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

Good afternoon, and welcome to Ionis' conference call to discuss the FDA approval of TRYNGOLZA for sHTG. As a reminder, note that this conference call is being recorded. At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Wade, please begin.

Thank you, Sylvie, and thank you to everyone who has joined us today as we discuss the FDA approval of TRYNGOLZA for sHTG, which is now approved in the U.S. to reduce triglycerides and the risk of acute pancreatitis in adults with severe hypertriglyceridemia. Please be sure to visit the Investors section of the Ionis website to see the press release and Ionis issued -- press release that Ionis issued earlier today, along with the slides accompanying today's webcast. Before we begin, 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 me on the call today are Brett Monia, Chief Executive Officer; Sam Tsimikas, SVP, Global Cardiovascular Development; and Kyle Jenne, Chief Global Product Strategy Officer. For our agenda today, Brett will provide opening remarks. Sam will provide a brief review of the data that supported the approval and label of TRYNGOLZA. Kyle will review our strategy to achieve launch success with TRYNGOLZA now that it's approved for the larger sHTG indication. And after Brett's brief conclusion, we will open the call for your questions regarding TRYNGOLZA. And with that, I'll turn the call over to Brett.

Thanks, Wade, and thanks to everybody for joining us today. I'm thrilled to share that TRYNGOLZA is now approved as the first and only therapy indicated to reduce triglycerides and the risk of acute pancreatitis in adults with severe hypertriglyceridemia. TRYNGOLZA's approval is a landmark milestone establishing it as the first-ever medicine approved to prevent acute pancreatitis for people living with sHTG. This approval is also a transformational achievement for Ionis. It not only demonstrates our continued leadership in translating groundbreaking science into the delivery of breakthrough medicines, but also further demonstrates our commitment in establishing Ionis as a leading fully integrated commercial stage biopharmaceutical company. The approval of TRYNGOLZA for sHTG was supported by the unprecedented Phase III results we reported last year in which TRYNGOLZA demonstrated rapid, substantial, durable and clinically meaningful reductions in triglycerides of up to 72% on top of standard of care. These reductions in triglycerides resulted in the reduction of acute pancreatitis events by up to 91%, making TRYNGOLZA the first and only treatment to achieve this outcome in sHTG. Importantly, 86% of treated patients reduced their mean triglyceride levels below 500 milligrams per deciliter, the threshold that defines sHTG, and up to 54% of patients achieved normal triglyceride levels. These groundbreaking results, together with our substantial first-mover advantage, position TRYNGOLZA to fundamentally change the treatment paradigm for people with sHTG and become the new standard of care in the management of this disease. Notably, the TRYNGOLZA label includes acute pancreatitis risk reduction in the indication statement, which underscores the importance of preventing these debilitating and potentially fatal attacks and further validates the unprecedented results from our clinical trials. We received approval for both the 50-milligram and 80-milligram doses administered once monthly, providing physicians with dosing flexibility to tailor treatment based on individual patient needs and treatment goals. This flexibility will resonate well with physicians who manage sHTG patients based on our extensive HCP research. With the label now in hand, we are reaffirming our full year 2026 guidance of $100 million to $110 million and our peak sales guidance for TRYNGOLZA of greater than $3 billion, positioning TRYNGOLZA to become our first Ionis wholly-owned multibillion-dollar medicine. Before I turn the call over to Sam, I want to extend my sincere thanks to the patients, families, clinical investigators, advocacy groups and research partners who made this approval possible, especially those who participated in our clinical trials. I also want to recognize the Ionis team whose dedication to patients and commitment to groundbreaking science in the TRYNGOLZA program were essential in achieving today's positive outcome. And with that, I'll turn the call over to Sam.

