Ionis Pharmaceuticals, Inc.

Good morning, and welcome to the IONIS Third Quarter 2025 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to turn the conference over to Mr. Wade Walk, Senior Vice President of Investor Relations, to lead off the call. Please begin, sir.

Thank you, Chuck. Before we begin, I encourage everyone to go to the Investor section of the IONIS website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany today's call. With me on the call this morning are Brett Monia, our Chief Executive Officer, Richard Geary, our Chief Development Officer, Kyle Jenea, our Chief Global Product Strategy Officer, and Beth Haugen, our Chief Financial Officer. Also joining us are Eugene Schneider, Chief Clinical Development Officer, and Eric Swayze, Executive Vice President of Research, who will join us for the Q&A portion of the call. I would like to draw your attention to slide three, which contains our forward-looking language statement. During this call, we will be making forward-looking statements that are based on our current expectations and beliefs. These 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. Good morning, everyone, and thank you for joining us on today's call. The third quarter was a watershed moment for Ionis as we made important progress advancing first and best in class medicines for several serious diseases, including in our core focus areas of neurology and cardiometabolic diseases. Our first independent launch for Trigulza the only FDA-approved treatment for familial chylomicronemius syndrome, or FCS, continues to build strong momentum. This performance reflects Tringolza's compelling clinical profile, strong launch execution, and the significant unmet need that we are addressing. Based on this performance and confidence in our continued success across the business, we are raising our 2025 financial guidance, including Tringolza revenues, which Beth will review in more detail shortly. Tringolza also recently received European approval, and we are pleased that our partner Sobe expects to begin bringing this transformative medicine to patients across Europe in the fourth quarter. In August, the FDA approved Donzara for hereditary angioedema, or HAE, marking our second independent launch. This is an important milestone for people living with HAE and for Ionis. I am especially proud of the launch execution by our commercial team, which Kyle will further highlight in a few moments. And in September, we reported positive top-line results from two pivotal programs from our wholly-owned pipeline, both of which were groundbreaking in their own right. Olazarsen in severe hypertriglyceridemia, or SHTG, showed highly significant reductions in triglycerides and became the first medicine ever to show a significant reduction in acute pancreatitis in this population. And in neurology, Zilgenersen showed the first ever disease-modifying effect and Alexander disease, a rare and often fatal neurologic disease. These results reinforce the strength of our science and position Ionis for two additional independent launches next year. Together, these two programs, along with Tringolza and Donzera, represent significant breakthroughs for patients and the potential for multibillion-dollar revenue for Ionis. And complementing our Rich-Holyone pipeline is our partner pipeline, which continues to progress very well. By the end of 2027, we anticipate four key launches from our partnered pipeline targeting both rare and highly prevalent life-threatening diseases. We expect these partnered programs will further expand the impact of Ionis discovered medicines and meaningfully increase total revenue for Ionis. With a strong momentum across our business, including our first two independent launches underway in advancing wholly owned late-stage pipeline and a robust partnered portfolio, IONIS is well-positioned to deliver transformative medicines for patients year after year, driving sustained growth. And with that, I'll turn the call over to Richard.

