管理層發言
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.
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. Ionis enters 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 and 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 one week. Based on its 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-owned multibillion-dollar medicine. DAWNZERA for hereditary angioedema also continues to gain momentum. We expect DAWNZERA 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 Zilganersen coming up soon, which is positioned to be the first disease-modifying treatment for Alexander disease and the first independent launch from our neurological disease pipeline. Following closely behind Zilganersen is Obudanersen, 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 eight 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 the 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 Lp(a) 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-TTRansform Phase III study for Eplontersen 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 we 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 Zilganersen. Holly will then 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 Zilganersen 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. 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 remains 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 next phase of TRYNGOLZA growth as we launch in the broader patient population. The recent approval of TRYNGOLZA for sHTG marked a 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 2 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 one, and both the 50-milligram and 80-milligram doses were in the channel within approximately one week. Since the approval, our team is 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, apoC-III 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 three 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 triglycerides 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 the 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 sHTG 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 one 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's strong efficacy and favorable safety profile, its differentiated RNA targeting mechanism, the positive switch data, which HCPs describe as differentiating and motivating, and DAWNZERA's patient-friendly profile that includes a self-administered auto-injector that can be stored at room temperature for up to six 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 HAE 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 Zilganersen. 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 Zilganersen, 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, centered around four key priorities. First, pending approval, we will work to transition patients who are currently receiving Zilganersen through the clinical study or the expanded access program to commercial therapy. Second, we will focus on getting patients already diagnosed with Alexander disease in the U.S. on Zilganersen. 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 Zilganersen approval. Importantly, we expect to leverage many of the capabilities we are building for Zilganersen for our future neurology medicine launches. We also recently took an important step toward bringing Zilganersen to people with Alexander disease outside the U.S. through our agreement with Recordati. Recordati plans to file for regulatory approval for Zilganersen 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's approval for the treatment of sHTG is a significant milestone for Ionis and for patients. TRYNGOLZA's approval was supported by the unprecedented results from the Phase III CORE and CORE 2 studies, in which TRYNGOLZA achieved rapid, substantial and clinically meaningful placebo-adjusted mean reductions in triglycerides of up to 72%. These triglyceride 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 triglyceride levels below 150 mg per deciliter and favorable safety and tolerability, which 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 open-label extension 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 validates 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 ION775, our next-generation medicine for the treatment of sHTG. We recently advanced ION775 into a Phase IIb study in patients with sHTG or moderately elevated triglycerides based on positive Phase I data in healthy volunteers with elevated triglycerides. These results show the potential for an optimized profile characterized by substantial, durable and sustained reductions in apoC-III 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 share detailed data from the Eplontersen CARDIO-TTRansform study at ESC. Turning next to our neurology franchise. We remain on track to bring Zilganersen to patients with Alexander disease later this year, assuming approval. This rare, progressive and often fatal leukodystrophy profoundly affects patients and families. 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 owned Phase III program is Obudanersen for the treatment of Angelman syndrome. Angelman syndrome is a neurodevelopmental disorder that causes profound and lifelong physical and cognitive impairment, estimated to affect 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 ION337 based on encouraging preclinical data, which we believe positions this program to become a best-in-class treatment for this devastating disease. ION337 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 Tonlamarsen 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 Tonlamarsen 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 AAIC for Diranersen in early Alzheimer's disease. These results are the first to demonstrate the significant potential of targeting intracellular tau as a treatment for AD. Diranersen showed significant reductions in CSF tau levels accompanied by a reversal of tau pathology as measured by tau PET. We also saw remarkable effects on cognition as shown by a 34% to 50% slower decline in MMSE 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 Biogen's plan to initiate Phase III development. We are also pleased with the recent initiation of the Phase III INTREPID study of Sapablursen by our partner, Ono. This study is evaluating Sapablursen in people with phlebotomy-dependent polycythemia vera, a rare but potentially life-threatening 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 III B-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, Ulefnersen for FUS-ALS with Otsuka and Sefaxersen 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 $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 Sapablursen. 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 DAWNZERA product sales. TRYNGOLZA 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 Zilganersen 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 toward commercial revenues. We remain on track to achieve our TRYNGOLZA and DAWNZERA 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 Bepirovirsen, Pelacarsen and other partnered 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 one-time Sapablursen license fee we earned 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, Zilganersen in 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 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 his greatest contributions were in the field of neurology, which led to the approvals of SPINRAZA for SMA and QALSODY for SOD1-ALS, along with the establishment of a rich pipeline poised to deliver a steady stream of breakthrough treatments for neurological diseases. On behalf of 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 in the field of oligonucleotide therapeutics. And with that, we'll open the call up for questions.
分析師問答
The conference is now open for questions.