Thank you, Brett. Like Brett, I'm very excited with today's approval and what it means for people living with severe hypertriglyceridemia. Severe hypertriglyceridemia, or sHTG, is characterized by markedly elevated triglyceride levels above 500 milligrams per deciliter. These patients are not able to get their triglyceride levels below 500 milligrams per deciliter, which defines the risk threshold for acute pancreatitis despite lifetime modifications and treatment with standard lipid-lowering therapies. Very high triglyceride levels are a well-recognized cause of acute pancreatitis, a serious and potentially life-threatening condition associated with hospitalization that often need intensive care admission as well as long-term complications that include repeat pancreatitis events and the destruction of pancreatic function. Traditional triglyceride-lowering treatments such as fibrates and omega-3 fatty acids offer only modest effectiveness and frequently fail to reduce triglycerides to below the threshold for pancreatitis risk. Moreover, none have demonstrated benefit in reducing acute pancreatitis events. sHTG is estimated to affect more than 3 million people in the U.S., and many of these people have a history of pancreatitis or are at high risk for a first event and often have additional comorbidities such as diabetes or cardiovascular disease. Until TRYNGOLZA's approval, patients and physicians were lack of therapy that could reliably lower triglycerides below the pancreatitis risk threshold. With TRYNGOLZA now approved, we believe that treatment gap is being addressed. sHTG is driven in large part by dysregulated triglyceride-rich lipoprotein metabolism. Apolipoprotein C-III, or apoC-III, is a key regulator of the system. Elevated apoC-III inhibits lipoprotein lipase, the enzyme that breaks down triglyceride-rich particles, and it also blocks the clearance of these particles from the circulation. We designed TRYNGOLZA to selectively reduce apoC-III production in the liver by targeting apoC-III messenger RNA. We were the first to demonstrate that lowering apoC-III results in substantial reductions in triglycerides and acute pancreatitis events in patients living with severely elevated triglycerides. Importantly, TRYNGOLZA was also highly effective on top of existing standard of care therapies, such as statins, fibrates and omega-3 fatty acid, adding a distinct and powerful new mechanism for lowering triglycerides. The sHTG approval was based primarily on positive results from the Phase III CORE and CORE2 studies, which evaluated TRYNGOLZA in adults with severe hypertriglyceridemia on stable background therapy in the largest pivotal program ever conducted in this patient population. Pivotal CORE and CORE2 studies demonstrated substantial and sustained reductions in triglyceride levels of up to 72% compared to placebo at 6 months with sustained reductions at 12 months. Furthermore, 86% of patients treating with TRYNGOLZA achieved triglyceride levels below 500 milligrams per deciliter, a threshold for acute pancreatitis. Notably, up to 54% of patients in this study also achieved normal triglyceride levels. We saw a remarkable reduction in the rate of pancreatitis events of up to 91% after only 12 months of treatment. In the overall pooled analysis from CORE and CORE2, treating just 20 patients with TRYNGOLZA for 1 year is estimated to prevent 1 potentially fatal pancreatitis attack. In the highest risk group, those with triglycerides above 880 milligrams per deciliter and a history of acute pancreatitis, the number needed to treat to prevent 1 potentially fatal acute pancreatitis attack is only 4 patients after just 12 months of treatment. Being a number to treat ranging from 4 to 20 or potentially life-threatening about like pancreatitis and achieved in just 1 year is very compelling to physicians, which we believe will provide a sense of urgency to treat patients with TRYNGOLZA. For context, statins used in primary prevention of cardiovascular disease have a number needed to treat in the range of 50 to 100, meaning 50 to 100 patients need to be treated for more than 5 years to prevent 1 cardiovascular event. TRYNGOLZA demonstrated an overall favorable safety profile in the Phase III studies with adverse events balanced across treatment arms. The most common adverse events were generally mild to moderate and manageable. The most common treatment-emergent events were injection site reactions, which were mostly mild and typically transient. At the 50-milligram dose, there were no imbalances in liver enzyme elevations. Asymptomatic liver enzyme elevations of greater than or equal to 3x the upper limit of normal were observed in 7% of participants treated with the 80-milligram dose versus 2% treated with placebo. These events were not associated with clinical complications, generally resolved with continued treatment and no cases met Hy's Law criteria. These unprecedented data from the TRYNGOLZA development program, beginning with FCS and now the broader severe hypertriglyceridemia population have also been presented in major cardiology and lipidology congresses and published in leading peer-reviewed medical journals. The level of external validation underscore the scientific rigor and clinical importance of targeting apoC-III in triglyceride-rich disorders. For patients and physicians who have struggled to control severe triglycerides with existing therapies, we believe TRYNGOLZA set a new standard for the management of sHTG. I'll now turn the call over to Kyle.

Thank you, Sam. The approval of TRYNGOLZA for sHTG is a defining moment in our journey to bring a much needed new medicine to this long underserved patient population. Our team is energized and focused on delivering a successful launch and capitalizing on our first-mover advantage. We have a highly experienced field organization with deep backgrounds in lipidology and cardiometabolic diseases. They have been preparing for this approval over the past several months by providing disease state education to the highest sHTG treaters. In parallel, they have been strengthening patient identification efforts and laying the foundation for a seamless expansion from FCS into sHTG. We expect the product to be available in the channel in the coming days, and our teams are ready to begin promoting TRYNGOLZA for sHTG. The U.S. market is both sizable and underserved with no effective treatments available until now. As represented by the pyramid shown on this slide, there are estimated to be more than 3 million people with sHTG in the U.S. Triglyceride management is concentrated among cardiologists, endocrinologists and lipidologists, which allows us to reach hundreds of thousands of eligible patients with a focused commercial footprint. Our customer-facing team plans to initially focus on the high-risk patient population, which includes patients with triglycerides of greater than 880 milligrams per deciliter or with triglycerides of greater than 500 milligrams per deciliter and a history of acute pancreatitis or other comorbidities. With our commercial footprint, we are positioned to engage approximately 20,000 high-volume prescribers across the country. As we did for FCS, we also plan to leverage Ionis' omnichannel marketing capabilities to further reach both physicians and patients with tailored educational content and support. Despite widespread use of statins, fibrates and omega-3s, many patients do not reach triglyceride targets and remain at high risk for pancreatitis. This treatment gap is well recognized by physicians and payers. Consistent with the label, TRYNGOLZA's compelling clinical profile and differentiated mechanism position it to play an important role alongside existing therapies to reduce the risk of acute pancreatitis. Until today, physicians have not had an effective therapy for severe hypertriglyceridemia. TRYNGOLZA changes that. It has demonstrated robust triglyceride lowering, statistically significant reduction in acute pancreatitis events, a compelling number needed to treat to prevent acute pancreatitis. We are pleased to offer both the 50-milligram and 80-milligram doses of TRYNGOLZA for sHTG packaged in a patient-friendly auto-injector designed for real-world use. This provides important flexibility for health care providers and patients and supports a tailored approach to treatment based on individual patient needs and treatment goals. Taken together, we believe TRYNGOLZA is a breakthrough for patients who are struggling with their disease and a meaningful advancement for physicians managing this high-risk population. Our launch strategy is designed for success and builds on our expanding commercial capabilities with 2 successful launches under our belt, including the launch of TRYNGOLZA in FCS. A key component of this strategy is our medical affairs effort with the team actively participating in major cardiology, endocrinology and lipid meetings to share data from CORE, CORE2 and related studies while also helping educate the market on apoC-III biology and the burden of sHTG. On the market access front, our reimbursement and payer teams have proactively engaged with U.S. payers. With the updated WACC price of $40,000 effective April 1, we are launching TRYNGOLZA and sHTG at a price that reflects its substantial clinical value and the high burden of disease while recognizing the need for broad responsible access. We are committed to ensuring affordability for patients who need TRYNGOLZA. For eligible commercially insured patients, our financial assistance programs can significantly reduce out-of-pocket costs, in some cases, to as little as $0 per prescription. Supporting patients throughout their treatment journey is central to our commercial approach. Ionis Every Step, our patient support program, will now be expanded to support the needs of sHTG patients and caregivers throughout their treatment journey. The program is designed to provide disease state and product education, meaningful caregiver support and reimbursement assistance that helps facilitate access and continuity of care. For health care providers, Ionis Every Step is intended to simplify the process of initiating therapy for appropriate patients while keeping the emphasis where it belongs on helping patients better understand their disease, navigate treatment options and access the support they need. Before I turn the call back to Brett, I want to underscore our excitement about this approval and the opportunity it creates to meaningfully improve outcomes for people living with severe hypertriglyceridemia. While we recognize that building awareness and changing treatment paradigms by integrating a new therapy into clinical practice will take time, we are highly encouraged by the HCP feedback and the opportunity to address the significant unmet need in sHTG. TRYNGOLZA's strong clinical profile and compelling label, including the significance of acute pancreatitis prevention in the indication statement, together with an experienced commercial organization that is launch-ready, position us to seamlessly execute. Most importantly, this helps us close an important gap in care for appropriate patients. More broadly, we believe this launch creates an important opportunity to expand the impact of TRYNGOLZA by bringing meaningful innovation to a larger population of patients with serious unmet need. With that, I'll turn the call back over to Brett.

