IONIS PHARMACEUTICALS INC — Call Transcript 2026

Good day, welcome to Ionis first quarter 2026 financial results conference call. As a reminder, this call is being recorded. At this time, I would like to turn over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Please begin. Thank you, Sabrina. 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 have 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; and Beth Hougen, Chief Financial Officer. Holly Kordasiewicz, Chief Development 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'd like to draw your attention to slide three, which contains our forward-looking language statement. During this call, we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail. With that, I'll turn the call over to Brett. Thanks, Wade. Good morning, everyone, and thank you for joining us today. Ionis entered 2026 with significant momentum, which continued to accelerate through the first quarter of this year. Our performance to date highlights our strong execution across the business, which positions us to fuel substantial growth for years to come. We are very pleased with the continued success of TRYNGOLZA. Demand continues to grow, reflecting both a compelling clinical profile and strong launch execution by our team. The launch of TRYNGOLZA is now also underway in Europe through our partner Sobi, expanding access to this transformational therapy for people with FCS. We also continue to advance our launch of DAWNZERA. We're very encouraged by the strong early trajectory and the breadth of prescribers across patient segments. Outside the U.S., DAWNZERA received European approval earlier this year, and our partner, Otsuka, has now initiated launch activities across the region. Together, TRYNGOLZA and DAWNZERA give us a strong foundation of successful commercial execution as we look ahead to two additional independent launches this year with more to come. We are on track for the launch of olezarsen in severe hypertriglyceridemia, which represents our first independent launch in a broad patient population. We are pleased to have received priority review by the FDA with a PDUFA date of June 30, reflecting the significant unmet need in sHTG and the groundbreaking results from our landmark CORE and CORE2 studies. In these studies, we demonstrated profound and highly statistically significant reductions in triglycerides and acute pancreatitis events, along with favorable safety and tolerability. Today, based on HCP demand and payer research, we are increasing our annual peak sales estimate for olezarsen from greater than $2 billion to now greater than $3 billion, positioning olezarsen to become Ionis' first wholly owned multibillion-dollar medicine as the new standard of care for treating patients with severe hypertriglyceridemia. Zilganersen for Alexander disease is our second planned independent launch this year and the first from our industry-leading neurology pipeline. Zilganersen is the first and only medicine to demonstrate clinically meaningful and disease-modifying benefit in Alexander disease, a devastating and often fatal leukodystrophy with no approved treatments today. We submitted our NDA in January, and based on the results of our pivotal study, the FDA accepted our NDA with priority review and a PDUFA date of September 22. Overall, we are on track to have three independent medicines for four indications on the market in 2026. TRYNGOLZA for FCS and sHTG, DAWNZERA for HAE, and zilganersen for Alexander disease. This marks a major step in Ionis' evolution as a fully integrated commercial biotech company. Complementing our wholly owned portfolio is our partner pipeline, a rich pipeline that continues to advance toward multiple value-driving events this year. Bepirovirsen, our potential first-in-class medicine for chronic hepatitis B, is on track to launch in the U.S. and Japan this year by our partner GSK. Just this week, bepirovirsen was granted breakthrough therapy designation and accepted for priority review by FDA with a PDUFA date of October 26. Next month at EASL, GSK will present the unprecedented results of the phase III program in which bepirovirsen achieved statistically significant and clinically meaningful functional cure rates in patients with chronic hepatitis B. We also remain on track for data from two major cardiovascular outcome trials from our partner pipeline this year. The pelacarsen Lp(a) HORIZON trial in patients with elevated Lp(a) and cardiovascular disease and the eplontersen CARDIO-TTRansform trial in transthyretin-mediated cardiomyopathy. Including these programs along with bepirovirsen, we expect five partner-led launches by the end of next year, creating a diversified stream of royalties and milestones for Ionis with multibillion-dollar potential well into the next decade. In addition to our commercial and pipeline achievements, we also delivered strong financial results in the first quarter. As a result of this strong Q1 performance and outlook for the balance of the year, today we are announcing a significant improvement to our financial guidance, which Beth will cover in details in a few moments. Ionis has achieved a great deal of late. Our pipeline and our launches are delivering tremendous value, and we continue to strengthen our financial position. Even more importantly, we are well-positioned and committed to build on this success to drive far greater value for patients and our shareholders. With that, I'll turn the call over to Kyle. Thank you, Brett. As we enter 2026, Ionis is capitalizing on the exceptional launch momentum we generated in 2025 to drive even greater impact. We are set up for continued success with our independent launches. TRYNGOLZA demand is accelerating. DAWNZERA early launch metrics are tracking extremely well, and enthusiasm continues to build for our upcoming olezarsen launch in sHTG and zilganersen launch in Alexander disease. TRYNGOLZA continues to build on the strong performance from last year. Q1 was our strongest quarter in terms of demand, with patient starts increasing significantly versus prior quarters and patients on treatment are doing extremely well. Our patient-finding initiatives continue to identify appropriate FCS patients, and we are successfully converting prescriptions to patients on treatment. We are seeing ongoing expansion in both breadth and depth of prescribing, with more clinicians initiating TRYNGOLZA and existing prescribers writing additional scripts. Prescribers span a broad mix of specialties, including cardiology, endocrinology, and lipidology, which is exactly the prescriber base we want as we prepare for the broader sHTG population. Physicians remain highly satisfied with TRYNGOLZA's overall profile, efficacy, safety, tolerability, and the patient experience. That is translating into an accelerating rate for new patient starts. Additionally, we are highly encouraged by the updated ACC and AHA clinical practice guidelines, which singles out olezarsen as the recommended treatment to lower triglycerides and reduce pancreatitis risk in patients with FCS. Outside the U.S., our partner, Sobi, is now in the early stages of launching TRYNGOLZA for FCS in Europe. This is expanding access for FCS patients and will bring in additional revenue over time. Following the groundbreaking CORE and CORE2 data in sHTG, we conducted extensive market research with high volume lipid specialists, cardiologists, and endocrinologists. That work consistently showed a clear understanding that preventing pancreatitis is the key treatment goal in sHTG and that current options fall short. Strong recognition of olezarsen's differentiated clinical profile, especially the acute pancreatitis data and the very low number needed to treat. HCPs have stated a high intent to prescribe across a range of patient types with initial use expected for individuals with triglyceride levels above 880 mg/dL or above 500 mg/dL with a history of acute pancreatitis or other high-risk comorbidities, including progressive cardiovascular disease and Type 2 diabetes. In line with our commitment to patient access and to a successful transition into the broader sHTG market, we recently announced an important pricing decision for TRYNGOLZA. Effective April 1st, we set the new annual wholesale acquisition cost to $40,000, which applies to the current FCS indication and will be maintained for the anticipated sHTG indication across both doses. Importantly, by establishing a new price ahead of the June 30th PDUFA date, we are integrating olezarsen into 2027 payer contracting cycles, positioning us for accelerating access following approval. From a go-to-market standpoint, our full U.S. field organization is now in place, trained, and deployed. Today, that team is focused on supporting TRYNGOLZA for FCS and deepening our relationships with the key specialists who also treat sHTG. With this expanded footprint, we are positioned to engage approximately 20,000 high-volume sHTG prescribers across the country. The DAWNZERA launch is gaining significant momentum in what is largely a switch market in the U.S. We are seeing increasing adoption across all patient segments, patients switching from existing prophylactic therapies, patients who were previously using on-demand treatment, and treatment-naive patients. Our free trial program has been very effective, with high conversion to paid therapy rate to date. Just as importantly, feedback from both physicians and patients has been consistently positive, highlighting DAWNZERA's strong efficacy, its differentiated RNA-targeted 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. We are also seeing a growing base of repeat prescribers, which is a key indicator that DAWNZERA is providing a substantial benefit for patients. While it will take time to fully transition appropriate patients off legacy therapies, especially in a well-established market like HAE, the launch fundamentals give us confidence that DAWNZERA will contribute significantly to the increase in our commercial revenue in 2026 and beyond. Outside the U.S., DAWNZERA is now approved in the EU, and our partner, Otsuka, has initiated launch activities. Over time, we expect ex-U.S. markets to become an important contributor to the global DAWNZERA franchise. Finally, we are preparing for our first independent launch from our neurology portfolio with zilganersen for Alexander disease. On the back of the positive phase III results, we now have FDA priority review with the PDUFA date set of September 22nd, and our expanded access program is underway. On the commercial side, our focus has been on continuing to strengthen current relationships and build new relationships with the highly specialized community of leukodystrophy and rare neurology HCPs, further advancing partnerships with patient advocacy groups and ensuring the right support infrastructure is in place for diagnosis, treatment, and ongoing care. Our medical affairs team has been engaging with top leukodystrophy centers, sharing data and helping to build awareness of Alexander disease. Our marketing and access teams are finalizing the launch strategy. We will hire the customer-facing team closer to approval. Zilganersen is not only an important medicine for people living with Alexander disease, but it's also a template for how we will commercialize future rare first-in-class neurology therapies emerging from our pipeline. With two independent launches building momentum, two additional launches anticipated this year, and a strong pipeline behind them, we believe Ionis is well-positioned to change the lives of patients around the world. With that, I'll turn the call over to Beth. Thank you, Kyle. The strong operational execution you've heard about this morning translated into very strong first quarter financial results. We delivered year-over-year revenue growth and maintained disciplined expense management while continuing to invest in our current and upcoming independent launches. First quarter total revenues were $246 million, an increase of 87% compared to the first quarter of 2025. This increase was driven by year-over-year commercial revenue growth from TRYNGOLZA and DAWNZERA and substantial R&D revenue, including approximately $95 million of milestone payments from multiple partnerships. Commercial revenue increased over 42% year-over-year in the first quarter, driven in large part from TRYNGOLZA and DAWNZERA growth. TRYNGOLZA delivered over $27 million in product sales, reflecting continued strong demand that was offset by an anticipated decline in net price. DAWNZERA contributed meaningfully to commercial revenue, delivering $16 million in the first quarter, an increase of 125% compared to the prior quarter. Collectively, our expanding commercial portfolio positions us for robust revenue growth and is expected to represent an increasing share of total revenue year-over-year. Operating expenses for the quarter were in line with expectations and increased 29% year-over-year, primarily driven by commercial investments supporting TRYNGOLZA and DAWNZERA and launch readiness activities for olezarsen in sHTG and zilganersen in Alexander disease. We ended the quarter with cash of approximately $1.9 billion. The change in cash from year-end 2025 was primarily related to $633 million we used to repay our 0% convertible notes, which were due on April 1st. The strength of our balance sheet is the result of our prudent fiscal management, which enables us to make strategic investments as we advance and launch our wholly-owned medicines. Our Q1 performance underscores the value of our diversified revenue model, which combines growing commercial revenue with substantial and recurring R&D revenue from partner programs. Based on our strong year-to-date financial results, accelerating launch momentum and positive outlook for the rest of the year, we are improving our 2026 financial guidance. We now expect total revenue in the range of $875 million-$900 million, an increase of $75 million versus prior guidance, with total revenue weighted slightly more toward commercial revenues. For the first time this year, we are also providing product-level guidance for TRYNGOLZA and DAWNZERA. We expect TRYNGOLZA product sales to be between $100 million and $110 million for the full year and generally in line with 2025 full-year TRYNGOLZA revenue. Our guidance assumes a significant decline in second quarter TRYNGOLZA revenue based on the updated price effective April 1st and a steady return to growth after the June 30th approval for sHTG. We are projecting DAWNZERA product sales to be between $110 million and $120 million for the full year. Our guidance assumes DAWNZERA will continue to be a significant contributor to year-over-year growth in 2026, with revenue steadily increasing as the launch advances. We also anticipate significant R&D revenue from existing collaborations, including potential development and regulatory milestones across our partnered portfolio, demonstrating that R&D revenue is indeed an important financial accelerator. In fact, we recently learned that the first patient-initiated treatment in the phase III program for salanersen, which triggered a $45 million payment we will recognize in the second quarter. Over the balance of the year, we also are eligible to earn additional milestones tied to sapablursen, bepirovirsen, pelacarsen, and other partnered programs as they advance. We expect our 2026 operating expenses to increase in the low teen percentage range compared to last year. This modest increase reflects our commitment to financial discipline as we bring multiple medicines directly to patients and advance our pipeline. The key drivers of expense growth will be sales and marketing investments to support TRYNGOLZA and DAWNZERA and to ensure successful launches for olezarsen in sHTG and zilganersen in Alexander disease, assuming approvals. We anticipate our R&D expenses to remain steady this year, similar to last year. As late-stage studies reach completion, we are redeploying our resources towards the drugs in our pipeline that we expect to fuel our next phase of growth. Our focus on improving operating leverage is enabling us to drop the full increase in revenue guidance to the bottom line. As a result, we expect a non-GAAP operating loss between $425 million and $475 million, a $75 million improvement over our previous guidance. This is similar to our 2025 operating loss after adjusting for the one-time sapablursen license fee we earned last year. We are projecting a 2026 year-end cash balance of greater than $1.6 billion. This reflects the repayment of the 0% convertible notes, which were due on April 1st. The strength of our balance sheet, combined with our diversified revenue streams, supports our continued strategic investments in ongoing and planned launches as we advance our wholly-owned pipeline. Our financial outlook reflects accelerating commercial launches, a progressing pipeline, and a diversified revenue base, positioning us for continued growth and keeping us on track for cash flow breakeven in 2028. With that, I'll turn the call back over to Brett. Thank you, Beth. The first quarter and our outlook for 2026 underscore the strength of Ionis today. With two successful independent launches underway, two more independent launches anticipated this year, a robust pipeline advancing toward multiple near and midterm catalysts, and a solid financial position that supports the continued investments we are making to maximize the value of our commercial medicines and pipeline. With all these key elements in place, we're confident in our ability to accelerate revenue growth and deliver increasing value for patients and for all Ionis stakeholders. In closing, I wanna highlight that this week at Ionis, we are holding our annual Why Week. It's a time when our employees come together to hear directly from patients and caregivers about their personal stories and reinforce our purpose, which is bringing better futures to people in need. I've never been prouder of the impact we are having on patient lives and clinical medicine, and I'm even more excited about the greater impact we are positioned to make in the near-term and sustainably well into the future. With that, we'll now open the call up for questions. Sabrina? Thank you. We will now begin the question-and-answer session. To ask a question, you may press star then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster. The first question comes from Jessica Fye of JPMorgan. Please go ahead. Hey, guys. Good morning. Thanks for taking my question. You once again raised peak expectations for TRYNGOLZA. Can you just spend a little time elaborating on what enabled you to increase it from at least $2 billion at JPMorgan to now at least $3 billion? Can you also talk about your expectation for gross to nets on TRYNGOLZA following this price reset? Thank you. Yes. Jess, thank you for the question. Our increase in peak product sales for TRYNGOLZA and sHTG and FCS combined in the U.S. to $3 billion was based on several factors. As you recall, we increased the price, or the peak sales to $2 billion in January, based really solely on the phase III data and some preliminary HCP demand research that we had conducted. The demand was very high. Since then, we've completed our HCP demand research, but more importantly, we completed our payer research, which landed on our $40,000 annual WAC price. Price, as well as priority review. Those were the biggest drivers of the increase in peak sales that we have put out today. As far as gross to net, we're not commenting on that at this time. Thank you. The next question comes from Mike Ulz of Morgan Stanley. Please go ahead. Good morning. Thanks for taking the question, and congratulations on the progress. Maybe just a question on the TRYNGOLZA trajectory for the year. You mentioned, you know, return to growth in the second half, really driven by the sHTG launch. Just curious, in some of your market research, are you picking up on maybe any pent-up demand? You know, could we anticipate a bolus early in the launch year, just given the groundbreaking data? Thanks. Kyle, would you take that, please? Yeah, Mike, appreciate that. I think what's important first is the strong performance that we saw in Q1 in terms of demand. It's the best quarter that we've had in terms of the FCS patient population, the number of scripts that were received, and the number of patients that are starting on therapy. That actually lends us a lot of confidence, not only in the FCS space, but also as we get closer to the June 30th PDUFA date in sHTG. I think it's indicating that there is a lot of interest in using olezarsen very broadly in this patient population. In terms of the launch in sHTG, we do know that there are a number of patients that are waiting, right? Especially the patients that have a history of acute pancreatitis, patients that are above 880 mg/dL, those are really the patients that we're gonna focus on out of the gate. The trajectory, I think, is gonna be modest at the beginning here in 2026. I think the revenue guidance that Beth shared, of $100 million-$110 million, is consistent with that expectation, we'll see it steadily grow over time with that focus being on the highest risk patient population. Some of the dynamics here, as typically seen, is it takes some time for the HCPs to be educated on the label. We've got to get those patients into those centers in order to get the prescriptions and then get the execution of the scripts to turn into patients on treatment. It'll be a build over time, and it will, you know, accumulate. We expect a modest and steady growth throughout the back half of this year. Great. Thank you. The next question comes from Gary Nachman, with Canaccord Genuity. Please go ahead. Hi, guys. Good morning and congrats on the progress. Again, on sHTG, just talk about how you expect the payer access to ramp up, the timing of that, when you think it'll really kick in. You got updated guidelines for FCS. Will you be able to get that for sHTG as well? How long before you think you could expand to a less severe patient population over time? Thanks. Kyle, you wanna take, you wanna start? I can touch on the guidelines. Sure. On, on the payer access piece, Gary, you know, part of the price change that decision that we made on April 1st to change the WAC price to $40,000 is directly in line with working with those payers, right? It fits into the annual review cycle as they're getting ready for their 2027 decisions to be made. We