Just wanted to key in a little bit on early adoption of TRYNGOLZA. 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, Jason. This is Kyle. Happy to cover that. First, I'll say that the FCS launch really was important to the launch now in sHTG. 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 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 mention is the FCS growth in Q2 and the demand continue to accelerate significantly. Having more treaters and more patients on drug will help us accelerate the sHTG launch as well. So the short answer 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 with payers where they are beginning to assess sHTG and establish coverage criteria so that there's a clear pathway for approval. Early in the launch, the majority of the coverage criteria is going to be through medical exception. That was to be anticipated. We would expect to see continued coverage improve through the back half of this year and as we start 2027 should look much better.
Our next question will come from Eliana Merle of Barclays.
Can you 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 TRYNGOLZA in patients with triglycerides over 500. But are you seeing any differences in how payers are treating coverage of patients with triglycerides over 880 versus those over 500? And then just a second question. What are your expectations for WAINUA sales in polyneuropathy now after the CARDIO-TTRansform data, given much of the polyneuropathy patients are mixed phenotype?
Yes, thanks, Eliana. I'll start with the TRYNGOLZA question. We are seeing coverage to label. The label is very strong here: greater than 500. It does not limit patients over 880 or those with a history of acute pancreatitis. The conversations we've had with payers and what we've seen from the early approvals through the medical exception process have all reflected the actual indication statement in the label, which is what we expected based on our payer research going into the launch. It will take a little bit of work for HCPs as expected at launch to do prior authorizations, provide a letter of medical necessity and justify the background therapy the patient has been on and what their triglyceride levels are. But that's consistent with what we expected the policies to represent. So things are on track, and we're encouraged by the early interactions and discussions we've had with payers. On the WAINUA side, demand continues to be strong for the hereditary polyneuropathy patient. The challenge we're seeing is with the mixed phenotype patient where a competitor has an indication for both polyneuropathy and cardiomyopathy. Otherwise, physicians are having a very positive experience prescribing and treating these patients and feedback has been strong in terms of control of TTR 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.
Our next question comes from Gary Nachman of Canaccord Genuity.
For sHTG, are you finding that most of these patients are already on some triglyceride-lowering or lipid-lowering drugs? Are they switching to TRYNGOLZA or adding TRYNGOLZA on top of their other treatments? And are there any true naive patients being put on drug at this point? Also, what are you hearing from physicians on TRYNGOLZA's profile as a monthly subcutaneous? And has there been any real concerns with the elevated liver fat holding back prescribing at all? How are you communicating that?
Thanks, Gary. The short answer to the first question is we're seeing a mix of patients. The majority are high-risk sHTG patients above 500 and they have been on some sort of background therapy, which is consistent with our CORE and CORE 2 trials. Almost all patients in the trials were on a fibrate, omega-3 or statin. That's consistent with how HCPs are using standard of care today and trying to lower triglycerides below 500, but many have been unable to do so. So the majority are adding TRYNGOLZA to their background therapy to get the benefit of up to 72% triglyceride reduction and up to a 91% reduction in acute pancreatitis risk. They are using it consistently with how the clinical trial was designed. The profile is coming across very strong. The indication statement, with acute pancreatitis represented, reflects the outcome of treating high triglycerides and what that means for patients. The monthly auto-injector is very well received: it's low dose, easy to use, and patients can take it once a month. From the FCS launch, we've seen adherence and persistency, with patients starting and staying on treatment. Regarding hepatic fat, I'll turn it over to Brett.
Gary, thanks. We believe the evidence that the small increases in liver fat are an on-target effect is very convincing. Prior to presenting the data at the National Lipid Association earlier this year, we didn't have pushback 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, which showed that with continued treatment the increase in liver fat was returning to baseline. Again, long-term treatment showed no association with clinical sequelae. As we continue to evaluate patients in the long-term open-label extension study, we're not seeing any emerging adverse events. So there are no concerns in the HCP community, and that has been reinforced by the long-term data.
Our next question comes from Moritz Reiterer of Guggenheim Securities.
This is Moritz on for Debjit. Two questions. First, on TRYNGOLZA, how, if at all, has the recent plozasiran data changed your outlook for TRYNGOLZA? Second, on HORIZON, what's your confidence in the trial? And should HORIZON disappoint, how are you thinking about your path to profitability?
Moritz, thanks. Based on everything we've seen so far, we continue to believe we have a best-in-class medicine when looking at the totality of the data for sHTG. When you look at the triglyceride lowering that Holly summarized, the overall reduction in acute pancreatitis, along with safety, tolerability and first-mover advantage, we have no concerns about competition. We continue to reiterate our peak product sales in the U.S. of more than $3 billion. There were no surprises in any data that has emerged since we've launched. With respect to HORIZON, our confidence remains high. We believe that Lp(a) is an independent cardiovascular risk factor and the evidence is strong. We have the right drug, and the baseline demographics and powering assumptions for the trial are appropriate. The drug has been well tolerated, and we're looking forward to the results later this year.