Thanks, Kyle. Today marks a pivotal moment for Ionis. With today's approval, we are poised to reach hundreds of thousands of people living with sHTG, and in turn, make TRYNGOLZA our first potential blockbuster medicine. Today's milestone underscores how we are delivering on our promise to bring a steady cadence of transformational medicines to people living with serious diseases. In just the last 18 months, we have successfully launched TRYNGOLZA for FCS, our first independently launched commercial medicine. We have also successfully launched DAWNZERA in hereditary angioedema, which is gaining significant momentum. And now, we're expanding TRYNGOLZA into sHTG, our first independent launch into a broad population. We also look forward to our anticipated approval of Zilganersen for Alexander disease with a PDUFA date in September and advancing our rich, wholly-owned pipeline of potential best-in-class medicines focused primarily on cardiometabolic and neurological diseases. The approval of TRYNGOLZA in sHTG underscores the strength of Ionis today. With 2 independent launches underway, TRYNGOLZA in sHTG expected to launch in the coming days and with more anticipated approvals and launches to come, we are well-positioned to deliver increasing value for patients and all Ionis stakeholders. And with that, I'll now open the call up for questions. Given the importance of today's news, we will keep the Q&A session focused entirely on TRYNGOLZA. Now, operator, please open up for questions.

[Operator Instructions] And your first question will be from Yaron Werber at TD Cowen.

This is Steven Ionov on for Yaron Werber. Congratulations on this landmark approval. One question from us. Could you give us some more color on where the conversations with payers currently stand on coverage? And specifically, are you expecting payers to try to narrow coverage to patients with an AP, acute pancreatitis, history? Or have you seen positive feedback on a more broad label across the board?

Thanks for the question, Steven. This is Kyle. I couldn't be more pleased with the interactions that we've had with payers up to this point. We've been able to share with them, obviously, information related to the CORE and CORE2 studies. They've also seen HCP demand research on where HCPs anticipate using this treatment. And the expectation is that the coverage will be broad and that anyone with triglyceride levels above 500 will have access to TRYNGOLZA. We're working on payer discussions currently, as you would expect, to getting the approval today. We'll need to go with the final label and have ongoing discussions with them. But all of our conversations have been for the broad population being greater than 500. That also represents the pricing that we set on April 1 at $40,000 for the WACC. That price point is intended to cover all patients and not limit it or restrict it to a high-risk sHTG patient population. That's exactly where HCPs are telling us that they want to treat and use this product based on the strength of the data. The 72% reductions in triglycerides, the 91% reduction in AP events and the ability to use this on top of standard of care today really make this a meaningful treatment to potentially change and advance the way that medicine is treated for these patients that haven't had a treatment up to this time. So broad payer access is what we expect, and those are the ongoing conversations we continue to have.

Next question will be from Yanan Zhu at Wells Fargo.

Congrats on the early approval and the great label. So maybe 2 questions from us. One is in terms of -- on the front page, the only warnings mentioned was the liver enzyme abnormalities. I think you went over it in the prepared remarks as well. I was wondering how do we think about any implication of this item in terms of the launch? Does this mean certain monitoring requirements? And then, another observation, you mentioned 91% risk reduction for the pancreatitis attacks, that actually -- it came from the 50 mg group. So it seems like you had even a better pancreatitis reduction at the lower dose than the 80 mg higher dose. How does that impact your launch activity or promotion activity? I would note that at that dose, the safety is overall even better than 80 mg, including liver fat.

