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

Good afternoon, and welcome to IONIS conference call to discuss Olisorsen's Phase III 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 [indiscernible]. Please begin.

Thank you, [indiscernible]. And thank you to everyone who has joined us today as we discuss the groundbreaking results from the landmark core and core 2 studies of olozorsen 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 Investors 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 pancreatitis Brett Monia, Chief Executive Officer, will provide opening remarks. Dr. Sam Tsimikas, Senior Vice President, Global Cardiovascular Development, will discuss the significant unmet need associated with sHTG and will then review the CORE and CORE2 study results. Kyle Jenne, Chief Global Product Strategy Officer, who will discuss our go-to-market approach to achieving launch success, assuming approval of olazarsen 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 are here today to discuss the groundbreaking results from the Phase III CORE and CORE 2 studies of olozarsen 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 olezarsen's ability to become the new standard of care for the broad SHTG patient population. In the Phase III results presented and published today, olezarsen demonstrated rapid substantial and significant reductions in triglycerides probably up to 72% on top of standard of care and reduce the risk of acute pancreatitis events by 85%. This makes lasers in the first and only investigational treatment to achieve this remarkable outcome in sHTG. Furthermore, patients treated with olezarsen 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 olezarsen 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 9 months of this year, we initiated our first 2 independent launches. We successfully launched TRYNGOLZA, the brand name for olezarsen in its first indication in January as the first and only FDA-approved treatment for people living with familial chylomicronemia syndrome. TRYNGOLZA 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. And this is just the beginning. Next year, we have 2 more independent launches planned, olezarsen for SHTG, which we're here to discuss today, and zilganersen for Alexander's 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 CORE2 results in hand and the meaningful impact olezarsen 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 olezarsen 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 olezarsen 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 olezarsen 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 olezarsen program have been instrumental in achieving the positive outcomes that we're discussing today. And with that, I'll pass the call over to Sam to provide an overview of sHTG, [indiscernible] program and our groundbreaking results. Sam?

