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

Good morning, and welcome to Ionis 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 Walke, 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 Investors 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've also posted slides on our website that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer; Kyle Jenne, Chief Global Product Strategy Officer; Holly Kordasiewicz, Chief Development Officer; and Beth Hougen, 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 3, 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. on the center is the second half of 2026, well positioned to achieve the strategic opportunities that lie ahead. We have the R&D engine, the pipeline, commercial capabilities and financial discipline we need to execute on and achieve our goals. We are continuing to build momentum across our commercial medicines. And in parallel, we continue to strengthen and advance our wholly owned pipeline to deliver our next wave of important medicines. Last month, we achieved a landmark milestone with the approval of TRYNGOLZA as the first and only FDA-approved medicine to reduce triglycerides in the risk of acute pancreatitis in adults with severe hypertriglyceridemia or SHTG. Although still early days, we are highly encouraged with our launch momentum to date. In fact, we began receiving prescriptions for TRYNGOLZA on the day of approval. We are also pleased that both the 50-milligram and 80-milligram doses were in the channel within 1 week. Based on a strong profile and the enthusiasm we are seeing in prescribing, we are confident that TRYNGOLZA is well positioned to help a large population of patients in need and become the first Ionis own multibillion-dollar medicine. DAWNZERA 0 for hereditary angioedema also continues to gain momentum, we expect Unser to continue driving growth as it becomes more established in the HAE prophylactic treatment landscape. 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 Zilganerse, coming up soon, which is positioned to be the first disease-modifying treatment for Alexander's disease and the first independent launch from our neurological disease pipeline. Following closely behind Zilganerse by the nurse, our medicine for Angelman Syndrome, which completed enrollment in the Phase III REVEAL study last month, keeping it on track for data next year. Earlier this month, we also announced the initiation of clinical development for ION337 in Dravet syndrome, expanding our clinical stage neurology pipeline, which now includes 8 medicines that are wholly owned. Complementing our wholly owned pipeline is our partnered pipeline, which includes medicines targeting both rare and highly prevalent diseases, providing significant additional value for Ionis. This includes Bepirovirsen, our medicine for chronic hepatitis B. With a PDUFA target action date of October 26 and additional global filings under review, Bepirovirsen 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. Data from the Phase III pelacarsen LPA horizon study in patients with elevated Lp(a) and cardiovascular disease is also a key catalyst coming up in the second half of this year. We were disappointed with the outcome of the cardio transform Phase III study for eplantersen in ATTR cardiomyopathy that we reported earlier this month. Although eplontersen 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 underscore 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 breakeven in 2028. With that, I'll now turn the call over to Kyle, who will speak to the commercial execution of TRYNGOLZA and DAWNZERA and launch preparations for zilginerson. Olli will going to discuss how we are advancing our pipeline, highlighting several important catalysts ahead and Beth 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 TRYNGOLZA and DAWNZERA launches and preparation for the zolginersen launch. Beginning with TRYNGOLZA, 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 TRYNGOLZA wholesale acquisition cost that went into effect on April 1. The -- we updated the price ahead of the anticipated SHTG approval to align with annual payer contracting cycles to accelerate access to TRYNGOLZA. Underlying demand in FCS remained strong with the second quarter delivering the highest number of patient starts since the launch began. Together with our commercial execution in FCS and early market access efforts we've established a strong foundation for the next phase of TRYNGOLZA growth as we launch in the broader patient population. The recent approval of TRYNGOLZA 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 TRYNGOLZA 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 in 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 1, and both the 50-milligram and 80-milligram doses were in the channel within approximately 1 week. Since the approval, our team has already engaged with many of our top physician targets who care for the majority of high-risk patients. In addition, our omnichannel launch campaign has produced strong engagement, which is further helping to rapidly build awareness of SHTG, APOC3 biology and TRYNGOLZA. 