Should the trial disappoint, what's the route to profitability?
In the event that Pelacarsen 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 hard to achieve that goal.
Our next question comes from Mike Ulz of Morgan Stanley.
A few on ION775. Can you give us a sense of what data we might expect at the upcoming ESC meeting, maybe in terms of endpoints and level of follow-up? And secondly, as we think about timelines for this program, how are you thinking about the path to market and number of clinical studies? Are there ways to shorten that given your experience with the CORE programs?
This is Holly. The ION775 data we'll be sharing at ESC is one-year data, including safety and efficacy activity on our key biomarkers. It should be a very interesting dataset. We are in the Phase IIb study now, and we are using our previous learnings to accelerate the program as much as possible. We haven't discussed timing externally, but we are applying what we've learned from our previous programs to this one.
Mike, to add, you'll see long-term data on triglycerides in the mildly elevated triglyceride population and the durability that 775 offers. As Holly mentioned, this can enable at least twice-a-year or even less frequent dosing. The focus is on convenience; TRYNGOLZA's efficacy is difficult to beat, so 775 is aimed at offering durable apoC-III reductions and triglyceride reductions with good tolerability. Enrollment for the Phase IIb is going well, and our focus is to complete that study, select a dose and move to Phase III as quickly as possible, but it's too early to give firm timelines.
Our next question comes from Yanan Zhu of Wells Fargo Securities.
For sHTG, based on the first few weeks of launch, how does that early momentum track with your internal expectation, especially relative to the full year guidance? You made that guidance without firsthand experience of the launch, so are you ahead of internal expectations at this point? Also, for CARDIO-TTRansform, is there a regulatory path for monotherapy and could data presented at ESC inform how you and AstraZeneca think about any potential regulatory path?
Yanan, we and AstraZeneca continue to review CARDIO-TTRansform data. There's a lot to analyze, and we're preparing to present at ESC. We have several public presentations at ESC, including the CARDIO-TTRansform study, the combination subgroup and a meta-analysis conducted by an independent group of academic physicians. Regarding regulatory path, AstraZeneca is weighing all options as they go through the data; there's nothing new to report at this time. The ESC data will further support the conclusions we've already made: in the group that was on monotherapy at baseline, the efficacy in the composite primary endpoint and secondary endpoints are in line with the silencer class. There was no benefit in the combination group, and you'll see that data in detail at ESC.
Yanan, internally we are meeting expectations for the launch, keeping in mind we're only four or five weeks in, so it's very early. Key priorities right out of the gate were to get drug into the channel. We did that within one week; both doses were in channel quickly, allowing prescriptions to go directly to patients when approved by payers. Training of field teams, approval of materials and deployment of content went extremely well. Our omnichannel capabilities operated as planned, enabling us to notify tens of thousands of HCPs who see high triglyceride patients. Payer engagements and patient services have also gone well. Operationally, I'm very pleased with the team's execution, and we're off to a very good start. Regarding full year guidance of $100 million to $110 million for TRYNGOLZA, we remain confident based on FCS performance earlier in the year and early signs from the sHTG launch combined with the strong label.
Our next question comes from Yaron Werber of TD Cowen.
Congrats on the progress. Kyle, do you think there will be an initial pent-up demand or bolus as clinics triage patients now that TRYNGOLZA is approved? And for DAWNZERA, you're seeing nice quarter-over-quarter growth; what is the main competitor at this point and what are you seeing in terms of demand?
Thanks, Yaron. For pent-up demand, we believe this will be a gradual and moderate build for a few reasons: it's a new mechanism and treatment, which takes time to educate HCPs; patients need to be identified and brought into clinics; and payer access is evolving, with medical exceptions early on as utilization management criteria are developed. We expect the build to progress through the back half of this year with 2027 seeing stronger uptake as HCPs gain experience. On DAWNZERA, the team is performing well. Q2 was $26 million in revenue, up 63% over Q1, less than one year in market, and we've gained meaningful share in a switch market. We see switches from existing prophylactic therapies, patients moving from on-demand therapies to prophylaxis and naive starts. There are multiple therapies in the class with different profiles; some patients switch due to efficacy challenges, some due to tolerability and some due to treatment frequency. We are seeing switches from all prophylactic therapies, and HCPs are having positive experiences prescribing DAWNZERA and returning to it.
Our next question comes from Manoj Eradath on for Akash Tewari of Jefferies.
One question on GTX-102. Do you expect GTX-102 to demonstrate a meaningful efficacy trend in the upcoming Angelman readout? How should we think about the potential read-through from that data to your program?