believe that it will help us get ahead of sHTG a little bit, not only in 2026, but also will help us in anticipation of 2027. That being said, some payers or all payers will actually wait for the final label, right, before they make any payer coverage decisions, because they wanna see what the indication statement is. They wanna see what information is in the label, you know, including, you know, acute pancreatitis, and some of the other clinical study data that will be included in the label. It'll take a little bit of time. Some payers will say, you know, "We're not gonna review anything for six to nine months," for example. That's standard policy with some payers. We hope that we'll be able to get ahead of that with the payers that do review earlier, by making that price change and also with our current interactions that we're having leading up to the sHTG approval. We're gonna work quickly, and I think we're in a good spot right now in terms of the way that we're approaching the payers. Gary, to your other question, you know, we're very pleased by the fact that the cardiovascular treatment guidelines for FCS has singled out TRYNGOLZA as the treatment of choice for this disease indication. we applaud the aggressiveness that they are taking to update their guidelines for treatments. we believe that sHTG will be part of that in the future, which again, we believe TRYNGOLZA will be a treatment of choice for severe hypertriglyceridemia. They've been very supportive of the new treatments that are coming out, and we think that they will move pretty quickly. We're also pleased by the fact that they have increased or updated their guidelines on Lp(a) testing, which bodes well for a potential positive phase III readout for pelacarsen and the subsequent launch. It's great news for patients, and it's great news for our pipeline. In terms of the less severe patient population, you know, we'll start with the over 880 mg/dL and over 500 mg/dL with history of AP. However, those same physicians that are treating that patient population also have patients that are 500-880 mg/dL, for example. The education will be ongoing. We're in the right segment of HCPs in terms of our targets, right? Focused on cardiology, endocrinology, and lipid specialists. They'll see a mix of those patients. I think some of those patients will already be picked up, especially if they have comorbidities, Type 2 diabetes and/or ASCVD. You know, the broader population will take a little bit of time just for awareness and for more of the data and information to come out and more experience of using olezarsen in the sHTG population. There's a lot of optimism and a lot of excitement around the category and around the use of a product like this because they've never seen the triglyceride-lowering effects that they're gonna see on top of standard of care, and they've never seen the outcomes in acute pancreatitis like they're, like they've seen with the CORE and CORE2 data. Great. Thank you very much. The next question comes from Jason Gerberry with Bank of America. Please go ahead. Hey, good morning. This is Chi on for Jason. Thanks for taking our question. On olezarsen sHTG, could you give us an update on the levels of liver fat you have observed in the CORE open-label extension studies? To what extent those open-label extension study data have been incorporated into the NDA as the FDA reviews the totality of the safety data? When would you expect to present the updated OLE data later this year? Thanks so much. Yeah, let me start, Chi. Thank you for the question, then I'll pass it on to Eugene. Maybe you could comment on where we are in the regulatory process for sHTG briefly. We're very pleased with the ongoing open-label extension data that we're continuing to accumulate with respect to MRI as assessment of hepatic fat fraction. As you recall, the increases in hepatic fat that we saw were relatively minor, there were no clinical sequelae associated with increase in the small increases in triglycerides. We strongly believe this is a non-target effect. It's consistent with other modalities that have taken that silencing approach in lowering ApoC-III in this patient population. It's completely logical based on the mechanism of inhibition of ApoC-III, which leads to a rapid and substantial clearance of triglycerides in large part through the liver. We've always felt that the observations in liver fat that we've seen here, again, no clinical sequelae associated, would be transient based on the liver just needing to have a little bit more time to clear out the liver that's being shunted through the liver. That's what we're seeing in the long-term extension data. We're seeing a return to baseline in liver fat. Again, no clinical associate sequelae associated with anything in the long-term extension. We look forward to presenting the data in the second half of this year at a major, medical, congress. Stay tuned for that. Eugene, you wanna provide an update on regulatory? Yeah. The application's under review. Everything is going as planned. Of course, the emerging safety data has been provided to the agency as part of routine day 90 safety updates. That's under review now with no questions asked so far. I'll also add that the discontinuations in the long-term extension are extremely low. We're seeing excellent compliance with long-term treatment in the open-label extension. Stay tuned. We're very much looking forward to presenting the results. Great. Thanks. The next question comes from Ellie Merle of Barclays. Please go ahead. Hi, this is Tejas on for Ellie. Thanks for taking our question. In sHTG, you have a set of competitor readouts coming up later this year. Curious just how you would frame those data in the context of the space and if any outcomes there would impact your peak sales view in sHTG. We'd rather not comment on competitor data that's doesn't even exist yet today. I mean, we're looking forward to seeing any additional data that comes out this year, next year, and years to come in sHTG from other programs. All I'll say is that the phase III data that we presented at American Heart Association in late-breaking clinical trial session last year is incredibly compelling. It's a very high bar to me with respect to efficacy, with respect to safety, with respect to tolerability. 85% reduction in acute pancreatitis, which has resonated very well in the HCP community as Kyle highlighted earlier in his prepared remarks. 72% reduction in triglycerides on top of standard of care. We're focused on our program. We're ready to launch in June. You know, we're not, you know. I'll just leave it right there. Thank you. I'll just add, this is a large market, greater than 3 million patients that are potentially addressable here. We have a lot of confidence in the greater than $3 billion peak that we've put out there. That's really based on the phase III clinical trial outcomes that we have. It's based on our HCP demand research. It's based on the comprehensive, payer research that we've done and also the final pricing decision that we made. You know, we stand behind the increase, and we're excited about launching this program and getting it to as many patients as possible after the June 30 PDUFA date. The next question comes from Jay Olson with Oppenheimer. Please go ahead. Oh, hey. Congrats on the quarter, and thank you for this update. Maybe I'll shift gears to DAWNZERA. Can you talk about how you expect the competitive landscape to evolve in HAE and any feedback that you're getting from patients and physicians on DAWNZERA and any color that you're getting on what percent of patients are currently on every eight-week dosing? Thank you. Take that. Yeah, happy to, Jay. Thanks for the question. The competitive landscape obviously is evolving. I mean, there was some, you know, recent announcement as late as this week related to some of the dynamics in the marketplace. Keep in mind that in the United States, over 75% of the patients are currently on a prophylactic treatment. You know, this is a switch market as we understand the dynamics to be. We are really pleased with the momentum that we're seeing in terms of the interest in using DAWNZERA, which is the first RNA-targeted therapy modality in order to treat these patients. The patient and HCP feedback has been extremely positive when they've been able to transition over to DAWNZERA or start DAWNZERA as a naive patient. What led into this, you know, in terms of our market research is consistently being played out in the market. Really this is about efficacy, it's about tolerability and convenience. All three of those things are stacking up very nicely with the profile of DAWNZERA, and patients are responding very positively to the therapy. Now, the majority of patients start on a four-week dosing schedule. This is to make sure that they get transitioned over, that they're well-controlled, and then they have the option, per the labeled indication, to move over to every eight weeks if they choose to do so. As early in the launch as we are right now, you would anticipate that the majority of patients would be on a four-week regimen. We will expect over time that they'll be able to progress onto an eight-week schedule as they're doing well on therapy, and we saw that in the clinical trial as well. Patients are doing great, momentum is very strong, and we're encouraged by what we're seeing in terms of the metrics with the launch at this point. Great. Thank you. The next question comes from Moritz Reiterer with Guggenheim Securities. Please go ahead. Hi, this is Moritz on for Debjit. Thanks for taking our questions. I'll continue on DAWNZERA. Your 2026 guidance for DAWNZERA is substantially above what consensus was going into the quarter. I was just trying to understand a little bit better what data drove this guidance number. Also if you could comment a little bit more on the current mix between new patient starts versus switches, and how you expect this to evolve through the end of the year. Thank you. Yeah, I'd be happy to touch on that. Thanks for the question. You know, we had a very strong first quarter, $16 million in net product sales. This is a 128% increase over Q4. And I just spoke about the momentum that we're seeing in this market and the dynamics and also the receptivity by both HCPs and patients as they get started and gain experience with DAWNZERA. All of those things that I just described are really what is encouraging us and I think where we feel very confident that $110 million-$120 million in sales this year is very achievable. In terms of the new patient starts, the majority are switches, right. This is a switch market. Greater than 75% of the patients are on a prophylactic therapy in the United States. So it's gonna take time and time to build, you know, the revenues quarter-over-quarter. That it's happening the way that we expected it based on what we're seeing in the trends with Q4 as well as Q1. In addition to that, we are seeing some patients that haven't been on a prophylactic therapy before start on DAWNZERA. Those patients, in addition to those that are being treated with an acute therapy only today, that are starting on DAWNZERA. You know, those three patient segments I think speak to the fact that, the profile is very strong in what patients and HCPs are looking for. We have a differentiated mechanism of action, and our sales execution and market access teams are doing a great job in terms of supporting these patients to get started and stay on treatment. The next question comes from Yaron Werber of TD Cowen. Please go ahead. Hi, this is Steve, and on for Yaron. Thank you very much for the update, and congratulations on the progress. On the collaborative revenues for the rest of the year and for maybe 2027, can you talk about what you're projecting? 'Cause those came out a bit higher, I think, than consensus may have. Further on zilganersen, can you talk about how any patients' awareness efforts have found any new updates to the size of the market? You had mentioned before that about 50% of patients have been identified. Any update to the sizing there would be helpful. Thank you very much. If you wanna start and then, Kyle take the second part. Sure. On the collaborative revenue for this year, the way to think about it is we've raised our revenue guidance for the total year to $875 million-$900 million. That is slightly weighted towards commercial revenue. You can think about that split being slightly more weighted towards commercial revenue versus R&D revenues. Obviously, we've already realized and recognized $95 million in milestones, plus our ongoing collaborative revenue, which put us, you know, well over $100 million, closer to $130 million, $140 million for the first quarter. We've got a host of other milestones that we could potentially earn over the remainder of this year, plus our ongoing collaborative revenue from Waylivra cost share and amortization. That is, you know, all the items that really give us confidence in the overall collaborative revenue for this year. For 2027, we've got, think about it this way, there's some very large potential milestones for approvals coming in 2027 with the phase III data that we're expecting to see from pelacarsen, eplontersen in particular. Those milestones are likely gonna drive collaborative revenue in 2027. Yeah. The, our launch preparations are going really well, right? Yeah. For zilganersen, I just, I want to, you know, just reinforce the excitement that we've got around this program. You know, this is gonna be our first anticipated neurology launch program. To be able to potentially bring this therapy to patients living with Alexander disease, I think is really an exciting opportunity for the community and also exciting for Ionis. In terms of the approach here, we're really gonna be focused on the patients that are currently on the clinical trial and helping get those patients moved over so that they can maintain treatment. The second area that we'll focus on are patients that are going to be enrolled in our expanded access program, which is ongoing and going very well. As, as you asked, what about the patients that are currently being identified and how do we help get those patients on treatment? We believe that there are approximately 300 or so Alexander disease patients in the United States. About 50% of those have been identified thus far. Some of them are on therapy that I just referenced. But we are doing some expanded work through our omni-channel and through our non-personal promotion campaigns to help identify more and more of these patients. Really what we want to make sure of is that they have the opportunity to experience zilganersen as the patients in the clinical trial did to potentially have the positive outcomes that were seen in that trial. Patient identification will be a key area of focus, and we're doing that while we're really making sure that we're gonna take care of the patients that are on treatment today and those that are awaiting treatment that have already been identified. The next question comes from Luca Issi of RBC Capital Markets. Please go ahead. Thank you. Thanks so much for taking our questions. This is Kasian for Luca. Good morning, team. Quick question on WAINUA. What happened to WAINUA for the quarter? Drug is actually down 35% versus the fourth quarter. What drove the weakness here? It looks like AstraZeneca is flagging the availability of the drug now as a prefilled syringe to be administered by healthcare provider. Did that have a negative impact on growth to net? Any color there is much appreciated. Thank you so much. At Q1, we continued to see very strong demand in terms of patients on therapy as well as new patient starts. Demand is still there. Oftentimes you see some January, February pressure as it relates to reauthorizations and the timing of those reauthorizations, which drove some of the pressure early in the quarter. We expect to see that pick up in subsequent quarters and in return to revenue growth as we move into Q2 and beyond in the U.S. You asked about the prefilled syringe. Really that's been put out there for optionality, right? It's flexibility of dosing, and it's to allow HCPs to determine if they want to use the auto-injector or if they want to be able to treat these patients in some of the major centers with a prefilled syringe. It's really optionality for the program. That is not impacting the gross to net at this point. It's way too early to see any impact of that. You know, I would just keep an eye towards future quarters. Again, this is the hereditary polyneuropathy space. The market is growing rapidly on the cardiomyopathy space and the eye towards CARDIO-TTRansform readout and getting ready for that launch is definitely where the line of sight is. Got it. Thank you. The next question is from Yanan Zhu with Wells Fargo Securities. Please go ahead. Great. Thanks for taking our questions. Wondering for the FCS, you mentioned a great continued growth in demand. Could you help quantify that a little bit in terms of percent growth, given that, you know, the price change making it difficult for us to appreciate? And then, can you talk about how to think about sHTG in 2027? What kind of growth could we expect from, you know, the initial launch quarters in 2026? Obviously, you guided for peak revenue at $3 billion. Any sense that how long that might take? Any color would be super helpful. Thank you. Yeah. Yanan, let me start, and then I'll. Kyle already touched on what expectations are for 2026 launch in sHTG. He could cover that again, maybe comment on 2027. For FCS, as Kyle mentioned earlier, our first quarter of this year is our strongest quarter to date on patient demand and gaining access to TRYNGOLZA for FCS. That's purely a product of patient finding and the great experiences the HCPs and patients are having with TRYNGOLZA in managing their disease from an efficacy standpoint and from a tolerability standpoint. Demand has never been higher. We're thrilled with what we're seeing, and we think that that's gonna bode quite well for the sHTG launch. Launch trajectory? Yeah, I think what's important again is to mention that in 2026, the revenue guidance is $100 million-$110 million for olezarsen this year. We expect that to grow steadily over time. As I also described, the focus initially is gonna be on the high risk sHTG patient population over 880 mg/dL or over 500 mg/dL with history of AP. As we get into 2027, I would expect that more and more patients will start to come on board that are broader than that, Type 2 diabetes, ASCVD, et cetera, as I described. The launch momentum will build, and so will the patient base. As we get these patients on, as HCPs get experience in seeing the triglyceride-lowering levels and seeing the reduction in acute pancreatitis, that were demonstrated in CORE and CORE2. I think that experience and that evidence ultimately, will help us drive the trajectory into next year. Great. Thanks. Very helpful. The next question comes from Salveen Richter of Goldman Sachs. Please go ahead. Hi, this is Mark on for Salveen. Thank you guys so much for taking our question. Congrats on the quarter. You kind of touched on the DAWNZERA quarterly dynamics. We were wondering, what are the specific drivers for the quarter-over-quarter jump? Are there quarterly dynamics we should be aware of for the rest of 2026? How are you thinking of these dynamics going into 2027 and beyond? Yeah, the real quarter-over-quarter growth is coming from the switch cadence that we are expecting to see, right? This being a switch market. We expect that to continue throughout the course of this year. That's the big driver, right? We know that, you know, that there's a need. We know that the profile of DAWNZERA meets the need of many of those patients, being efficacy, tolerability and convenience. We've got the data with the switch data to help support how to move those patients over from existing prophylactic treatments over to DAWNZERA. As HCPs are gaining experience, we're seeing more and more HCPs not only prescribe for the first time, but we're also seeing those that have used the treatment before use it again and again. I think that plus payer coverage tells us that we've got an optimistic outlook in terms of what 2026 looks like. I think the $110 million-$120 million guidance is in line with that expectation. We have time for one more question, please. The last question comes from Myles Minter with William Blair. Please go ahead. Hey, thanks for sending me in and congrats on the quarter. Just on the TTR cardiomyopathy market, you know, Pfizer did settle for a potential generic entry from VYNDAMAX in mid-2031 versus something like, you know, in 2035. Does that change the way you or AstraZeneca are thinking about the cardiomyopathy market moving forward? How much emphasis you're gonna place on that stabilizer background therapy subgroup in CARDIO-TTRansform? Thanks very much. Thank you, Myles. You know, the news that has been emerging this past week or so on genericizing tafamidis versus brand pricing has not come terribly surprising to us. It's consistent with our product sales guidance that we've put out there with AstraZeneca previously. We believe, we remain completely and believe that the silencer class will end up being the mechanism of choice for TTR amyloidosis. We believe that the silencer class will be utilized as first-line treatment, as well as in those patients that inevitably progress on stabilizers. Combination usage, to your question, will also be utilized very, very, you know, robustly, especially if there's data supporting that combination usage will add further benefit to these patients that inevitably are progressing on current treatments. Our study is designed to actually generate the data that we believe could be convincing to HCPs who are asking the question whether or not combination of a stabilizer with a silencer will add further benefit to these patients. It's the largest study ever conducted in ATTR cardiomyopathy, and the combination subgroup is quite sizable. We're looking forward to the data in the second half of this year. We're prepared to submit the NDA by the end of this year and to launch next year. Thank you, Myles, for that. Thank you for the question, Myles. Thank you everybody who joined us today and participated on our call. We're looking forward to an outstanding year and sharing our progress along the way. Until then, thank you and have a great day, everybody. Goodbye.