Thank you, Brad. We're making excellent progress across our pipeline, reinforcing IONIS' ability to deliver on our mission of bringing transformational medicines to patients for years to come. Just last month, we reported positive top-line results from the phase three core and core two studies of olisarcin in people with SHTG who had triglyceride levels substantially higher than 500 milligram per deciliter despite being on standard of care lipid-lowering therapies at baseline, putting them at risk of life-threatening acute pancreatitis. In these pivotal studies, olisarcin demonstrated highly statistically significant and clinically meaningful mean reductions of up to 72% in placebo-adjusted fasting triglycerides at six months, the primary endpoint of these studies. In these studies, olisarcin also significantly reduced acute pancreatitis events, making it the first and only treatment to achieve this positive outcome in people with SHTG. Olisarcin achieved a highly statistically significant 85% reduction in adjudicated acute pancreatitis events. It's important to remember that the main goal of triglyceride management in SHTG is to prevent these AP events, and olosarcin is the first medicine to demonstrate it can do just that. We believe these unprecedented results position olosarcin to meet the substantial unmet needs of people with SHTG, a large patient population in great need for more effective triglyceride lowering, to reduce the risk of potentially fatal acute pancreatitis. In terms of next steps, we're looking forward to presenting additional data from the Core and Core 2 studies at AHA on November 8th. Following that, we are on track to submit our SNDA in the U.S. by the end of the year with additional global filings expected next year. And as Kyle will highlight, Launch preparations are already underway, and we are moving with urgency as we look to deliver olisarcin to people with SHTG next year. Turning our attention to Zilgenersen, our medicine to treat Alexander disease, an ultra-rare leukodystrophy that profoundly impacts patients and families who today have no approved disease-modifying therapies. With the positive phase three results in hand, we are on track for another independent launch next year. And we expect this to be the first of numerous additional independent launches from our leading neurology pipeline. In our phase three study, Zilgenersen achieved statistically significant and clinically meaningful stabilization on the primary endpoint of gait speed. This is an assessment of gross motor function. as measured by the 10-meter walk test. At week 61, Zilgenersen showed a 33% mean benefit in gait speed versus control with a favorable safety and tolerability profile. Zilgenersen also demonstrated consistent benefit across key secondary endpoints. These results represent the first time an investigational medicine has shown a positive disease-modifying impact in Alexander disease. We plan to submit a new drug application to the FDA in the first quarter of 2026, and we are also initiating an expanded access program in the U.S. Turning to ION582, our investigational medicine for Angelman syndrome, the newest addition to our late-stage pipeline. Angelman syndrome is a serious, rare neurodevelopmental disorder that causes profound and lifelong physical and cognitive impairments estimated to affect more than 100,000 people. Earlier this month at our Innovation Day, we shared additional 12- and 18-month data from the long-term extension portion of the HALO study. Results from this study showed consistent and durable improvement on expressive communication over 18 months, exceeding what is seen in natural history, while maintaining a favorable safety and and tolerability profile. Improvements were also observed across multiple other functional domains, including cognition and motor function, suggesting meaningful disease-modifying potential for ION582. As a reminder, the primary endpoint in our Phase III reveal study is expressive communication, reflecting what families have reported matters most to them. And just last month, the FDA granted ION582 breakthrough therapy designation, recognizing the encouraging results from the Phase I-II HALO study and the significant unmet need. Enrollment in the Phase III registration study is progressing well, and we remain on track to be fully enrolled next year with data in 2027. With multiple data readouts, and regulatory milestones expected this year and next, our advancing pipeline underscores the strength of our science and our commitment to addressing unmet need in people with serious diseases. With that, I'll turn the call over to Kyle.

