Ionis Pharmaceuticals Inc (IONS) Q2 2026 Earnings Call Transcript

Good morning and welcome to IONUS Second Quarter 2026 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walk, Senior Vice President of Investor Relations, to lead off the call. Please go ahead.

Thank you, Andrea. 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 financials' results better represent the economics of our business and how we manage our business. We've also posted slides on our website that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer, Kyle Janay, Chief Global Product Strategy Officer, Olly Kortasevich, Chief Development Officer, and Beth Haugen, Chief Financial Officer. Eugene Schneider, Chief Clinical Development Officer, and Eric Swayze, Executive Vice President of Research, will also 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 I encourage you to consult the risk factors contained in our SEC filings.

Thanks, Wade. Good morning, everyone, and thank you for joining us on today's call. The engine, the profile, and the enthusiasm we are seeing in prescribing, we are confident that Tringolza is well-positioned to help a large population of patients in need and become the first Ionis-owned multi-billion-dollar medicine. Gonzerra for hereditary angioedema also continues to gain momentum. We expect Onzeria to continue driving growth as if in the HAE prophylactic. We also continue to advance our leadership in the development of breakthrough treatments for a wide range of neurological diseases. We remain on track for the anticipated launch of Zilganurcin, coming up soon, which is positioned to Alexander disease and the first independent launch from our neurological disease. Zilganurcin is Ovidanurcin, our medicine for Angelman syndrome, which completed enrollment in the Phase III reveal study last month, keeping it on track for data next year. This month, we also announced the initiation of clinical development for Ion-337 in Dravet syndrome, stage neurology pipeline, which now includes AIDS medicines that are wholly owned. Complementing our wholly owned pipeline is our partner pipeline, which includes medicines targeting both rare and highly prevalent diseases, providing significant additional value for Ionis. This includes Peperaverse and our medicine for chronic hepatitis B. With a Purdue for target action date of October 26 and additional global filings under review, Pepe reversion is on track for a global launch this year, positioning it to be a first-in-class medicine for the millions of people around the world living with this disease. Repel a Carson Lp little a horizon study in patients with elevated Lp little a in cardiovascular disease is also a key catalyst coming up in the second half of this year. We're disappointed with the outcome of the cardio-transformed phase three study for eplontersin in ATTR cardiomyopathy that we reported earlier this month. Although Evalon-Terson demonstrated substantial and durable reductions in TTR, nominally significant results in the monotherapy subgroup and favorable safety, it did not meet the primary efficacy endpoint in the overall population. We and AstraZeneca continue to analyze the data and will present the results at ESC in August. Our strong commercial execution, continued pipeline progress, and our strong second-quarter financial performance underscored the many opportunities we have to continue building substantial value. We remain on track to deliver on our 2026 financial guidance and achieve our goal of cash flow break even in 2028. With that, I'll now turn the call over to Kyle, who will speak to the commercial execution of Tringolze and Donzera and launch preparations for Zilgenersen. Holly will then discuss how we are advancing our pipeline, highlighting several important catalysts ahead. And that will review our financial results and outlook. And with that, I'll turn it over to Kyle.

