Good afternoon and welcome to Ionis conference call to discuss Olizarsan phase 3 detailed results. As a reminder, this call is being recorded. At this time, I would like to turn the conference over to Wade Walke, Senior Vice President of Investor Relations, to lead up the call. Please begin.
Thank you, Ludi. Thank you to everyone who has joined us today as we discuss the groundbreaking results from the landmark Core and Core 2 studies of Olizarsan in people with SHTG. These data were presented earlier today at a late-breaking American Heart Association scientific session and published simultaneously in the New England Journal of Medicine. Please be sure to visit the investor section of the Ionis website to see the AHA presentation, along with the press release issued and the slides accompanying today's webcast. With me on the call today are Brett Monia, Chief Executive Officer, who will provide opening remarks; Dr.
Sam Tsimikas, Senior Vice President, Global Cardiovascular Development, who will discuss the significant unmet need associated with SHTG, and will then review the Core and Core 2 study results, Kyle Jenay, Chief Global Product Strategy Officer, who will discuss our go-to-market approach to achieving launch success, assuming approval of Olizarsan for SHTG, and Richard Geary, Chief Development Officer, who will join us for Q&A after Brett's conclusion. Before passing the call over 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 afternoon. We're here today to discuss the groundbreaking results from the phase 3 Core and Core 2 studies of Olizarsan in people with severe hypertriglyceridemia, or SHTG, that were presented earlier today in the late-breaking session of AHA and simultaneously published in the New England Journal of Medicine. These positive data further strengthen our confidence in Olizarsan's ability to become the new standard of care for the broad SHTG patient population. In the phase 3 results presented and published today, Olizarsan demonstrated rapid, substantial, and significant reductions in triglycerides by up to 72% on top of standard of care and reduced the risk of acute pancreatitis events by 85%. This makes Olizarsan the first and only investigational treatment to achieve this remarkable outcome in SHTG.
Furthermore, 86% of patients treated with Olizarsan achieved triglyceride levels below 500 milligrams per deciliter, which is the triglyceride threshold that defines SHTG, and a substantial percentage of patients achieved normal triglyceride levels. These unprecedented efficacy results, together with a favorable safety and tolerability profile, position Olizarsan to fundamentally change the treatment paradigm for people living with SHTG. 2025 has been a year of accelerating growth for Ionis as we entered a new era as a fully integrated commercial-stage biotechnology company. In just the first nine months of this year, we initiated our first two independent launches. We successfully launched Tringulsa, the brand name for Olizarsan, in its first indication in January as the first and only FDA-approved treatment for people living with familial chylomicronemia syndrome. The Tringulsa launch continues to go very well.
In August, our second independent launch got underway with the approval of Dawnzera as a prophylactic treatment for hereditary angioedema, or HAE. The early feedback from physicians and the patient community has been very encouraging, with strong enthusiasm for Dawnzera's compelling profile and novel mechanism of action. This is just the beginning. Next year, we have two more independent launches planned: Olizarsan for SHTG, which we're here to discuss today, and Zilgenersan for Alexander disease. With positive pivotal results for both programs now in hand, Ionis is well positioned to continue delivering a steady cadence of important medicines to patients next year and for years to come. With the compelling Core and Core 2 results in hand and the meaningful impact Olizarsan is already having for people with FCS, we're in a very strong position to capitalize on our first-mover advantage in SHTG.
We remain on track to submit our supplemental NDA for Olizarsan by the end of this year and to launch in the fourth quarter of next year. As you'll hear from Kyle, our U.S. launch preparations for the SHTG indication are well underway, setting the stage for Olizarsan to reach the broad patient population and drive the next phase of growth for Ionis. Before I turn the call over to Sam, I'd like to recognize the patients, families, and clinicians who participated in the Olizarsan studies. Their commitment made these important results possible. I'd also like to acknowledge the Ionis team, whose continued dedication to patients and to the Olizarsan program have been instrumental in achieving the positive outcomes that we're discussing today. With that, I'll pass the call over to Sam to provide an overview of SHTG, our Olizarsan clinical program, and our groundbreaking results. Sam?
Thank you, Brett. Hello to everyone with us on the call. Before I begin, I'd also like to recognize and thank everyone whose contributions made today's results possible, including our colleagues at the TIMI Study Group who collaborated with us on the Olizarsan phase 3 program. The Core and Core 2 studies were designed to evaluate Olizarsan in people with SHTG. SHTG is defined by fasting serum triglyceride levels of 500 milligrams per deciliter or higher, driven by factors such as genetics, diabetes, obesity, and metabolic syndrome, all of which can impair triglyceride clearance. When triglycerides exceed 500, large lipid particles called chylomicrons begin to accumulate in the bloodstream, increasing the risk of acute pancreatitis.
At high enough concentrations, chylomicrons can become toxic to the pancreas and lead to acute pancreatitis, a serious and potentially life-threatening condition associated with hospitalization, intensive care admissions, and long-term complications, including repeat pancreatitis events. As triglycerides increase, chylomicrons also increase, and the risk for acute pancreatitis becomes even greater, especially at levels exceeding 880. For many people living with SHTG, current triglyceride-lowering treatments such as fibrates and omega-3 fatty acids fail to sufficiently lower their triglycerides. Moreover, none have shown a proven benefit in lowering the risk of acute pancreatitis, which highlights the need for more effective therapies. With the relationship between SHTG and acute pancreatitis well understood, clinical guidelines already recommend aggressive triglyceride lowering for people living with SHTG. However, despite these recommendations, current treatment options and lifestyle interventions remain insufficient, leaving these people at continued and substantial risk.
Olizarsan's remarkable efficacy is based on targeting ApoC3, a novel mechanism that Ionis pioneered for managing conditions associated with high triglycerides. As a central regulator of triglyceride metabolism, ApoC3 elevates triglyceride levels through two primary mechanisms. First, it represses lipoprotein lipase, the enzyme that breaks down triglyceride-rich particles. Second, it blocks the clearance of these particles from the circulation. The result is an accumulation of triglyceride-rich lipoproteins, like chylomicrons, that cause complications like pancreatitis. Olizarsan works by reducing the production of ApoC3, effectively resetting triglyceride metabolism. This allows triglyceride-rich particles to be broken down and cleared. With the understanding of how Olizarsan works, here is an overview of the studies that made up our comprehensive phase 3 development program. First are the pivotal placebo-controlled Core and Core 2 studies, which comprise the largest pivotal program ever conducted in SHTG.