Speaker 12: Good day, welcome to Ionis first quarter 2026 financial results conference call. As a reminder, this call is being recorded. At this time, I would like to turn over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Please begin. Good day, welcome to Ionis first quarter 2026 financial results conference call. good day welcome to ionis first quarter 2026 financial results conference call As a reminder, this call is being recorded. as a reminder this call is being recorded At this time, I would like to turn over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. at this time i would like to turn over to wade walke senior vice president of investor relations to lead off the call Please begin. please begin

Speaker 13: Thank you, Sabrina. 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 have 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; and Beth Hougen, Chief Financial Officer. Holly Kordasiewicz, Chief Development 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'd like to draw your attention to slide three, which contains our forward-looking language statement. Thank you, Sabrina. thank you sabrina 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. 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 believe non-gaap financial results better represent the economics of our business and how we manage our business We have also posted slides on our website that accompany today's call. we have 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; and Beth Hougen, Chief Financial Officer. with me this morning are brett monia chief executive officer kyle jenne chief global product strategy officer and beth hougen chief financial officer Holly Kordasiewicz , Chief Development 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. holly kordasiewicz chief development 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'd like to draw your attention to slide three, which contains our forward-looking language statement. i'd like to draw your attention to slide three which contains our forward-looking language statement During this call, we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail. With that, I'll turn the call over to Brett. During this call, we will be making forward-looking statements that are based on our current expectations and beliefs. 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. 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. 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. with that i'll turn the call over to brett

Speaker 2: Thanks, Wade. Good morning, everyone, and thank you for joining us today. Ionis entered 2026 with significant momentum, which continued to accelerate through the first quarter of this year. Our performance to date highlights our strong execution across the business, which positions us to fuel substantial growth for years to come. We are very pleased with the continued success of TRYNGOLZA. Demand continues to grow, reflecting both a compelling clinical profile and strong launch execution by our team. The launch of TRYNGOLZA is now also underway in Europe through our partner Sobi, expanding access to this transformational therapy for people with FCS. We also continue to advance our launch of DAWNZERA. We're very encouraged by the strong early trajectory and the breadth of prescribers across patient segments. Outside the U.S., DAWNZERA received European approval earlier this year, and our partner, Otsuka, has now initiated launch activities across the region. Thanks, Wade. thanks wade Good morning, everyone, and thank you for joining us today. good morning everyone and thank you for joining us today Ionis entered 2026 with significant momentum, which continued to accelerate through the first quarter of this year. ionis entered 2026 with significant momentum which continued to accelerate through the first quarter of this year Our performance to date highlights our strong execution across the business, which positions us to fuel substantial growth for years to come. our performance to date highlights our strong execution across the business which positions us to fuel substantial growth for years to come We are very pleased with the continued success of TRYNGOLZA. we are very pleased with the continued success of tryngolza Demand continues to grow, reflecting both a compelling clinical profile and strong launch execution by our team. demand continues to grow reflecting both a compelling clinical profile and strong launch execution by our team The launch of TRYNGOLZA is now also underway in Europe through our partner Sobi, expanding access to this transformational therapy for people with FCS. the launch of tryngolza is now also underway in europe through our partner sobi expanding access to this transformational therapy for people with fcs We also continue to advance our launch of DAWNZERA. we also continue to advance our launch of dawnzera We're very encouraged by the strong early trajectory and the breadth of prescribers across patient segments. we're very encouraged by the strong early trajectory and the breadth of prescribers across patient segments Outside the U.S., DAWNZERA received European approval earlier this year, and our partner, Otsuka, has now initiated launch activities across the region. outside the u.s dawnzera received european approval earlier this year and our partner otsuka has now initiated launch activities across the region Together, TRYNGOLZA and DAWNZERA give us a strong foundation of successful commercial execution as we look ahead to two additional independent launches this year with more to come. We are on track for the launch of olezarsen in severe hypertriglyceridemia, which represents our first independent launch in a broad patient population. We are pleased to have received priority review by the FDA with a PDUFA date of June 30, reflecting the significant unmet need in sHTG and the groundbreaking results from our landmark CORE and CORE2 studies. In these studies, we demonstrated profound and highly statistically significant reductions in triglycerides and acute pancreatitis events, along with favorable safety and tolerability. Together, TRYNGOLZA and DAWNZERA give us a strong foundation of successful commercial execution as we look ahead to two additional independent launches this year with more to come. together tryngolza and dawnzera give us a strong foundation of successful commercial execution as we look ahead to two additional independent launches this year with more to come We are on track for the launch of olezarsen in severe hypertriglyceridemia, which represents our first independent launch in a broad patient population. we are on track for the launch of olezarsen in severe hypertriglyceridemia which represents our first independent launch in a broad patient population We are pleased to have received priority review by the FDA with a PDUFA date of June 30, reflecting the significant unmet need in sHTG and the groundbreaking results from our landmark CORE and CORE2 studies. we are pleased to have received priority review by the fda with a pdufa date of june 30 reflecting the significant unmet need in shtg and the groundbreaking results from our landmark core and core2 studies In these studies, we demonstrated profound and highly statistically significant reductions in triglycerides and acute pancreatitis events, along with favorable safety and tolerability. in these studies we demonstrated profound and highly statistically significant reductions in triglycerides and acute pancreatitis events along with favorable safety and tolerability Today, based on HCP demand and payer research, we are increasing our annual peak sales estimate for olezarsen from greater than $2 billion to now greater than $3 billion, positioning olezarsen to become Ionis' first wholly owned multibillion-dollar medicine as the new standard of care for treating patients with severe hypertriglyceridemia. Zilganersen for Alexander disease is our second planned independent launch this year and the first from our industry-leading neurology pipeline. Zilganersen is the first and only medicine to demonstrate clinically meaningful and disease-modifying benefit in Alexander disease, a devastating and often fatal leukodystrophy with no approved treatments today. We submitted our NDA in January, and based on the results of our pivotal study, the FDA accepted our NDA with priority review and a PDUFA date of September 22. Overall, we are on track to have three independent medicines for four indications on the market in 2026. Today, based on HCP demand and payer research, we are increasing our annual peak sales estimate for olezarsen from greater than $2 billion to now greater than $3 billion, positioning olezarsen to become Ionis' first wholly owned multibillion-dollar medicine as the new standard of care for treating patients with severe hypertriglyceridemia. today based on hcp demand and payer research we are increasing our annual peak sales estimate for olezarsen from greater than $2 billion to now greater than $3 billion positioning olezarsen to become ionis' first wholly owned multibillion-dollar medicine as the new standard of care for treating patients with severe hypertriglyceridemia Zilganersen for Alexander disease is our second planned independent launch this year and the first from our industry-leading neurology pipeline. zilganersen for alexander disease is our second planned independent launch this year and the first from our industry-leading neurology pipeline Zilganersen is the first and only medicine to demonstrate clinically meaningful and disease-modifying benefit in Alexander disease, a devastating and often fatal leukodystrophy with no approved treatments today. zilganersen is the first and only medicine to demonstrate clinically meaningful and disease-modifying benefit in alexander disease a devastating and often fatal leukodystrophy with no approved treatments today We submitted our NDA in January, and based on the results of our pivotal study, the FDA accepted our NDA with priority review and a PDUFA date of September 22. we submitted our nda in january and based on the results of our pivotal study the fda accepted our nda with priority review and a pdufa date of september 22 Overall, we are on track to have three independent medicines for four indications on the market in 2026. overall we are on track to have three independent medicines for four indications on the market in 2026 TRYNGOLZA for FCS and sHTG, DAWNZERA for HAE, and zilganersen for Alexander disease. This marks a major step in Ionis' evolution as a fully integrated commercial biotech company. Complementing our wholly owned portfolio is our partner pipeline, a rich pipeline that continues to advance toward multiple value-driving events this year. Bepirovirsen, our potential first-in-class medicine for chronic hepatitis B, is on track to launch in the U.S. and Japan this year by our partner GSK. Just this week, bepirovirsen was granted breakthrough therapy designation and accepted for priority review by FDA with a PDUFA date of October 26. Next month at EASL, GSK will present the unprecedented results of the phase III program in which bepirovirsen achieved statistically significant and clinically meaningful functional cure rates in patients with chronic hepatitis B. TRYNGOLZA for FCS and sHTG, DAWNZERA for HAE, and z ilganersen for Alexander disease. tryngolza for fcs and shtg dawnzera for hae and z ilganersen for alexander disease This marks a major step in Ionis' evolution as a fully integrated commercial biotech company. this marks a major step in ionis' evolution as a fully integrated commercial biotech company Complementing our wholly owned portfolio is our partner pipeline, a rich pipeline that continues to advance toward multiple value-driving events this year. complementing our wholly owned portfolio is our partner pipeline a rich pipeline that continues to advance toward multiple value-driving events this year Bepirovirsen, our potential first-in-class medicine for chronic hepatitis B, is on track to launch in the U.S. and Japan this year by our partner GSK. bepirovirsen our potential first-in-class medicine for chronic hepatitis b is on track to launch in the u.s and japan this year by our partner gsk Just this week, bepirovirsen was granted breakthrough therapy designation and accepted for priority review by FDA with a PDUFA date of October 26. just this week bepirovirsen was granted breakthrough therapy designation and accepted for priority review by fda with a pdufa date of october 26 Next month at EASL, GSK will present the unprecedented results of the phase III program in which bepirovirsen achieved statistically significant and clinically meaningful functional cure rates in patients with chronic hepatitis B. next month at easl gsk will present the unprecedented results of the phase iii program in which bepirovirsen achieved statistically significant and clinically meaningful functional cure rates in patients with chronic hepatitis b We also remain on track for data from two major cardiovascular outcome trials from our partner pipeline this year. The pelacarsen Lp(a) HORIZON trial in patients with elevated Lp(a) and cardiovascular disease and the eplontersen CARDIO-TTRansform trial in transthyretin-mediated cardiomyopathy. Including these programs along with bepirovirsen, we expect five partner-led launches by the end of next year, creating a diversified stream of royalties and milestones for Ionis with multibillion-dollar potential well into the next decade. In addition to our commercial and pipeline achievements, we also delivered strong financial results in the first quarter. As a result of this strong Q1 performance and outlook for the balance of the year, today we are announcing a significant improvement to our financial guidance, which Beth will cover in details in a few moments. Ionis has achieved a great deal of late. We also remain on track for data from two major cardiovascular outcome trials from our partner pipeline this year. we also remain on track for data from two major cardiovascular outcome trials from our partner pipeline this year The pelacarsen Lp(a) HORIZON trial in patients with elevated Lp(a) and cardiovascular disease and the eplontersen CARDIO-TTRansform trial in transthyretin-mediated cardiomyopathy. the pelacarsen lp(a) horizon trial in patients with elevated lp(a) and cardiovascular disease and the eplontersen cardio-ttransform trial in transthyretin-mediated cardiomyopathy Including these programs along with bepirovirsen, we expect five partner-led launches by the end of next year, creating a diversified stream of royalties and milestones for Ionis with multibillion-dollar potential well into the next decade. including these programs along with bepirovirsen we expect five partner-led launches by the end of next year creating a diversified stream of royalties and milestones for ionis with multibillion-dollar potential well into the next decade In addition to our commercial and pipeline achievements, we also delivered strong financial results in the first quarter. in addition to our commercial and pipeline achievements we also delivered strong financial results in the first quarter As a result of this strong Q1 performance and outlook for the balance of the year, today we are announcing a significant improvement to our financial guidance, which Beth will cover in details in a few moments. Ionis has achieved a great deal of late. as a result of this strong q1 performance and outlook for the balance of the year today we are announcing a significant improvement to our financial guidance which beth will cover in details in a few moments. ionis has achieved a great deal of late Our pipeline and our launches are delivering tremendous value, and we continue to strengthen our financial position. Even more importantly, we are well-positioned and committed to build on this success to drive far greater value for patients and our shareholders. With that, I'll turn the call over to Kyle. Our pipeline and our launches are delivering tremendous value, and we continue to strengthen our financial position. our pipeline and our launches are delivering tremendous value and we continue to strengthen our financial position Even more importantly, we are well-positioned and committed to build on this success to drive far greater value for patients and our shareholders. even more importantly we are well-positioned and committed to build on this success to drive far greater value for patients and our shareholders With that, I'll turn the call over to Kyle. with that i'll turn the call over to kyle