Thank you, Brett. Our commercial momentum continues to build, positioning us to deliver even greater impact in the second half of the year and beyond. We are executing well against our commercial priorities, including strong progress on the Tringolza and Donzera launches and preparation for the Zulganersen launch. Beginning with Trindolza, demand continues to build in FCS, driven by an increasing number of patients initiating and remaining on treatment. As expected, second quarter product sales reflected the reduced Trindolza wholesale acquisition costs that went into effect on April 1st. We updated the price ahead of the anticipated SHTG approval to align with annual payer contracting cycles to accelerate access to Tringolza. Underlying demand in FCS remained strong, with the second quarter delivering the highest number of patient starts since launch began. Together with our commercial execution in FCS and early market access efforts, we've established a strong foundation for the launch in the broader patient population. The recent approval of Tringolza for SHTG marked the defining moment for Ionis. Importantly, it expanded our opportunity to serve millions of people living with severely elevated triglycerides. We were particularly pleased with the Tringolza label, which includes prevention of acute pancreatitis in the indication statement. The label is supported by the groundbreaking results from the Phase III core and core II studies, which further underscores the importance of preventing acute pancreatitis and people with SHTG. Building on this strong foundation, I'm happy to share that the SHTG launch is off to an encouraging start in the first few weeks. Thanks to the exceptional execution of our commercial team, we began receiving prescriptions on day one, and both the 50 milligram and 80 milligram doses were in the channel within approximately one week. Since the approval, our team has already engaged with many of our top position targets who care for the majority of high-risk patients in addition our omni-channel launch campaign has produced strong engagement which is further helping to rapidly build awareness of shtg apoc3 biology and tringolza there are an estimated 3 million people in the u.s with shtg including approximately 1 million people with high-risk shtg who have triglycerides above 880 milligrams per deciliter or triglycerides above 500 and a history of acute pancreatitis or other comorbidities the risk of acute pancreatitis begins to increase at triglyceride levels above 500 and rises exponentially in people with triglycerides above 8080 as the first to market therapy with a novel mechanism proven to reduce the risk of painful costly and potentially fatal acute pancreatitis attacks, Tringolza is well-positioned. The majority is high-risk, it's between 20,000 cardiologists, endocrinologists, and to a meaningful contribution from primary care physicians. We've also seen physicians prescribe Tringolza to people with high-risk SHTG and those with TGs between 500 and 800 milligrams per deciliter with no history of acute pancreatitis. Tactic therapies are already established. Outside the U.S., our partner, Otzuka, is making good progress with Donzera in the launch in the EU. Over time, we expect ex-U.S. countries to become an important contributor to overall Donzera crew. Turning to Zilga Nursen, we are well prepared for the launch for the treatment of Alexander disease coming up. Based on the positive phase three results for Zilga Nursen, we received FDA priority review with PidufiDate. The access program underway, and our commercial preparations are prioritizing engagement with The team is now in place to bridge many of the capabilities we are building for Zilga for the approval, for Zilga nursing in the EU, and with our first broad patient population launch now underway, growing momentum across our commercial portfolio, and a strong pipeline behind it for important medicines. And with that, I'll turn the call over to Holly.

This quarter we made meaningful progress across our pipeline. Tremgold's approval for the treatment of SHCG is a significant milestone for IONIS and for Tringolza's approval was supported by the unprecedented results from the Phase III core and core II studies, in which Tringolza achieved rapid, substantial, and clinically meaningful placebo-adjusted mean reductions in triglycerides. These triglyceride reductions resulted in a profound reduction in acute pancreatitis Tringolza's treatment also led to 86% of patients reaching triglyceride levels below 500 mx per deciliter, the threshold that defines that phase TG. Up to 54% of patients reaching normal triglyceride levels below 150 mx per deciliter. and favorable safety and tolerability, which were further reinforced by longer-term data from the CORE and CORE-II Open Label Extension Study, which we recently presented at the National Lipid Association Scientific Session. We will share additional data from the OLE at ESC in August. As Kyle mentioned, the Tringolza label includes acute pancreatitis risk reduction in the indication statement, which underscores the importance of preventing use debilitating and potentially fatal attacks and further validates our unprecedented. With its groundbreaking clinical profile, Trigosa is poised to redefine the treatment. Beyond Trigosa, we are advancing a number of promising whole-real and cardiobanabolic disease medicines, including ION-775, our next-generation medicine for the treatment of FHTG. We recently advanced ION-775 into a Phase IIb study in patients with FHTG or moderately elevated triglycerides based on positive Phase I data and healthy volunteers with elevated triglycerides. These results show the potential for an optimized profile characterized by substantial, durable, and sustained reductions in A4C3 and triglycerides with the potential for semi-annual or less frequent dosing. We look forward to presenting these data on ION-775 at ESC next month, and as Brett mentioned, we will also show detailed data from the epilonturtsin cardiotransform study at ESC. Turning next for a neurology franchise, we remain on track to bring Zildanurtsin to patients with Alexander disease later this year, assuming approval. This rare, progressive, and often fatal leukodystrophy profoundly affects patients and families. And today, there are no approved disease-modifying therapies. Our positive Phase III results mark the first time any therapy demonstrated a disease-modifying impact in these patients. Our next Holyoke Phase III program is open inerfment for the treatment of Angelman syndrome. Angelman syndrome is a neurodevelopmental disorder that causes profound and lifelong physical and cognitive impairments. That may affect more than 100,000 people globally. We recently announced that enrollment in the Phase 3 reveal study is complete, which keeps us on track to report data in the second half of next year, bringing us an important step closer to potentially delivering this medicine to families in need. We recently advanced our medicine for the treatment of Dravet syndrome, a rare, severe, and lifelong neurological disorder, into a Phase 1, 2, first-in-human study. We advanced ION337 based on encouraging preclinical data, which we believe positions this program to become a best-in-class treatment for this devastating disease. Bion337 is our first wholly-owned medicine that uses our proprietary NMA chemistry, designed to achieve maximal and sustained modulation of SDN1A with a long dosing interval. Our NMA chemistry is the same breakthrough technology that enabled salinersin to achieve substantial efficacy and favorable safety with annual dosing in a Phase I study in patients with spinal muscular atrophy. Our partner, Biogen, recently advanced salinersin into Phase III development based on these positive results. Positioning it to meet the remaining unmet needs of people living with spinal muscular atrophy. We were also encouraged by the Phase II CELIA data Biogen presented at AEIC for Deer-Nursin in early Alzheimer's disease. These results are the first to demonstrate the significant potential of targeting intercellular tau as a treatment for AD. Deer-Nursin shows significant reductions in CSF tau levels, accompanied by a reversal of tau pathology as measured by TauPAT. We also saw remarkable effects on cognition, as shown by a 34-50% flow decline in MMSC versus placebo, and a meaningful effect on composite endpoints that include both cognitive and functional domains. Although the Phase II study did not meet the primary endpoint, the totality of these data support Biden's plan to initiate Phase III development. We are also pleased with the recent initiation of the Phase III Intrepid study of Sapo-Blurson by our partner, Ono. This study is evaluating Stapoblersin in people with phlebotomy-dependent polycemia vera, a rare but potentially life-threatening hematologic disease with significant unmet needs. Assuming positive data, Stapoblersin would represent an important value driver from our partner pipeline. In Bethleharson, our medicine for the treatment of chronic hepatitis B partnered with GSK, is on track for approval in the U.S. and Japan later this year, with multiple additional global approvals anticipated next year. Based on positive data from the Phase III B-Well studies demonstrating unprecedented fungical cure rates, Veseviersin is positioned to become a first-in-class treatment for chronic hepatitis B, a disease affecting millions of people around the world. Also, in the second half, we expect late-stage readouts from several partnered programs, including telecarsin for LPA-A-driven cardiovascular disease with Novartis, Ulusnursin for FUS-ALS with Otsuka, and Sifaxosin for IgA necropathy with Roche. Overall, the progress we have made across the pipeline this year reinforces both the strength of our R&D engine and our confidence in the next wave of opportunities to reach more and more patients in need and drive future growth. And with that, I'll turn the call over to Beth.