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 in 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 880. As the first-to-market therapy with a novel mechanism proven to reduce the risk of painful, costly and potentially fatal acute pancreatitis attacks TRYNGOLZA is well positioned to serve patients across both segments. The majority of high-risk SHTG patients are treated by approximately 20,000 cardiologists, endocrinologists and lipidologists across the U.S. with additional patients treated by primary care physicians. Early in the launch, we are seeing prescriptions from all 3 specialties in addition to a meaningful contribution from primary care physicians. We've also seen physicians prescribe TRYNGOLZA to people with high-risk SHTG and those with TGs between 500 and 800 milligrams per deciliter with no history of acute pancreatitis. Physicians are prescribing both the 50- and 80-milligram doses, highlighting the importance of dosing flexibility, which enables treating physicians to tailor treatment to the individual needs of each patient. Importantly, we are executing on our market access strategy as planned. We have made good progress obtaining coverage for the broad population in patients with triglycerides above 500 milligrams per deciliter and across both commercial and government plans. Ultimately, we expect the SHTG market to comprise approximately 60% commercial and 40% government-covered patients. We also expect payer coverage to continue expanding through the remainder of this year and into next year as payers complete their reviews. We're also making progress in expanding access to TRYNGOLZA outside the U.S. In the EU, Sobi is continuing to advance the launch in FCS, while also actively laying the groundwork for a strong launch in the broader SHTG indication anticipated next year. With this early SCG launch momentum, TRYNGOLZA is on track to meet our full year 2026 revenue guidance and positioned to achieve our projections for more than $3 billion in peak annual revenue. The DAWNZERA launch also continued to gain momentum. In less than 1 year on the market, DAWNZERA has already captured a meaningful share of the U.S. HAE prophylaxis market, which is largely a switch market. This growth is driven by increasing adoption across all patient segments, including patients switching from existing prophylactic therapies, patients who were previously only using on-demand treatment and treatment-naive patients. Physicians and patients consistently provide positive feedback on DAWNZERA, highlighting DAWNZERA strong efficacy and favorable safety profile Its differentiated RNA targeted mechanism, the positive switch data, which HCPs described as "differentiating and motivating" and on Zara's patient-friendly profile that includes a self-administered auto-injector that can be stored at room temperature for up to 6 weeks. The base of repeat prescribers continues to grow. This is a key indicator that DAWNZERA is providing substantial benefit for patients and HCPs are having a positive experience prescribing it. Given that most patients on HE prophylactic medicines are already established on existing therapies Continued penetration will take time. However, the launch fundamentals give us confidence that DAWNZERA will contribute meaningfully to our commercial revenue growth in 2026 and beyond. Outside the U.S., our partner Otsuka is making good progress with DAWNZERA and the launch in the EU. Over time, we expect ex U.S. countries to become an important contributor to overall DAWNZERA growth. Turning to Zilganerse. We are well prepared for the launch for the treatment of Alexander disease coming up later this year. Based on the positive Phase III results for Zilganerse, we received FDA priority review with a PDUFA date of September 22. We have an expanded access program underway, and our commercial preparations are right on track to center around 4 key priorities. First, pending approval, we will work to transition patients who are currently receiving Zilganerse through the clinical study or the expanded access program to commercial therapy. Second, we will focus on getting patients already diagnosed with Alexander's disease in the U.S. on Zilganerse. It's estimated that about half of the approximately 300 patients in the U.S. are already identified through ICD-10 codes and patient registries. Third, we will drive disease awareness among physicians who care for people with rare neurological diseases, prioritizing engagement with the dozen U.S. leukodystrophy centers. Following approval, we expect these centers as key referral and treatment hubs to play a central role in identifying more patients and providing them with treatment. And fourth, we are building a dedicated patient services platform, which we have designed based on feedback from stakeholders to address the specific needs of the Alexander disease community. Additionally, our customer-facing team is now in place and prepared to rapidly reach patients upon our potential Zilganerse approval. Importantly, we expect to leverage many of the capabilities we are building for Zilganerse for our future neurology medicine launches. We also recently took an important step toward bringing Zilganerse to people with Alexander's disease outside the U.S. to our agreement with Recordati. Recordati plans to file for regulatory approval for Zilganerse in the EU and Japan next year with additional global filings to follow. With our first broad patient population launch now underway, growing momentum across our commercial portfolio and a strong pipeline behind it, we believe Ionis is well positioned to bring more important medicines to people with serious diseases. And with that, I'll turn the call over to Holly.

