I think for some investors, one of the most intuitive comps here is actually Vascepa. That drug, I believe, peaked at $600 million in revenues. I'm wondering if it's common or whether you think that that is a reasonable comp for us to think about it or whether you think you can do a lot better than that. Maybe related to it, I think sales for that drug actually inflected only after that company ran a cardiovascular outcome trial. I wonder if running a cardiovascular outcome trial here is part of the plan. Any call there much appreciated. Thanks so much.
Yeah, thanks for the question, Luca. I'll just reiterate, these are landmark studies. This has never been proven before. Olezarsen is the first treatment to show a reduction, a statistically significant reduction in acute pancreatitis. I think that's very, very important in terms of the patient population that is going to be treated here and also the value of the medication in the way that that's going to be reflected in the marketplace. We need to go out and test in a comprehensive way with both physicians and payers to make sure that we understand and can put a stake in the ground in terms of what the cost and the pricing structure will look like here.
That being said, we do expect Olezarsen to be a blockbuster opportunity based on this data, based on the patient population that's addressable that we were talking about previously of greater than a million patients that have a high-risk sHTG. We believe that we'll be able to work effectively with these specialists and get them on Olezarsen quickly and realize the blockbuster potential that this represents.
Yeah, and I'd like Sam to add some color on the Vascepa comparison that you alluded to, Luca. Vascepa has modest, at best, triglyceride-lowering effects. No comparison to what we're seeing for Olezarsen in the 70% median range, mean range here. Sam, you should touch on that and also the.
Yeah, absolutely. Yeah, thanks for the question. I think it's going to be night and day in terms of how physicians view Vascepa use versus what you see here. The effect of Vascepa in the lower triglycerides is only 19%, and it's maybe up to 30% in the higher TG values. There's absolutely no data that it affects pancreatitis. We're going to be getting 60%, 70% reduction in triglycerides. If you just picture the physician sitting there, if you have a patient with a 700 and they give Vascepa, they might go to like 550, 500 if they're lucky. When they get Olezarsen, they're going to go down to probably under 200. You have this massive reduction in pancreatitis, which is unprecedented.
You're going to have a drug that's two or three times more potent, and it has the kind of data that physicians have been looking for for five decades. We think it's going to be way ahead of any kind of comp that you probably have envisioned, and it's going to set a new standard for how physicians, I think, look at hypertriglyceridemia and what effectiveness they'll get from the current drug Olezarsen.
Thanks, Sam. Yeah, I mean, we have our outcome data, acute pancreatitis, and we nailed it. Thanks, Luca.
Your next question comes from the line of Mike Ulz with Morgan Stanley. Please go ahead.
Good morning. Thanks for taking the question, and congratulations on the data as well. Maybe just to follow up on the market opportunity. Now, with your significant reductions in acute pancreatitis events, how does that impact the thinking in terms of the addressable patient population? Could you capture a broader set of patients maybe earlier than you were previously thinking? Thanks.
Yeah, thanks, Mike. I think we're really excited about the market opportunity. I showed the one slide that shows the million or so patients that have high-risk sHTG, and that will be the beachhead. Specialists are treating these patients. It's a manageable number of HCP targets and a very broad number of patients that can benefit from Olezarsen. That's where we will start. In addition to that, we're able to do very broad disease state education through our marketing efforts, including our omnichannel capabilities to reach tens of thousands of HCPs in this space. I believe that this is very strong data. I think it's going to be very motivating. Sam has reflected the view of this data and what it's going to mean to HCPs. This is really unprecedented, and these are landmark studies.
I think we're looking forward to doing some more market research and getting ready for potential approval towards the fourth quarter of next year.
Thank you. Your next question comes from the line of David Lebowitz with Citi. Please go ahead.
Hi. Thanks for taking our question. This is [actually] on for David Lebowitz. When you say manageable number of HCP targets, how do you think about the capital allocation when it comes to hiring a larger sales force? Have you done the work yet? Do you know about a ballpark on what the outlay is going to be when it comes time for this launch, which is significantly larger than FCS?
Yeah, thanks, [Ike], for the question. A manageable number of targets is probably in the ballpark of about 20,000 specialists today. That covers cardiology, endocrinology, and lipidology. They are managing hundreds of thousands of these sHTG patients that could potentially benefit from Olezarsen. In terms of the scale-up and the size of the organization, we will build a team that is sized appropriately in order to reach about 20,000 or so HCPs. The costs associated with that have been built into our commercial plan and our commercial build-out. As you think about the commercial organization and what we've done from the very beginning with Wainua, and then Tryngolza, Dawnzera, and now potentially sHTG, we've done this very thoughtfully and very strategically in terms of our build. We've done it very responsibly in terms of how we've invested in the commercial organization in order to get there.
We'll continue to invest accordingly as we move forward. This is all in the budget, and we're looking forward to building the team out in 2026.
Thank you. Your next question comes from the line of Yaron Werber with TD. Please go ahead.
All right. Thanks for taking my question and congrats on that really terrific data. Just two interrelated questions, one for Kyle, one for Sam. Maybe Sam, for you first. I know you did a, I believe, an abdominal MRI sub-study to look at fat around hepatic fat. Any topline results on that? For Kyle, of the $1.2 million patients, do you have a sense? I'm trying to get the ones that really have greater than 80, and a history of AP, and are being treated currently. How many patients fit that criteria? That's sort of the initial low-hanging fruits. Thank you.