Thank you, Richard. With our first independent launch gaining momentum, a second now underway, and two more anticipated next year, our commercial team is focused on flawless execution to bring these important medicines to patients. In the third quarter, Tringolza continued to exhibit strong momentum as we reported $32 million in net product sales, reflecting a nearly 70% increase in revenues quarter over quarter. Our patient identification initiatives are proving effective. The breadth and depth of unique physicians prescribing Tringolza continued to expand through the third quarter, underscoring the positive experience of both clinicians and patients. This demand also spans a broad mix of specialties, with cardiologists and endocrinologists representing nearly 70% of prescribers and lipidologists and internal medicine providers making up the balance. This favorable provider mix will support awareness and familiarity when we expand into the broader SHTG patient population next year, assuming approval. Access and coverage have also remained strong. To date, the coverage mix for patients on Trigulza is approximately 60% commercial and 40% government. Importantly, both clinically diagnosed and genetically confirmed patients have continued to obtain coverage through a growing number of formal policies or via the medical exception process. We're proud of Tringol's early momentum, but we know we're still in the early innings. The vast majority of the estimated 3,000 people living with FCS in the U.S. remain unidentified. As a result, we're continuing to focus on our patient finding efforts and HCP education. Our customer-facing team has reached over 3,000 physicians, and over 30,000 HCPs have been targeted through our omni-channel capabilities, further increasing awareness of FCS, expanding patient identification, and educating on the potential benefits of Trigulza treatment. Backed by an experienced and high performing team, we are well positioned to continue to take advantage of our first mover position to bring Trigulza to patients in need. Building on our early success in FCS, we are preparing for a launch in the severe hypertriglyceridemia patient population. SHTG represents a large patient population, many of whom struggle to manage their triglyceride levels with current treatments. In the U.S. alone, more than 1 million people have high-risk SHTG, defined as individuals with triglyceride levels above 880 milligrams per deciliter or above 500 milligrams per deciliter with a history of acute pancreatitis or other comorbidities. With a significant first-mover advantage and groundbreaking positive Phase III data in hand, as Richard just outlined, we believe olizarcin is well-positioned to address the unmet needs of patients with severe hypertriglyceridemia. Our commercial team is making excellent progress as we prepare for an expected launch next year. To unlock the potential of olizarcin and SHTG, we plan to initially target approximately 20,000 HCPs in the U.S. who are high-volume treaters of high-risk SHTG patients and expand this outreach even further via our omni-channel capabilities. Our commercial strategy leverages the strong foundation we have built with healthcare providers already prescribing Tringolza many of whom manage SHTG patients. At the same time, we are broadening our reach to additional prescribers who treat SHTG patients. To support this effort, we are expanding awareness through targeted disease education and continued investment in our commercial infrastructure. With key field leadership now in place, we plan to scale the Tringolza Field Force to approximately 200 representatives ahead of launch. At the same time, we have begun engaging payers to ensure broad patient access at launch. We believe there is strong recognition of the value in treating SHTG, given the potential to reduce the risk of life-threatening triglyceride-induced acute pancreatitis at the cost associated with treating these patients. Now turning to Donzara. The approval of Donzara marked a major milestone for Ionis, and our team is energized and focused on executing a successful launch. We built a top-tier commercial organization with deep experience in allergy and immunology, including in HAE. Within 10 days of approval, we shipped our first prescriptions, and the first patient self-administered their initial dose. We're pleased to see strong early adoption of Donzera, with patients switching from prior prophylactic or on-demand therapies, as well as treatment-naive patients starting on Donzera. And the initial feedback from both physicians and patients has been very encouraging, with clear early excitement around Don's era. Notably, we are already seeing repeat prescribers. The U.S. prophylactic HEE market is well-established, yet many patients remain dissatisfied with their current therapies. Approximately 20% of patients switch treatments each year, highlighting the ongoing need for better treatment options. While educating patients and physicians and supporting transition from existing therapies will take time, we believe Donzera, with its differentiated profile and focused launch strategy, is well-positioned to meet this unmet need. As with Tringol's NFCS, we are committed to providing appropriate and comprehensive support to the HEE community, including ensuring broad and timely access for patients who need Donzera. We have established differentiated patient assistance and financial support programs. We are offering a free trial program, which allows patients in collaboration with their healthcare providers to determine if Donzera is the right fit for them. For eligible commercially insured patients, out-of-pocket costs can be reduced to as little as $0. With this foundation in place, we are confident in the anticipated trajectory of Donzera as we work to transform the treatment landscape for patients with HAE. Now turning to Zylgenersen for Alexander disease. Zylgenersen could deliver the first meaningful advance for patients and caregivers where there are currently no approved disease-modifying treatments. This program represents another important opportunity to extend our commercial capabilities. We will build on IONIS's longstanding partnerships with the neurology community and patient advocacy groups to support awareness, diagnosis, and access. At launch, our focus will be on ensuring continued access for clinical trial participants to Xilganersen, expediting access for diagnosed patients, and improving identification of new patients, including enhanced genetic screening. Additionally, we will be working to ensure treatment availability at appropriately equipped centers. With preparations well underway, we are confident that Xilganersen can provide a first-in-class disease-modifying treatment option for patients and caregivers, and opens the door to further strengthen our foundation as we advance our leading neurology pipeline. Our experienced commercial organization is already delivering strong results, as reflected in the early momentum of both Tringolza and Donzera. Building on this success, we remain focused on maximizing the full potential of these therapies while preparing to execute two additional launches by the end of next year, expanding Ionis' reach to even more patients in need of our medicines. With that, I will now turn it over to Beth.

We delivered another strong quarter driven by continued commercial execution and disciplined financial management, which enables us to raise our financial guidance once again. Our results reflect accelerating revenue growth with strong contributions from our marketed medicines and sustained progress across our pipeline. We remain focused on executing our strategy, advancing our late-stage portfolio, and maintaining the financial strength that enables us to invest in future growth. In the third quarter, we generated $157 million in revenue, representing a 17% increase year over year. For the first nine months of this year, revenue totaled $740 million, an increase of 55% compared with the prior year. As you heard from Kyle, the Tringolza launch continues to perform exceptionally well. We earned $32 million in product sales, representing a nearly 70% increase over the second quarter. Royalty revenues increased by approximately 13% to $76 million in the third quarter, anchored by meaningful contributions from both Spinraza and Wainua. As planned, total non-GAAP operating expenses year-to-date increased 9% year-over-year, highlighting our commitment to disciplined investment and driving operating leverage. Our sales and marketing expenses increased year over year, driven by our investments in the U.S. launch of Tringolza and Danzera. R&D expenses decreased year over year, as several of our late-stage studies recently concluded. Importantly, we continued to strategically fund our advancing pipeline, with more than two-thirds of our total R&D expenses funding our late-stage programs. Based on this continued strong performance and fourth quarter outlook, we are once again increasing our 2025 financial guidance, our third consecutive increase this year. We now expect to generate between $875 million and $900 million in total revenue for the year, an increase of $50 million versus our prior guidance. Our guidance reflects meaningful contributions from our commercial portfolio, including continued strong performance of Tringolza, We now anticipate turn goals of product sales between $85 and $95 million for the full year, also an increase from prior guidance. Given the timing of approval, we expect OnZero will provide a modest revenue contribution this year with a greater impact beginning next year. We now expect an operating loss between $275 and $300 million for the full year. This improvement includes our planned acceleration in investments to support commercial preparations for Olazarsen and Zilgenersen, following the strong Phase III data and anticipated launches next year. Additionally, we now expect to end the year with a cash balance of more than $2.1 billion, highlighting our strong balance sheet that will support continued investment to drive accelerating growth. Our third quarter results demonstrate strong execution across our business. With two product launches now underway and more on the horizon, Ionis is well-positioned to deliver transformative medicines to patients in need and achieve our goal of cash flow break-even by 2028, driving long-term value creation. With that, I'll turn the call back over to Brett.