Thank you, Holly. We delivered strong financial results in the first half of this year, supported by increased revenue from our commercial medicines and meaningful R&D revenue from our partnered programs, while we've continued to invest in our long-term growth. Revenues in the second quarter and first half of this year were $268 million and $514 million, respectively, representing significant year-over-year growth of 56% and 69% compared to the same period last year, excluding the $280 million one-time payment we received from ONO in the first half of last year for SAP Oblarsan. Commercial revenue increased to $119 million in the second quarter and $226 million in the first half, up 15% and 27% respectively from the same period last year. These increases were driven primarily by Donzera product sales. Tringolza generated product sales of $5 million and $32 million in the second quarter and first half of this year. The decrease in revenues in the second quarter followed the April 1st reduction in the Tringolza WAC price, which we implemented strategically ahead of our expansion into the broader FHTG indication. We continue to expect Tringolza to return to revenue growth in the second half of this year as the FHTG launch gains momentum. Donzera generated $26 million in the second quarter and $42 million in the first half, with second quarter sales increasing by 63% compared to this year's first quarter research and development revenue was 149 million dollars in the second quarter and 288 million dollars year to date reflecting continued progress across our partner pipeline operating expenses increased as expected in the second quarter and first half of this year compared to the same period last year driven by costs associated with with commercializing Tringolza and Banzara, preparations to launch Zilga-Nursen later this year, and advancing medicines in our rich pipeline. We ended the second quarter with $2.1 billion in cash, cash equivalents, and short-term investments, enabling us to continue investing in our commercial medicines and wholly owned pipeline. Looking into the remainder of the year, our strong first-half results keep us on track to achieve our full-year 2026 financial guidance. We continue to project full-year revenue in the range of $875 to $900 million, with results weighted slightly more toward commercial revenues. We remain on track to achieve our Tringolza and Donsera product-level guidance. This includes full-year Tringolza product sales of $100 to $110 million, with Tringolza expected to return to revenue growth in the second half of this year as the FHTG launch gained momentum. And full-year dons there a product sales of $110 to $120 million with continued growth forecasted in the second half of this year. Additionally, we anticipate meaningful R&D revenue from existing collaborations, including the potential for additional milestones tied to the Puraverson, Pella-Carson, and other partner programs as they advance. On the expense side, we continue to expect 2026 operating expenses to increase in the low team's percentage range compared to last year, driven primarily by sales and marketing expenses related to our ongoing and upcoming commercial launches. We project R&D expenses to remain consistent with last year. as several of our late-stage studies conclude and we redeploy resources to earlier-stage programs within our wholly owned pipeline. And as a result of our focus on improving our operating leverage, we expect a non-GAAP operating loss between $425 and $475 million. This is similar to our 2025 operating loss after adjusting for the one-time staff of Larson license fee we are at last year. And finally, we are projecting a 2026 year-end cash balance of greater than $1.6 billion. With our strong first-half financial performance and our outlook for the remainder of this year, we remain on track to achieve our full-year 2026 financial guidance and cash flow break-even in 2028 while continuing to drive substantial growth and longer-term value creation. With that, I'll turn the call back over to Brett.