Thank you, Brett. And 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 [indiscernible] Study Group who collaborated with us on the olezarsen Phase III program. The CORE and CORE2 studies were designed to evaluate olezarsen and people with sHTG. sHTG is defined by fasting served triglycerides 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 chylomicron to 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 particularly life-threatening condition associated with hospitalization, intensive care admissions and long-term complications, including repeat pancreatitis events. As triglycerides rates increase, chylomicron also increased, and the risk for acute pancreatitis becomes even greater, especially a level exceeding 880. For many people living with sHTG, current triglyceride lowering treatments, such as fibrates and omega-3 fatty acids failed to sufficiently lower the 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 at substantial risk. Olezarsen's remarkable efficacy is based on targeting ApoC-III, a novel mechanism that I own has pioneered from managing conditions associated with high triglycerides. As a central regulator of triglyceride metabolism, ApoC-III elevates triglyceride levels through 2 primary mechanisms. First, it represses lipoprotein lipase the enzyme that breaks down triglyceride-rich particles. And 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. Olezarsen works by reducing the production of ApoC-III, effectively resetting triglyceride metabolism. This allows triglyceride-rich particles to be broken down and cleared. With the understanding of how Olezarsen works, here's an overview of the studies that made up our comprehensive Phase III development program. First, the pivotal placebo-controlled CORE and CORE2 studies, which comprise the largest pivotal program ever conducted in sHTG. Data from these studies were presented earlier today at and simultaneously published in the [indiscernible]. We also conducted the Phase III 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 we're also simultaneously published in the New England Journal of Medicine in August. Now let's go over the CORE and CORE2 study design and the groundbreaking results. Participants in CORE and CORE2 were required to be on stable standard of care lipid-lowering therapy throughout the trial. Diet will stabilize during screening and maintained with the support of Counseling throughout the treatment period. Participants were effectively randomized 1:1:1 to olezarsen 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 percent reduction in fasting triglycerides was assessed at 6 months. Key prespecified secondary endpoint was a percent change in adjudicated acute pancreatitis events with pooled olezarsen compared to pooled placebo at 12 months. Additional key secondary endpoints included the portion of patients we achieved triglycerides below 880 and 500 as well as a reduction in ApoC-III 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 we're pleased to report that more than 90% of eligible participants elected to participate. Based on characteristics from CORE and Core2 highlight the severity of shh in the study population. BD and baseline fasting triglyceride levels were in the mid-700 to 800 range [indiscernible] were over 1,000. Around 40% to 50% of participants had baseline fasting triglyceride levels greater than 880. About 13% to 23% of participants had at least 1 event of a acute pancreatitis. All participants were on stable treatment with at least 1 lipid-lowering therapy and more than 60% were on 2 or more lipid-lowering therapies, underscoring the lack of effective therapies. Now to the results. beginning with the primary efficacy endpoint of fasting triglycerides reduction at 6 months. As reported in the top line data, olezarsen 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 6 months were sustained through 12 months of ongoing olein treatment, underscoring the durability of response over time. in both the 50- and 80-milligram doses and across both CORE and CORE2 studies, patients experience 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 triglycerides reductions below this critical level. 86% of patients achieved triglycerides levels below 500, a threshold for sHTG and acute pancreatitis risk demonstrated olezarsen potential to bring patients below this important level. And up to 54% of patients reached normal triglycerides levels below 150, highlighting olezarsen 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 olezarsen to approve placebo across the 2 studies. We're very pleased that olezarsen 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 7 events in 5 patients treated with olezarsen. Clinical evidence demonstrates the patients with triglycerides above 880 faced significantly increased risk of acute pancreatitis. Looking at the breakdown of acute pancreatitis events in these high-risk patients in our study confirm this relationship with the majority of events concentrated among these patients. These results provide definitive evidence that substantial triglyceride reduction with olezarsen translates to clinically meaningful protection against pancreatitis -- against acute pancreatitis for sHTG patients. Now let's take a look at the number needed to treat for NNT. NNT is a measure of clinical efficacy that tells us how many patients need to receive therapy to prevent one additional event. For context, statins used for primary prevention have an NNT in the range of 50 to 100 to prevent one cardiovascular event over 5 years. With olezarsen, NNT is substantially lower and in a much shorter time period in the overall pooled analysis, treating just 20 patients with olezarsen is estimated to prevent one acute pancreatitis event in only 12 months. And as you can see, the 2 curves separate quickly that [indiscernible] in the placebo group beginning to accumulate early and continuing to rise over time. In contrast, the olezarsen group shows a substantially lower rate of events throughout the 12-month period demonstrating olezarsen'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 4 patients after just 12 months. Being an NNT ranging from 4 to 20 for a potentially fatal event like pancreatitis and achieved in just 1 year is very compelling to physicians and provides a sense of urgency to treat with olezarsen. Olezarsen also showed improvements across additional key lipid measures. We saw significant reductions in ApoC-III 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 with 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 overall favorable lipid profile. Olezarsen demonstrated a favorable safety and tolerability profile in CORE and CORE2. Adverse events were generally balanced across treatment arms. Notably, serious adverse events occur less frequently in the olezarsen-treated participants. The most common treatment-emergent events were injection site reactions, which were mostly mild and occurred more frequently with olezarsen. This table shows several additional parameters we measured in CORE and CORE2, 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 3x the upper limit of normal. These elevations were not associated with clinical complications and generally resolved with continued dosing. Sit with previously reported results with ApoC-III 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 nondiabetic patients. Olezarsen delivered [indiscernible] outcomes in severe hypertriglyceridemia. 86% of patients reach triglyceride levels below 500 and acute pancreatitis incidents was reduced by 85% compared to placebo. These results established olezarsen 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 NDA by the end of the year setting us up to bring olezarsen to people with sHTG in the fourth quarter of next year. These results mark an historical achievement in lipidology and positions to become the new standard of care for people living with sHTG. And with that, I'll turn the call over to Kyle.