Thanks, Yanan. I'll start, and then, I'll pass over to Sam. I'd love for him to give his perspective on the recommendation to consider testing for liver enzymes prior to treating -- beginning treatment with TRYNGOLZA or escalating dose because it's very common practice in the business. But let me start with your second question first. So the 91% reduction in acute pancreatitis was called out by the FDA, the AP reductions of 91% for the 50-milligram dose, as you pointed out, Yanan, we were thrilled with the 85% reduction in the pooled analysis, of course, an AP reduction unprecedented. The 91% in the 50-milligram dose, we just want to be consistent with the label, which reflects up to 91% in there. As for the reasons between 80 and 50 showing slightly different reductions in acute pancreatitis on a percentage basis, we don't have an explanation for that. It's remarkable data for both doses, and we do not believe that that's going to impact in any way the preference for 50 or 80 milligrams in the launch in the marketing commercialization of TRYNGOLZA for sHTG in any way. I do want to point out that the 80-milligram dose is very well tolerated. And as we highlighted in our prepared remarks, it provides dosing flexibility for physicians, which is common practice and also preference so that patients can -- or physicians can use the dose that they believe is going to provide the greatest benefit depending on the patient's needs. Regarding the second part of your question, no monitoring. There's no monitoring in this label required for anything, let alone liver enzymes. But I'd like to send it over to Sam to provide his perspective on how this is so consistent with available treatments today for cardiovascular diseases.

Yes. I think what the label is basically saying is you just need to make sure you're a good doctor, right? If you give a chronic therapy, you need to know their baseline values of their labs, including the liver test. And if you want to change the dose, then you just check it again. So it just tells you why you should check it once before you start and if you want to change the dose, that's it, and you don't need to worry in between about checking regular labs all the time. So this is consistent with good medical care and nothing out of the ordinary in terms of checking LFTs.

And Yanan, maybe I can address a little bit on the launch implications here because all of them are favorable, everything that we're discussing here. To have AP in the indication statement, number one, is going to strengthen the position and strengthen the understanding by HCPs in terms of how and why to use this treatment for sHTG patients, any patient that's above 500. So that strengthens the argument there. Number two, the 50- and 80-milligram doses allow for dosing flexibility, which is exactly what HCPs are telling us that they want and that they will use in this patient population. Therefore, again, strengthening the launch implications. No monitoring required strengthens the launch implications. So for us, everything is pointed towards very strong favorability in terms of what this label looks like and it represents.

Next question will be from Salveen Richter at Goldman Sachs.

With regard to liver monitoring, could you just speak to how it's done in practice, how much of an extra lift this is and whether you think doctors will actually do that? And then, just noting the label's language around liver fat, what feedback have you been getting from stakeholders on the open-label extension data? And why do you believe the 50-milligram to 80-milligram transition patients saw that kind of elevation or did not see the decreases in their HFF elevations within the follow-up?

So Salveen, as we addressed in the last question, there's no monitoring required at all for anything -- liver enzymes or anything for TRYNGOLZA. It's a very clean label. As Sam pointed out, it's common practice by physicians when they move a patient onto a new treatment for the first time to do some -- to recommend some initial testing of liver enzymes or you don't have to continue testing in any way. And prior to a dose escalation, it's recommended, not required to consider testing again before you dose escalate. Again, no monitoring, no monitoring at all in the label for TRYNGOLZA. As far as hepatic fat fraction, as we presented at NLA last week and as predicted, the on-target small increases in liver fat that we observed in our Phase III sHTG studies are returning to baseline as we presented at NLA last week. Again, there's no clinical sequelae, no emerging AEs with long-term treatment, no -- obviously, no monitoring, as I covered. And this profile that includes the small increases of what appeared to be transient increases in liver fat are completely consistent with our $3 billion product sales -- peak sales that we've guided to. Maybe you can talk a little bit about that, Kyle, on how all this is contained within our -- with our expectation for peak product sales.

Yes, that's exactly right. I mean, we have tested after the CORE and CORE2 data came out, the exact profile from the Phase III trial, these data with HCPs. They are very supportive. They are -- they do not have concerns around hepatic fat, for example, or needing to consider testing for something like liver enzymes. The strength of the data here, the need in the patient population, how clean overall this profile is and how strong the data are, HCPs and the demand research are very supportive of using this drug. We did the same presentation to payers, similar response, payers understand it and payers are very accepting of this. I think we are set up for tremendous success based on the label that we received today.

And Sam, maybe you want to comment on how it's common practice to have when you have 2 doses approved starting with a 50-milligram dose or the lower dose before you go to dose escalate.

Sure. Yes, we're used to using different doses for lipid-lowering therapy. So this is going to be completely consistent in practice how we use statins, right? So it's going to be very similar, almost identical to it. Before you start a statin, you need to know what the lipid levels are and what the labs are. And then, after you give it, you want to see what effect it has. So you'll check labs again, and you'll check the liver test and you'll check the lipid panel. That's basically what's going to happen here. I think clinicians will be very used to doing exactly what they do now with statin. There's not going to be any other extra burden on anybody.

Next question will be from Michael at Morgan Stanley.

Congrats on the approval as well. Maybe just a quick one around pricing, and it has to do with the addition of the 50-milligram dose in addition to the current 80-milligram dose. Just to clarify, is it going to be flat pricing across both those doses?

Yes. Thanks for the question, Mike. It will be flat pricing. So from a payer standpoint, again, all of the testing that we've done and the conversations that we've had with them around utilization management criteria, WACC pricing, et cetera, they've been very supportive of that. And I think flat pricing, 50 and 80 just helps us even more with payers and streamline access ultimately for HCPs to prescribe and patients to receive an appropriate medication.

Next question will be from Jessica Fye at JPMorgan.

This is [ Sylvia ] on for Jeff Fye. Two questions from me. First, can you talk about how the label compares to your expectations? And my second question is, can you remind us of how you think about the size of the subgroups in the high-risk sHTG population, so those with AP history and NG without as well as any differences to how you may approach these subgroups commercially?