Thanks, Beth. The third quarter was marked by strong execution and accelerating momentum across our business. With two independent launches underway, continued pipeline progress, and key regulatory milestones achieved, we are delivering on our strategy. The commercial organization continues to perform very well. The Tringolza launch is strong, and the approval of Donzera for HAE marked another important milestone, with encouraging early feedback from physicians and patients. And positive phase three results for Olisarcin and SHTG and Zilgenersen in Alexander disease are paving the way for two additional independent launches next year. Together, these achievements strengthen our foundation for long-term growth. With a deep pipeline, outstanding execution, and a clear path to achieve cash flow break-even in 2028, Ionis is well-positioned to deliver transformative medicines for patients and accelerating value creation for shareholders. Now, before I move to the Q&A, I'd like to take a moment to recognize and thank Richard Geary, for his tremendous impact on Ionis over the past 30 years. With his retirement at the end of this year, this will be his last earnings call with us. Richard has been a driving force behind our innovation, leading dozens of development programs and guiding six transformative medicines through regulatory approvals and to patients. His leadership, vision, and unwavering commitment to patients have been instrumental in shaping Ionis into the company we are today. On behalf of the entire IONIS team, I want to thank Richard for his remarkable contributions and his dedication to improving the lives of patients around the world. And with that, we'll now open the call up for questions. Chuck?

Thank you. We will now begin the question and answer session. To ask a question, you may press star then 1 on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the key. If at any time your question has been addressed, and you would like to withdraw your question, please press star, then two. And at this time, we'll take our first question. Excuse me. We'll come from Ms. Jessica Fye with J.P. Morgan. Please go ahead.

Hey, guys. Good morning. Thanks for taking our question. I was hoping you could talk a little bit about how we should best think about the shape of the launch curve for Olazarsen in SHTG. And I guess what I mean by that is kind of like In terms of the positions you're targeting and the number of patients they cover, do you perceive that there's pent-up demand or almost like a warehouse effect where you could see rapid adoption the way we have in this obviously much, much smaller FCS setting? Or if not, what is the right way to think about the shape of that ramp? Thank you.

Yeah, thanks, Jess. This is Kyle. It's a great question. First, I'll just mention that there's strong interest in trying to expand the use of Tringolza and interest to use olazarsin in the SHCG patient population. It's an ongoing question that we get from HCPs as we're interacting with them today. Our current target population of HCPs is about 3,000 that we're reaching with our existing sales force. We're going to expand that to reach approximately 20,000 HCPs. Those 20,000 HCPs are covering approximately 360,000 patients that have SHTG. Some of those are high-risk patients, meaning above 880 or above 500 with a history of AP. Many of those patients are currently on standard of care treatments. So they're on fibrates and fish oils and statins and PCSK9s and other background therapies. So what we are expecting is that if those patients are on standard of care treatment and they're not getting to goal today, that there will be interest in using olizarcin in that population, you know, based on the phase three data that we generated in core and core two. So that will be the beachhead in which we will approach this. And, you know, we expect strong uptake based on the interest in what we've learned about the market thus far.

Thank you. The next question will come from Gina Wang with Barclays.

Please go ahead.

Thank you for taking my questions. So maybe I will also ask, one is all assassin, core and core two data. Since you will have updated AHA, we already have a top line data. Anything that will be concerning regarding, say, the acute pancreatitis events, you know, if it's a, I know the rate ratio is super impressive. but, you know, you didn't have approved two studies, would that be anything will be, you know, we should be pay attention to? Would that be well balanced between the core and the core two regarding the acute pancreatitis events and also any other things we should be pay attention to? So that was one question. And the second high level, I know you give a peak revenue potential for Donzera, over $500 million. Do you have a view regarding, say, Olasazan and also Alexander disease?