Thank you, Sam, and good afternoon, everyone. The CORE and CORE2 results reinforce our confidence that olezarsen 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. Side available treatments, physicians consistently tell us that they are dissatisfied with the current standard of care. Existing therapies offer only modest triglyceride reductions and don't 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 faced a fivefold 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 inducement, but also increase 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 olezarsen comes in. The groundbreaking results from the CORE and CORE2 studies demonstrate that olezarsen 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, olezarsen offers the convenience of once-monthly self-administration with an auto-injector 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 olezarsen is that game changer. At launch, we planned 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 TRYNGOLZA and FCS to engage with health care 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 olezarsen, we see a clear path to blockbuster potential. We recently conducted additional HCP research based on olezarsen's overall profile presented today. Industrial research results confirmed the high level of enthusiasm for olezarsen and particularly its remarkable ability to lower triglycerides and reduce pancreatitis events. To realize the potential of olezarsen, we're leveraging the strong commercial foundation built with TRYNGOLZA, including disease education, patient finding and payer engagement as we prepare the market for olezarsen'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 U.S. while also expanding our reach through omnichannel education campaigns. With key field metal 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 engaged 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. Olezarsen 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 TRYNGOLZA and FCS, we are on track to bring olezarsen this broad patient population in the fourth quarter of next year. And with that, I'll turn the call back over to Brett.

Thanks, Kyle. Today's data from the CORE and CORE2 studies reinforce our confidence that olezarsen 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 losartan results, we're well positioned to launch next year. We're also on track to bring Zilganersen people with Alexander disease in the same time frame. These anticipated launches build on the continued momentum of TRYNGOLZA 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 4 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 and expanding commercial footprint and a proven ability to bring first-in-class therapies to patients need the 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.

[Operator Instructions] Our first question comes from the line of Jay Olson with Oppenheimer.

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. And does evidence suggest that based on the significant reduction in normalization of triglyceride and the reduction of acute pancreatitis that olezarsen would enable patients to normalize their diets and lifestyles and reduce the use of background medications?

This is Sam. I'm happy to answer that. So as we mentioned, the patients got dietary counseling at the beginning of the study before randomization and throughout the whole time. So that should have been balanced across the groups. And in terms of background therapies, you saw that they're very intensively treated and still have high triglycerides, large number of patients on statins, 2/3 on [indiscernible], 1/3 on omega-3 fatty acids. We did look at GLP-1 receptor agonist. That was about 15%. It was also balanced during the trial. And so the bottom line is the 3 groups [indiscernible] 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 hyper triglycerides. They're not purely related to diet, diabetes or obesity to have multiple abnormalities and triglyceride genes. So they probably would have been hypertriglyceridemic or would have been no matter of those background therapies. So they need a real therapy for their problem. Now whether you can liberalize a diet and that sort of thing is unknown. We do know it from the FCS population that they have to stay on their diet. So 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, et cetera. We do know, as you saw the curves, we have rock solid reductions in triglycerides through out to 12 months. They're not budging at all. There's no fluctuations. And so the therapy is very effective and to prevent pancreatitis, I think we need that robust effectiveness.

And if I could please ask one follow-up. Since we've never seen triglyceride reduction or AP reduction like this before, I want to recognize that it might be difficult to predict the impact that olezarsen could have on clinical practice. But 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 meet a 72% placebo-corrected reduction in triglycerides. When we do cardiovascular outcomes trials, we hope for 15% to 20% reduction. Here, we had an 85% reduction of pancreatitis. And in 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 can lower LDL with, for example, [indiscernible], but we didn't have any clinical data. This trial is going to be in that historic context and because that, it should go in the top line of the guidelines when people talk about sHTG, and we'll see how that goes going forward, but it would be highly surprising if it didn't make it to the very top.

And the next question comes from the line of Mani Foroohar with Leerink.

Congrats on great data. A couple of quick questions, if that's 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 [indiscernible] priority voucher pilot program recognizing that, obviously, that's something that has to get down there 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 olezarsen. And then separately, moving over to the data, I and you guys have had a couple of relative bears arguing that perhaps accumulation of liver fat in the liver could be an issue? I know [indiscernible] 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 -- it doesn't have a clinical consequence? Or just how to think about that given that, that is a bare thesis has been floating around there.