Our outlook for the remainder of 2026 and beyond reflects Ionis' strength and the substantial opportunity for continued success that lies ahead. We are executing well on our independent launches for Tringolza and Donzera and are well prepared for our next launch, Zilganersen and Alexander disease, anticipated later this year. In addition to driving value through commercial success, we also have many important near- and midterm catalysts from across our development pipeline, each with the potential to further try a substantial position to continue executing successfully on our commercial launches and to deliver a steady cadence of breakthrough medicines. I'd like to take a moment to recognize Frank Bennett, our chief scientific officer, whose planned retirement we announced earlier this morning. Frank is one of Ionis' founding scientists, and has helped shape Ionis and advance the field of RNA-targeted medicines. While his leadership helped create this new sector for human therapeutics, some of his greatest contributions were in the field of neurology, which led to the approvals of Spinraza for SMA and CalSati for SAD1 ALS, along with the establishment of a rich pipeline ploys to deliver a steady stream of breakthrough treatments for neurological disease. The entire IONIS team, I want to thank Frank for his many contributions, his dedication to patients, and the lasting impact he has had on IONIS and the field of oligonucleotide.

With that, we will now begin the question and answer session. To ask a question, you may press star then 1 on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then 2. And our first question will come from Jason Gerberry of Bank of America. Please go ahead.

Hey guys, thanks for taking my question. I just wanted to key in a little bit on early adoption of Tringolza, how much of that's being driven by physicians with overlapping FCS patients that they were treating, is that sort of the core early prescriber in this initial kind of six to nine months? And where physicians are attempting to write prescriptions, can you talk a little bit about the average processing time for them to go from an enrollment form to getting a script covered. Is that through medical exceptions, I assume? So those are my questions. Thanks.

Kyle, happy to cover off on those. First, I'll say that the FCS launch really was important to the launch now in SHCG. Obviously, that laid the groundwork and the foundation for the readiness to bring the drug forward to a prevalent population. Many of the early prescribers are previous treaters of FCS. They have experience using the drug, and they've had really, really positive results from doing so. But we're also seeing more physicians than just the FCS prescribers starting to use Tringolza for SHTG. The other thing that I'll just mention here is the FCS growth in Q2 and the demand continue to accelerate significantly. More treaters and more patients on drug obviously will help us accelerate the shtg launch as well so the short answer to your question is yes there are treaters of sds that are also prescribing but it goes well beyond that um in terms of process time um it's really too early to uh to discuss those details uh you know we're being from payers so far is very encouraging the rx but also just in terms of our conversations that we're having shtg ellie merrill of barclays please go ahead

Okay, thanks for taking the question, and congrats on all the progress. Can you just elaborate a little bit more in terms of what you're seeing in terms of reimbursement? I know you mentioned that you're seeing reimbursement for triglycerides in patients with triglycerides over 500, but are you seeing any differences in how pairs are treating the coverage of patients with triglycerides over 880 versus those over 500? And then just a second question, what are your expectations for WANUA sales in polynorepathy now after the cardiotransform data, given much of the polynorepathy patients are a mixed phenotype?