Okay, let's try to, those three questions, you know, let's try to go through them quickly, but thank you. So, I'll start with the AHA presentation, then I'll turn it over to Kyle for Donzera and Alexander disease. So, We're very much looking forward to presenting the detailed data at American Heart Association in a prestigious, weight-breaking clinical trial session on November 8th. Nothing to be concerned about. The AP data is groundbreaking. And I think that people are going to really be impressed when we share the detailed data on the AP. outcome, including how rapid the protection is against acute pancreatitis and how durable those effects are. Remember, this was a pre-specified statistical plan analysis of core and core 2 purposefully because we wanted to ensure the maximum powering for a positive outcome, which was proven to be a very smart thing to do. Core and Core 2 have been published on the baseline demographics, and what you see in the baseline demographics is that there's a higher triglyceride median amount in Core versus Core 2, and that will reflect the few pancreatitis events in the study, too, but you'll see all that data at the AHA, and there's nothing else to be concerned about. We're very much looking forward to it. Again, groundbreaking results, and the AHA will be A great venue. We're also encouraged that with where we are in the review process for a publication, no guarantees, but we're hoping for a simultaneous publication with the presentation. If we can get that done and then all the details that we can't get to in the presentation will be in the publication. So stay tuned for all that. Looking forward to it. Touch on Donzera and Alexander?

Yeah, I'll just touch on peak sales for each of the programs. So peak sales for Donzera, as you referenced, are expected to be greater than $500 million. For Olazarsen, our first anticipated blockbuster launch, we're expecting to be greater than $1 billion. And for Alexander's disease is greater than $100 million are the expectations.

Thank you very much. The next question will come from Mike Yoles with Morgan Stanley.

Please go ahead.

Good morning, and thanks for taking the question. Maybe just a follow-up on Olazarsson and SHTG. Just curious if you have any updated thoughts on pricing. I know this is an area where you're doing some extra work, so just curious if there's anything there to share, or if not, when we might expect a little bit more clarity on the pricing question. Thank you.

Yeah, thanks, Mike. This is Kyle again. The work is ongoing. We do have the Core and Core 2 data, the Essence data, and we've got a lot of work to go through with our information related to ER visits, hospitalization rates, number needed to treat, which is some information that will come out at AHA as well. So there's still a lot for us to pull together. The research will kick off and we expect to have additional information next year for us to be able to make some decisions around in terms of final pricing recommendation. I think what some early signals continue to tell us and is consistent with research that we've done in the past is that this is a market of greater than 3 million patients and that payers are going to look at this market in terms of their total exposure to potentially covering olizarcin in an SHTG indication of greater than 500 milligrams per deciliter patient population. So we're still doing that work, and we will announce the final price upon the approval of the SHTG indication, similar to how we've done with the FCS indication as well as the HE indication for Donzara.

Great. Thank you. The next question will come from Jeroen Warber with TD Cowan.

Please go ahead. Great. Thanks so much. Congrats on a really nice quarter, and hopefully it should be very good next year as well. A couple of questions. Number one, just for AHA, when we're looking at the data, should we be expecting that the reduction in AP is going to be principally in patients with a history of AP or Or is there a chance that you're going to show potentially a prevention of new events in patients that did not have AP events in the past? And then secondly, you know, some of the other companies in the HAE space are actually beginning to talk that there's considerably more patients in the U.S. market. I think some are mentioning as many as 11,000 patients and 75% on prophylaxis. I know you're mentioning 7,000. Maybe can you help us kind of maybe understand the difference a little bit? Thank you.

Sure, Yaron. Thank you for the question. Kyle will address the market research and the prevalence in HAE in the U.S. Regarding AH, American Heart Association meeting, AHA. So again, I don't want to get ahead of the details, Yaron, but what I can say is this. You know, all of the research that has been done over the decades has indicated that the higher the triglycerides, the more AP events that you're going to get in a study. And that's exactly what we've seen in our study. So the higher the triglycerides, the more AP events you're going to get in the study. And that, you know, will correspond to the data that we present at AHA. There's going to be in the patients not only with AP above 880, also consistent with research. If you've had an AP prior event, your chances of having another one is higher. So that is consistent with the data that we will present at AHA. So you're going to see more events in the high-risk patient population as you would expect. So there's no surprises there, and that's actually very comforting because that means that all the work that we've done, all the research we've done is holding up, and triglycerides are driving these AP events. Kyle?

Yeah, in terms of the prevalence in the United States, we're still working off of the 7,000 estimated patients in the U.S. That's the information that we've documented and be able to work from up to this point. You've referenced that about 75% of those patients are on a current prophylactic therapy today. And so this is a switch market, and that's really the market that we're focused on is moving patients over that could potentially do better on a therapy with a profile like Donzera. And there are some patients that were on-demand therapy patients only that have added Donzera up to this point. And we'll also get newly diagnosed patients, as you're referencing. But, yeah, I'm not aware of an 11,000 number. We're still working off of the 7,000 population that has been addressable up to this point.

And, Jeroen, I'd like to come back to your first question, too. You know, one point I didn't make that I think is very important is, is to remember that the AP data that we have generated in Core 1 and Core 2 is after only 12 months of treatment, right? So, you know, when you think about a cardiovascular outcome trial, when you're looking at outcome data, it's years of treatment. This is only 12 months, so we expect there to be even more AP events eventually in all segments of the SHCG population with longer-term observation, longer-term treatment.