Yes. Thanks, Mani. Very quickly, I'll touch on the path to regulatory approval in the U.S. and then Sam can talk about on target what his thoughts are on mechanism of small increases in liver fat that we've seen. So we're going to -- 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 could also include potentially seeking national priority review under the new program, under the new administration that you flagged. So we're working on all that internally right now. But right now, we're just getting that sNDA submitted by the end of the year, and that's where our laser focused. Yes, go ahead.

So on the [indiscernible], a couple of important issues. One is there were no clinical [indiscernible] that we noticed. So 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. And it was fairly small overall. And so the -- if you think about the mechanism of that, it's speculation at this point, but the way that olezarsen works and other drugs, which have had similar findings, is that they allow increased uptake of hepatic of circulating triglycerides into the liver. That's one of their mechanisms to clear it out of the circulation. And the livers in these patients already congested. So we think it's probably a finite phenomenon where moving triglyceride from a very dangerous compartment [indiscernible] acute pancreatitis into the liver and the liver probably just need some time to kind of process that. So we don't anticipate this being a chronic issue, but it is requiring some calibration of where the triglycerides are going. We are doing studies to evaluate these patients in the open label, and we'll have more data going forward.

Great. Do you mind you guys want to [indiscernible] one more in there? Commercially, there's been obviously a discussion on a potential price point. That's always dependent upon clinical data and the value to the patient and system, of course. As I previously talked about a price point more suitable for a mass specialty market, something in the 20 and 30s range. A number of my colleagues elsewhere have commented that perhaps something closer to where [indiscernible] in the high 40s range could be -- could make sense for the 1 million patient more severe population. Given what you disclosed about the number needed to treat for being really got 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, like 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. And 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 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. So 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. So we'll be able to put that totality of data together and go out and conduct that work. we're comfortable today is in the $15,000 to $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. And the patient population, they feel that they will potentially have a budget impact around is potentially up to 3 million-plus patients. So 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 in 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 at 500 and above who do not respond adequately to existing generic drugs. And as you know, the vast majority of patients do not respond well to existing fibrates or fish oils. They don't want that first acute pancreatitis attack to happen. They know the consequences. Once you get one, the chance of having another one is recurring and increases substantially, causing pancreatic failure. Mortality rate for an acute pancreatitis event is 6%. They don't want that to happen. So we're going after a large population here, not just recurring patients with a history of AP. Of course, those patients will be aggressively treated by physicians because they're the ones in the greatest immediate need, but this is a very broad population we're going to go after.

And the next question comes from the line of Jessica Fye with JP Morgan.

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? And do you think we might learn anything interesting from that extra follow-up on AP? And then second, I was hoping you could just remind us the number of sales reps you plan to have in place for the FACT 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, [indiscernible]

So we were very pleased to see that the OLE was oversubscribed. It's almost unheard of to get 90% of patients, pretty much everybody to finish the trial got into it. And we have very, very positive reflection of that because now the patients can see their triglyceride levels were during the trial, they were blinded [indiscernible]. And we have an overwhelming positive responses. In fact, we've been asked to extend the OLE as much as we can. So yes, we are capturing pancetitis events. We are following those patients very carefully because it's really a study. It's not just a random given the drug and just follow them late. So 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. So there's all [indiscernible] that will have something because there's something that continue to have this. But the vast majority should the pancreatitis free, and that should sustain. And I think if we had done a 3-year study that was randomized, those curves would continue to expand. So 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. But we should have 2 years of OLE data in the future to be able to report on some of these issues.

Yes, Jess. And 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, and there are approximately 350,000 patients within that population that they're currently treating today.

Next question comes from the line of Debjit Chattopadhyay with Guggenheim.

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 to 20,000 price point. So any thoughts on what it costs? And number two, given the focus somehow seems to be on liver fat, the 50-milligram dose was largely undifferentiated from the 80 milligrams in overall efficacy, but it's clearly differentiated on safety. So do you think physicians will just use the 50-milligram dose and I'm assuming you're going to price it at a flat price Clarification would be great.