Data from these studies were presented earlier today at AHA and simultaneously published in the New England Journal of Medicine. We also conducted the phase 3 Essence study to contribute to the safety database in our planned sNDA filing. Essence primarily enrolled participants with moderate hypertriglyceridemia and elevated cardiovascular risk. Positive data from this study were presented at the European Society of Cardiology and were also simultaneously published in the New England Journal of Medicine in August. Now, let's go over the Core and Core 2 study design and the groundbreaking results. Participants in Core and Core 2 were required to be on stable standard of care lipid-lowering therapy throughout the trial. Their diet was stabilized during screening and maintained with the support of counseling throughout the treatment period. Participants were effectively randomized 1:1:1 to Olizarsan 50/80 milligrams or placebo.
Participants were stratified based on triglyceride levels greater than or less than 880 and with or without a history of acute pancreatitis in the 10 years prior to enrollment. The treatment period was 12 months, and the primary efficacy endpoint, the placebo-adjusted mean % reduction in fasting triglycerides, was assessed at six months. The key pre-specified secondary endpoint was the % change in adjudicated acute pancreatitis events with pooled Olizarsan compared to pooled placebo at 12 months. Additional key secondary endpoints included the portion of patients who achieved triglycerides below 880 and 500, as well as reduction in ApoC3 and a variety of lipid parameters. Participants who completed the placebo-controlled portion of the studies were eligible to enroll in an open-label extension study and were pleased to report that more than 90% of eligible participants elected to participate.
Baseline characteristics from Core and Core 2 highlight the severity of SHTG in the study population. Median baseline fasting triglyceride levels were in the mid-700-800 range, while the means were over 1,000. Around 40-50% of participants had baseline fasting triglyceride levels greater than 880. About 13-23% of participants had at least one event of acute pancreatitis. All participants were on stable treatment with at least one lipid-lowering therapy, and more than 60% were on two or more lipid-lowering therapies, underscoring the lack of effective therapies. Now to the results, beginning with the primary efficacy endpoint of fasting triglyceride reduction at six months. As reported in the top-line data, Olizarsan significantly reduced triglycerides by up to 72%, with both doses in both studies achieving highly statistically placebo-adjusted mean reductions.
Now, I want to share with you new compelling data that were presented and published earlier today. The substantial triglyceride reductions achieved at six months were sustained through 12 months of ongoing Olizarsan treatment, underscoring the durability of response over time. In both the 50 and 80 milligram dose groups and across both Core and Core 2 studies, patients experienced dose-dependent, rapid, and robust reductions in triglyceride levels. Importantly, these rapid, durable, and highly statistically significant reductions were achieved on top of standard of care therapy. At 12 months, a substantial proportion of participants achieved meaningful triglyceride reductions across key clinical thresholds. Nearly 90% of participants with baseline triglyceride levels above 880, the level associated with the highest risk of acute pancreatitis, achieved triglyceride reductions below this critical level.
86% of patients achieved triglyceride levels below 500, the threshold for SHTG and acute pancreatitis risk, demonstrated Olizarsan's potential to bring patients below this important level. Up to 54% of patients reached normal triglyceride levels below 150, highlighting Olizarsan's potential to restore triglycerides to a healthy range for people living with SHTG. Now, let's turn our focus to the most clinically relevant secondary endpoint of this population, a reduction in acute pancreatitis events, which were assessed in a comparison of pooled Olizarsan to pooled placebo across the two studies. We're very pleased that Olizarsan achieved a highly statistically significant 85% reduction in adjudicated acute pancreatitis events after only 12 months of treatment. These results were based on a total of 22 events in 17 patients in the placebo group compared to seven events in five patients treated with Olizarsan.
Clinical evidence demonstrates that patients with triglycerides above 880 face significantly increased risk of acute pancreatitis. Looking at the breakdown of acute pancreatitis events in these high-risk patients in our study confirmed this relationship with the majority of events concentrated among these patients. These results provide definitive evidence that substantial triglyceride reduction with Olizarsan translates to clinically meaningful protection against acute pancreatitis for SHTG patients. Now, let's take a look at the number needed to treat, or NNT. NNT is a measure of clinical efficacy that tells us how many patients need to receive a therapy to prevent one additional event. For context, statins used for primary prevention have an NNT in the range of 50-100 to prevent one cardiovascular event over five years. With Olizarsan, NNT is substantially lower and in a much shorter time period.
In the overall pooled analysis, treating just 20 patients with Olizarsan is estimated to prevent one acute pancreatitis event in only 12 months. As you can see, the two curves separate quickly, with events in the placebo group beginning to accumulate early and continuing to rise over time. In contrast, the Olizarsan group shows a substantially lower rate of events throughout the 12-month period, demonstrating Olizarsan's potential to meaningfully improve outcomes for patients with SHTG. Now, in the highest risk subgroup, those with triglycerides above 880 and a history of acute pancreatitis, the NNT is only four patients after just 12 months. Seeing an NNT ranging from 4-20 for a potentially fatal event like pancreatitis and achieved in just one year is very compelling to physicians and provides a sense of urgency to treat with Olizarsan. Olizarsan also showed improvements across additional key lipid measures.
We saw significant reductions in ApoC3, remnant cholesterol, and non-HDL cholesterol, along with substantial increases in HDL cholesterol. As expected, we saw a modest rise in LDL cholesterol, consistent with the known effect that occurs when triglycerides are reduced in this patient population. Additionally, the increase was proportional to the decreases in remnant and non-HDL cholesterol. ApoB, which reflects a total number of atherogenic lipoprotein particles, decreased slightly. Together, these results demonstrate an overall favorable lipid profile. Olizarsan demonstrated a favorable safety and tolerability profile in Core and Core 2. Adverse events were generally balanced across treatment arms. Notably, serious adverse events occurred less frequently in the Olizarsan-treated participants. The most common treatment emergent events were injection site reactions, which were mostly mild and occurred more frequently with Olizarsan.