Thank you, Kyle. This quarter, we made meaningful progress across our pipeline. TRYNGOLZA approval for the treatment of SHTG is a significant milestone for Ionis and for patients. Our goals of approval was supported by the unprecedented results from the Phase III CORE and HRI study, in which TRYNGOLZA acheived rapid, substantial and clinically meaningful placebo-adjusted main reductions in triglycerides of up to 72%. -- these trigoside reductions resulted in a profound reduction in acute pancreatitis events by up to 91%. TRYNGOLZA treatment also led to 86% of patients reaching triglyceride levels below 500 mg per deciliter, the threshold that defines SHTG. Up to 54% of patients reaching normal levels below 150 mg per deciliter and favorable safety and tolerability, which resulted were further reinforced by longer-term data from the core and core 2 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 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 validate our unprecedented results. With this groundbreaking clinical profile, TRYNGOLZA is poised to redefine the treatment of this underserved disease. Beyond TRYNGOLZA, we are advancing a number of promising wholly-owned cardiometabolic disease medicines, including IN-775, our next-generation medicine for the treatment of STG. We recently advanced IN775 into a Phase IIb study in patients with SHTG are moderately elevated triglycerides based on positive Phase I data in healthy volunteers with elevated triglycerides. These results showed the potential for an optimized profile characterized by substantial durable and sustained reductions in APOC3 and triglycerides with the potential for semiannual or less frequent dosing. We look forward to presenting these data on ION775 at ESC next month. And as Brett mentioned, we will also show detailed data from the aplontersen cardiotransform study at ESC. Turning next to our neurology franchise. We remain on track to bring Zilganerse 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 marked the first time any therapy demonstrated a disease-modifying impact in these patients. Our next wholly on Phase III program is open in expense for the treatment of Angelman syndrome. Angelman Syndrome is a neurodevelopmental disorder that causes profound and lifelong physical and cognitive impairment, estimated effect more than 100,000 people globally. We recently announced that enrollment in the Phase III 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 I/II first-in-human study. We advanced IM337 based on encouraging preclinical data, which we believe positions this program to become a best-in-class treatment for this devastating disease. IO-337 is our first wholly owned medicine that uses our proprietary NMA chemistry, designed to achieve maximal and sustained modulation of SCN1a with a long dosing interval. Our NMA chemistry is the same breakthrough technology that enables Zilganerse 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 Zilganerse on 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 Celio data, Biogen presented at AAIC for derinersen in early Alzheimer's disease. These results are the first to demonstrate the significant potential of targeting intracellular tile as a treatment for AD. Zilganerse showed significant reductions in CSF to levels, accompanied by a reversal of how pathology as measured by Tapad. We also saw remarkable effects on cognition as shown by a 34% to 50% slow decline in MMSE versus placebo and a meaningful effect on composite endpoints that include both cognitive and functional domain. Although the Phase II study did not meet the primary endpoint, the totality of these data support Biogen's plan to initiate Phase III development. We are also pleased with the recent initiation of the Phase III INTREPID study of sapablersen by our partner, Ono. This study is evaluating sapablarsen in people with phlebotomy-dependent policemavera a rare, but potentially lipreading hematologic disease with significant unmet need. Assuming positive data, sapablursen would represent an important value driver from our partner pipeline. In Bepirovirsen, 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 IIIb well studies demonstrating unprecedented functional cure rates, Bepirovirsen 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 partner programs, including pelacarsen for Lp(a)-driven cardiovascular disease with Novartis, ulusnersen for FUS-ALS with Otsuka and Sutaxtison for IgA nephropathy 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 continued to invest in our long-term growth. Revenues in the second quarter and first half of this year were $268 million and $540 million, respectively, representing significant year-over-year growth of 56% and 69% compared to the same period last year. Excluding the $280 million onetime payment we received from Ono in the first half of last year for Sapoblursen. 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 periods last year. These increases were driven primarily by DAWNZERA product sales. Shinola 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 1 reduction in the TRYNGOLZA WAC price. -- which we implemented strategically ahead of our expansion into the broader SHTG indication. We continue to expect TRYNGOLZA to return to revenue growth in the second half of this year as the SHTG launch gains momentum. DAWNZERA 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 in the second quarter and $288 million year-to-date, reflecting continued progress across our partnered 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 commercializing TRYNGOLZA and DAWNZERA preparations to launch Zigonersen 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 to 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 million to $900 million, with results weighted slightly more towards commercial revenues. We remain on track to achieve our TRYNGOLZA and DANZ product level guidance. This includes full year TRYNGOLZA product sales of $100 million to $110 million with TRYNGOLZA expected to return to revenue growth in the second half of this year as the SHTG launch gains momentum. And full year DAWNZERA product sales of $110 million 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 bepuraversen, palocarsen and other partner programs as they advance. On the expense side, we continue to expect 2026 operating expenses to increase in the low teens 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 million and $475 million. This is similar to our 2025 operating loss after adjusting for the onetime Safalorsen license fee we are 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 breakeven in 2028, while continuing to drive substantial growth and longer-term value creation. With that, I'll turn the call back over to Brett.