[indiscernible] on the cost of AP?

Yes. 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 costs leading up to as well as the hospitalization and then the cost to treat after that. So 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.

And Debjit, you are correct that indeed that the 50-milligram dose showed a really stunning efficacy as, 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 [indiscernible] normal levels below 150. There are other -- the overall mean reductions in triglycerides too were better for the 80 milligrams too. And this is only 12 months of treatment. So the 80-milligram is going to show -- continue to show even better efficacy with long-term treatment, including potentially reductions in acute pancreatitis versus 50, we'll see about that. But we believe that offering dosing flexibility to treaters with both doses will be a very significant advantage on commercially. And 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?

Well, we're very used to having multiple doses in cardiology. As you know, we have this sort of blood pressure meds. We have this for lipid-lowering therapy. So -- and in some cases where you want to start low and go up, but there are the cases when you want to start very high, especially if somebody's had like an acute event or some issue like that. So we do that, for example, with statin. So 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 don't think the hepatic fat fraction is going to be a major differentiator in this case because we don't know if that's a serious issue. It looks like it isn't. And so we don't 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 they may just speak the potency of the drug that's driving that. So bottom line is I think physicians would want to have 2 doses, and we will trust them to be smart enough to know how to manage their patients with those doses.

And in terms of pricing, I would anticipate flat pricing, just to make sure that we've got the access that Sam just described for any patient population that needs to be treated.

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

This is Denis Reznik on for Gary. Congrats to the whole team on the [indiscernible] today. So 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? And then commercially, how do you expect both payers and physicians to look at this specific data point? And then when we think about the upcoming SNDA filing, how much of this AP level data do you think could make it way into the label to supplement what's already in the FCS label? And how much does it really matter commercially to have it there in the label versus just being able to share and promote their recent journal publication?

. Maybe, Sam, you take [indiscernible]

Yes. Well, I started a [indiscernible] study today, which had really excellent data, the NNT was about 60. So when you get to NNT under 50...

[indiscernible]

So that's -- yes. So we're at 20 for the overall population, we're 4 for the very high risk. So NNT the numbers are phenomenal and very in the ballpark where they're considered clinically relevant and cost-effective. So we couldn't be more pleased with those numbers actually. And I think physicians will latch on to them because you don't have to treat 100 patients [indiscernible] benefit, you need to treat 4 high risk and only 20 average risk. And so I would say that this exceeds what is generally done in the lipid lowering world and is more closer to what we've seen with defibrillators and kind of life-saving procedures that we do.

We believe that this groundbreaking these groundbreaking results on acute pancreatitis should be in the label to lower triglycerides prevent acute pancreatitis from happening. But we can't speak for the FDA, Dennis. So we'll see what happens. At the end of the day, we are now -- we've now published data in the most reputable clinical journal in the world. And everybody knows about the data. Everybody sees it. So 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.

I completely agree with that. And 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. And unfortunately, it's suboptimal care in a lot of instances, and they're looking for something better. So consistent with the way that we designed the clinical trial, adding olezarsen 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 olezarsen. 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 -- excuse me, the payer research so that we can come up with the appropriate pricing. The triglyceride lowering acute pancreatitis rates, hospitalizations, ER, number needed to treat, cost of an AP event, et cetera, everything that we've been talking about here, all of that creates the strength and 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.

And the next question comes from the line of Akash Tewari with Jefferies.

This is Zaki on for Akash. So 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, like were they already near that 3x, 5x boundary before therapy and just kind of the -- did they -- through the therapy just cross that boundary. I just wanted 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.

So because these patients are known to have elevation of baseline LFTs, we actually allowed them to come in at 3x about normal -- up to 3x about normal. So the best way to answer your question is, if you look at the placebo group, 2% had just random increases 3x 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. So 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. So I think the best way to characterize the LFTs that we [indiscernible] during the trial is that in the ones that had an increase, they can continue dosing the levels, in general, stayed flat or declined over time. So it wasn't a progressive phenomenon. It wasn't a phenomenon where you had this abrupt change. There was no [indiscernible] and really nobody got over 5x. So these were kind of in the borderline range in terms of 3x for the ones that had the increases. In the overall population, the patients stayed at the mean level stayed in the normal range. So that wasn't in the paper, but that's the data. So overall, it's not a major issue from that perspective, and it's usually checked. We don't think there's going to need to be monitoring on this because there were no clinical quality associated with it. in terms of any specific monitoring we probably just have to have routine labs when they get them.