This is a relatively short study, which makes our results even more remarkable. The next question will come from Gary Nachman with Raymond James. Please go ahead.

Thanks, and congrats on all the progress. So, Tringolza accelerated really nicely in the third quarter. Where are most of those additional FCS patients coming from? So, how many physicians are prescribing right now? And maybe describe the percent genetic versus clinical that are diagnosed. And based on your full year guidance, you have that acceleration slowing a bit in the fourth quarter. Is there any good reason for that? Could you explain that? And then just on the Olazarsen filing for severe high trigs, any chance you can get a priority review for it, especially if it's going to be lowering the cost of the drug significantly I mean, you're still working through that, but it would be a significant drop. So I don't know if that's an argument that could be made to get it on the market sooner. Thank you.

Gary, I'll take the second question first, and then Kyle could address the, you know, your question about trend goals. So our assumptions right now are as a standard review, supplemental NDA by the end of the year, 10-month review. However, we will pursue all avenues to potentially bring this medicine to the market as quickly as possible. So stay tuned for that. But right now, we're assuming a 10-month review. We don't see any reason why it couldn't be considered for other paths forward with regulators.

Yeah, in terms of the FCS patient population, there are a couple of things that we've been doing. Number one is identification of patients, and you move them through the diagnosis and then the prescription. We focused on those highest prescribing SHTG physicians, the first 3,000, right, that we've been working through throughout the balance of this year. And we've also supplemented that with some of our marketing and our omni-channel capabilities to drive more disease state awareness and an understanding of about the need to treat patients with high triglycerides and specifically how to assess and diagnose FCS. The clinical scoring tools, either the North America FCS scoring tool or the Moulin criteria, are also driving the clinical diagnosis ability for these HCPs. So they're looking for these patients. They know these patients are in need. They want to get them out of harm's way of acute pancreatitis. and they're using the available tools and resources to either clinically confirm or genetically confirm these patients. The other thing I'll mention is on the payer dynamics, the policies are getting put in place to where it's a streamlined process for HCPs to be able to prescribe once they've made the diagnosis for FCS. So I won't get into specific numbers around HCPs or the split between genetic and clinical confirmation, but what's going well is Disease education is improving. The awareness of the need to treat continues to go up. And Tringolza is performing very well when HCPs are using it, and they're looking for more appropriate patients in order to treat with Tringolza because of the performance of the drug. Q4? Oh, for Q4, I don't want to say it's a slowdown. We took a look at a couple of things. One thing is the duration. It's 10 weeks as opposed to 13 weeks because we've got the holidays in there. And then also, we don't know the seasonality yet, if there's some implications here at the end of the year, because this is our first full year of the Tringolza launch. So, you know, we're just making sure that we're taking into account some of the unknowns as we're considering the guidance for the quarter.

All right, great. Thank you, and best of luck to you, Richard, on your retirement.

Thank you. The next question will come from Jason Gerberry with Bank of America. Please, go ahead.

Hey, guys. Thanks for taking my questions. There's two for me. Ahead of CardioTransform next year, I just wonder, you know, get your latest thoughts. How do you maybe maximize the benefit of the data in combination with Tifaminis if it hits stats to the disproportionate benefit of Eplon-Tersen in that there isn't sort of a free-riding effect that happens for your competitor? as it pertains to the validated benefit of the silencers and stabilizers together. That's question one. Question two, into AHA and the update on NNT, just wondering if you can contextualize, as we think about the NNT both in the all-comer and the high-risk group, if obviously the NNT is more compelling in the high-risk group, but that's a small proportion of the overall population, How important is that to the overall kind of value proposition in the eyes of payers from your perspective?

Thanks, Jason. You know, on CardioTransform, as you know, it's the largest study ever conducted in TTR cardiomyopathy, I mean, by far. And we will have the largest amount of data for combination usage as well as monotherapy usage in the study. And, you know, the combination usage is a key secondary endpoint in the statistical plan for CardioTransform as well. So, you know, how important, how valuable that will be once we launch Eplon-Tersen in TTR cardiomyopathy is to be seen, to be determined. Obviously, the mechanisms are highly complementary in theory, and we expect to see added benefit. over monotherapy in the study, but that remains to be seen and proven. But if anyone is going to be able to show a benefit of combination usage and for that to drive value and resulting in driving value for, you know, the commercial opportunity for epilontursin, it'll be this program. I don't want to comment on whether that provides, you know, tailwinds for other competitor programs and those sorts of things. We're focused on epilontursin And we think we have the right trial design, we have the right drug, and we're very much looking forward to the data in the second half of next year. We will be sharing some data on NNT in different subgroup populations in SHTG at AHA, and if we can get a simultaneous publication as well. I think the results are going to be strikingly positive in both groups or in all the subgroups that we've looked at. But I don't want to get ahead of that data at this time. Jason, as far as the value for payers, I'll leave it to Kyle to comment on that.