Speaker 8: Thank you, Brett. As we enter 2026, Ionis is capitalizing on the exceptional launch momentum we generated in 2025 to drive even greater impact. We are set up for continued success with our independent launches. TRYNGOLZA demand is accelerating. DAWNZERA early launch metrics are tracking extremely well, and enthusiasm continues to build for our upcoming olezarsen launch in sHTG and zilganersen launch in Alexander disease. TRYNGOLZA continues to build on the strong performance from last year. Q1 was our strongest quarter in terms of demand, with patient starts increasing significantly versus prior quarters and patients on treatment are doing extremely well. Our patient-finding initiatives continue to identify appropriate FCS patients, and we are successfully converting prescriptions to patients on treatment. We are seeing ongoing expansion in both breadth and depth of prescribing, with more clinicians initiating TRYNGOLZA and existing prescribers writing additional scripts. Thank you, Brett. thank you brett As we enter 2026, Ionis is capitalizing on the exceptional launch momentum we generated in 2025 to drive even greater impact. as we enter 2026 ionis is capitalizing on the exceptional launch momentum we generated in 2025 to drive even greater impact We are set up for continued success with our independent launches. we are set up for continued success with our independent launches TRYNGOLZA demand is accelerating. tryngolza demand is accelerating DAWNZERA early launch metrics are tracking extremely well, and enthusiasm continues to build for our upcoming olezarsen launch in sHTG and zilganersen launch in Alexander disease. dawnzera early launch metrics are tracking extremely well and enthusiasm continues to build for our upcoming olezarsen launch in shtg and zilganersen launch in alexander disease TRYNGOLZA continues to build on the strong performance from last year. tryngolza continues to build on the strong performance from last year Q1 was our strongest quarter in terms of demand, with patient starts increasing significantly versus prior quarters and patients on treatment are doing extremely well. q1 was our strongest quarter in terms of demand with patient starts increasing significantly versus prior quarters and patients on treatment are doing extremely well Our patient-finding initiatives continue to identify appropriate FCS patients, and we are successfully converting prescriptions to patients on treatment. our patient-finding initiatives continue to identify appropriate fcs patients and we are successfully converting prescriptions to patients on treatment We are seeing ongoing expansion in both breadth and depth of prescribing, with more clinicians initiating TRYNGOLZA and existing prescribers writing additional scripts. we are seeing ongoing expansion in both breadth and depth of prescribing with more clinicians initiating tryngolza and existing prescribers writing additional scripts Prescribers span a broad mix of specialties, including cardiology, endocrinology, and lipidology, which is exactly the prescriber base we want as we prepare for the broader sHTG population. Physicians remain highly satisfied with TRYNGOLZA's overall profile, efficacy, safety, tolerability, and the patient experience. That is translating into an accelerating rate for new patient starts. Additionally, we are highly encouraged by the updated ACC and AHA clinical practice guidelines, which singles out olezarsen as the recommended treatment to lower triglycerides and reduce pancreatitis risk in patients with FCS. Outside the U.S., our partner, Sobi, is now in the early stages of launching TRYNGOLZA for FCS in Europe. This is expanding access for FCS patients and will bring in additional revenue over time. Following the groundbreaking CORE and CORE2 data in sHTG, we conducted extensive market research with high volume lipid specialists, cardiologists, and endocrinologists. Prescribers span a broad mix of specialties, including cardiology, endocrinology, and lipidology, which is exactly the prescriber base we want as we prepare for the broader sHTG population. prescribers span a broad mix of specialties including cardiology endocrinology and lipidology which is exactly the prescriber base we want as we prepare for the broader shtg population Physicians remain highly satisfied with TRYNGOLZA's overall profile, efficacy, safety, tolerability, and the patient experience. physicians remain highly satisfied with tryngolza's overall profile efficacy safety tolerability and the patient experience That is translating into an accelerating rate for new patient starts. that is translating into an accelerating rate for new patient starts Additionally, we are highly encouraged by the updated ACC and AHA clinical practice guidelines, which singles out olezarsen as the recommended treatment to lower triglycerides and reduce pancreatitis risk in patients with FCS. additionally we are highly encouraged by the updated acc and aha clinical practice guidelines which singles out olezarsen as the recommended treatment to lower triglycerides and reduce pancreatitis risk in patients with fcs Outside the U.S., our partner, Sobi, is now in the early stages of launching TRYNGOLZA for FCS in Europe. outside the u.s our partner sobi is now in the early stages of launching tryngolza for fcs in europe This is expanding access for FCS patients and will bring in additional revenue over time. this is expanding access for fcs patients and will bring in additional revenue over time Following the groundbreaking CORE and CORE2 data in sHTG, we conducted extensive market research with high volume lipid specialists, cardiologists, and endocrinologists. following the groundbreaking core and core2 data in shtg we conducted extensive market research with high volume lipid specialists cardiologists and endocrinologists That work consistently showed a clear understanding that preventing pancreatitis is the key treatment goal in sHTG and that current options fall short. Strong recognition of olezarsen's differentiated clinical profile, especially the acute pancreatitis data and the very low number needed to treat. HCPs have stated a high intent to prescribe across a range of patient types with initial use expected for individuals with triglyceride levels above 880 mg/dL or above 500 mg/dL with a history of acute pancreatitis or other high-risk comorbidities, including progressive cardiovascular disease and Type 2 diabetes. In line with our commitment to patient access and to a successful transition into the broader sHTG market, we recently announced an important pricing decision for TRYNGOLZA. That work consistently showed a clear understanding that preventing pancreatitis is the key treatment goal in sHTG and that current options fall short. that work consistently showed a clear understanding that preventing pancreatitis is the key treatment goal in shtg and that current options fall short Strong recognition of olezarsen's differentiated clinical profile, especially the acute pancreatitis data and the very low number needed to treat. strong recognition of olezarsen's differentiated clinical profile especially the acute pancreatitis data and the very low number needed to treat HCPs have stated a high intent to prescribe across a range of patient types with initial use expected for individuals with triglyceride levels above 880 mg/dL or above 500 mg/dL with a history of acute pancreatitis or other high-risk comorbidities, including progressive cardiovascular disease and Type 2 diabetes. hcps have stated a high intent to prescribe across a range of patient types with initial use expected for individuals with triglyceride levels above 880 mg/dl or above 500 mg/dl with a history of acute pancreatitis or other high-risk comorbidities including progressive cardiovascular disease and type 2 diabetes In line with our commitment to patient access and to a successful transition into the broader sHTG market, we recently announced an important pricing decision for TRYNGOLZA. in line with our commitment to patient access and to a successful transition into the broader shtg market we recently announced an important pricing decision for tryngolza Effective April 1st, we set the new annual wholesale acquisition cost to $40,000, which applies to the current FCS indication and will be maintained for the anticipated sHTG indication across both doses. Importantly, by establishing a new price ahead of the June 30th PDUFA date, we are integrating olezarsen into 2027 payer contracting cycles, positioning us for accelerating access following approval. From a go-to-market standpoint, our full U.S. field organization is now in place, trained, and deployed. Today, that team is focused on supporting TRYNGOLZA for FCS and deepening our relationships with the key specialists who also treat sHTG. With this expanded footprint, we are positioned to engage approximately 20,000 high-volume sHTG prescribers across the country. The DAWNZERA launch is gaining significant momentum in what is largely a switch market in the U.S. Effective April 1st, we set the new annual wholesale acquisition cost to $40,000, which applies to the current FCS indication and will be maintained for the anticipated sHTG indication across both doses. effective april 1st we set the new annual wholesale acquisition cost to $40,000 which applies to the current fcs indication and will be maintained for the anticipated shtg indication across both doses Importantly, by establishing a new price ahead of the June 30th PDUFA date, we are integrating olezarsen into 2027 payer contracting cycles, positioning us for accelerating access following approval. importantly by establishing a new price ahead of the june 30th pdufa date we are integrating olezarsen into 2027 payer contracting cycles positioning us for accelerating access following approval From a go-to-market standpoint, our full U.S. field organization is now in place, trained, and deployed. from a go-to-market standpoint our full u.s field organization is now in place trained and deployed Today, that team is focused on supporting TRYNGOLZA for FCS and deepening our relationships with the key specialists who also treat sHTG. today that team is focused on supporting tryngolza for fcs and deepening our relationships with the key specialists who also treat shtg With this expanded footprint, we are positioned to engage approximately 20,000 high-volume sHTG prescribers across the country. with this expanded footprint we are positioned to engage approximately 20,000 high-volume shtg prescribers across the country The DAWNZERA launch is gaining significant momentum in what is largely a switch market in the U.S. the dawnzera launch is gaining significant momentum in what is largely a switch market in the u.s We are seeing increasing adoption across all patient segments, patients switching from existing prophylactic therapies, patients who were previously using on-demand treatment, and treatment-naive patients. Our free trial program has been very effective, with high conversion to paid therapy rate to date. Just as importantly, feedback from both physicians and patients has been consistently positive, highlighting DAWNZERA's strong efficacy, its differentiated RNA-targeted 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. We are also seeing a growing base of repeat prescribers, which is a key indicator that DAWNZERA is providing a substantial benefit for patients. We are seeing increasing adoption across all patient segments, patients switching from existing prophylactic therapies, patients who were previously using on-demand treatment, and treatment-naive patients. we are seeing increasing adoption across all patient segments patients switching from existing prophylactic therapies patients who were previously using on-demand treatment and treatment-naive patients Our free trial program has been very effective, with high conversion to paid therapy rate to date. our free trial program has been very effective with high conversion to paid therapy rate to date Just as importantly, feedback from both physicians and patients has been consistently positive, highlighting DAWNZERA's strong efficacy, its differentiated RNA-targeted 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. just as importantly feedback from both physicians and patients has been consistently positive highlighting dawnzera's strong efficacy its differentiated rna-targeted 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 We are also seeing a growing base of repeat prescribers, which is a key indicator that DAWNZERA is providing a substantial benefit for patients. we are also seeing a growing base of repeat prescribers which is a key indicator that dawnzera is providing a substantial benefit for patients While it will take time to fully transition appropriate patients off legacy therapies, especially in a well-established market like HAE, the launch fundamentals give us confidence that DAWNZERA will contribute significantly to the increase in our commercial revenue in 2026 and beyond. Outside the U.S., DAWNZERA is now approved in the EU, and our partner, Otsuka, has initiated launch activities. Over time, we expect ex-U.S. markets to become an important contributor to the global DAWNZERA franchise. Finally, we are preparing for our first independent launch from our neurology portfolio with zilganersen for Alexander disease. While it will take time to fully transition appropriate patients off legacy therapies, especially in a well-established market like HAE, the launch fundamentals give us confidence that DAWNZERA will contribute significantly to the increase in our commercial revenue in 2026 and beyond. while it will take time to fully transition appropriate patients off legacy therapies especially in a well-established market like hae the launch fundamentals give us confidence that dawnzera will contribute significantly to the increase in our commercial revenue in 2026 and beyond Outside the U.S., DAWNZERA is now approved in the EU, and our partner, Otsuka, has initiated launch activities. outside the u.s dawnzera is now approved in the eu and our partner otsuka has initiated launch activities Over time, we expect ex-U.S. markets to become an important contributor to the global DAWNZERA franchise. over time we expect ex-u.s markets to become an important contributor to the global dawnzera franchise Finally, we are preparing for our first independent launch from our neurology portfolio with zilganersen for Alexander disease. finally we are preparing for our first independent launch from our neurology portfolio with zilganersen for alexander disease On the back of the positive phase III results, we now have FDA priority review with the PDUFA date set of September 22nd, and our expanded access program is underway. On the commercial side, our focus has been on continuing to strengthen current relationships and build new relationships with the highly specialized community of leukodystrophy and rare neurology HCPs, further advancing partnerships with patient advocacy groups and ensuring the right support infrastructure is in place for diagnosis, treatment, and ongoing care. Our medical affairs team has been engaging with top leukodystrophy centers, sharing data and helping to build awareness of Alexander disease. Our marketing and access teams are finalizing the launch strategy. We will hire the customer-facing team closer to approval. On the back of the positive phase III results, we now have FDA priority review with the PDUFA date set of September 22nd, and our expanded access program is underway. On the commercial side, our focus has been on continuing to strengthen current relationships and build new relationships with the highly specialized community of leukodystrophy and rare neurology HCPs, further advancing partnerships with patient advocacy groups and ensuring the right support infrastructure is in place for diagnosis, treatment, and ongoing care. on the back of the positive phase iii results we now have fda priority review with the pdufa date set of september 22nd and our expanded access program is underway. on the commercial side our focus has been on continuing to strengthen current relationships and build new relationships with the highly specialized community of leukodystrophy and rare neurology hcps further advancing partnerships with patient advocacy groups and ensuring the right support infrastructure is in place for diagnosis treatment and ongoing care Our medical affairs team has been engaging with top leukodystrophy centers, sharing data and helping to build awareness of Alexander disease. our medical affairs team has been engaging with top leukodystrophy centers sharing data and helping to build awareness of alexander disease Our marketing and access teams are finalizing the launch strategy. our marketing and access teams are finalizing the launch strategy We will hire the customer-facing team closer to approval. we will hire the customer-facing team closer to approval Zilganersen is not only an important medicine for people living with Alexander disease, but it's also a template for how we will commercialize future rare first-in-class neurology therapies emerging from our pipeline. With two independent launches building momentum, two additional launches anticipated this year, and a strong pipeline behind them, we believe Ionis is well-positioned to change the lives of patients around the world. With that, I'll turn the call over to Beth. Zilganersen is not only an important medicine for people living with Alexander disease, but it's also a template for how we will commercialize future rare first-in-class neurology therapies emerging from our pipeline. zilganersen is not only an important medicine for people living with alexander disease but it's also a template for how we will commercialize future rare first-in-class neurology therapies emerging from our pipeline With two independent launches building momentum, two additional launches anticipated this year, and a strong pipeline behind them, we believe Ionis is well-positioned to change the lives of patients around the world. with two independent launches building momentum two additional launches anticipated this year and a strong pipeline behind them we believe ionis is well-positioned to change the lives of patients around the world With that, I'll turn the call over to Beth. with that i'll turn the call over to beth