And the next question comes from the line of Salveen Richter with Goldman Sachs.

Congratulations on these very impressive results. This is Tommie 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, [indiscernible] level and if they had a history of AP?

So that information -- a lot of that information is in the paper, maybe 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 80 and acute pancreatitis. That's 17 patients, 22 cases in the placebo group. But there were 3 patients, 3 events below that. Pancreatitis event rates were 5 patients and 7 events in the pool placebo. But in under 880, there was actually only 1 patient, 1 event. So kind of the trends are there on both sides. Of course, we have a lot more [indiscernible] answer the question about over 880 in history pancreatitis. This is a 1-year study. I think [indiscernible] 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. So the bottom line is yes. Most of the patients, the had events were in the high-risk category, but not all of them, a fair number had events in the under 880. And so based on this, we think the entire population benefits and this doesn't take into account when you look at these numbers, it doesn't take into account postprandial excursions. These patients are at risk every time they eat 3 times a day, [indiscernible] and falls in the triglyceride level. So that's not captured in these fasting levels and the epidemiology data clearly documents anything over 500 to put short risk. Maybe not in 1 year, but long term, these patients have to be treated for a very long time. And so overall, we're very happy with the data we think in totality, the way we design the trial have both primary prevention and secondary prevention really was the best designed to be able to look at the pancreatitis events.

The next question comes from the line of Yanan Zhu with Wells Fargo Securities.

Great. I wanted to add my congrats as well. Wanted to -- 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 1-year period? And do you expect it to continue to increase after that? And the other perhaps a question similar to the earlier question about monitoring, do you expect there might be monitoring requirement on this measure? And lastly, on the mechanism, I think the New England Journal paper today attributed this signal to [indiscernible] mentioning that [indiscernible] didn't have this signal, but olezarsen and [indiscernible] both have it? Any thoughts there?

Those are 3 questions. Let me see if I can tackle them all at once because it's all interrelated. First of all, we only had 2 imaging studies or imaging studies done in this group, baseline in 1 year. And so we don't have the luxury of having a middle one or a longer one. So the answer is we don't know what will happen long term. What we do have so far is a small number of MRIs at 2 years and what we're seeing so far is a stabilization and maybe a decline in the 80-milligram dose. So we think that this mechanism is related to the fact that olezarsen shifts these particles from the circulation to a congested liver. Remember, these patients have baseline elevation of hepatic fat 3x above normal between 13% and 16% already. So now they're getting another load, and so they have to manage that. And -- but there's a finite amount of triglyceride in the circulation. So it's not going to keep accumulating, right? Once you get out of the circulation, it's done. So our anticipation is that this phenomenon will quiet down and go away and we'll be able to look at this long term. So most likely reflects a distribution of lipid from the [indiscernible] to the liver. We didn't see any clinical consequences of this and it wasn't correlated with [indiscernible]. So right now, investors we can tell and from the hepatology consultants that we consulted is that this represents a noninflammatory 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?

No, no, monitoring doing MRIs in patients and given the [indiscernible], 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 to ask for this. And if those aren't going up, you don't really need to worry about any serious things happening to the patient. So that's probably the most that will be required. We don't anticipate any imaging studies to be part of this going forward.

The next question comes from the line of Paul Matteis with Stifel.

This is Julian on for Paul. Congrats on the strong data. Another question on [indiscernible] elevation. I guess in the 80-meg 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 5 and then progressing to 80, if they're not responsive? And 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 and 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.