Yeah, I want to comment on the totality of the data and how the evidence is stacking up for Core and Core 2 and how that will be interpreted by the payers, right? Reductions in triglyceride levels to the magnitude that we're seeing of up to 72%, for example, on top of standard of care. So these are patients that are being treated already that aren't getting to goal, that aren't getting out of harm's way of AP on the current standard. And by adding olizarcin, you're seeing significant reductions in triglycerides. An 85% reduction in acute pancreatitis is really incredible to see. And payers, I think, will react accordingly when they see that data. Hospitalizations and ER visit data. the NNT data will just add value and will complement that. It'll talk about some of the subpopulations. But overall, I think the quality and the totality of the data here is what's going to drive payer engagement and effective reimbursement here. Keep in mind that the focus here is to prevent a first AP attack from ever occurring. And HCPs understand that. The guidelines represent that. And HCPs are trying to treat the goal, and they just can't with the current existing therapies that are out there. The other thing that I'll mention is these are fasting triglyceride levels. And you're going to have postprandial spikes in these patients, you know, even if they are between 500 and 880, that increases their risk of having an acute pancreatitis event. So that whole story and the comprehensive nature of the data that I just talked through, I think, is going to be the value story and the proposition for the payers.

Thanks, guys.

The next question will come from Yunan Zhu with Wells Fargo Securities.

Please go ahead.

Oh, great. Thanks for taking our questions, and congrats on the quarter. Maybe a couple of questions, one on Donzera launch, one on Whenua. Can you give a little more color on the early prescriptions for Donzera? Are these from switching patients or newly diagnosed patients? And if it's switching patients, any pattern of the previous therapy? For Wainua, there's also a sizable bump in the polyneuropathy revenue, looks like 25%. Is that due to the growing of the market via newly diagnosed patients, or is that reflecting you taking share, and any updated metrics like new to brand numbers. Thank you.

Yeah, I'll start with the Donzera launch.

First, it's going very well. As were highlighted in the opening comments, both HCPs and payers, the feedback has been very positive. The commercial team has executed extremely well, getting product into channel, getting the first prescriptions in, getting those patients onto treatment in patient self-administering with Donzera. So the launch is going very well. It's very early, right? I mean, the PDUFA was August 21st. You know, we're a month or so into this launch. So I don't want to provide too many details or specifics at this point in time, but I'll just share with you that the receptivity by HCPs has been very strong. The profile of the drug, the data to support it, the label, and specifically the switch data has been very valuable so that they can understand that they can move these patients over safely and effectively and get them started on Donzera and have a positive experience there using our Ionis EveryStep patient support program. So I think all signals are very positive. We are seeing switches from all of the currently approved prophylactic treatments We're seeing Donzera added to on-demand treatments where patients weren't on a prophylactic treatment. And then, you know, we're seeing newly diagnosed patients as well. So I won't get into the details on the splits, but all signals are very positive so far with the early signs of the launch.

And the bump in Wainua revenue?

Yeah, the bump in Wainua revenue, again, so this is a growth market. And, you know, as we've said all along, it's about new patient identification. And that's predominantly where the demand is coming from in the third quarter for Wainua. The product's performing very well in terms of quality of life improvements. Access is going very strong in terms of coverage. The majority of patients paying $0 out of pocket. You know, we do expect continued growth with the identification of new patients, especially in the centers of excellence where these amyloidosis centers are using Wainua very broadly for the polyneuropathy indication. And I think we just continue to be encouraged by AstraZeneca's execution around the launch and their focus on the program.

Great. Thank you. The next question will come from with William Blair. Please go ahead.

Hi. Thanks for taking the question. First off, congratulations to Richard on his retirement. Thoroughly deserved. The question is on hepatic fat fraction data in the core studies and if you can comment on that and if we'll see it. I've just been getting some questions considering you've got, you know, robust serum triglyceride reductions there, whether you're shunting, you know, maybe too much to the liver at any one time and it's accumulating there, you know, also acutely aware that you have the way liver data presented that actually showed reductions in hepatic fat fraction. So any sort of color on that metric would be helpful. Thanks.

Yeah, Miles, I don't want to get ahead of the AHA presentation because, you know, that is a secondary endpoint, so it will be covered in the presentation and publication. So, you know, we're going to present, we're going to do a deep dive at AHA on the primary endpoint of triglyceride lowering, including both doses through 12 months, time courses, and that kind of thing. You'll see the durability of triglyceride reductions. You'll see details on the acute pancreatitis, which is a secondary endpoint, and you'll see all the data listed out on all the secondary endpoints, including hepatic fat fraction. We'll also talk a little bit about the NNT that we touched on in the earlier question. So I don't want to get ahead of that. We're just a couple of weeks away from AHA, and let's just leave it there.