This table shows several additional parameters we measured in Core and Core 2, all of which were generally consistent with previous study results. At the 80 milligram dose, some patients experienced asymptomatic increases in liver enzymes equal to or greater than three times the upper limit of normal. These elevations were not associated with clinical complications and generally resolved with continued dosing. Consistent with previously reported results with ApoC3 targeting drugs, small absolute mean increases in liver fat and hemoglobin A1C were observed. Increases in liver fat were not correlated with transaminase elevations and were not associated with clinical sequelae. There were no imbalances in hemoglobin A1C in non-diabetic patients. Olizarsan delivered clinically significant outcomes in severe hypertriglyceridemia. 86% of patients reached triglyceride levels below 500, and acute pancreatitis incidence was reduced by 85% compared to placebo.
These results established Olizarsan as the first and only investigational treatment to significantly reduce such events in this population. With these compelling data in hand, we are on track to submit our sNDA by the end of the year, setting us up to bring Olizarsan to people with SHTG in the fourth quarter of next year. These results marked a historical achievement in lipidology and position Olizarsan to become the new standard of care for people living with SHTG. With that, I'll turn the call over to Kyle. Thank you, Sam, and good afternoon, everyone. The Core and Core 2 results reinforce our confidence that Olizarsan is poised to become the new standard of care for SHTG, addressing a large patient population with significant unmet need.
People with SHTG live with a substantial risk of acute pancreatitis, a painful and potentially life-threatening complication that can lead to hospitalization and long-term organ damage. Despite available treatments, physicians consistently tell us that they are dissatisfied with the current standard of care. Existing therapies offer only modest triglyceride reductions and do not eliminate the risk of pancreatitis. In the U.S. alone, more than 3 million people live with SHTG, including over 1 million with high-risk SHTG. People with SHTG face a five-fold greater risk of an acute pancreatitis event. Each event not only carries the potential for severe, even fatal outcomes, with mortality rates reaching up to 8% per triglyceride-induced event, but also increases the likelihood of recurrence and long-term pancreatic injury. Beyond the human toll, the economic burden is substantial, driven by hospitalizations, intensive care admissions, and long recovery periods.
This serious and recurring risk highlights the urgent need for a medicine that can both lower triglycerides effectively and reduce the risk of pancreatitis itself, something current treatments have not been able to achieve. That's where Olizarsan comes in. The groundbreaking results from the Core and Core 2 studies demonstrate that Olizarsan is uniquely positioned to address these unmet needs. In addition to its strong efficacy and favorable safety and tolerability profile demonstrated in the Core studies, Olizarsan offers the convenience of once-monthly self-administration with an autoinjector, which is highly valued by patients and physicians alike. As a KOL summarized perfectly, "A treatment that meaningfully lowers triglycerides and reduces acute pancreatitis risk, something we've never seen before, would be a game changer." We believe Olizarsan is that game changer.
At launch, we plan to focus on more than 1 million high-risk SHTG patients, those with triglycerides above 880 milligrams per deciliter, or those above 500 with a history of acute pancreatitis or other comorbidities. These are the patients most in need, and the physicians treating them already understand the urgency. Our commercial strategy leverages our early success with Tringulsa and FCS to engage with healthcare providers who are already prescribing the therapy, many of whom manage SHTG patients. In parallel, we are broadening our reach to additional prescribers who treat these patients. To support this effort, we are expanding awareness of SHTG through targeted disease education and continued investment in our commercial infrastructure. Over time, we anticipate penetrating deeper into the 3 million-plus patient population with triglycerides above 500. With Olizarsan, we see a clear path to blockbuster potential.
We recently conducted additional HCP research based on Olizarsan's overall profile presented today. Initial research results confirm the high level of enthusiasm for Olizarsan and particularly its remarkable ability to lower triglycerides and reduce pancreatitis events. To realize the potential of Olizarsan, we're leveraging the strong commercial foundation built with Tringulsa, including disease education, patient finding, and payer engagement, as we prepare the market for Olizarsan's broader SHTG indication, assuming approval. Our cardiometabolic field team will consist of roughly 200 specialists who will target the approximately 20,000 highest-treating HCPs in the US, while also expanding our reach through omnichannel education campaigns. With key field medical and commercial leadership in place, we've begun scaling the team to expand our capabilities to ensure we have the reach and expertise in place ahead of launch.
We're also engaging payers, and they already recognize the value of treating people with SHTG, given the substantial cost and clinical burden of pancreatitis. Together, these efforts are setting us up for a strong launch. Olizarsan is well-positioned to be the new standard of care in SHTG. It is backed by groundbreaking data, our first-mover advantage, and a growing base of engaged physicians, patients, and payers. With an experienced commercial organization building on the success of Tringulsa and FCS, we're on track to bring Olizarsan to this broad patient population in the fourth quarter of next year. With that, I'll turn the call back over to Brett. Thanks, Kyle. Today's data from the Core and Core 2 studies reinforce our confidence that Olizarsan will establish a new standard of care, offering a potentially transformative therapy for this large patient population.
It's another example of how we're turning groundbreaking science into meaningful medicines that change lives. With these strong Olizarsan results, we're well-positioned for launch next year. We are also on track to bring Zilgenersan to people with Alexander disease in the same time frame. These anticipated launches build on the continued momentum of Tringulsa and Dawnzera as we deliver on our goal to bring a steady cadence of important new medicines to patients. Beyond our independent launches, by the end of 2027, we expect four launches from key late-stage partnered medicines to treat a range of serious life-threatening diseases. These medicines are poised to significantly expand the reach of Ionis Discovered Medicines to many more patients in need. World-class science, an expanding commercial footprint, and a proven ability to bring first-in-class therapies to patients who need them most, our exceptional progress positions Ionis for substantial growth and sustained value creation.
Most importantly, we remain steadfast in our mission to profoundly improve the lives of people with serious diseases. Thank you again for joining us today, and now we'll open up the call for questions. Thank you. Ladies and gentlemen, we will now begin the question and answer session. To ask a question, you may press a star followed by the number one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press a star followed by the number two. With that, our first question comes from the line of Jay Olsen with Oppenheimer. Please go ahead. Oh, hey. Congrats on achieving this major milestone for the treatment of SHTG. We're curious if you measured the participants' use of background medications, dietary, and lifestyle interventions during the Core studies.