Yes. On the choice of dose, I think you have to look at 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 there stable and [indiscernible] not a lot, you might choose the 50-milligram dose. So I can see both of those being played out, depending on the patient's ultimate risk. So we do this for statins. If somebody is stable, we might start at the lowest dose and go up. But if somebody just had a [indiscernible] coronary syndrome, we started with [indiscernible]. So 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 extremely potent drug. Now for pancreatitis, 500 is the threshold. So we're very happy with the 85% to 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 normal. First, we want to get everyone to 500. What we're seeing with TRYNGOLZA in FCS is that a substantial of our patients are getting into that normal range. So if it happens, great. And so -- but we're not going to actually target 150, but we'd love to see those numbers if they come up naturally with either dose.

The next question comes from the line of Luca Issi with RBC Capital Markets.

Great. Maybe, Sam, if I can circle back on the hepatic fat signal here. Can 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 discussion here at American Heart. I think try to make an argument that this is related to your molecule and not the target as your competitor has not seen such signal. So would love to kind of hear what's your pushback to that. And then on A1c, if I capture it correctly, I think 3 goals of label sites HbA1c increases below 0.2%. However, I think today, the increase were a little bit higher than that. So 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?

Sure. Well, I think a lot of people are not going to agree with the discussion. I think I can kind of just summarize it that way. And the reason I say that is if this wasn't seen with any other drug, you can think maybe it's old disarm related, but it was seen with the 50-milligram dose of [indiscernible], and it was in the same range as we're seeing here. So that would tell me that it's most likely target related and it kind of goes with the mechanism that I mentioned before, which is the triglycerides in the periphery, has to go somewhere. If you start with 1,200 milligrams per deciliter, you get to a whole gram per 100 per deciliter, that's about 60 grams after those that has to move out. And so it makes sense that some of it ends up in the liver and accumulates and then it's a finite phenomenon. So -- we don't have evidence right now that it's olezarsen-related. We have evidence that it's probably mechanism related. And that's I would probably just [indiscernible]. 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, so this is an interesting phenomenon. It's probably related to the hepatic fat in some ways, right? When the liver gets this amount of energy, you can do 3 things with it, store it, you can convert it to ATP and burn it up or it can take the free fatty acids and they come into glucose and secrete them. So the patients that have diabetes already have insulin resistance. They can't manage this extra glucose somehow, and it goes up a little bit. But it goes up so little that it's not a clinically relevant issue. It's easily managed in these patients. In the patients that don't have diabetes, we don't see this phenomenon probably because they have this in sensitivity and they can manage the extra glucose. That would be my explanation why as a class effect, all 3 drugs, [indiscernible] 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 and it's probably a mechanism earlier also.

And the next question comes from the line of Myles Minter with William Blair.

Congrats on the [indiscernible]. Maybe just on the hepatic steatosis adverse events that are reported in the New England Journal article. I think there was like a numerical increase in those on as and I know you don't have cleaning calls to quite to the hepatic fat fraction, but maybe you can help me understand why the sites may have reported any imbalance there. That's the first one. And then second one is just talking to someone here should we maybe be just excluding diabetic patients from these trials I guess where I'm coming from is like is the only reason why you're saying the [indiscernible] because they needed to stay blinded and they couldn't actually adjust their underlying metformin or SGLT2 inhibitor treatment throughout the trial.

Yes. 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. So there really -- there may be some sort of metical differences, but those don't look like they're very different in terms of the overall significance. So I don't think those are necessarily imbalanced based on that table that you're referring to.

The other question was should we be treating diabetic patients?

Well, absolutely. We should be treating those are the highest risk patients. And there's no reason to exclude them. The hemoglobin is not really an issue. They have a lot more serious problems than a tiny change in the hemoglobin A1C. And the other part of this that we measured HOMA-IR and [indiscernible], which are indicators of insulin resistance and pancreatic function, and those have been in change. So nothing is changing in terms of their ability or diabetes situation. All that's happening is they're now producing a little more glucose and so these are the patients that probably need the most treatment honestly, because they represent 2/3 of the population and they're very high risk of pancreatitis. So I don't see this as a reason not to treat at all.

And the next question comes from the line of [indiscernible] with Barclays.