Yes. Kyle will address the -- how we're planning to address the various subsegments of the sHTG population commercially. With respect to label expectations, we were hopeful to have acute pancreatitis in the label based on the compelling data that we generated from our Phase III CORE and CORE2 studies. It is highly unusual to include an outcome like acute pancreatitis in the indication state when it's not a primary endpoint in the trial. It was a key secondary endpoint in our trial, but we were hopeful, and we achieved it. And that really reflects the compelling and importance of the data that we generate showing that or potentially significantly we can prevent potentially fatal acute pancreatitis attacks in sHTG patients for the first time ever for any medicine. So I think the FDA got it, and they recognized the importance of this, and they wanted it in the label because it's to the benefit of patients. And so physicians get their attention and they prescribe. Talk a little bit about segments in the population.

Sure. Yes. The overall population, as we have been discussing, is greater than 3 million patients. The high-risk sHTG population has approximately 50,000 patients that are over 500 with a history of AP. There are approximately 550,000 patients that are over 880, and there are several hundred thousand -- 400,000-plus patients that are over 500 with comorbidities, such as ASCVD or type 2 diabetes that could potentially be well controlled, but still be above 500 with their triglyceride levels and be at high risk for acute pancreatitis. So out of the gates, that's where the focus will be. Obviously, the highest risk patients and the urgency to treat those patients. HCPs are largely aware of who these patients are. They're trying to treat them today with omega-3s and fibrates and other triglyceride-lowering agents that just are suboptimal and not effective enough to get the patients out of harm's way. And we know from the core studies that by adding TRYNGOLZA on to those patients that you can have up to 72% reductions in addition to that in their triglyceride levels. So this fits in very nicely with a number of patients that the HCPs are seeing and treating today and need a better therapy to address them. And we believe that TRYNGOLZA is going to be that therapy to be able to step in and help them. And it's very nice to have a first-mover advantage here as well, where we're going to be able to have access to this very broad prevalent patient population with no competitor directly working against us at this point.

Next question will be from Jason Gerberry at Bank of America.

Kyle, curious, what do you think are the most important distinctions relative to the Vascepa launch in sHTG? Why couldn't TRYNGOLZA sort of have a similar sort of patient level demand in the first few quarters? Has it just come down to a simple oral versus injectable barrier to entry? Do you think it's payer related? I'm just kind of curious if you can offer some perspective there. And then secondly, it appears like some health care providers who are intimately familiar with CORE talk about having an early bolus of patients. But these could just be a small subset perhaps of early adopters. And so I guess -- I know you guys have been asked this question before, but what would be your expectation for the proportion of doctors that have an early bolus of patients? And is really the challenge there just pulling those patients through under medical exceptions in the first few quarters?

Yes. Thanks, Jason. So a couple of things on this launch. We believe with TRYNGOLZA, this is -- I'm describing it as a moderate launch at this point. That is based on -- this is a new therapy, new class of therapy. We're going to a very broad number of HCPs, greater than 20,000 HCPs. So educating those HCPs on the label, the product, where to use, why to use, et cetera, will take a little bit of time. Number two, these are patients that typically see their HCP 1 to 2 times per year. So they're not just coming in on a monthly basis to see their HCP. So there are a little bit of that dynamic in terms of getting these patients in to be, again, assessed and diagnosed and then receive their prescription. And then the third thing that you mentioned is part of this as well, which is the payer dynamic. We know out of the gate based on the fact that this is a new indication for a product that payers will need to go through the P&T process and make decisions around the coverage criteria for these patients. So it will take a little bit of time for us to navigate that, and there will be medical exceptions that will be in place for a period of time. However, the work that we've done leading up to this, we believe, is going to help us streamline that process, but we still have to fit that into the process that each individual payer takes as it relates to assessing a new indication for a product. So those are the dynamics there. We're very encouraged. We'll learn more in the second half of this year. And I think 2027, you'll see obviously, acceleration as we get into the new year and more experience comes from using the product. In terms of the bolus of patients, we're working through that right now. We know from the data where -- which HCPs are using high volumes of omega-3s and fibrates today. That kind of puts you in the general vicinity of who's treating patients with high triglycerides to begin with. But then you've got to get in there, again, and educate on the product and then talk to them about that patient population to see who is potentially still eligible to take the drug and still above 500, for example. So we are doing that currently, and the launch team is ready to execute against that now that we have the approval, and we can speak directly to the label, and we can compliantly sell for sHTG in the broad patient population. So I think a lot more to learn here over the next couple of months, but I am super excited about the label, and I know the sales team is ready to get out there and help as many patients as possible.

And I'll just add very quickly, Jason. We don't believe Vascepa is a good analog for TRYNGOLZA in any way. I mean, there's differences in administration, as you mentioned, the efficacy that we have reported that's in our label now on TG reductions and AP reductions is unprecedented. It's never been shown for that medicine. So we don't -- we just don't think it's a good analog for several different reasons.

Next question will be from Jasmine Fels at Barclays.

This is Jasmine on for Ellie Merle from Barclays. Congratulations. So first, what kind of launch metrics should we expect you to give in the initial quarters of the launch? And then second, do you have a plan to give free drug to patients who are working to secure access but haven't yet?