Does the evidence suggest that, based on the significant reduction and normalization of triglycerides and the reduction of acute pancreatitis, Olizarsan would enable patients to normalize their diets and lifestyles and reduce the use of background medications? Hi, this is Sam. I'm happy to answer that. As we mentioned, the patients got dietary counseling at the beginning of the study before randomization and throughout the whole time. That should have been balanced across the groups. In terms of background therapies, you saw that they're very intensively treated and still have high triglycerides. Large number of patients on statins, two-thirds on fibrates, one-third on omega-3 fatty acids. We did look at GLP-1 receptor agonist. That was about 15%. It was also balanced during the trial. The bottom line is the three groups were fairly well-balanced in all of the background therapies.
Regarding your question about liberalizing diet, we really didn't study that in this population. What we know is that despite optimal diet, these patients have a polygenic etiology for their hypertriglycerides. They're not purely related to diet, diabetes, or obesity. They have multiple abnormalities in triglyceride genes. They probably would have been hypertriglyceridemic or would have been no matter of those background therapies. They need a real therapy for their problem. Now, whether you can liberalize their diet and that sort of thing is unknown. We do know from the FCS population that they have to stay on their diet. We wouldn't recommend that at this point, but it's something that could be studied as we go forward in the open label, for example, etc. We do know, as you saw the curves, we have rock-solid reductions in triglycerides throughout the 12 months.
They're not budging at all. There's no fluctuations. The therapy is very effective. To prevent pancreatitis, I think we need that robust effectiveness. Thank you. If I could please ask one follow-up. Since we've never seen triglyceride reduction or ApoC3 reduction like this before, I want to recognize that it might be difficult to predict the impact that Olizarsan could have on clinical practice. If I could maybe ask you to speculate a little bit on how these impressive results could change treatment guidelines. Sure. I think the results are unprecedented. I don't think it'd be very difficult for another trial to beat a 72% placebo-corrected reduction in triglycerides. When we do cardiovascular outcomes trials, we hope for 15-20% reduction. Here we had an 85% reduction for pancreatitis, and it was the first study.
I equate this trial result to what we saw with 4S, which was the very first study with statins to show a clinical benefit. We knew we could lower LDL with, for example, resins and niacin, but we did not have any clinical data. This trial is going to be in that historic context. Because of that, it should go in the top line of the guidelines when people talk about SHTG. We will see how that goes going forward, but it would be highly surprising if it did not make it to the very top. Great. Congrats again on the results. Thanks for taking the questions. The next question comes from the line of Manny Ferrehar with Luring. Please go ahead. Hey, guys. Congrats on the great data. A couple of quick questions, if that is all right.
I think, first of all, this data would seem to align very closely with what is described as an appropriate agent for the Commissioner's National Priority Voucher Pilot Program, recognizing that obviously that's something that has to get nominated from inside the FDA. Could you comment on to what extent you've been engaged with the agency and whether or not you see this as being sort of an opportunity for this Olizarsan? Then separately, moving over to the data, I and you guys have had a couple of relative bears arguing that perhaps the accumulation of fat in the liver could be an issue. I know the discussion commented on the lack of correlation between increased liver fat and elevated liver enzymes. Could you comment on how you think about resolution of the liver fat signal?
Is that simply an on-mechanism phenomenon that doesn't have clinical consequence, or just how to think about that, given that that is a bear thesis that's been floating around there? Yeah. Thanks, Mani. Very quickly, I'll touch on the path to regulatory approval in the U.S., and then Sam can talk about OnTarget, what his thoughts are on mechanism of the small increases in liver fat that we've seen. Our plan right now is to submit the NDA, as we mentioned in the webcast earlier, by the end of the year. We're assuming right now a standard review that puts us into the fourth quarter for approval and launch. However, we are looking at all possible opportunities to accelerate that path forward. That can include, for example, seeking priority review.
It could also include potentially seeking national priority review under the new program, under the new administration that you've flagged. We're working on all that internally right now. Right now, we're just getting that sNDA submitted by the end of the year, and that's where our laser focus is on. Yeah, go ahead. In the hepatic fat, a couple of important issues. One is there were no clinical sequelae that we noticed. There were no complaints from patients or physicians about that issue. It was not correlated to transaminases, so it suggests there's no inflammatory response going on in these patients. It was fairly small overall.
If you think about the mechanism of that, it's speculation at this point, but the way that Olizarsan works and other drugs, which have had similar findings, is that they allow increased uptake of circulating triglycerides into the liver. That's one of their mechanisms to clear it out of the circulation. The livers in these patients are already congested. We think it's probably a finite phenomenon where you're moving triglycerides from a very dangerous compartment that causes acute pancreatitis into the liver, and the liver probably just needs some time to kind of process that. We don't anticipate these being a chronic issue, but it is requiring some equilibration of where the triglycerides are going. We are doing studies to evaluate these patients in the open label, and we'll have more data on this going forward. Great.
Do you guys mind if I slip one more in there? Sure. Commercially, there's been obviously discussion of a potential price point that's always dependent upon clinical data and value to the patient and system, of course. I think I previously talked about a price point more suitable for a mass specialty market, something in the $20,000-$30,000 range. A number of my colleagues elsewhere have commented that perhaps something closer to where Madrigal puts the Resifra in the high $40,000 range could make sense for the 1 million patient more severe population. Given what you disclosed about the number needed to treat, 4 being really gaudy and even 20 being pretty damn good, how should we be thinking about modeling this at launch once it's reset down from the FCS price?
How should we think about modeling potential price, value, and where in that band should we be landing, either on a growth or a net basis, however you want to talk about it? Sure. Thanks for the question. Obviously, that's ongoing work, and it's one of the critical questions that we want to make sure that we answer the right way. The key here is to make sure that there is broad access and availability for physicians to be able to prescribe and patients to be able to receive this medication. What we know today is that these are very meaningful results, is what you just outlined. The number needed to treat is very substantial and is going to be very helpful in terms of the case to price this accordingly.
The big picture that we're looking at on pricing is how do we make sure that we maximize value for the asset and we don't limit the ability for this to reach the broad population that's in need of triglyceride lowering. The work that we're doing right now will encompass all of the data that's been represented today. We'll also include hospitalization as well as emergency room data. We'll be able to put that totality of data together and go out and conduct that work. Where we're comfortable today is in the $15,000-$20,000 range is what we continue to see come back from payers.