Speaker 1: Thank you, Kyle. The strong operational execution you've heard about this morning translated into very strong first quarter financial results. We delivered year-over-year revenue growth and maintained disciplined expense management while continuing to invest in our current and upcoming independent launches. First quarter total revenues were $246 million, an increase of 87% compared to the first quarter of 2025. This increase was driven by year-over-year commercial revenue growth from TRYNGOLZA and DAWNZERA and substantial R&D revenue, including approximately $95 million of milestone payments from multiple partnerships. Commercial revenue increased over 42% year-over-year in the first quarter, driven in large part from TRYNGOLZA and DAWNZERA growth. TRYNGOLZA delivered over $27 million in product sales, reflecting continued strong demand that was offset by an anticipated decline in net price. Thank you, Kyle. thank you kyle The strong operational execution you've heard about this morning translated into very strong first quarter financial results. the strong operational execution you've heard about this morning translated into very strong first quarter financial results We delivered year-over-year revenue growth and maintained disciplined expense management while continuing to invest in our current and upcoming independent launches. we delivered year-over-year revenue growth and maintained disciplined expense management while continuing to invest in our current and upcoming independent launches First quarter total revenues were $246 million, an increase of 87% compared to the first quarter of 2025. first quarter total revenues were $246 million an increase of 87% compared to the first quarter of 2025 This increase was driven by year-over-year commercial revenue growth from TRYNGOLZA and DAWNZERA and substantial R&D revenue, including approximately $95 million of milestone payments from multiple partnerships. this increase was driven by year-over-year commercial revenue growth from tryngolza and dawnzera and substantial r&d revenue including approximately $95 million of milestone payments from multiple partnerships Commercial revenue increased over 42% year-over-year in the first quarter, driven in large part from TRYNGOLZA and DAWNZERA growth. commercial revenue increased over 42% year-over-year in the first quarter driven in large part from tryngolza and dawnzera growth TRYNGOLZA delivered over $27 million in product sales, reflecting continued strong demand that was offset by an anticipated decline in net price. tryngolza delivered over $27 million in product sales reflecting continued strong demand that was offset by an anticipated decline in net price DAWNZERA contributed meaningfully to commercial revenue, delivering $16 million in the first quarter, an increase of 125% compared to the prior quarter. Collectively, our expanding commercial portfolio positions us for robust revenue growth and is expected to represent an increasing share of total revenue year-over-year. Operating expenses for the quarter were in line with expectations and increased 29% year-over-year, primarily driven by commercial investments supporting TRYNGOLZA and DAWNZERA and launch readiness activities for olezarsen in sHTG and zilganersen in Alexander disease. We ended the quarter with cash of approximately $1.9 billion. The change in cash from year-end 2025 was primarily related to $633 million we used to repay our 0% convertible notes, which were due on April 1st. DAWNZERA contributed meaningfully to commercial revenue, delivering $16 million in the first quarter, an increase of 125% compared to the prior quarter. dawnzera contributed meaningfully to commercial revenue delivering $16 million in the first quarter an increase of 125% compared to the prior quarter Collectively, our expanding commercial portfolio positions us for robust revenue growth and is expected to represent an increasing share of total revenue year-over-year. collectively our expanding commercial portfolio positions us for robust revenue growth and is expected to represent an increasing share of total revenue year-over-year Operating expenses for the quarter were in line with expectations and increased 29% year-over-year, primarily driven by commercial investments supporting TRYNGOLZA and DAWNZERA and launch readiness activities for olezarsen in sHTG and zilganersen in Alexander disease. operating expenses for the quarter were in line with expectations and increased 29% year-over-year primarily driven by commercial investments supporting tryngolza and dawnzera and launch readiness activities for olezarsen in shtg and zilganersen in alexander disease We ended the quarter with cash of approximately $1.9 billion. we ended the quarter with cash of approximately $1.9 billion The change in cash from year-end 2025 was primarily related to $633 million we used to repay our 0% convertible notes, which were due on April 1st. the change in cash from year-end 2025 was primarily related to $633 million we used to repay our 0% convertible notes which were due on april 1st The strength of our balance sheet is the result of our prudent fiscal management, which enables us to make strategic investments as we advance and launch our wholly-owned medicines. Our Q1 performance underscores the value of our diversified revenue model, which combines growing commercial revenue with substantial and recurring R&D revenue from partner programs. Based on our strong year-to-date financial results, accelerating launch momentum and positive outlook for the rest of the year, we are improving our 2026 financial guidance. We now expect total revenue in the range of $875 million-$900 million, an increase of $75 million versus prior guidance, with total revenue weighted slightly more toward commercial revenues. For the first time this year, we are also providing product-level guidance for TRYNGOLZA and DAWNZERA. The strength of our balance sheet is the result of our prudent fiscal management, which enables us to make strategic investments as we advance and launch our wholly-owned medicines. the strength of our balance sheet is the result of our prudent fiscal management which enables us to make strategic investments as we advance and launch our wholly-owned medicines Our Q1 performance underscores the value of our diversified revenue model, which combines growing commercial revenue with substantial and recurring R&D revenue from partner programs. our q1 performance underscores the value of our diversified revenue model which combines growing commercial revenue with substantial and recurring r&d revenue from partner programs Based on our strong year-to-date financial results, accelerating launch momentum and positive outlook for the rest of the year, we are improving our 2026 financial guidance. based on our strong year-to-date financial results accelerating launch momentum and positive outlook for the rest of the year we are improving our 2026 financial guidance We now expect total revenue in the range of $875 million-$900 million, an increase of $75 million versus prior guidance, with total revenue weighted slightly more toward commercial revenues. we now expect total revenue in the range of $875 million-$900 million an increase of $75 million versus prior guidance with total revenue weighted slightly more toward commercial revenues For the first time this year, we are also providing product-level guidance for TRYNGOLZA and DAWNZERA. for the first time this year we are also providing product-level guidance for tryngolza and dawnzera We expect TRYNGOLZA product sales to be between $100 million and $110 million for the full year and generally in line with 2025 full-year TRYNGOLZA revenue. Our guidance assumes a significant decline in second quarter TRYNGOLZA revenue based on the updated price effective April 1st and a steady return to growth after the June 30th approval for sHTG. We are projecting DAWNZERA product sales to be between $110 million and $120 million for the full year. Our guidance assumes DAWNZERA will continue to be a significant contributor to year-over-year growth in 2026, with revenue steadily increasing as the launch advances. We also anticipate significant R&D revenue from existing collaborations, including potential development and regulatory milestones across our partnered portfolio, demonstrating that R&D revenue is indeed an important financial accelerator. We expect TRYNGOLZA product sales to be between $100 million and $110 million for the full year and generally in line with 2025 full-year TRYNGOLZA revenue. we expect tryngolza product sales to be between $100 million and $110 million for the full year and generally in line with 2025 full-year tryngolza revenue Our guidance assumes a significant decline in second quarter TRYNGOLZA revenue based on the updated price effective April 1st and a steady return to growth after the June 30th approval for sHTG. our guidance assumes a significant decline in second quarter tryngolza revenue based on the updated price effective april 1st and a steady return to growth after the june 30th approval for shtg We are projecting DAWNZERA product sales to be between $110 million and $120 million for the full year. we are projecting dawnzera product sales to be between $110 million and $120 million for the full year Our guidance assumes DAWNZERA will continue to be a significant contributor to year-over-year growth in 2026, with revenue steadily increasing as the launch advances. our guidance assumes dawnzera will continue to be a significant contributor to year-over-year growth in 2026 with revenue steadily increasing as the launch advances We also anticipate significant R&D revenue from existing collaborations, including potential development and regulatory milestones across our partnered portfolio, demonstrating that R&D revenue is indeed an important financial accelerator. we also anticipate significant r&d revenue from existing collaborations including potential development and regulatory milestones across our partnered portfolio demonstrating that r&d revenue is indeed an important financial accelerator In fact, we recently learned that the first patient-initiated treatment in the phase III program for salanersen, which triggered a $45 million payment we will recognize in the second quarter. Over the balance of the year, we also are eligible to earn additional milestones tied to sapablursen, bepirovirsen, pelacarsen, and other partnered programs as they advance. We expect our 2026 operating expenses to increase in the low teen percentage range compared to last year. This modest increase reflects our commitment to financial discipline as we bring multiple medicines directly to patients and advance our pipeline. The key drivers of expense growth will be sales and marketing investments to support TRYNGOLZA and DAWNZERA and to ensure successful launches for olezarsen in sHTG and zilganersen in Alexander disease, assuming approvals. We anticipate our R&D expenses to remain steady this year, similar to last year. In fact, we recently learned that the first patient-initiated treatment in the phase III program for salanersen, which triggered a $45 million payment we will recognize in the second quarter. in fact we recently learned that the first patient-initiated treatment in the phase iii program for salanersen which triggered a $45 million payment we will recognize in the second quarter Over the balance of the year, we also are eligible to earn additional milestones tied to sapablursen, bepirovirsen, pelacarsen, and other partnered programs as they advance. over the balance of the year we also are eligible to earn additional milestones tied to sapablursen bepirovirsen pelacarsen and other partnered programs as they advance We expect our 2026 operating expenses to increase in the low teen percentage range compared to last year. we expect our 2026 operating expenses to increase in the low teen percentage range compared to last year This modest increase reflects our commitment to financial discipline as we bring multiple medicines directly to patients and advance our pipeline. this modest increase reflects our commitment to financial discipline as we bring multiple medicines directly to patients and advance our pipeline The key drivers of expense growth will be sales and marketing investments to support TRYNGOLZA and DAWNZERA and to ensure successful launches for olezarsen in sHTG and zilganersen in Alexander disease, assuming approvals. We anticipate our R&D expenses to remain steady this year, similar to last year. the key drivers of expense growth will be sales and marketing investments to support tryngolza and dawnzera and to ensure successful launches for olezarsen in shtg and zilganersen in alexander disease assuming approvals. we anticipate our r&d expenses to remain steady this year similar to last year As late-stage studies reach completion, we are redeploying our resources towards the drugs in our pipeline that we expect to fuel our next phase of growth. Our focus on improving operating leverage is enabling us to drop the full increase in revenue guidance to the bottom line. As a result, we expect a non-GAAP operating loss between $425 million and $475 million, a $75 million improvement over our previous guidance. This is similar to our 2025 operating loss after adjusting for the one-time sapablursen license fee we earned last year. We are projecting a 2026 year-end cash balance of greater than $1.6 billion. This reflects the repayment of the 0% convertible notes, which were due on April 1st. As late-stage studies reach completion, we are redeploying our resources towards the drugs in our pipeline that we expect to fuel our next phase of growth. as late-stage studies reach completion we are redeploying our resources towards the drugs in our pipeline that we expect to fuel our next phase of growth Our focus on improving operating leverage is enabling us to drop the full increase in revenue guidance to the bottom line. our focus on improving operating leverage is enabling us to drop the full increase in revenue guidance to the bottom line As a result, we expect a non-GAAP operating loss between $425 million and $475 million, a $75 million improvement over our previous guidance. as a result, we expect a non-gaap operating loss between $425 million and $475 million a $75 million improvement over our previous guidance This is similar to our 2025 operating loss after adjusting for the one-time sapablursen license fee we earned last year. this is similar to our 2025 operating loss after adjusting for the one-time sapablursen license fee we earned last year We are projecting a 2026 year-end cash balance of greater than $1.6 billion. we are projecting a 2026 year-end cash balance of greater than $1.6 billion This reflects the repayment of the 0% convertible notes, which were due on April 1st. this reflects the repayment of the 0% convertible notes which were due on april 1st The strength of our balance sheet, combined with our diversified revenue streams, supports our continued strategic investments in ongoing and planned launches as we advance our wholly-owned pipeline. Our financial outlook reflects accelerating commercial launches, a progressing pipeline, and a diversified revenue base, positioning us for continued growth and keeping us on track for cash flow breakeven in 2028. With that, I'll turn the call back over to Brett. The strength of our balance sheet, combined with our diversified revenue streams, supports our continued strategic investments in ongoing and planned launches as we advance our wholly-owned pipeline. the strength of our balance sheet combined with our diversified revenue streams supports our continued strategic investments in ongoing and planned launches as we advance our wholly-owned pipeline Our financial outlook reflects accelerating commercial launches, a progressing pipeline, and a diversified revenue base, positioning us for continued growth and keeping us on track for cash flow breakeven in 2028. our financial outlook reflects accelerating commercial launches a progressing pipeline and a diversified revenue base positioning us for continued growth and keeping us on track for cash flow breakeven in 2028 With that, I'll turn the call back over to Brett. with that i'll turn the call back over to brett