Thank you, Beth. 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 TRYNGOLZA and DAWNZERA and are well prepared for our next launch zilgonersen in Alexander's 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 drive substantial value. We are well positioned to continue executing successfully on our commercial launches and to deliver a steady cadence of breakthrough medicines to patients. Now before we move to Q&A, 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 the greatest contributions were in the field of neurology, which led to the approval of SPINRAZA for SMA and Kaldi for SOD1 ALS, along with the establishment of a rich pipeline poised to deliver a steady stream of breakthrough treatments for neurological thesis. On behalf of the entire Ionis team, I want to thank Frank for his many contributions, his dedication to patients and lasting impact he has had on Ionis in the field of organically type therapeutics. And with that, we'll open the call up for questions.

[Operator Instructions] Our first question will come from Jason Gerberry of Bank of America.

Just wanted to key in a little bit on early adoption of TRYNGOLZA. How much of that is 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 6 to 9 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, Jason. This is Kyle. Happy to cover off on those. First, I'll say that the FCS launch really was important to the launch now in SHTG. 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 TRYNGOLZA for SHTG. The other thing that I'll just mention here is the FCS growth in Q2 and the demand continued to accelerate significantly. Having 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 FCS that are also prescribing, but it goes well beyond that. In terms of process time, it's really too early to discuss those details. We're just a couple of weeks into the launch. What we've seen from payers so far is very encouraging, not only in terms of the Rx to approval time so far, but also just in terms of our conversations that we're having with the payers where they are beginning to assess SHTG and assess to put coverage criteria in place so that there's a clear pathway for approval. Here early in the launch, the majority of the coverage criteria is going to be through medical exception. That was to be anticipated. And we would expect to see continued coverage improve through the back half of this year and as we start 2027 should look much better.

Next question comes from Elie Merrill of Barclays.

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 firing, patients with triglycerides over 500. But are you seeing any differences in how payers 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 wage sales in polyneuropathy now after the cardiotransform data given much of the polyneuropathy patients are mixtape.

Yes. Thanks, Ellie. Let me -- I'll start with the Trengolza 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 through the medical exception process, has all reflected the actual indication statement in the label, which is what we expected based on our payer research going into the launch. So it will take a little bit of work for the HCPs as expected at launch to do these prior authorizations to provide a letter of medical necessity potentially to justify the background therapy that the patient has been on and what their triglyceride levels are, but that's all very consistent with what we expected the policies to represent. So I think things are on track, and we're very encouraged by the early interactions and discussions that we've had with payers. On the WAINUA side, demand continues to be strong for the hereditary polyneuropathy patient -- the challenge that we are seeing on the WAINUA side is with the mixed phenotype patient where Ambutra has an indication for both polynopathy and cardiomyopat but otherwise, physicians are having very positive experience prescribing and treating these patients, and feedback has been very strong in terms of control of TTR and knockdown, control of polyneuropathy symptoms, payer access and coverage and the ability to self-administer with an auto-injector. So we expect sales to continue in polyneuropathy and the teams continue to do a nice job.

The next question comes from Gary Nachman of Canaccord Genuity.

So for SHTG, are you finding that most of these patients are already on SMCG lowering or lipid lowering drugs? Are they switching to TRYNGOLZA . -- we're adding TRYNGOLZA on top of their other treatments? And are there any real true naive patients that are being put on drug at this point? And then -- just what are you hearing from physicians on TRYNGOLZA's profile as the monthly subcu -- and has there been any real concerns with the elevated liver fat holding back prescribing at all? And how are you communicating that.

Yes. 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 -- the majority of these patients have been on some sort of background therapy, which is very consistent with our core and CORE II 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 HCPs 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 of care therapy, and they are adding TRYNGOLZA to those patients in order to get the benefit of up to 72% risk -- excuse me, 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 up to this time. The profile is coming across very strong. First, I'll just mention the indication statement having AP represented there. It really reflects the outcome of treating high triglycerides and what that means for patients and what that means for HCPs that are trying to treat these patients and get them out of harm's wave acute pancreatitis. The monthly auto injector is very well received. It's low dose. It's very easy to use. The patients can take it once a month. They don't have to try to figure out, is it month 1 or month 2 or month 3. And we're finding that consistent with the FCS launch, adherence and persistency in patients are starting and staying on and doing very well on the monthly administration with the auto-injector. And for hepatic fat, I'll turn it over to Brett.