The reason that we are hearing that today is they are looking at the potential indication for this product to be consistent with what the primary endpoint was in the clinical trial, which is appropriate for any patient that's greater than 500 milligrams per deciliter. They don't look at this as being a subset of population in terms of above 880 or above 500 with a history of acute pancreatitis. The patient population that they feel that they will potentially have a budget impact around is potentially up to 3 million plus patients. That's the work we're continuing to do. Obviously, the quality and the strength of this data are going to help us come to a final pricing determination, and we'll work through that and announce price upon approval like we've done with the FCS population as well as with our HAE program and Dawnzera.
Mani, I'll just add to that with respect to population. We have consistently heard from a large list of physicians that manage SHTG patients that their plan is to treat patients that are 500 and above who do not respond adequately to existing generic drugs. As you know, the vast majority of patients do not respond well to existing fibrates or fish oils. They do not want that first acute pancreatitis attack to happen. They know the consequences. Once you get one, the chances of having another one is recurrent and increases substantially, can cause pancreatic failure. Mortality rate for an acute pancreatitis event is 6%. They do not want that to happen. We are going after a large population here, not just recurrent patients with a history of AP. Of course, those patients will be aggressively treated by physicians because they are the ones in the greatest immediate need.
This is a very broad population we're going to go after. Thanks. That's really helpful. I'll back off. Thanks, guys. Thanks, Mani. The next question comes from the line of Jessica Farr with JP Morgan. Please go ahead. Hey, guys. Good afternoon. Thanks for taking my questions. I had two. First, with greater than 90% of patients going into the OLE, are you continuing to capture AP events in the extension portion? Do you think we might learn anything interesting from that extra follow-up on AP? Second, was hoping you could just remind us the number of sales reps you plan to have in place for the SHTG launch and what proportion of the 1 million high-risk patients you expect to be able to access with that initial sales force? Thanks, Jess. Sam, still coming from the OLE? Yeah.
We were very pleased to see that the OLE was oversubscribed. It's almost unheard of to get 90% of patients. Pretty much everybody that finished the trial got into it. We have very, very positive reflections of that because now the patients can see their triglyceride levels where during the trial they were blinded. Same for the physicians. We're having overwhelming positive responses. In fact, we've been asked to extend the OLE as much as we can. Yes, we are capturing pancreatitis events. We are following those patients very carefully because it's really a study. It's not just a random give them the drug and just follow them laxly. We're capturing as much information as we can.
What we've seen in the other studies, and we anticipate to see in this study, is this is not a cure for pancreatitis, but it reduces basically 9 out of 10 cases, essentially. There'll always be an occasional patient that will have something because there are some patients that continue to have this. The vast majority should be pancreatitis-free, and that should sustain. I think if we had done a three-year study that was randomized, those curves would have continued to expand. Bottom line is, yes, we'll be able to report on some of that information as we go into the future. The last patient was in June, so we need to wait a little bit to give you some information on that. We should have two years of OLE data in the future to be able to report on some of these issues.
Yeah, Jess. On the scale-up for SHTG, we'll be able to build a team of approximately 200 customer-facing team members. They will cover approximately 22,000 of the highest treaters of SHTG. There are approximately 350,000 patients within that population that they're currently treating today. Thanks. Next question comes from the line of Detroit Cador Paddy with Guggenheim. Please go ahead. Hey, good afternoon. I have a couple of questions. How much does it currently cost to treat a pancreatitis event? I'm only going back to your $15,000-$20,000 price point. Any thoughts on what it costs? Number two, given the focus somehow seems to be on liver fat, the 50 milligram dose was largely undifferentiated from the 80 milligrams overall efficacy, but it's clearly differentiated on safety. Do you think physicians will just use the 50 milligram dose?
I'm assuming you're going to price it at a flat price. Clarifications would be great. Thank you. Yeah. Comment on the cost of AP? Yeah. The cost of AP, there's been a recent publication on this, actually, is estimated to be about $100,000. That's inclusive of the cost leading up to, as well as the hospitalization, and then the cost to treat after that. That will factor into the totality of the data that we work with payers on to justify the price point for treating this patient population. Deb G, you're correct that indeed the 50 milligram dose showed really stunning efficacy, as did, of course, the 80 milligram dose. We did see better in totality, better efficacy for 80 milligrams over 50 on several parameters, including the patients that we got to normal levels below 150.
There are other the overall mean reductions in triglycerides too were better for the 80 milligrams too. This is only 12 months of treatment. The 80 milligrams could continue to show even better efficacy with long-term treatment, including potentially reductions in acute pancreatitis versus 50. We'll see about that. We believe that offering dosing flexibility to treaters with both doses will be a very significant advantage commercially. I'd like maybe Sam to talk a little bit about how he sees maybe physicians considering the use of one dose versus another and what that flexibility may entail. Sure. We're very used to having multiple doses in cardiology. As you know, we have this for blood pressure meds. We have this for lipid-lowering therapy.
There are some cases where you want to start low and go up, but there are other cases when you want to start very high, especially if somebody's had an acute event or some issue like that. We do that, for example, with statin. I think we want to give the physicians optionality to be able to choose what they think is best for their patient and monitor them. I do not think the hepatic fat fraction is going to be a major differentiator in this case because we do not even know if that is a serious issue. It looks like it is not. We do not want to say that that is going to limit what we do down the road. That could be a transient phenomenon that may not even factor into it, and it may just be the potency of the drugs that is driving that.
Bottom line is, I think physicians will want to have two doses, and we will trust them to be smart enough to know how to manage their patients with those doses. In terms of pricing, I would anticipate flat pricing just to make sure that we have the access that Sam just described for any patient population that needs to be treated. Thank you. The next question comes from the line of Gary Nachman with Raymond James. Please go ahead. Hey, everyone. Good afternoon. This is Dennis Resnick on for Gary. Thanks for taking our question. Big congrats to the whole team on the incredible data shared today. When we look at the NNT analysis presented for AP events, can you just help contextualize those numbers a little bit more for us as it relates to the other therapies?
Commercially, how do you expect both payers and physicians to look at this specific data point? When we think about the upcoming sNDA filing, how much of this acute pancreatitis-level data do you think could make its way into the label to supplement what is already in the FCS label? How much does it really matter commercially to have it in there in the label versus just being able to share and promote the recent journal publication? Thanks so much. Maybe Sam, you can take the— I can do the NNT. I saw the Vesalius study today, which had really excellent data. The NNT was about 60. When you get to NNT under 50, that is for Ebo. That was for Ebo. For Evolocumab, right? That is for— yeah. We are at 20 for the overall population. We are 4 for the very high risk.