Yeah, thanks, Ellie. Let me, I'll start with the Tringolda question. We are seeing coverage to label. The label is very strong here, right, greater than 500. It does not limit patients over 880. it does not limit a history of acute pancreatitis. So the conversations that we've had with payers and what we've seen from the early approvals has all reflected the actual indication state. And continues to be shut down and continue in polyneuropathy, and the teams continue to do a nice job.

The question comes from Gary Nachman of Canaccord Genuity. Please go ahead.

Hi, thanks, and good morning. So for SHTG, are you finding that most of these patients are already on some TG-lowering or lipid-lowering drugs? Are they switching to tringolza or adding tringolza on top of their other treatments? And are there any real true naïve patients that are being put on drugs at this point? And then, you know, just what are you hearing from physicians on tringolza's profile as a monthly sub-Q? you, and has there been any real concerns with the elevated liver fat holding back prescribing at all, and how are you communicating that?

Yeah, thanks, Gary. So the short answer to the first question is we're seeing a mix of patients. The majority of these patients obviously are high-risk SHTG patients. They're above 500. The majority of these patients have been on some sort of background therapy, which is very consistent with our core and core two trials i mean almost 100 of the patients were on some sort of fibroid or omega-3 or statin in the clinical trial and that's consistent with how acps are using standard of care today and doing everything they can to try to get triglycerides lowered below 500 and get these patients out of the risk of acute pancreatitis but have just been unable to do so so the majority of these patients are on background standard care therapy and they are adding tringolza to those patients in order to get the benefit of, you know, up to 72% reduction in triglycerides and up to a 91% reduction in acute pancreatitis. So they're using it very consistent with the way that the clinical trial was designed and the way that HCPs have been treating these patients. The profile is coming up first. I'll just mention the indication statement, how it really reflects out of harm's way of acute pancreatitis. the monthly auto-reinforced with long-term data.

Great. Thank you.

It comes from Moritz, writer of Guggenheim Securities. Please go ahead.

Hi there. This is Moritz on for Dugit. Thanks so much for taking your question. I have two questions. The first one on Tringolza. How, if at all, has the recent Pazazoram data changed your outlook for Tringolza? And the second one on Horizon. What's your confidence in the trial? And should Horizon disappoint, how are you thinking about your path to profitability? Thank you so much.

Yeah. So, Morris, thank you for the question. We believe we have, based on everything we've seen so far, we continue to believe that we have a best-in-class medicine when you look at the totality of data for the treatment of SHTG. And when you look at the triglyceride lowering that Holly summarized in her prepared remarks and the overall reduction in acute pancreatitis, along with safety and tolerability and first-mover advantage. Also, we have no concerns about competition. We continue to reiterate our peak product sales in the U.S. have been $3 billion plus, so there is no surprises in any data that has emerged since we've launched. With respect to Horizon, our confidence will be the same. We believe that LP little A is a cardiovascular risk factor, independent risk factor. The evidence is overwhelming. We have the right drug. The baseline demographics lays it all out on the powering assumptions in that study. And the drug has been well-tolerated. And we're looking forward to the results in the – later this – I'm sorry, the third part of the question.

Should the client disappoint what's the real-to profitability?

Good morning. So I would say in the event that Pella Carson Phase 3 were not to be positive, it would not have an impact on our 2026 financial guidance. It would put some pressure on our ability to achieve our goal of cash flow breakeven in 2028. But I want to emphasize that's a very important goal for us at IONIS, and we will work very, very hard to achieve that goal.

Our next question comes from Mike Olds of Morgan Stanley. Please go ahead.

Good morning. Thanks for taking the question. Maybe a few just on ION 775. Just curious if you can give us a sense of what data we might expect at the upcoming ESC meeting, maybe in terms of endpoints, you know, level of follow-up, et cetera there. And then maybe just secondly, as we think about timelines for this program, you know, maybe you can share how you're thinking about that in terms of path to market, a number of clinical studies, and is there ways to sort of shorten that just given your experience with the core programs?

This is Holly. Thank you. The IN77 part 5 data that we'll be sharing at ESP, it's year-long data. It's safety as well as our efficacy and activity data and our key biomarkers. So it should be a very interesting data set for everybody to view. In terms of where we're at, so we are in the Phase 2B study right now. Of course, we are using all of our previous learnings to accelerate the program as much as we can. We haven't discussed timing externally, but we are absolutely using everything that we've learned from our previous programs and data sets to apply to this program.