Yes. Great question, Jasmine. Thank you for that. So for launch metrics, I think the most important one is going to be -- is quarterly revenues. We will share how the product is performing on a quarterly basis and what the revenues look like during our earnings calls. We will give some color probably around HCP specialties, who is prescribing and what that mix looks like, payer dynamics and how coverage is coming along, et cetera. I don't anticipate, consistent with the FCS and our HAE launch, going far beyond that in terms of how many HCPs are prescribing or how many patients are receiving prescriptions yet. It is a competitive space. And I think some of those metrics we'll probably keep in-house for our own knowledge and make decisions around that. In terms of free product, we will offer the typical programs that you would expect for this type of treatment. So there will be a quick start program, and patients who are navigating the reimbursement process, there will be drug available for them while they're working through the prior authorizations that might be required in order to get patients started on treatment.

Next question will be from Gary Nachman at Canaccord Genuity.

My congrats as well on the early approval. With this first approval in severe high trigs, how soon can the guidelines be updated for this indication? And how much will that help you in this market, both with physicians and payers? Is that even needed here? And just remind us where you are in terms of the full sales force that's in place for the launch, the size and experience? And any more hirings that need to occur, especially given the broad label?

Thank you, Gary. Sam, what do you think about guidelines?

Yes. So guidelines, there are a lot of different guidelines, ACC/AHA, Canadian, European. So it depends on the timing when that group is meeting. So we anticipate whenever a new guideline comes out, this has to be on there. I mean, this is unprecedented data. And so I'm sure it's going to be a Class I indication as best as I can tell based on the label and the data that we got. But it will depend on the geographic flow in terms of which guidelines. So just recently, we did have the ACC/AHA guidelines just get updated, olezarsen to get a recommendation for FCS -- sorry, yes, TRYNGOLZA. So that one may be a little bit delayed when they do the next one. But sometimes they also have to give updates. When something really cool happens, they need to be able to keep up with the times. So we'll see. We anticipate this going in all the guidelines eventually, though, when they get updated.

Before handing over to you, Kyle, I do want to highlight something that you said, Sam. TRYNGOLZA is the only approved, recommended medicine in the guidelines for FCS today. That's a huge step forward for TRYNGOLZA, and we're hopeful that we're going to get a similar -- that will also be reflected for sHTG as quickly as possible. Impact tailwinds for the launch and then on sales force?

Yes. And let me just add to what Sam said for a second. There are guidelines in place today that reflect the 500 milligram per deciliter threshold for acute pancreatitis. And we've been using those already, both cardiology and endocrinology have those guidelines. So in terms of being able to help us with HCPs and payers, I think we have very strong evidence today and very strong supporting guidelines to be able to do what we need to, to communicate the message and the story and the value that this treatment offers. And there's also a very strong understanding from HCPs of that 500 milligram per deciliter threshold, right? If they've seen a patient that has had an AP event, they never want to see that patient have another event, and they also never want to see any of their patients above 500 have their first event. And these guidelines help that, but also the evidence and the experience of these HCPs is helping drive that understanding. The field force size today, we did an expansion at the very beginning of this year. There are approximately 200 customer-facing field team members in place right now. That is a specialty-sized launch field force. It's exactly where we need to be to reach the audience of the highest treaters of sHTG being the endocrinologists, cardiologists and lipidologists. So right now, I think we've got the right size, the right team and the right strategy in place in order to go forward with the launch.

Next question will be from Luca Issi at RBC Capital Markets.

This is [ Cathy ] for Luca and adding our congrats on an extremely strong label. A quick follow-up on the 50 mg dose seeing 91% acute pancreatitis event reduction. Did you maybe also see more patients in the 50 mg cohort to have trig normalized? And then separately, Kyle, in the same spirit of prior questions asked on the launch and the bolus demand, but looking more longer term, how should we draw our launch curve to look like? What you would anticipate to reach the 1 million versus 3 million patient segment? And specifically, what are some potential scenarios where you would see competition to be more intense than you expect in a year or so?

Sam, anything in the baseline demographics that could explain a slightly better AP rate in 50 milligram versus 80 milligram?

We look -- there's nothing really that we can explain this. This is, of course, pool data from both trials. There were some differences in the trials in terms of slightly different triglyceride levels, geographic location. But the drug was -- both doses were highly effective. So we're talking about differences, but in the very high range, right, in the mid-80s is on average. So no, I can't say that we found anything obvious. It could be just a play of chance. So there's nothing I think that can explain it right now that we found.

Yes. And let me talk a little bit about the patient populations. Obviously, I mentioned starting with the 1 million or so high-risk sHTG patients, which, by the way, is a very large patient population that's very underserved that has tremendous need for a treatment like this. That will give us runway for a couple of years in terms of being able to penetrate and work within that existing 1 million patient population or so. To go from 1 million to 3 million, you start getting into patients that are largely in the 500 to 880 range. A lot of those patients are treated in a different care setting, either internal medicine or primary care. So that will take a little bit more work to educate and bring forward a novel therapy like this and educate that audience in terms of why to treat and how to treat that patient population. We'll be able to do that in parallel, as we're launching into this 1 million patient population. I made reference to our omnichannel marketing capabilities, for example, we can do things that are very efficient and very targeted to help address some of that education and drive disease state awareness to the broader HCP treating community. So we will obviously do that. And you mentioned competition as well. We know what's coming up behind us. And I think having more than one share of voice in this space is not a bad thing. When we're going to conferences right now, we're seeing multiple podium presentations on triglycerides, the importance of treating triglycerides, what levels should you treat, why should you be treating, et cetera. Share of voice, I think, is just going to elevate the entire market. And we do believe that we're in a great position to continue to get this launch off to a great start and make things happen.

Next question will be from Mitchell Kapoor at H.C. Wainwright.