The NNT numbers are phenomenal and in the ballpark where they're considered clinically relevant and cost-effective. We couldn't be more pleased with those numbers, actually. I think physicians will latch on to them because you don't have to treat 100 patients to see a benefit. You need to treat four high-risk and only 20 average risk. I would say that this exceeds what is generally done in the lipid-lowering world and is more closer to what we see with defibrillators and kind of life-saving procedures that we do. We believe that these groundbreaking results on acute pancreatitis should be in the label to lower triglycerides to prevent acute pancreatitis from happening. We can't speak for the FDA, Dennis. We'll see what happens.
At the end of the day, we've now published the data in the most reputable clinical journal in the world, and everybody knows about the data. Everybody sees it. I mean, from a commercial standpoint, Kyle, we're hopeful. We'll have it in the label. It's nice to have it in the label, but I don't think it's necessary for commercial success. Completely agree with that. The treaters of SHTG today understand the risk of acute pancreatitis. They're using all the available medications that are at their disposal to try to get these patients under control. Unfortunately, it's suboptimal care in a lot of instances, and they're looking for something better. Consistent with the way that we designed the clinical trial, adding Olizarsan on for this patient population, I think, is going to be well received and largely adopted fairly quickly, I would anticipate.
In terms of it being in the label, the indication statement versus if it's in section 14, regardless, I think as long as the data are available and we can discuss the information, as Brett just described, we'll be able to communicate the strength of the data and the information so that clinicians can make the right decisions in terms of treating appropriate patients with Olizarsan. The other question was around payers and the strength of the number needed to treat. That absolutely is going to help us with the total body of evidence that we have when we go out to do the physician or, excuse me, the payer research so that we can come up with the appropriate pricing.
The triglyceride-lowering, acute pancreatitis rates, hospitalizations, number needed to treat, cost of an AP event, etc., everything that we've been talking about here, all of that creates the strength in the body of evidence for us to say, "If you're treating within a population that's over 500, regardless if they've had an AP event or not, what's the appropriate pricing for this?" is the exact work that we're going to do right now in order to come to the right conclusion. Thanks so much. Congrats again. The next question comes from the line of Akash Diwari with JetPreet. Please go ahead. Hi. This is Zaki on for Akash. Thanks so much for taking our question. Just on the liver enzyme elevations, can you tell us just a little bit more about the baseline rate of those patients in that 80 milligram arm?
Were they already near that 3x, 5x boundary before therapy? And just kind of did they, through the therapy, just cross that boundary? I just want to know if they were kind of already near before they got on drug. And then secondly, would you anticipate, based on this data, that there may be a need for liver monitoring on the label, particularly for those patients on 80 milligrams? Thank you so much. Yep. Because these patients are known to have elevation of baseline LFTs, we actually allowed them to come in at three times above normal, up to three times above normal.
The best way to answer your question is if you look at the placebo group, 2% had just random increases three times above normal during the trial, which is more than you typically see in these lipid-lowering trials, and about 30% had an increase above normal. These patients tend to have elevated LFTs, and they're very sensitive to a lot of things, like eating a lot of fat, alcohol, antibiotics. They tend to have spikes up and down. I think the best way to characterize the LFTs that we saw during the trial is that in the ones that had an increase, they could continue dosing. The levels in general stayed flat or declined over time. It was not a progressive phenomenon. It was not a phenomenon where you had this abrupt change. There was no HIGHS law. Really, nobody got over 5x.
These were kind of in the borderline range in terms of 3x for the ones that had the increases. In the overall population, the mean level stayed in the normal range. That was not in the paper, but that is the data. Overall, it is not a major issue from that perspective, and it is easily checked. We do not think there is going to be a need to be monitoring on this because there were no clinical sequelae associated with it in terms of any specific monitoring. They will probably just have to have routine labs when they get them. Okay. The next question comes from the line of Salveen Richter with Goldman Sachs. Please go ahead. Thanks for taking our question, and congratulations on these very impressive results. This is Tommy on for Salveen.
Wondering if we could just get some more detail on the treated patients who had AP events, maybe with their response with regard to their TG levels or A1C3 levels, and if they had a history of AP. Thank you. Yeah. So a lot of the information is in the paper. Maybe it's not to a lot of granularity, but the bottom line is that the majority of events, but not all of them, happened in the patients that had triglycerides over 880 and acute pancreatitis. That's 17 patients, 22 cases in the placebo group. But there were three patients, three events below that. The pancreatitis event rates were five patients and seven events in the pooled placebo. But in the under 880, there was actually only one patient, one event. So kind of the trends are there on both sides.
Of course, we had a lot more power to answer the question about over 880 and a history of pancreatitis. This is a one-year study. I think if we had done a longer study where we had more patients in the lower threshold, I think the trends that you see here would have maintained and been very significant. The bottom line is, yes, most of the patients that had events were in the high-risk category, but not all of them. A fair number had events in the under 880. Based on this, we think the entire population benefits. This does not take into account when you look at these numbers, it does not take into account postprandial excursions. These patients are at risk every time they eat three times a day to have rises and falls in the triglyceride levels. That is not captured in these fasting levels.
The epidemiology data clearly documents anything over 500 puts you at risk. Maybe not in one year, but long-term, these patients have to be treated for a very long time. Overall, we're very happy with the data. We think in totality, the way we designed the trial to have both primary prevention and secondary prevention really was the best design to be able to look at this pancreatitis events. Thanks, Tommy. The next question comes from the line of Yan and Zhu with Wells Fargo Security. Please go ahead. Oh, great. Thanks for taking our question. I wanted to add my congrats as well. Can you talk about for the hepatic fat fraction increase, how does it evolve over time? Is it still increasing at the end of the one-year period? Do you expect it to continue to increase after that?
The other, perhaps a question similar to the earlier question about monitoring, do you expect there might be monitoring requirements on this measure? Lastly, on the mechanism, I think the New England Journal paper today attributed this signal to Galnack, mentioning that valenosourcine did not have this signal, but Olizarsan and prazosin both have it. Any thoughts there? Thank you. Thanks. Those are three questions. Let me see if I can tackle them all at once because it is all interrelated. First of all, we only had two imaging studies or imaging studies done in this group, baseline and one year. We do not have the luxury of having a middle one or a longer one. The answer is we do not know what will happen long-term. What we do have so far is a small number of MRIs at two years.