Yes. Thanks, Kyle. And Gary, thanks for the question. So -- we are -- we believe that the evidence that the effects on the liver fat -- small increases in liver that we see is an on-target effect, is very convincing. And prior to us presenting the data at National Lipid Association earlier this year, we didn't even have push back at that time from HCPs on concerns over the small increases in liver fat, especially because there was no association with any clinical sequelae. There were no clinical complications associated with the small increases in liver fat that we saw. That was further reinforced when we presented the NLA data, the data NLA, which we showed that with continued treatment, the increase in liver fat was returning to baseline. Again, long-term treatment, no association with clinical sequel. So that was just reinforced there. And as we continue to evaluate patients in the long-term, even further long-term open-label extension. Again, we're not seeing any emerging adverse events in the study. So no concerns on the HCP community and that's been further reinforced with long-term data.

The next question comes from Moritz writer of Guggenheim Securities.

This is Marc on for Doucet. I have 2 questions. The first 1 on Cingular, How, if at all, has the recent precaseran data changed your outlook for rings -- and the second 1 on Horizon. What's your confidence in the trial? And should Horizon disappoint how are you thinking about your path to profitability?

Yes. So Marc, 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 the data for the treatment of SHTG. And when you look at the triglyceride lowering, that Holly summarized in her prepared remarks and the and the overall reduction in acute pancreatitis along with safety and tolerability and first-mover advantage. Also, we have no we have no concerns about competition. We continue to reiterate our peak product sales in the U.S. of being $3 billion plus. So there was no surprises in any data that has emerged since we've launched. With respect to Horizon, our confidence remains -- continues to be the same high -- we believe that Las cardiovascular risk factor, independent risk factor, the evidence is overwhelming. We have the right drug. The baseline demographics last all manuscript 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 year. And then -- I'm sorry, the third part of the question was.

Should anoint what's the route to profitability?

Yes. So I would say in the in the event that helecarsen Phase III 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.

The next question comes from Mike Os of Morgan Stanley.

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 end point level of follow-up, et cetera, there? And then maybe just secondly, as we think about time lines for this program, maybe you can share how you're thinking about that in terms of path to market 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 IN 775 data that we'll be sharing at ESC, it's this year-long data, safety as well as our efficacy and activity data on 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 IIB 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.

Yes. And just to add to that, Mike. So you'll see the long-term data on triglycerides in the mildly elevated triglyceride population and the durability that 775 is offering, as Holly mentioned, in our prepared remarks, this is at least twice a year or even less frequent dosing opportunity. So it's a pure play on convenience. We don't believe that we can do much better than the efficacy that TRYNGOLZA is already presenting. I mean it's best-in-class efficacy profile. It's really allowing us to get to maybe twice a year once a year dosing. I mean, that's what we're going to focus on. And the data will show APOC3 reductions that support that conclusion, triglyceride reductions that support that conclusion as well as the good tolerability. And also just to add, the enrollment is going well for -- although it's early innings for the Phase IIb study, it's going well. And our focus is to get that study done selected dose and move to Phase III as quickly as possible, but it's still too early to put time lines on when we can get that done.

The next question comes from Lana Zao of Wells Fargo Securities.

Great. 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 full year guidance. Apparently, you made that guidance without any first-hand experience of the launch. So just curious, are you do you think you're ahead of that internal expectation at this point of time or in line? And for cardio transform, I was wondering if there regulatory path for monotherapy? And could any of the data to be presented at ESC inform how you and estrogenic think about any potential range path?

Thanks, Ann. And I'll take the first -- the second question first, and then I'll hand it over to Kyle to talk about how the HCG is tracking with respect to guidance and so on. So we and AstraZeneca continue to review the data from the cardio transform studies, a lot of data. We're preparing to present at ESC. We present -- I'm referring to published. We have several public presentations at ESC, including the cardio transform study, the combination subgroup as well as a meta-analysis study that is being conducted by an independent group of academic physicians. As far as regulatory path, AstraZeneca is weighing all their options in and they're still going through the data. There's a lot to process there. So -- there's nothing new to report with that. And the data at ESC, I think will support all the conclusions we've made already, which is very clear that in the mogroup that was on monotherapy at baseline, so not tafamidis at baseline. The efficacy in the composite primary endpoint as well as the secondary end points are in line with the silencer class. There was no benefit in the combination group, and you'll see that data in quite detailed at the ESC meeting. Kyle?