Speaker 2: Thank you, Beth. The first quarter and our outlook for 2026 underscore the strength of Ionis today. With two successful independent launches underway, two more independent launches anticipated this year, a robust pipeline advancing toward multiple near and midterm catalysts, and a solid financial position that supports the continued investments we are making to maximize the value of our commercial medicines and pipeline. With all these key elements in place, we're confident in our ability to accelerate revenue growth and deliver increasing value for patients and for all Ionis stakeholders. In closing, I wanna highlight that this week at Ionis, we are holding our annual Why Week. It's a time when our employees come together to hear directly from patients and caregivers about their personal stories and reinforce our purpose, which is bringing better futures to people in need. Thank you, Beth. thank you beth The first quarter and our outlook for 2026 underscore the strength of Ionis today. the first quarter and our outlook for 2026 underscore the strength of ionis today With two successful independent launches underway, two more independent launches anticipated this year, a robust pipeline advancing toward multiple near and midterm catalysts, and a solid financial position that supports the continued investments we are making to maximize the value of our commercial medicines and pipeline. with two successful independent launches underway two more independent launches anticipated this year a robust pipeline advancing toward multiple near and midterm catalysts and a solid financial position that supports the continued investments we are making to maximize the value of our commercial medicines and pipeline With all these key elements in place, we're confident in our ability to accelerate revenue growth and deliver increasing value for patients and for all Ionis stakeholders. with all these key elements in place we're confident in our ability to accelerate revenue growth and deliver increasing value for patients and for all ionis stakeholders In closing, I wanna highlight that this week at Ionis, we are holding our annual Why Week. in closing i wanna highlight that this week at ionis we are holding our annual why week It's a time when our employees come together to hear directly from patients and caregivers about their personal stories and reinforce our purpose, which is bringing better futures to people in need. it's a time when our employees come together to hear directly from patients and caregivers about their personal stories and reinforce our purpose which is bringing better futures to people in need I've never been prouder of the impact we are having on patient lives and clinical medicine, and I'm even more excited about the greater impact we are positioned to make in the near-term and sustainably well into the future. With that, we'll now open the call up for questions. Sabrina? I've never been prouder of the impact we are having on patient lives and clinical medicine, and I'm even more excited about the greater impact we are positioned to make in the near- term and sustainably well into the future. i've never been prouder of the impact we are having on patient lives and clinical medicine and i'm even more excited about the greater impact we are positioned to make in the near- term and sustainably well into the future With that, we'll now open the call up for questions. with that we'll now open the call up for questions Sabrina? sabrina

Speaker 12: Thank you. We will now begin the question-and-answer session. To ask a question, you may press star then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster. The first question comes from Jessica Fye of JPMorgan. Please go ahead. Thank you. thank you We will now begin the question- and- answer session. we will now begin the question- and- answer session To ask a question, you may press star then one on your telephone keypad. to ask a question you may press star then one on your telephone keypad If you are using a speakerphone, please pick up your handset before pressing the keys. if you are using a speakerphone please pick up your handset before pressing the keys If at any time your question has been addressed and you would like to withdraw your question, please press star then two. if at any time your question has been addressed and you would like to withdraw your question please press star then two At this time, we will pause momentarily to assemble our roster. at this time we will pause momentarily to assemble our roster The first question comes from Jessica Fye of JP Morgan. the first question comes from jessica fye of jp morgan Please go ahead. please go ahead

Speaker 7: Hey, guys. Good morning. Thanks for taking my question. You once again raised peak expectations for TRYNGOLZA. Can you just spend a little time elaborating on what enabled you to increase it from at least $2 billion at JPMorgan to now at least $3 billion? Can you also talk about your expectation for gross to nets on TRYNGOLZA following this price reset? Thank you. Hey, guys. hey guys Good morning. good morning Thanks for taking my question. thanks for taking my question You once again raised peak expectations for TRYNGOLZA. you once again raised peak expectations for tryngolza Can you just spend a little time elaborating on what enabled you to increase it from at least $2 billion at JP Morgan to now at least $3 billion? can you just spend a little time elaborating on what enabled you to increase it from at least $2 billion at jp morgan to now at least $3 billion Can you also talk about your expectation for gross to nets on TRYNGOLZA following this price reset? can you also talk about your expectation for gross to nets on tryngolza following this price reset Thank you. thank you

Speaker 2: Yes. Jess, thank you for the question. Our increase in peak product sales for TRYNGOLZA and sHTG and FCS combined in the U.S. to $3 billion was based on several factors. As you recall, we increased the price, or the peak sales to $2 billion in January, based really solely on the phase III data and some preliminary HCP demand research that we had conducted. The demand was very high. Since then, we've completed our HCP demand research, but more importantly, we completed our payer research, which landed on our $40,000 annual WAC price. Price, as well as priority review. Those were the biggest drivers of the increase in peak sales that we have put out today. Yes. yes Jess, thank you for the question. jess thank you for the question Our increase in peak product sales for TRYNGOLZA and sHTG and FCS combined in the U.S. to $3 billion was based on several factors. our increase in peak product sales for tryngolza and shtg and fcs combined in the u.s to $3 billion was based on several factors As you recall, we increased the price, or the peak sales to $2 billion in January, based really solely on the phase III data and some preliminary HCP demand research that we had conducted. as you recall we increased the price or the peak sales to $2 billion in january based really solely on the phase iii data and some preliminary hcp demand research that we had conducted The demand was very high. the demand was very high Since then, we've completed our HCP demand research, but more importantly, we completed our payer research, which landed on our $40,000 annual WAC price. since then we've completed our hcp demand research but more importantly we completed our payer research which landed on our $40,000 annual wac price Price, as well as priority review. price as well as priority review Those were the biggest drivers of the increase in peak sales that we have put out today. those were the biggest drivers of the increase in peak sales that we have put out today As far as gross to net, we're not commenting on that at this time. As far as gross to net, we're not commenting on that at this time. as far as gross to net we're not commenting on that at this time

Speaker 7: Thank you. Thank you. thank you

Speaker 12: The next question comes from Mike Ulz of Morgan Stanley. Please go ahead. The next question comes from Mike Ulz of Morgan Stanley. the next question comes from mike ulz of morgan stanley Please go ahead. please go ahead

Speaker 9: Good morning. Thanks for taking the question, and congratulations on the progress. Maybe just a question on the TRYNGOLZA trajectory for the year. You mentioned, you know, return to growth in the second half, really driven by the sHTG launch. Just curious, in some of your market research, are you picking up on maybe any pent-up demand? You know, could we anticipate a bolus early in the launch year, just given the groundbreaking data? Thanks. Good morning. good morning Thanks for taking the question, and congratulations on the progress. thanks for taking the question and congratulations on the progress Maybe just a question on the TRYNGOLZA trajectory for the year. maybe just a question on the tryngolza trajectory for the year You mentioned, you know, return to growth in the second half, really driven by the sHTG launch. you mentioned you know return to growth in the second half really driven by the shtg launch Just curious, in some of your market research, are you picking up on maybe any pent-up demand? just curious in some of your market research are you picking up on maybe any pent-up demand You know, could we anticipate a bolus early in the launch year, just given the groundbreaking data? you know could we anticipate a bolus early in the launch year just given the groundbreaking data Thanks. thanks

Speaker 2: Kyle, would you take that, please? Kyle, would you take that, please? kyle would you take that please

Speaker 8: Yeah, Mike, appreciate that. I think what's important first is the strong performance that we saw in Q1 in terms of demand. It's the best quarter that we've had in terms of the FCS patient population, the number of scripts that were received, and the number of patients that are starting on therapy. That actually lends us a lot of confidence, not only in the FCS space, but also as we get closer to the June 30th PDUFA date in sHTG. I think it's indicating that there is a lot of interest in using olezarsen very broadly in this patient population. In terms of the launch in sHTG, we do know that there are a number of patients that are waiting, right? Yeah, Mike, appreciate that. yeah mike appreciate that I think what's important first is the strong performance that we saw in Q1 in terms of demand. i think what's important first is the strong performance that we saw in q1 in terms of demand It's the best quarter that we've had in terms of the FCS patient population, the number of scripts that were received, and the number of patients that are starting on therapy. it's the best quarter that we've had in terms of the fcs patient population the number of scripts that were received and the number of patients that are starting on therapy That actually lends us a lot of confidence, not only in the FCS space, but also as we get closer to the June 30th PDUFA date in sHTG. that actually lends us a lot of confidence not only in the fcs space but also as we get closer to the june 30th pdufa date in shtg I think it's indicating that there is a lot of interest in using olezarsen very broadly in this patient population. i think it's indicating that there is a lot of interest in using olezarsen very broadly in this patient population In terms of the launch in sHTG, we do know that there are a number of patients that are waiting, right? in terms of the launch in shtg we do know that there are a number of patients that are waiting right Especially the patients that have a history of acute pancreatitis, patients that are above 880 mg/dL, those are really the patients that we're gonna focus on out of the gate. The trajectory, I think, is gonna be modest at the beginning here in 2026. I think the revenue guidance that Beth shared, of $100 million-$110 million, is consistent with that expectation, we'll see it steadily grow over time with that focus being on the highest risk patient population. Some of the dynamics here, as typically seen, is it takes some time for the HCPs to be educated on the label. Especially the patients that have a history of acute pancreatitis, patients that are above 880 mg/dL , those are really the patients that we're gonna focus on out of the gate. especially the patients that have a history of acute pancreatitis patients that are above 880 mg/dl those are really the patients that we're gonna focus on out of the gate The trajectory, I think, is gonna be modest at the beginning here in 2026. the trajectory i think is gonna be modest at the beginning here in 2026 I think the revenue guidance that Beth shared, of $100 million- $110 million, is consistent with that expectation, we'll see it steadily grow over time with that focus being on the highest risk patient population. i think the revenue guidance that beth shared of $100 million- $110 million is consistent with that expectation we'll see it steadily grow over time with that focus being on the highest risk patient population Some of the dynamics here, as typically seen, is it takes some time for the HCPs to be educated on the label. some of the dynamics here as typically seen is it takes some time for the hcps to be educated on the label We've got to get those patients into those centers in order to get the prescriptions and then get the execution of the scripts to turn into patients on treatment. It'll be a build over time, and it will, you know, accumulate. We expect a modest and steady growth throughout the back half of this year. We've got to get those patients into those centers in order to get the prescriptions and then get the execution of the scripts to turn into patients on treatment. we've got to get those patients into those centers in order to get the prescriptions and then get the execution of the scripts to turn into patients on treatment It'll be a build over time, and it will, you know, accumulate. it'll be a build over time and it will you know accumulate We expect a modest and steady growth throughout the back half of this year. we expect a modest and steady growth throughout the back half of this year

Speaker 9: Great. Thank you. Great. great Thank you. thank you

Speaker 12: The next question comes from Gary Nachman, with Canaccord Genuity. Please go ahead. The next question comes from Gary Nachman, with Canaccord Genuity. the next question comes from gary nachman with canaccord genuity Please go ahead. please go ahead

Speaker 5: Hi, guys. Good morning and congrats on the progress. Again, on sHTG, just talk about how you expect the payer access to ramp up, the timing of that, when you think it'll really kick in. You got updated guidelines for FCS. Will you be able to get that for sHTG as well? How long before you think you could expand to a less severe patient population over time? Thanks. Hi, guys. hi guys Good morning and congrats on the progress. good morning and congrats on the progress Again, on sHTG, just talk about how you expect the payer access to ramp up, the timing of that, when you think it'll really kick in. again on shtg just talk about how you expect the payer access to ramp up the timing of that when you think it'll really kick in You got updated guidelines for FCS. you got updated guidelines for fcs Will you be able to get that for sHTG as well? will you be able to get that for shtg as well How long before you think you could expand to a less severe patient population over time? how long before you think you could expand to a less severe patient population over time Thanks. thanks