What we're seeing so far is a stabilization and maybe a decline in the 80-milligram dose. We think that this mechanism is related to the fact that olosarsan shifts these particles from the circulation to a congested liver. Remember, these patients have baseline elevation of hepatic fat three times above normal, between 13-16% already. Now they're getting another load, and they have to manage that. There is a finite amount of triglyceride in the circulation. It is not going to keep accumulating, right? Once you get it out of the circulation, done. Our anticipation is that this phenomenon will quiet down and go away, and we'll be able to look at this long-term. Most likely, it reflects a distribution of lipid from a dangerous compartment to the liver. We did not see any clinical consequences of this, and it was not correlated with transaminases.
Right now, the best as we can tell and from the hepatology consultants that we consulted is that this represents a non-inflammatory accumulation of bland lipid that hopefully will just resolve with time as the patients get kind of holistic care of their diabetes, their obesity, and their triglycerides. Great. And monitoring requirement? No, no. Monitoring, doing MRIs in patients and giving them gadolinium—sorry, I forgot to mention that. It's not something that you do routinely. This is really a study technique. The simplest thing is liver function tests for this. And if those aren't going up, you don't really need to worry about any serious things happening to the patient. That's probably the most that will be required. We don't anticipate any imaging studies to be part of this going forward. Great. Thanks and congrats again.
The next question comes from the line of Paul Matisse with Steeple. Please go ahead. Hey, this is Julian on for Paul. Thanks so much for taking our questions and congrats on the strong data. Another question on the liver enzyme elevation. I guess in the 80 mg arm, Sam, you talked about how it's not a progressive phenomenon. I guess any thoughts on having the vast majority of patients starting on 50 and then progressing to 80 if they're not responsive? I guess just can you talk a little bit more about how important it is to get patients below that 150 mg per deciliter level to reduce risk in AP and improve long-term outcomes? Just looking at the data, both doses seem to do very well in getting patients below 500.
I know we don't have long-term data, but just curious on how you're thinking about longer-term data playing out and informing commercialization and clinical decision-making. Thank you. Yeah. On the choice of dose, I think you have to look at it in the totality of the patient's risk. They've just had a recent pancreatitis episode, and they're running 2,000. You really want to get them down fast and robustly. If they're stable and their triglyceride is not as elevated, you might choose the 50 mg dose. I can see both of those being played out depending on the patient's ultimate risk. We do this for statins. If somebody's stable, we might start at the lowest dose and go up. If somebody just had an acute coronary syndrome, we start them with 80 of atorvastatin.
We have paradigms to manage that, and some of that will play into it the way we see about. I think we need both doses, though, to be able to address all of the needs that clinicians will have. Getting numbers to normal is a big deal. I mean, 54% of patients getting under 150 is unprecedented versus 1.2% in the placebo. That tells us it's an extremely potent drug. Now, for pancreatitis, 500 is the threshold. We are very happy with the 85-90% of patients getting below that threshold. Getting them lower, of course, is going to be better, but that probably is not going to be our primary aim is to get everybody to normal. First, we want to get everyone to 500. What we're seeing with Tringulsa and FCS is that a substantial number of patients aren't getting into that normal range.
If it happens, great. We are not going to actually target 150, but we'd love to see those numbers if they come up naturally with either dose. Really helpful. Thanks very much. The next question comes from the line of Luca Issi with RBC Capital Markets. Please go ahead. All right. Thanks so much for taking my question. Maybe Sam, if I can circle back on the hepatic fat signal here, could you just talk about whether you think that signal is related to the target more broadly, or this is related to your drug specifically? I think the discussant here at American Heart, I think, tried to make an argument that this is related to your molecule and not the target as your competitor has not seen such signals. We'd love to kind of hear what's your pushback to that.
Then on A1C, if I captured it correctly, I think Tringulsa's label cites HbA1c increases below 0.2%. However, I think today the increases were a little bit higher than that. Wondering what's the kind of best way to rationalize why you're seeing maybe a little bit higher increase in A1C for this population versus FCS. Thanks so much. Sure. I think a lot of people are not going to agree with the discussant. I think I can kind of just summarize it that way. The reason I say that is if this was not seen with any other drug, you can think maybe it's olizarsan related, but it was seen with the 50 mg dose of prazosin, and it was in the same range as we're seeing here. That would tell me that it's most likely target-related.
It kind of goes with the mechanism that I mentioned before, which is the triglyceride in the periphery has to go somewhere. If you start with 1,200 milligrams per deciliter, you get to 200. That is a whole gram per deciliter. That is about 60 grams of triglyceride has to move out. It makes sense that some of it ends up in the liver and accumulates, and then it is a finite phenomenon. We do not have evidence right now that it is olizarsan related. We have evidence that it is probably mechanism-related. I would probably just leave it at that. We need to see larger studies from the other compounds to be able to kind of be a little more clear on that. On the hemoglobin A1C, this is an interesting phenomenon. It is probably related to the hepatic fat in some ways, right?
When the liver gets this amount of energy, it can do three things with it. Store it. It can convert it to ATP and burn it up. Or it can take the free fatty acids and make them into glucose and secrete them. The patients that have diabetes already have insulin resistance. They can't manage this extra glucose that's sent out, and it goes up a little bit. It goes up so little that it's not a clinically relevant issue. It's easily managed in these patients. The patients that don't have diabetes, we don't see this phenomenon probably because they have insulin sensitivity, and they can manage the extra glucose. That would be my explanation why, as a class effect, all three drugs, donidalorsen, olizarsan, prazosin, had the same kind of glucose issue. We don't think this is clinically important because it's a small change.
It's not like 0.5 or more where you have to start changing their medications. It has to be monitored, though, just like you would a typical patient with diabetes. Nothing special. It's probably mechanism-related also. Got it. Thanks so much. The next question comes from the line of Miles Minter with William Blair. Please go ahead. Hey, thanks, guys. Congrats on the data. Maybe just on the hepatic steatosis adverse events that are reported in the New England Journal article, I think there was a numerical increase in those on Olizarsan. I know you don't have clinicals to collide it to the hepatic fat fraction, but maybe you can help me understand why the sites may have reported an imbalance there. That's the first one. The second one is just talking to someone here at AHR.