We're really, you know, due to a variety of reasons, particularly presentation at meetings, et cetera, we can only present what we thought was material secondary endpoints, and that's pancreatitis. Your question is a good one, but we'll have to address that as we go forward and have a little bit more time to analyze that aspect of the study.
We will be presenting all the secondary endpoints in addition to AP at a medical meeting later this year. We're pleased with all the secondary endpoints related to efficacy and safety.
As it relates to the patient population in the $1.2 million, greater than 500 mg with a history of AP , there are approximately 60,000 of those patients in the U.S. today. Greater than 880 mg and are also being treated are upwards of 600,000, and that includes patients on fibrates and fish oils and other triglyceride-lowering agents. That is what we believe to be the highest unmet need today and the greatest opportunity for us to establish a beachhead and then grow the market and the opportunity for Olezarsen from there.
Thank you. Your next question comes from the line of Myles Minter with William Blair. Please go ahead.
Hi, this is Jake on for Miles. Thanks for taking our question and congrats on the data. You guys noted the percentage of patients in each study that have above 880 mg/dL triglycerides at baseline, but was just wondering if you have a percentage of patients that are considered high-risk sHTG when you consider pancreatitis history. Secondly, just wanted to hear any color about potential differences that you saw in trig lowering in the placebo arm of your CORE and CORE2 studies. Thanks.
Yeah, Sam, why don't you take the second question first? You know, the changes in placebo between CORE and CORE2, explanations?
Sure. Yeah, we're looking into this now. We're very pleased with the CORE study, which was the first one and the larger of the two. There's a lot of variability in triglycerides in general. It's much more than for LDL, for LPA, for HDL. That often can be part of the natural variability. For some reason, the second study had more of that. We did try to mitigate that, and I think we did a really good job in CORE. We did that with dietary advice. We asked the patient not to go on medications during the trial. They had to be on stable medications, et cetera, et cetera. The inclusion criteria were identical, but the sites were a bit different, and some of the geographic areas where they were recruited were different because we couldn't obviously do two trials in the same site. We are looking into this now.
I can't answer your question right now, but the truth is probably somewhere in the middle. Either way, if you just look at the data from the take the placebo out of it, the drug is very potent if you just look at baseline to change. We had a 63% reduction with the 50 mg in both arms, and we had like a 68% and a 73% if you just do pre and post. The drug is behaving extremely well in these patients, but there's variability in the placebo group, and we'll hopefully be able to figure out why there were differences when we have more time to analyze the data.
Jake, regarding the makeup of the triglyceride in the studies, Sam mentioned in his prepared remarks the mean levels of triglycerides in both studies were over 1,000 mg. We had plenty of patients that were above 880 mg in this study. We published that in our baseline demographics paper, as I recall, but it was a substantial number of patients that would be considered using one of Kyle's definitions of high risk above 880 mg. We also had patients that had had a history of acute pancreatitis within the last 10 years, 13% in CORE2 and 21% or so, 22% in CORE, reflecting higher triglyceride mean levels in CORE versus CORE2. We are going to have plenty of patients that meet the criteria Kyle laid out as high-risk sHTG patients in our CORE studies. We will share all that data later this year.
I think we have time for one more question for wrap-up.
Thank you. Our last question will be from Mani Foroohar with Leerink Partners. Please go ahead.
Hey, guys. Thanks for sneaking us in. You have Ryan on for Mani, and congrats on the data. Maybe just one last AP question, and more conceptually speaking. Based off all the Olezarsen data that you guys have seen across Phase II and Phase III studies, do you think that AP reduction continuously improves as you lower TGs below 400 mg or even sub 200 mg /dL ? Do you think it's more about getting patients below a predefined protective threshold that almost eliminates the development of AP events? Thanks.
That's a great question and a lot of interest for us. We don't have the answer whether it's a threshold effect or a linear effect. What we do have is a tremendous database now of close to 4,000 patients where we can address that. What we can tell you is that unlike statin trials, where sometimes it takes a year to two to see separation of the curves, as Brett mentioned earlier, you get an immediate benefit when you lower triglycerides. Recall in the [Volana Sourcemet] analysis in New England Journal of Medicine, within the first couple of weeks, there were already placebo cases, and they just continued to accumulate. Same thing with the balanced study. One difference between, say, an LDL-type study versus a triglyceride study is you get an immediate benefit, and then the curve, the slope seems to stay the same.
It continues to accrue events in placebo. When you look at the treatment groups, you do get some events, but they're usually in the single digits, maybe two, three, something like that, and then they just stay flat all the way across. We'll know when we do our local label studies and when there's clinical use of the drug in the broader population, those questions will be addressed plus mining our data. It looks like both could be true. Whatever the underlying mechanism is, once you get people on this drug, you basically get about an 80%- 90% reduction in pancreatitis. We've shown that now in every study that we've done. We feel like this is really an amazing advance for the patients and for documenting the hypothesis. We anticipate that benefit to continue to accrue over time as the patient gets treated for 5, 10 years or more.
Thanks, Sam. Thanks, Ryan. Thanks, everybody, for joining us today on this really exciting day. We look forward to sharing additional information on the Olezarsen program, as well as our rich pipeline throughout the year. I want to remind everybody that we are hosting, Ionis is hosting our biannual Innovation Day in New York City on October 7th. We're certainly going to do a deep dive into the Olezarsen program, as well as our technology and the rest of our rich pipeline and our commercial strategy going forward. We really do hope to see you all there. Until then, have a great day, everybody.