Yeah, and just to add to that, the long-term data on, you know, triglycerides in the mildly elevated triglyceride population and the durability that 775 is offering. As Holly mentioned in her prepared remarks, this is at least a twice-a-year or even less frequent dosing opportunity. It's a pure play on convenience. We don't believe that we can do much better than the efficacy that Tringolza is already presenting. I mean, it's a best-in-class efficacy profile. It's really allowing us to get the maybe twice-a-year, once-a-year dosing. And that's what we're going to focus on. And the data will show A plus E3 reductions that support that conclusion, triglyceride reductions that support that conclusion, as well as the good tolerability. And also, just to add, you know, the enrollment's going well for all those early innings for the Phase 2's going well. And...

This comes from Riana Zhao of Wells Fargo Securities. Please go ahead.

Great. Thanks for taking our questions. For SHTG, I was wondering, based on the first few weeks of launch, how does that early momentum track with your internal expectation, especially in relationship to the four-year guidance? Apparently, you made that guidance without any firsthand experience of the launch. So just curious, do you think you're ahead of that internal expectation at this point of time or in line? And for CardioTransform, I was wondering if there are regulatory paths for monotherapy, and could any of the data to be presented at ESC inform how you and Estrodenica think about any potential already preparing to present and keeping in mind that, you know,

out of the gate, obviously, is to get drug into channel. We did that within things around training.

From Yaren Werver of TD Callen, please.

Thanks so much, and congrats on the progress. Maybe, Callen, two questions for you commercially. On SHTG, one of the questions we've been getting is do you think there's going to be sort of an initial pent-up demand or bolus or some clinics already kind of triaging patients to get treated with tringolus and now that it's approved. And then secondly, for Donzera, I mean, you're seeing very nice kind of quarter-over-quarter growth. You mentioned, obviously, it's a switch market. What sort of is the main competitor at this point? What do you think in terms of demand? Thank you.

Yeah, thanks for the questions. In terms of pent-up demand, you know, we believe this is going to be a gradual build and a moderate build over time for a couple of reasons. Number one, this is a new mechanism and a new treatment, and it takes some time to educate the HCPs. Number two, we've got to get those patients into the clinic to see these HCPs. So we've got to drive that awareness and interest to the patient so that they're motivated to get into these clinics and can be treated. And then the third component is the payer access piece, right? We've got medical exception process here early on as we couldn't be more pleased with how the team is performing and how we are building the momentum you know Q2 we did 26 million dollars in revenue T challenge some have a tolerability

challenge to worry of Jeffrey's please go ahead okay this is my own for others that's one from our end do you expect GPS GPS 10 to demonstrate a meaningful and how should we think about the potential read-through from the data to expectations for IONIS582? Can you repeat the question, please? I really didn't quite get that. For the Angelman's upcoming read-out for GTX-102, how should we think about the read-through from that data to your program? Yeah, yeah.

Yeah, this is Holly. I'd be happy to take that. So the ultrogenic data readout, we're expecting that later this year. That will teach us a couple of things. One of the big things that we're looking for from that is to understand the placebo effect that the patient population will have. That's not something that we know from it, so we are looking to do that. In terms of the read-through to our program for the ultrogenic data itself, you have to remember that those are very different molecules. So they're dosing at a much lower dose than we're dosing, so we hope that they have positive effects that are encouraging for the community, However, if they don't, it'll likely be because they're dosing lower than we are for ourselves.

Yeah, and I'll just add marking, obus-anderson compared to IM582. So we have a highly potent molecule, and as Holly said...

The question comes from Salveen Richter of Goldman Sachs. Please go ahead.

Thanks for taking your question. This is Tommy on for Salveen and just two on Trincolda. So in FCS, maybe some more color on the impact from switches from Arrowhead and on the capture of new starts, if you're seeing any. And on SHTG, maybe if you could lean more into what you're seeing from the primary care side.