Should we maybe be just excluding diabetic patients from these trials? I guess where I'm coming from is the only reason why you're seeing the hyperglycemia is because they needed to stay blinded, and they couldn't actually adjust their underlying metformin or SGLT2 inhibitor treatment throughout the trial. Thanks very much. Yeah. On the first question, what you're referring to is very small numbers. They're in single digits in hepatic adverse events. I don't think we can read that there was anything into that. You're talking about 1 out of 100 patients, 2 out of 100 patients. There may be some small numerical differences, but those don't look like they're very different in terms of the overall significance. I don't think those are necessarily imbalanced based on that table that you're referring to. I'm sorry. The other question was, should we be treating diabetic patients? Oh, absolutely.
We should be treating those who are the highest-risk patients. There's no reason to exclude them. The hemoglobin A1C is not really an issue. They have a lot more serious problems than a tiny change in the hemoglobin A1C. The other part of this is that we measured HOMA-IR and HOMA-B, which are indicators of insulin resistance and pancreatic function. Those did not change. Nothing is changing in terms of their diabetes situation. All that's happening is they're now producing a little more glucose. These are the patients that probably need the most treatment, honestly, because they represent two-thirds of the population, and they're very high risk for pancreatitis. I do not see this as a reason not to treat at all. Awesome. Congrats on the data. The next question comes from the line of Gina Wang with Barclays. Please go ahead. Thank you.
Since we are discussing about glycemia and also the hepatic fat fraction, maybe I just ask a few more questions here. Just want to confirm, did I hear correct that you expect the initial target 1 million patients will be two-thirds will have diabetes? And then also, I don't know if you've seen any, have you checked the hepatic fat fraction in the FCS patient? Any differences there? Is there any elevation there? And also, related question is the HFF between the patient with diabetic and without diabetics, any differences there? Why don't we take those last two first, Sam? FCS, HFF, and. So we did not measure hepatic fat in the balance study of FCS, but we did measure it in the APPROACH trial with valenosourcine. And there, those patients are thin. Their BMI is at 24. They don't have a lot of liver fat.
It's about 5%-6%. These aren't the kind of patients that we're studying here that are much higher risk for having liver issues. We don't know about balance, but when we did it in the APPROACH trial, there was about a 20% reduction with valenosourcine. There was no reason to keep checking it in this population. We don't know the answer to that. The LFT stuff was pretty low. We didn't see any hepatic issues. We don't anticipate that was a significant issue in those patients either. Sorry, what was your? The HFF in diabetics versus diabetics. Oh, yeah. Yeah. We're starting to look at this in more detail. The initial look is that we didn't see any obvious differences in the hepatic fat. We did look at some groups of those. We didn't see any differences.
We have to do a lot more work on that to try to understand all of that a little more carefully with the different subgroups, background therapies. There are a lot of baseline characteristics that we need to look at. Once we get through all of this, we can be able to report more data on that coming down the road in the future. Gina, we would expect a good portion, I would imagine, about a good 40%-50% maybe of SHTG patients might be diabetic, I would imagine. Kyle's nodding his head. Yeah. That is kind of where we are. As Sam eloquently laid out, the small increase in HbA1C is manageable. We are not concerned about it. With that, we are going to take two more questions. Thank you. The next question comes from the line of Mike Ols with Morgan Stanley.
Please go ahead. Good afternoon. Thanks for taking the question, and congrats on the data as well. Maybe just a quick one on the triglyceride thresholds. You mentioned around more than 50% of patients actually reached normal levels. I was just curious, among those patients, which started as sort of high-risk patients? Thanks. Yeah, that data. Yeah. So the data on the exact triglyceride levels at entry, we have not looked at that in a lot of detail. You saw that most of the pancreatitis cases were in those over 880. We are going to be doing more work to define, is there a threshold effect? Is there a percent effect in terms of who benefits? Those results we do not have right now. We will be able to get them for you down the road. Yeah. Commercially, Mike, those thresholds are very meaningful.
Obviously, the data being so strong, being able to get patients below 500, 86%, is very relevant here, and 54% in the normal range. I think it just demonstrates the value and the quality of this data. I think it's going to be really hard for anyone to match this, as Sam stated earlier. I think it's time for looking at the clock for one last question. Yes. Our final question comes from Jeroen Werber with TD Cowen. Please go ahead. Great. Thanks so much, and congrats on the really nice results. Maybe just two questions, maybe Sam for you and one for Kyle. One of the big debates was about primary prevention, and of course, the numbers are extremely low. But encouragingly, you are seeing three events on primary events in placebo and one on olosarsan.
The question really is, as you continue to evaluate over two years, do you expect that those numbers will increase, or is everybody crossing over? For Kyle, I mean, it looks like initially you're going to be looking at 350,000 patients as the initial target population. Maybe again, just given our survey, there's certainly going to be a very high uptake in patients with risk, but people want to use it broadly. Why not price it with a resistive price at that point? Thank you. I can go first on that. That's a great question. The fact that we saw three and one, they're small numbers, but you can call that a 66% reduction. It's consistent with the overall findings. I think if we had done more patients, larger trial, that would have continued.
As we go into the open label, of course, everybody is now on 80 milligrams of olizarsan. We will not be able to have any more randomized data. We anticipate the very small number of events in the treatment arm to persist. We do not anticipate crossing over to a lot more cases. We know this in many ways from our experience with Tringulsa and FCS. Once they get on the drug, they stop having events. It is really dramatic. We anticipate this 80-90% reduction in pancreatitis to persist as long as the patients can take the drug. In terms of the targeting strategy, the 22,000 HCPs that I referenced are HCPs that we have prioritized that see the highest volume of SHTG patients. These are just patients that are above 500. We can reach that with a couple of hundred representatives.
That's the starting point. What I didn't expand on is how broad we can go with our omnichannel capabilities, our other marketing tactics, non-personal promotion, and other means to reach tens of thousands of HCPs to educate around the disease, around the need to treat, and around the benefits of Olizarsan. We will go much further than beyond the audience of just the 22,000. Okay. I think it's time to wrap things up. I'd like to thank everybody again for joining us today on our call. We're very excited about the Olizarsan opportunity and all the opportunities that lie ahead for Ionis. We look forward to updating you all on our continued progress going forward. With that said, folks, have a great day. Thanks for joining us. Thank you. Ladies and gentlemen, this concludes today's presentation. Thank you all for joining me.