Speaker 2: Kyle, you wanna take, you wanna start? I can touch on the guidelines. Kyle, you wanna take, you wanna start? kyle you wanna take you wanna start I can touch on the guidelines. i can touch on the guidelines

Speaker 8: Sure. On, on the payer access piece, Gary, you know, part of the price change that decision that we made on April 1st to change the WAC price to $40,000 is directly in line with working with those payers, right? It fits into the annual review cycle as they're getting ready for their 2027 decisions to be made. We believe that it will help us get ahead of sHTG a little bit, not only in 2026, but also will help us in anticipation of 2027. That being said, some payers or all payers will actually wait for the final label, right, before they make any payer coverage decisions, because they wanna see what the indication statement is. Sure. sure On, on the payer access piece, Gary, you know, part of the price change that decision that we made on April 1st to change the WAC price to $40,000 is directly in line with working with those payers, right? on on the payer access piece gary you know part of the price change that decision that we made on april 1st to change the wac price to $40,000 is directly in line with working with those payers right It fits into the annual review cycle as they're getting ready for their 2027 decisions to be made. it fits into the annual review cycle as they're getting ready for their 2027 decisions to be made We believe that it will help us get ahead of sHTG a little bit, not only in 2026, but also will help us in anticipation of 2027. we believe that it will help us get ahead of shtg a little bit not only in 2026 but also will help us in anticipation of 2027 That being said, some payers or all payers will actually wait for the final label, right, before they make any payer coverage decisions, because they wanna see what the indication statement is. that being said some payers or all payers will actually wait for the final label right before they make any payer coverage decisions because they wanna see what the indication statement is They wanna see what information is in the label, you know, including, you know, acute pancreatitis, and some of the other clinical study data that will be included in the label. It'll take a little bit of time. Some payers will say, you know, "We're not gonna review anything for six to nine months," for example. That's standard policy with some payers. We hope that we'll be able to get ahead of that with the payers that do review earlier, by making that price change and also with our current interactions that we're having leading up to the sHTG approval. We're gonna work quickly, and I think we're in a good spot right now in terms of the way that we're approaching the payers. They wanna see what information is in the label, you know, including, you know, acute pancreatitis, and some of the other clinical study data that will be included in the label. they wanna see what information is in the label you know including you know acute pancreatitis and some of the other clinical study data that will be included in the label It'll take a little bit of time. it'll take a little bit of time Some payers will say, you know, "We're not gonna review anything for six to nine months," for example. some payers will say you know "we're not gonna review anything for six to nine months," for example That's standard policy with some payers. that's standard policy with some payers We hope that we'll be able to get ahead of that with the payers that do review earlier, by making that price change and also with our current interactions that we're having leading up to the sHTG approval. we hope that we'll be able to get ahead of that with the payers that do review earlier by making that price change and also with our current interactions that we're having leading up to the shtg approval We're gonna work quickly, and I think we're in a good spot right now in terms of the way that we're approaching the payers. we're gonna work quickly and i think we're in a good spot right now in terms of the way that we're approaching the payers

Speaker 2: Gary, to your other question, you know, we're very pleased by the fact that the cardiovascular treatment guidelines for FCS has singled out TRYNGOLZA as the treatment of choice for this disease indication. we applaud the aggressiveness that they are taking to update their guidelines for treatments. we believe that sHTG will be part of that in the future, which again, we believe TRYNGOLZA will be a treatment of choice for severe hypertriglyceridemia. They've been very supportive of the new treatments that are coming out, and we think that they will move pretty quickly. Gary, to your other question, you know, we're very pleased by the fact that the cardiovascular treatment guidelines for FCS has singled out TRYNGOLZA as the treatment of choice for this disease indication. we applaud the aggressiveness that they are taking to update their guidelines for treatments. we believe that sHTG will be part of that in the future, which again, we believe TRYNGOLZA will be a treatment of choice for severe hypertriglyceridemia. gary to your other question you know we're very pleased by the fact that the cardiovascular treatment guidelines for fcs has singled out tryngolza as the treatment of choice for this disease indication we applaud the aggressiveness that they are taking to update their guidelines for treatments we believe that shtg will be part of that in the future which again we believe tryngolza will be a treatment of choice for severe hypertriglyceridemia They've been very supportive of the new treatments that are coming out, and we think that they will move pretty quickly. they've been very supportive of the new treatments that are coming out and we think that they will move pretty quickly We're also pleased by the fact that they have increased or updated their guidelines on Lp(a) testing, which bodes well for a potential positive phase III readout for pelacarsen and the subsequent launch. It's great news for patients, and it's great news for our pipeline. In terms of the less severe patient population, you know, we'll start with the over 880 mg/dL and over 500 mg/dL with history of AP. However, those same physicians that are treating that patient population also have patients that are 500-880 mg/dL, for example. The education will be ongoing. We're in the right segment of HCPs in terms of our targets, right? Focused on cardiology, endocrinology, and lipid specialists. They'll see a mix of those patients. We're also pleased by the fact that they have increased or updated their guidelines on Lp(a) testing, which bodes well for a potential positive phase III readout for pelacarsen and the subsequent launch. we're also pleased by the fact that they have increased or updated their guidelines on lp(a) testing which bodes well for a potential positive phase iii readout for pelacarsen and the subsequent launch It's great news for patients, and it's great news for our pipeline. it's great news for patients and it's great news for our pipeline In terms of the less severe patient population, you know, we'll start with the over 880 mg/dL and over 500 mg/dL with history of AP. in terms of the less severe patient population you know we'll start with the over 880 mg/dl and over 500 mg/dl with history of ap However, those same physicians that are treating that patient population also have patients that are 500- 880 mg/dL, for example. however those same physicians that are treating that patient population also have patients that are 500- 880 mg/dl for example The education will be ongoing. the education will be ongoing We're in the right segment of HCPs in terms of our targets, right? we're in the right segment of hcps in terms of our targets right Focused on cardiology, endocrinology, and lipid specialists. focused on cardiology endocrinology and lipid specialists They'll see a mix of those patients. they'll see a mix of those patients I think some of those patients will already be picked up, especially if they have comorbidities, Type 2 diabetes and/or ASCVD. You know, the broader population will take a little bit of time just for awareness and for more of the data and information to come out and more experience of using olezarsen in the sHTG population. There's a lot of optimism and a lot of excitement around the category and around the use of a product like this because they've never seen the triglyceride-lowering effects that they're gonna see on top of standard of care, and they've never seen the outcomes in acute pancreatitis like they're, like they've seen with the CORE and CORE2 data. I think some of those patients will already be picked up, especially if they have comorbidities, Type 2 diabetes and/or ASCVD. i think some of those patients will already be picked up especially if they have comorbidities type 2 diabetes and/or ascvd You know, the broader population will take a little bit of time just for awareness and for more of the data and information to come out and more experience of using olezarsen in the sHTG population. you know the broader population will take a little bit of time just for awareness and for more of the data and information to come out and more experience of using olezarsen in the shtg population There's a lot of optimism and a lot of excitement around the category and around the use of a product like this because they've never seen the triglyceride-lowering effects that they're gonna see on top of standard of care, and they've never seen the outcomes in acute pancreatitis like they're, like they've seen with the CORE and CORE2 data. there's a lot of optimism and a lot of excitement around the category and around the use of a product like this because they've never seen the triglyceride-lowering effects that they're gonna see on top of standard of care and they've never seen the outcomes in acute pancreatitis like they're like they've seen with the core and core2 data

Speaker 5: Great. Thank you very much. Great. great Thank you very much. thank you very much

Speaker 12: The next question comes from Jason Gerberry with Bank of America. Please go ahead. The next question comes from Jason Gerberry with Bank of America. the next question comes from jason gerberry with bank of america Please go ahead. please go ahead

Speaker 3: Hey, good morning. This is Chi on for Jason. Thanks for taking our question. On olezarsen sHTG, could you give us an update on the levels of liver fat you have observed in the CORE open-label extension studies? To what extent those open-label extension study data have been incorporated into the NDA as the FDA reviews the totality of the safety data? When would you expect to present the updated OLE data later this year? Thanks so much. Hey, good morning. hey good morning This is Chi on for Jason. this is chi on for jason Thanks for taking our question. thanks for taking our question On olezarsen sHTG, could you give us an update on the levels of liver fat you have observed in the CORE open-label extension studies? on olezarsen shtg could you give us an update on the levels of liver fat you have observed in the core open-label extension studies To what extent those open-label extension study data have been incorporated into the NDA as the FDA reviews the totality of the safety data? to what extent those open-label extension study data have been incorporated into the nda as the fda reviews the totality of the safety data When would you expect to present the updated OLE data later this year? when would you expect to present the updated ole data later this year Thanks so much. thanks so much

Speaker 2: Yeah, let me start, Chi. Thank you for the question, then I'll pass it on to Eugene. Maybe you could comment on where we are in the regulatory process for sHTG briefly. We're very pleased with the ongoing open-label extension data that we're continuing to accumulate with respect to MRI as assessment of hepatic fat fraction. As you recall, the increases in hepatic fat that we saw were relatively minor, there were no clinical sequelae associated with increase in the small increases in triglycerides. We strongly believe this is a non-target effect. It's consistent with other modalities that have taken that silencing approach in lowering ApoC-III in this patient population. Yeah, let me start, Chi. yeah let me start chi Thank you for the question, then I'll pass it on to Eugene. thank you for the question then i'll pass it on to eugene Maybe you could comment on where we are in the regulatory process for sHTG briefly. maybe you could comment on where we are in the regulatory process for shtg briefly We're very pleased with the ongoing open-label extension data that we're continuing to accumulate with respect to MRI as assessment of hepatic fat fraction. we're very pleased with the ongoing open-label extension data that we're continuing to accumulate with respect to mri as assessment of hepatic fat fraction As you recall, the increases in hepatic fat that we saw were relatively minor, there were no clinical sequelae associated with increase in the small increases in triglycerides. as you recall the increases in hepatic fat that we saw were relatively minor there were no clinical sequelae associated with increase in the small increases in triglycerides We strongly believe this is a non-target effect. we strongly believe this is a non-target effect It's consistent with other modalities that have taken that silencing approach in lowering ApoC-III in this patient population. it's consistent with other modalities that have taken that silencing approach in lowering apoc-iii in this patient population It's completely logical based on the mechanism of inhibition of ApoC-III, which leads to a rapid and substantial clearance of triglycerides in large part through the liver. We've always felt that the observations in liver fat that we've seen here, again, no clinical sequelae associated, would be transient based on the liver just needing to have a little bit more time to clear out the liver that's being shunted through the liver. That's what we're seeing in the long-term extension data. We're seeing a return to baseline in liver fat. Again, no clinical associate sequelae associated with anything in the long-term extension. It's completely logical based on the mechanism of inhibition of ApoC-III, which leads to a rapid and substantial clearance of triglycerides in large part through the liver. it's completely logical based on the mechanism of inhibition of apoc-iii which leads to a rapid and substantial clearance of triglycerides in large part through the liver We've always felt that the observations in liver fat that we've seen here, again, no clinical sequelae associated, would be transient based on the liver just needing to have a little bit more time to clear out the liver that's being shunted through the liver. we've always felt that the observations in liver fat that we've seen here again no clinical sequelae associated would be transient based on the liver just needing to have a little bit more time to clear out the liver that's being shunted through the liver That's what we're seeing in the long-term extension data. that's what we're seeing in the long-term extension data We're seeing a return to baseline in liver fat. we're seeing a return to baseline in liver fat Again, no clinical associate sequelae associated with anything in the long-term extension. again no clinical associate sequelae associated with anything in the long-term extension We look forward to presenting the data in the second half of this year at a major, medical, congress. Stay tuned for that. Eugene, you wanna provide an update on regulatory? We look forward to presenting the data in the second half of this year at a major, medical, congress. we look forward to presenting the data in the second half of this year at a major medical congress Stay tuned for that. stay tuned for that Eugene, you wanna provide an update on regulatory? eugene you wanna provide an update on regulatory

Speaker 4: Yeah. The application's under review. Everything is going as planned. Of course, the emerging safety data has been provided to the agency as part of routine day 90 safety updates. That's under review now with no questions asked so far. Yeah. yeah The application's under review. the application's under review Everything is going as planned. everything is going as planned Of course, the emerging safety data has been provided to the agency as part of routine day 90 safety updates. of course the emerging safety data has been provided to the agency as part of routine day 90 safety updates That's under review now with no questions asked so far. that's under review now with no questions asked so far

Speaker 2: I'll also add that the discontinuations in the long-term extension are extremely low. We're seeing excellent compliance with long-term treatment in the open-label extension. Stay tuned. We're very much looking forward to presenting the results. I'll also add that the discontinuations in the long-term extension are extremely low. i'll also add that the discontinuations in the long-term extension are extremely low We're seeing excellent compliance with long-term treatment in the open-label extension. we're seeing excellent compliance with long-term treatment in the open-label extension Stay tuned. stay tuned We're very much looking forward to presenting the results. we're very much looking forward to presenting the results

Speaker 12: Great. Thanks. The next question comes from Ellie Merle of Barclays. Please go ahead. Great. great Thanks. thanks The next question comes from Ellie Merle of Barclays. the next question comes from ellie merle of barclays Please go ahead. please go ahead

Speaker 15: Hi, this is Tejas on for Ellie. Thanks for taking our question. In sHTG, you have a set of competitor readouts coming up later this year. Curious just how you would frame those data in the context of the space and if any outcomes there would impact your peak sales view in sHTG. Hi, this is Tejas on for Ellie. hi this is tejas on for ellie Thanks for taking our question. thanks for taking our question In sHTG, you have a set of competitor readouts coming up later this year. in shtg you have a set of competitor readouts coming up later this year Curious just how you would frame those data in the context of the space and if any outcomes there would impact your peak sales view in sHTG. curious just how you would frame those data in the context of the space and if any outcomes there would impact your peak sales view in shtg