All right. Thanks. The next question will come from Luca Essie with RBC.

Please go ahead.

Oh, great. Thanks so much for taking my question. And then, Richard, congrats on a fantastic run and all the best on your next chapter there. Maybe if I can circle back on severe half-drug dysrhodemia, Kyle and Beth, you have obviously a billion-dollar-plus peak revenue opportunity for the drug. Is that conservative? The reason why I'm asking is because if the TAM is truly a million patients, the price is $20,000 per patient, which seems consistent with your commentary, that all implies like 5% penetration at peak, which again feels a little conservative to me. So we'd love to hear you talk about some of the assumptions that went into that $1 billion plus number that you have articulated. And then maybe sticking on severe hyperglyceridemia, what's the latest prediction? thinking on whether you're going to file just the 80 milligram, which is obviously the same dose of proof in FCS, versus filing both the 50 and the 80 milligram to give docs more options to kind of tailor the dose based on the need of the patient. Any call there, much appreciated. Thanks so much.

Thanks, Luke. I'll take the easy question. We're filing on both doses. Both doses look great. And we believe that dosing flexibility is in the hands of cardiologists, endocrinologists, lipid specialists, will be very well received once we get to the market. So that's that. And with respect to DECA sales.

Yeah, Luca, I mean, you know, I keep referencing that it's a prevalent patient population, right, greater than 3 million patients. The high-risk SHCG patients, you've got approximately a million of that you were just referencing as well. I think we still have some unknowns here around the payer dynamics. We also have some unknowns around pricing dynamics in order to factor into these assumptions. What we felt comfortable with, I think, going into this and have been consistent all along is greater than a billion in peak sales is where we've landed up to this point. We're continuing to assess the market. We've got a lot of good learnings from FCS as well in terms of how the launch trajectory has gone here. We're doing more market research to understand HCP and payer and patient perceptions around the SHCG marketplace. And, you know, we will provide, you know, updated information as we learn more and feel more comfortable and confident with the way the information comes together.

But, yeah, it's greater than a billion dollars is where we feel comfortable today.

Nice. Thanks so much, guys. The next question will come from Jay Olson with Oppenheimer. Please go ahead.

Oh, hey, congrats on all the progress, and I'll add my best wishes to Richard as well. Beth, I know you commented a little bit about this on your opening remarks, but with your strong balance sheet, could you share your priorities for capital allocation, especially with regards to any external versus internal investments? Thank you.

We're happy to. We do have a strong balance sheet, very healthy cash balance, and expect with the increased guidance that we'll maintain that as we go into next year and continue to execute on these launches as well as the Olazarsson, SHTG, and Zilgenersen launches next year. Our top priority for capital allocation is for internal growth. We think that that that there's tremendous opportunity in our pipeline and behind these existing marketed products and the ones coming to market here shortly. So we will continue to prioritize growth for capital allocation. We'll do that with discipline as we've done historically, but that's where you should expect to see us using our balance sheet.

Great. Thank you. I think we have time for one more question.

Our last questions for the day will come from Mitchell Kapoor with HC Wainwright. Please go ahead.

Hey, thanks for taking the questions. Just wanted to ask, with an impressive 90% rolling into the open label extension in the SHTG trials, can you name some of the more prevalent dropout reasons and whether there's any, you know, reasons that we should be cautious going into a launch because of some of those?

Thanks, Mitch. And I'm going to let Richard answer the final question of this earnings call. Any reasons to be concerned with dropouts in the Core 2 studies? Richard, anything you want to highlight?

Yeah, so first I would say the dropout rate was about half what we expected from the beginning. Very well tolerated medicine. There isn't actually any one issue that led to discontinuations. They varied across the study. Some of them had to do with personal reasons, moves, vacations, different things that needed to be taken care of, pregnancies, et cetera. And so I can't point to like a main reason. And for that reason, I'm very bullish on this medicine in terms of its tolerability and safety.

Great. Excellent. Thank you all very much, and congrats, Richard.

Thanks, Richard. Thanks, Mitch. Thanks, everybody, for joining us and participating in our call today. We really do look forward to building on the remarkable momentum that we've achieved this year so far and for years to come and sharing additional updates along the way. Just as a reminder, The detailed data from the landmark phase three core and core two studies for olizarcin will be presented for SHCG, will be presented during a late-breaking session on November 8th at AHA. We encourage you to listen in to our webcast. Until then, thanks for participating, and everybody have a great day.

The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.