Thanks, Tommy. We've seen no meaningful impact from the competition in FCS. Q2 was by far our strongest demand quarter and the highest quarter that we've had for new patient starts. the profile of Tringolda is being very well received by HCP for the first time are looking to come back to it and when they see the triglyceride lowering and the ability to self-administer with the auto injector the profile is stacking up very very strong in terms of primary care side of things RBC please go ahead

oh great thanks so much for taking my question congrats on the progress maybe Kyle one more for you from the launch of severe hyperglyceridemia, obviously clear enthusiasm here from the KOL community to prescribe drugs. However, we have heard from a couple of docs that one of the barriers is that there's no dedicated ICD-10 code specifically for severe hyperglyceridemia. The docs need to use codes for related conditions like hyperchylonemia syndrome or maybe hyperglyceria. So that can sometimes create some barriers and confusions to get the drug reimbursed. Is that consistent with what you've been hearing, and if so, can you talk about how you're planning to address that? And then maybe second, for TTR colomyopathy, Brad, if I can circle back on the prior question, you mentioned at ESD you will present this meta-analysis done by an independent group of physicians. Can you maybe just expand what's the purpose of that analysis and how should you think about the implication of that analysis for the broader field? Thanks so much.

Yeah, thanks, Luca. On the ICD-10 code side, I'll start by saying that has been on our radar for quite some time, and it's something that we are looking for opportunities to help the community come up with an ICD-10 code that they can use to explicitly reference SHTG. So that work is ongoing with the agencies, and we'll see what we can do in order to help that happen. But in terms of reimbursement, there are other things that they can use to justify the appropriate use of the drug and get reimbursement. You know, first is the labeled indication, second is to support that labeled indication with the patient's medical history and, you know, reference the drugs that those patients are being treated on as well as the triglyceride levels that the patients still exhibit even though that they're on those medications. So, you know, doing a prior authorization, including a letter of medical necessity, is pretty standard for a specialty product like this at launch. And we're working with the different HCPs in order to make sure they understand what's required in order to do that and also supporting them, you know, in a compliant way so that they can do that successfully.

And, Luca, I'm going to ask Holly to take the question I'm expanding on the meta-analysis at ESC.

Yes, so the meta-analysis is really focused on the silencer class and understanding the totality of data within that class, including our new cardio transform data, and comparing them both as monotherapies as well as on top of the stabilizers.

That's the main presentation. It's going to be comparing single agents as well as combinations.

Next question will come from Jessica Pye of JPMorgan. Please go ahead. Hey, guys. Good morning. I was curious about ION337 for Grave. Can you help us think about when we might see the Part 1 data from the Phase 1-2 and just given the long lead time for Zura Vinersen, how might 337 differentiate? Thank you.

Yeah, I'm happy to take that one. So for 337, we just started dosing. So it's too early to talk about timelines, but we are – there's a lot of enthusiasm them from the community, the KOLs know IONIS and know our technology, and we're excited to get that moving quickly as is the community. In terms of differentiation, because we're using our new NMA technology, it's more potent than the MOE chemistry, our previous chemistry that we used for splice modulation, so you get increased potency, and that allows you to spread out your dosing interval and increase your efficacy.

All right, last question comes from Eric Joseph of Citi. Please go ahead.

Hi, thanks for taking the questions. Just thinking about the upcoming core OLE data at APSV, maybe just a little bit of expectation setting there. What incremental endpoints in addition to the OLE presentation are of interest, or would you have a focus on there to what extent, I guess, is the ongoing AP event rate, something that you're tracking in the OLE portion? And then just perhaps a clarifying question on the strategy with 775. Is the goal here predominantly to be a convenience play over Trimgolda in SHTG, or is there an expansion opportunity in moderate HTG that you think is worth pursuing, and if so, what would a TPP look like there?

Yeah, thanks, Eric. I'll ask Holly to talk a little bit about what we're planning to present at ESC on the long-term data on core and core 2. I'll take 7.75. So the goal is primarily, we're primarily focused right now on severe hypertriglyceridemia. 7.75 is a follow-on molecule for this indication, and it isn't primarily a convenience play. I think I mentioned earlier that, you know, the efficacy and tolerability safety profile of trincolza and FHTG is difficult to beat, so I think that we can dose this drug twice a year, maybe once per year, based on our Phase I data, and that Phase I data will be presented at ESC, and I think it will be clear how durable 775 is. We'll always consider other indications, but primarily, and we haven't laid out, we have not established our Phase III plan yet, we're still working through that in these We need more phase 2 data before we can really make those decisions, but it's really a primarily focus on SHTG. And Holly, what can we expect on the long-term data for CORE?

This is looking at one year into the OLE. So, of course, we'll be looking at triglyceride levels as well as full safety data and all of the key biomarkers, looking at remnant cholesterol, ApoC3, non-HGL, all of those.

The durability of efficacy as well as. Thanks, everybody. Have a great day.

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