Since we are discussing about glycemia and also the hepatic fat fraction. Maybe I'll 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 2/3 will have diabetes? And then also, I don't know if you see any have you checked the hepatic fat fraction in the FCS patients? Any differences there? Is there any elevation there? And also related question is the [indiscernible] between the patient with diabetic and without diabetics, any differences there?

Let me take the last 2 first. [indiscernible]-- so we did not measure hepatic fat in the BALANCE study of FCS. We did measure it in the APPROACH trial with [indiscernible] and there those patients have thin their BMI at 24. They don't have a lot of liver fat. It's about 5% to 6%. And so these aren't the kind of patients that we're studying here that are much higher risk for having liver issues. So we don't know about balance, but when we did it in the APPROACH trial, there was about a 20% reduction with [indiscernible]. And so there was no reason to keep checking it in this population. So we don't know the answer to that. But the LFT stuff was pretty low. We didn't see any hepatic issues. So we don't anticipate that was a significant issue in those patients either. Sorry, what was your.

[indiscernible] diabetics.

Yes, 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 in those -- we did look at some groups of those -- we didn't see any differences. But 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's a lot of baseline characteristics that we need to look at. And so once we get through all of this, we can be able to report more data on that coming down the road in the future.

Gena, we would expect a good portion, I would imagine about good 40%, 50% maybe of SHTG patients might be diabetic, I would imagine. But Kyle, not in his head, yes. So that's kind of where we are. But again, as Sam eloquently laid out, the -- the small increase in HBOC is manageable. We're not concerned about it. And with that, we're going to take 2 more questions.

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

Congrats on the data as well. Maybe just a corn 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?

Yes. So the data on the exact regulatory levels of entry, we haven't looked at that in a lot of detail. You saw that most of the pancreatitis cases we know over we're going to be doing more work to define is there a threshold effect? Is there a percent effect in terms of who benefits and those results we don't have right now, we'll be able to get them for you down the road.

And commercially, Mike, those thresholds are very meaningful. Obviously, the data being so strong of 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. And I think it's going to be really hard for anyone to match this, as Sam stated earlier. SP1 I think it's time looking at the clock for 1 last question.

Our final question comes from Yaron Werber with TD Cowen.

Congrats on really nice results. Maybe just 2 questions. Maybe, Sam, for you, one for Kyle. So One of the big debates was about primary prevention and of course, the numbers are extremely low. But encouragingly, you are seeing 3 events on primary events and placebo and one on olezarsen and so the question really is as you continue to evaluate over 2 years, do you expect that those numbers will increase? Or is everybody crossing over? And then for Kyle, I mean it looks like the initial you're going to be looking at 350,000 patients is the initial target population. So maybe, again, just given our survey that there's certainly going to be a very high uptake in patients with risk, but people want to use it broadly. why not [indiscernible] it with like a reticle price at that point?

So I can go first on -- that's a great question. The fact that we saw 3 and 1 the small numbers, but you can call it a 66% reduction. So it's consistent with the overall findings. And I think if we had done more patients a larger trial, that will continue -- as we go into the open label, of course, everybody is now on 80 milligrams of all olezarsen. So we won't be able to have any more randomized data. But we anticipate the very small number of events in the treatment arm to persist. We don't anticipate crossing over to a lot more cases. And we know this in many ways from our experience with TRYNGOLZA and FCS. Once they get on the drug, they stop having a vent. It's really dramatic. So we anticipate this 80% to 90% reduction in pancreatitis to persist the longer the patients can take the drug.

And in terms of the targeting strategy, the 22,000 HCPs that I referenced are HCPs that we've prioritized that see the highest volume of sHTG patients. So these are just patients that are above 500 and 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, a nonpersonal 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 olezarsen. So we will go much further than beyond the audience of just the 22,000.

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 olezarsen opportunity and all the opportunities that lie ahead for IONIS, and we look forward to updating you all on our continued progress going forward. So with that said, folks have a great day. Thanks for joining us.

Ladies and gentlemen, this concludes today's presentation. Thank you all for joining. You may now disconnect.