This is Holly. Regarding the Ultragenyx data readout expected later this year, it will teach us a couple of things, including the placebo effect in that patient population, which we don't currently know. In terms of read-through to our program, those are very different molecules. They are dosing at much lower doses than we are. We hope they have positive effects that encourage the community; however, if they don't, it could be because they're dosing lower than we are in our study.
Our research organization has benchmarked Obudanersen and ION582 against other molecules in development, and we don't see potency advantages of those other molecules compared to ION582. We have a highly potent molecule and have been able to dose to drive efficacy as an 80-milligram quarterly dose. We're looking forward to emerging data and to reading out our study next year.
Our next question comes from Tommie Reerink on for Salveen Richter of Goldman Sachs.
Two on TRYNGOLZA. In FCS, any color on impact from switches from Arrowhead and on capture of new starts? And on sHTG, any more detail on what you're seeing from primary care?
Thanks, Tommie. We've seen no meaningful impact from competition in FCS. Q2 was our strongest demand quarter and the highest quarter for new patient starts. The profile of TRYNGOLZA is being well received by HCPs. HCPs using TRYNGOLZA for the first time are coming back to it. The triglyceride lowering and the ability to self-administer with the auto-injector are strong attributes. On the primary care side, part of our 20,000 targeted HCPs includes PCPs who see high-risk sHTG patients. Predominant prescriptions are expected from cardiology, endocrinology and lipidology, but PCPs are seeing these patients and are willing to prescribe because they've been trying standard of care like fibrates, omega-3s and statins without sufficient success. We'll continue broad awareness and disease education across all specialties, and early indicators are positive.
Our next question comes from Luca Issi of RBC.
On the sHTG launch, some doctors have said one barrier is there's no dedicated ICD-10 code specifically for severe hypertriglyceridemia, and they must use related codes like hyperchylomicronemia syndrome or hyperglyceridemia, which can create barriers for reimbursement. Is that consistent with what you're hearing and how are you addressing it? Also, Brett, on TTR cardiomyopathy, you mentioned a meta-analysis by an independent group to be presented at ESC. Can you expand on the purpose of that analysis and its broader implications?
On the ICD-10 code, that has been on our radar and we are looking for opportunities to help the community develop an explicit ICD-10 code for sHTG. That work is ongoing with agencies. In terms of reimbursement, there are other ways to justify appropriate use of the drug: reference the labeled indication, document the patient's medical history, background therapies and triglyceride levels in a prior authorization and include a letter of medical necessity. That's standard for a specialty product at launch, and we're supporting HCPs to do that successfully.
The meta-analysis is focused on the silencer class to understand the totality of data within that class, including our new CARDIO-TTRansform data, and to compare results both as monotherapies and on top of stabilizers.
Our next question comes from Jessica Fye of JPMorgan.
Curious about ION337 for Dravet. When might we see Part 1 data from the Phase I/II? And given the long lead time for Zilganersen, how might 337 differentiate?
This is Holly. We just started dosing in ION337, so it's too early to give timelines, but there's a lot of enthusiasm from the community. KOLs know Ionis and our technology and are excited. In terms of differentiation, because we're using our NMA chemistry, it's more potent than MOE chemistry used previously for splice modulation, which provides increased potency and allows for extended dosing intervals and increased efficacy.
We have time for one more question.
Our last question comes from Eric Joseph of Citi.
Regarding the CORE open-label extension data at ESC, what incremental endpoints beyond the NLA presentation should we focus on? To what extent is ongoing acute pancreatitis event rate being tracked in the OLE? And a clarifying question on ION775 strategy: is the goal predominantly to be a convenience successor to TRYNGOLZA in sHTG or is there an expansion opportunity in moderate hypertriglyceridemia? If so, what would the target product profile look like?
ION775 strategy: our goal is primarily focused on severe hypertriglyceridemia as a follow-on molecule. It's not solely a convenience play, although convenience is a major aspect; ION775 aims to offer semiannual or even annual dosing while maintaining strong reductions in apoC-III and triglycerides and good tolerability. TRYNGOLZA's efficacy profile is difficult to beat, so we'll focus on convenience and durability. We'll consider other indications, but we need more Phase II data before establishing Phase III plans. Holly will speak to the CORE open-label extension expectations.
At ESC we'll present one-year data from the open-label extension. We'll look at triglyceride levels, full safety data and key biomarkers such as remnant cholesterol, apoC-III and non-HDL cholesterol. Acute pancreatitis event rates and durability of effect are tracked, and we'll provide comprehensive data on efficacy and safety at one year.
It's very exciting long-term data showing durability of efficacy and lack of emerging safety issues. Thank you, everyone, for joining and participating. We look forward to an exciting second half of the year for Ionis and will share our progress. Until then, thanks and have a great day.
The conference has now concluded. Thank you for attending today's presentation, and you may now disconnect.