This is [ Manav ] for Mitchell. Congrats on the approval and strong label. Just a few questions on the TRYNGOLZA. So do you expect it will be used mostly as an add-on after fibrates and omega-3s? Or could it move earlier for appropriate patients? And do you expect payers based on your conversations to require prior use or inadequate response to fibrates? And in your conversations with physicians, is TRYNGOLZA to be layered on top of legacy triglyceride-lowering therapy indefinitely? Or should physicians deescalate those agents once patients get below the 500 mg level?

Thank you for the question. I'd like to give you a medical perspective on that as well as a commercial perspective on that. It's a very important question.

Thanks. This is Sam. First, we designed our trials for this to get an add-on therapy. So the data that you're seeing is actually on top of fibrates or omega-3 fatty acids. In fact, in our trials, over 80% of patients were on statins, 70% or so were on fibrates, 33% were on omega-3 fatty acids. So the results that you're seeing are on top. Now, the patients are coming in with high triglycerides despite treatment of all those. And so this is really meant to be on top of standard of care. Now, what that standard of care may differ among some patients. Right now, we don't know how it's going to pan out in the community, but we have to have some patients have dramatic responses. So the 70% reduction is mean, but we have some patients have over 90%. So there, the physicians may need to kind of tweak their meds around a little bit and figure out where one is optimal. So there could be some management of the medication depending on the responses. But really, our data is on top of everything that the patients still need for their care. I think that's where the initial focus will be. How that pans out later, we'll have to see. One thing to keep in mind is that physicians have not seen this kind of reduction in any lipid-lowering therapy, not just with this drug. But when you give a statin, 30%, 40%, 50%, 60% if you're lucky. Here, we're going to be getting 60%, 70%, 80%. They're going to be shocked how effective this drug is, I think. And there's going to be some recalibration about concomitant therapies. But we're not in a position right now to be able to answer your question until we get some further experience.

In other words, although our clinical trials were on top of standard of care, physicians that manage these patients today are fully aware of the marginal decreases in triglycerides that they can achieve with existing therapies. So they're going to be very enthusiastic to move to TRYNGOLZA as quickly as possible.

Absolutely.

Yes. Yes.

Once they see the results, it's going to make a bigger impact in their practice, and they'll find these patients because up to now, there wasn't anything they could even treat. They would give a drug, and they would get a triglyceride from 800 to 600, and it's very unsatisfying. Now, they're going to have a real potent therapy.

Right. And it's not a requirement in the label to be treated with anything prior to TRYNGOLZA for sHTG, but there's a commercial perspective, too.

Yes, absolutely. So on the payer dynamics, and as I said, we've been having these conversations for quite a while with payers. They typically take 2 steps. The first step is what is your indication statement, right, which this indication statement is so strong with the inclusion of all patients greater than 500 as well as having the inclusion of to reduce AP events, it's just telling us that from a payer standpoint, that's going to hopefully provide broad access as we work on those negotiations, and I would expect it to do so. Then, there's the utilization management criteria, which is the second step. And for that step, what we would expect is the coverage to be consistent with what the clinical trial represented, which is exactly what Sam just said. So on some sort of background triglyceride-lowering therapy for a period of time, and then, they should be eligible to go directly on to TRYNGOLZA at that point.

Got it. If I can just follow up real quick on the competition question that came up earlier, as we think about the competition, is your view that the bar is now acute pancreatitis reduction on top of triglycerides lowering? And given the label and data you have shown, what would a competitor need to show to change your view of the $3 billion U.S. opportunity?

So we're not focused on competition. We're focused on TRYNGOLZA and the upcoming launch and to maximize value for patients and for all our shareholders. That's where we're focused on. Certainly, the data we presented, including acute pancreatitis is an unprecedented very high bar with respect to efficacy as it is on safety and tolerability. So we love our profile. But as Kyle mentioned before, having multiple players in this open green space where the unmet need is so large, just expands the share of voice, which can help everybody. And that's really where our view on that.

Next question is from Jay Olson at Oppenheimer.

Congrats on the early approval and solid label. How quickly do you expect TRYNGOLZA adoption in sHTG to move beyond lipid specialists into broader prescriber bases? And do you think sHTG treatment goals may eventually come down now that there's finally an effective treatment available just as we've seen with LDL cholesterol?

Why don't you take the first part of that question, Kyle?

Yes. So I think out of the gates here, the focus really is on the specialists, as I mentioned. That's where the highest volume of patients are being treated today. It's where the highest risk patients are being seen. It's where you're seeing the highest volumes of other triglyceride-lowering agents be prescribed because of the patient population that I just mentioned. So it's definitely going to start there. But I believe this is going to start to bleed out fairly quickly. I think Sam's comment about once you start to get experience using TRYNGOLZA and you see the magnitude of effect and reductions in triglycerides, number one, those HCPs that I just referenced that are specialists will begin using it more broadly than just their high-risk patients, and we believe that will happen fairly quickly over time as they gain that experience. And then the second thing is it will bleed out into the community. Whenever some of these patients go back to see their primary care physician or internal medicine physician and they're on TRYNGOLZA and that physician starts to see the response that these patients are getting, that will help, right? You start with the top of the pyramid and work your way down. That will help, I think, instill that broad education and awareness about the product. So it will happen over time, and we're going to do everything we can to support that through our other tactics and means that we have available to us.

Treatment goals?

Yes. Treatment goals, I don't think we're ready for something like with LDL, it has to be under 55 or 70 yet, but we're close. What I think you're going to see, as the guidelines evolve, right now, as Kyle said, they're more like check triglycerides or XYZ, pay attention to the patient. And now what they're going to say is exactly what's in the label. If somebody is over 500, your drug will be indicated as a Class I, let's say, to reduce the risk of pancreatitis. So there'll be that much more firm now, I think, level of which you should treat and what you would expect to get out of that treatment, which is pancreatitis. How low it'll go beyond that? I think at this point, under 500 is perfectly fine because that's where the pancreatitis risk is. Whether it goes lower than that, I doubt it. Based on these data, it's really pancreatitis focused. But as the field evolves, we might see some -- give some numbers that's close to target.

Next question will be from Eric Joseph at Citigroup.

Let me add my congrats on the expanded label. It seems like there are a couple of new data points in the label versus prior publications, specifically ApOB-48, and also, the month 1, fasting TG declines. Can you talk a little bit about the intent behind the inclusion and how they might resonate with clinicians? And then just on the commercial side, I wonder if you could speak to where -- sort of the lead time to where you might achieve coverage -- the conclusion of coverage reviews for say like a milestone of greater than 80% of covered lives? And what the lead time is like for medical exemption as will be sort of has to be leveraged near term?

Before we go to you, Kyle, Sam, thoughts on ApoB-48.

Yes. So clinicians focus on the typical lipid panel, right? That includes total cholesterol, LDL, triglycerides, HDL and LDL. And so that's what they're going to be using clinically to help them. So it's going to be basically triglycerides. The ApoB-48 is important because that's where the chylomicrons are, and this is a chylomicronemic population. So as you see here, it's elevated. By having ApoB-48 in the label, it's going to tell us basically that we're targeting the right particles that are triglyceride rich. And there's a marked reduction in ApoB-48, right, 76%. So this goes along with the drug is doing what it's supposed to, it's targeting the particles that cause pancreatitis. So that's going to resonate very well. And the rest of the question about timing, these drugs are not giving daily, right? So there has to be some steady state to reach before you expect the full effect. And that's seen in the curves, I think, that you saw in the label. So there's nothing unusual there from that perspective in terms of what the clinician might anticipate.

Right. We have a fast onset of action, and that's highlighted in the label where triglycerides are coming down at the first time in which we've measured, which is at 1 month after starting. But we do encourage and support the label with respect to testing after 3 months when we're at steady state, where a physician can actually see the maximum efficacy that TRYNGOLZA offers on triglycerides and make decisions on whether to -- for example, whether they want to dose escalate at that point. Kyle?

Yes. As it relates to payers and the process in terms of getting coverage and access in place, I think this is going to be very consistent with what you've seen with other products that have a new indication. The indication is there. We have first-mover advantage. There's no other treatment out there that's able to do what TRYNGOLZA is now labeled and approved to do. So we do believe that this is going to accelerate the review process with some payers, but the payers are still going to have to fit us into their P&T review processes. So I would expect the first 3 to 6 months, the payers to start to come on board. As I mentioned in my earlier remarks, starting next year in 2027, I would expect that to accelerate even more broadly. And the expectation is that we've got coverage of all patients above 500 regardless of -- if they're high risk or not. And coverage the label, as I described earlier, in terms of consistent with the clinical trial design is exactly what we expect for payer coverage. So access will happen. We're at the mercy of the payers, but we're working very closely with them in order to open that up and make sure that HCPs can prescribe for the patients they want to treat and patients obviously can benefit from a tremendous therapy that was approved today.

Thanks, Eric. And I think we have time for one last question.

And our last question comes from Myles Minter at William Blair.

Congrats on the approval here. It's great to see. I completely get the messaging about treating patients and getting them below 500 mg per deciliter and reducing the AP risk as per label. What's your messaging to clinicians on how to sort of combat that LDL-C increase? Is that an issue at all? Do you just expect patients to up titrate on statins? Maybe you can explain to me how it's done in FCS currently and if there's any parallels that's going on with this broader population. Congrats again.

Thank you, Myles. I'm going to ask Sam to comment on the biology and from a clinical perspective and everything.

Yes. Thank you, Myles. The best way to characterize these patients, both with FCS and sHTG is that because a lot of their cholesterol is on larger particles, chylomicrons, LDL, their LDL is suppressed. So FCS, LDLs are 50 and that continued to 60. So they're kind of recalibrating back to where they would have gone if the patient didn't have a triglyceride disorder. In this case, we correct the triglyceride disorder. So you're right, there is a small increase in the LDL, but it's in the normal range essentially, and it's recalibrating. It's very easy to treat that with just adjusting their LDL medications. So it's not a clinical issue. Clinicians are not going to be concerned if somebody goes from, say, 50 to 65. That's not really a problem. And so the bottom line is it's consistent with the pathophysiology. It's easily to manage, and we don't see this as a major issue at all, even a minor issue for managing these patients.

Any commercial perspective?

Yes. I'll just mention on the FCS side, this is -- it's not been a sticking point. It's not been a major question or concern. It's been manageable as Sam just mentioned. But in the FCS space, it's not been an issue. I'll also add that we've tested this profile very broadly with CORE and CORE2 data in its totality with HCPs. HCPs are aware of the data, and that's -- it's not really coming up as something that they're concerned about. They're more concerned about being over 500 risk of AP and the strength of the data that's represented in the label.

Thanks, Myles. Appreciate the question, and thanks to everybody again for joining us on today's important news. The approval of TRYNGOLZA in sHTG is a major step forward for patients and an important milestone in Ionis' evolution as a fully integrated biotechnology company, something we're incredibly proud of. We look forward to updating you all on our launch progress and our momentum as we advance our pipeline, bring additional transformational medicines to patients around the world. So thanks again, everybody, for joining. Have a great day.

Thank you, sir. Ladies and gentlemen, this does indeed conclude your conference call for today. Once again, thank you for attending. And at this time, we do ask that you please disconnect your lines.