Speaker 2: We'd rather not comment on competitor data that's doesn't even exist yet today. I mean, we're looking forward to seeing any additional data that comes out this year, next year, and years to come in sHTG from other programs. All I'll say is that the phase III data that we presented at American Heart Association in late-breaking clinical trial session last year is incredibly compelling. It's a very high bar to me with respect to efficacy, with respect to safety, with respect to tolerability. 85% reduction in acute pancreatitis, which has resonated very well in the HCP community as Kyle highlighted earlier in his prepared remarks. 72% reduction in triglycerides on top of standard of care. We'd rather not comment on competitor data that's doesn't even exist yet today. we'd rather not comment on competitor data that's doesn't even exist yet today I mean, we're looking forward to seeing any additional data that comes out this year, next year, and years to come in sHTG from other programs. i mean we're looking forward to seeing any additional data that comes out this year next year and years to come in shtg from other programs All I'll say is that the phase III data that we presented at American Heart Association in late-breaking clinical trial session last year is incredibly compelling. all i'll say is that the phase iii data that we presented at american heart association in late-breaking clinical trial session last year is incredibly compelling It's a very high bar to me with respect to efficacy, with respect to safety, with respect to tolerability. 85% reduction in acute pancreatitis, which has resonated very well in the HCP community as Kyle highlighted earlier in his prepared remarks. 72% reduction in triglycerides on top of standard of care. it's a very high bar to me with respect to efficacy with respect to safety with respect to tolerability 85% reduction in acute pancreatitis which has resonated very well in the hcp community as kyle highlighted earlier in his prepared remarks 72% reduction in triglycerides on top of standard of care We're focused on our program. We're ready to launch in June. You know, we're not, you know. I'll just leave it right there. Thank you. We're focused on our program. we're focused on our program We're ready to launch in June. we're ready to launch in june You know, we're not, you know. you know we're not you know I'll just leave it right there. i'll just leave it right there Thank you. thank you

Speaker 8: I'll just add, this is a large market, greater than 3 million patients that are potentially addressable here. We have a lot of confidence in the greater than $3 billion peak that we've put out there. That's really based on the phase III clinical trial outcomes that we have. It's based on our HCP demand research. It's based on the comprehensive, payer research that we've done and also the final pricing decision that we made. You know, we stand behind the increase, and we're excited about launching this program and getting it to as many patients as possible after the June 30 PDUFA date. I'll just add, this is a large market, greater than 3 million patients that are potentially addressable here. i'll just add this is a large market greater than 3 million patients that are potentially addressable here We have a lot of confidence in the greater than $3 billion peak that we've put out there. we have a lot of confidence in the greater than $3 billion peak that we've put out there That's really based on the phase III clinical trial outcomes that we have. that's really based on the phase iii clinical trial outcomes that we have It's based on our HCP demand research. it's based on our hcp demand research It's based on the comprehensive, payer research that we've done and also the final pricing decision that we made. it's based on the comprehensive payer research that we've done and also the final pricing decision that we made You know, we stand behind the increase, and we're excited about launching this program and getting it to as many patients as possible after the June 30 PDUFA date. you know we stand behind the increase and we're excited about launching this program and getting it to as many patients as possible after the june 30 pdufa date

Speaker 12: The next question comes from Jay Olson with Oppenheimer. Please go ahead. The next question comes from Jay Olson with Oppenheimer. the next question comes from jay olson with oppenheimer Please go ahead. please go ahead

Speaker 6: Oh, hey. Congrats on the quarter, and thank you for this update. Maybe I'll shift gears to DAWNZERA. Can you talk about how you expect the competitive landscape to evolve in HAE and any feedback that you're getting from patients and physicians on DAWNZERA and any color that you're getting on what percent of patients are currently on every eight-week dosing? Thank you. Oh, hey. oh hey Congrats on the quarter, and thank you for this update. congrats on the quarter and thank you for this update Maybe I'll shift gears to DAWNZERA. maybe i'll shift gears to dawnzera Can you talk about how you expect the competitive landscape to evolve in HAE and any feedback that you're getting from patients and physicians on DAWNZERA and any color that you're getting on what percent of patients are currently on every eight-week dosing? can you talk about how you expect the competitive landscape to evolve in hae and any feedback that you're getting from patients and physicians on dawnzera and any color that you're getting on what percent of patients are currently on every eight-week dosing Thank you. thank you

Speaker 2: Take that. Take that. take that

Speaker 8: Yeah, happy to, Jay. Thanks for the question. The competitive landscape obviously is evolving. I mean, there was some, you know, recent announcement as late as this week related to some of the dynamics in the marketplace. Keep in mind that in the United States, over 75% of the patients are currently on a prophylactic treatment. You know, this is a switch market as we understand the dynamics to be. We are really pleased with the momentum that we're seeing in terms of the interest in using DAWNZERA, which is the first RNA-targeted therapy modality in order to treat these patients. Yeah, happy to, Jay. yeah happy to jay Thanks for the question. thanks for the question The competitive landscape obviously is evolving. the competitive landscape obviously is evolving I mean, there was some, you know, recent announcement as late as this week related to some of the dynamics in the marketplace. i mean there was some you know recent announcement as late as this week related to some of the dynamics in the marketplace Keep in mind that in the United States, over 75% of the patients are currently on a prophylactic treatment. keep in mind that in the united states over 75% of the patients are currently on a prophylactic treatment You know, this is a switch market as we understand the dynamics to be. you know this is a switch market as we understand the dynamics to be We are really pleased with the momentum that we're seeing in terms of the interest in using DAWNZERA, which is the first RNA-targeted therapy modality in order to treat these patients. we are really pleased with the momentum that we're seeing in terms of the interest in using dawnzera which is the first rna-targeted therapy modality in order to treat these patients The patient and HCP feedback has been extremely positive when they've been able to transition over to DAWNZERA or start DAWNZERA as a naive patient. What led into this, you know, in terms of our market research is consistently being played out in the market. Really this is about efficacy, it's about tolerability and convenience. All three of those things are stacking up very nicely with the profile of DAWNZERA, and patients are responding very positively to the therapy. Now, the majority of patients start on a four-week dosing schedule. This is to make sure that they get transitioned over, that they're well-controlled, and then they have the option, per the labeled indication, to move over to every eight weeks if they choose to do so. The patient and HCP feedback has been extremely positive when they've been able to transition over to DAWNZERA or start DAWNZERA as a naive patient. the patient and hcp feedback has been extremely positive when they've been able to transition over to dawnzera or start dawnzera as a naive patient What led into this, you know, in terms of our market research is consistently being played out in the market. what led into this you know in terms of our market research is consistently being played out in the market Really this is about efficacy, it's about tolerability and convenience. really this is about efficacy it's about tolerability and convenience All three of those things are stacking up very nicely with the profile of DAWNZERA, and patients are responding very positively to the therapy. all three of those things are stacking up very nicely with the profile of dawnzera and patients are responding very positively to the therapy Now, the majority of patients start on a four-week dosing schedule. now the majority of patients start on a four-week dosing schedule This is to make sure that they get transitioned over, that they're well-controlled, and then they have the option, per the labeled indication, to move over to every eight weeks if they choose to do so. this is to make sure that they get transitioned over that they're well-controlled and then they have the option per the labeled indication to move over to every eight weeks if they choose to do so As early in the launch as we are right now, you would anticipate that the majority of patients would be on a four-week regimen. We will expect over time that they'll be able to progress onto an eight-week schedule as they're doing well on therapy, and we saw that in the clinical trial as well. Patients are doing great, momentum is very strong, and we're encouraged by what we're seeing in terms of the metrics with the launch at this point. As early in the launch as we are right now, you would anticipate that the majority of patients would be on a four-week regimen. as early in the launch as we are right now you would anticipate that the majority of patients would be on a four-week regimen We will expect over time that they'll be able to progress onto an eight-week schedule as they're doing well on therapy, and we saw that in the clinical trial as well. we will expect over time that they'll be able to progress onto an eight-week schedule as they're doing well on therapy and we saw that in the clinical trial as well Patients are doing great, momentum is very strong, and we're encouraged by what we're seeing in terms of the metrics with the launch at this point. patients are doing great momentum is very strong and we're encouraged by what we're seeing in terms of the metrics with the launch at this point

Speaker 6: Great. Thank you. Great. great Thank you. thank you

Speaker 12: The next question comes from Moritz Reiterer with Guggenheim Securities. Please go ahead. The next question comes from Moritz Reiterer with Guggenheim Securities. the next question comes from moritz reiterer with guggenheim securities Please go ahead. please go ahead

Speaker 10: Hi, this is Moritz on for Debjit. Thanks for taking our questions. I'll continue on DAWNZERA. Your 2026 guidance for DAWNZERA is substantially above what consensus was going into the quarter. I was just trying to understand a little bit better what data drove this guidance number. Also if you could comment a little bit more on the current mix between new patient starts versus switches, and how you expect this to evolve through the end of the year. Thank you. Hi, this is Moritz on for Debjit. hi this is moritz on for debjit Thanks for taking our questions. thanks for taking our questions I'll continue on DAWNZERA. i'll continue on dawnzera Your 2026 guidance for DAWNZERA is substantially above what consensus was going into the quarter. your 2026 guidance for dawnzera is substantially above what consensus was going into the quarter I was just trying to understand a little bit better what data drove this guidance number. i was just trying to understand a little bit better what data drove this guidance number Also if you could comment a little bit more on the current mix between new patient starts versus switches, and how you expect this to evolve through the end of the year. also if you could comment a little bit more on the current mix between new patient starts versus switches and how you expect this to evolve through the end of the year Thank you. thank you

Speaker 8: Yeah, I'd be happy to touch on that. Thanks for the question. You know, we had a very strong first quarter, $16 million in net product sales. This is a 128% increase over Q4. And I just spoke about the momentum that we're seeing in this market and the dynamics and also the receptivity by both HCPs and patients as they get started and gain experience with DAWNZERA. All of those things that I just described are really what is encouraging us and I think where we feel very confident that $110 million-$120 million in sales this year is very achievable. Yeah, I'd be happy to touch on that. yeah i'd be happy to touch on that Thanks for the question. thanks for the question You know, we had a very strong first quarter, $16 million in net product sales. you know we had a very strong first quarter $16 million in net product sales This is a 128% increase over Q4. this is a 128% increase over q4 And I just spoke about the momentum that we're seeing in this market and the dynamics and also the receptivity by both HCPs and patients as they get started and gain experience with DAWNZERA. and i just spoke about the momentum that we're seeing in this market and the dynamics and also the receptivity by both hcps and patients as they get started and gain experience with dawnzera All of those things that I just described are really what is encouraging us and I think where we feel very confident that $110 million-$120 million in sales this year is very achievable. all of those things that i just described are really what is encouraging us and i think where we feel very confident that $110 million-$120 million in sales this year is very achievable In terms of the new patient starts, the majority are switches, right. This is a switch market. Greater than 75% of the patients are on a prophylactic therapy in the United States. So it's gonna take time and time to build, you know, the revenues quarter-over-quarter. That it's happening the way that we expected it based on what we're seeing in the trends with Q4 as well as Q1. In addition to that, we are seeing some patients that haven't been on a prophylactic therapy before start on DAWNZERA. Those patients, in addition to those that are being treated with an acute therapy only today, that are starting on DAWNZERA. In terms of the new patient starts, the majority are switches, right. in terms of the new patient starts the majority are switches right This is a switch market. this is a switch market Greater than 75% of the patients are on a prophylactic therapy in the United States. greater than 75% of the patients are on a prophylactic therapy in the united states So it's gonna take time and time to build, you know, the revenues quarter-over-quarter. so it's gonna take time and time to build you know the revenues quarter-over-quarter That it's happening the way that we expected it based on what we're seeing in the trends with Q4 as well as Q1. that it's happening the way that we expected it based on what we're seeing in the trends with q4 as well as q1 In addition to that, we are seeing some patients that haven't been on a prophylactic therapy before start on DAWNZERA. in addition to that we are seeing some patients that haven't been on a prophylactic therapy before start on dawnzera Those patients, in addition to those that are being treated with an acute therapy only today, that are starting on DAWNZERA. those patients in addition to those that are being treated with an acute therapy only today that are starting on dawnzera You know, those three patient segments I think speak to the fact that, the profile is very strong in what patients and HCPs are looking for. We have a differentiated mechanism of action, and our sales execution and market access teams are doing a great job in terms of supporting these patients to get started and stay on treatment. You know, those three patient segments I think speak to the fact that, the profile is very strong in what patients and HCPs are looking for. you know those three patient segments i think speak to the fact that the profile is very strong in what patients and hcps are looking for We have a differentiated mechanism of action, and our sales execution and market access teams are doing a great job in terms of supporting these patients to get started and stay on treatment. we have a differentiated mechanism of action and our sales execution and market access teams are doing a great job in terms of supporting these patients to get started and stay on treatment

Speaker 12: The next question comes from Yaron Werber of TD Cowen. Please go ahead. The next question comes from Yaron Werber of TD Cowen. the next question comes from yaron werber of td cowen Please go ahead. please go ahead

Speaker 18: Hi, this is Steve, and on for Yaron. Thank you very much for the update, and congratulations on the progress. On the collaborative revenues for the rest of the year and for maybe 2027, can you talk about what you're projecting? 'Cause those came out a bit higher, I think, than consensus may have. Further on zilganersen, can you talk about how any patients' awareness efforts have found any new updates to the size of the market? You had mentioned before that about 50% of patients have been identified. Any update to the sizing there would be helpful. Thank you very much. Hi, this is Steve, and on for Yaron. hi this is steve and on for yaron Thank you very much for the update, and congratulations on the progress. thank you very much for the update and congratulations on the progress On the collaborative revenues for the rest of the year and for maybe 2027, can you talk about what you're projecting? 'Cause those came out a bit higher, I think, than consensus may have. on the collaborative revenues for the rest of the year and for maybe 2027 can you talk about what you're projecting 'cause those came out a bit higher i think than consensus may have Further on zilganersen, can you talk about how any patients' awareness efforts have found any new updates to the size of the market? further on zilganersen can you talk about how any patients' awareness efforts have found any new updates to the size of the market You had mentioned before that about 50% of patients have been identified. you had mentioned before that about 50% of patients have been identified Any update to the sizing there would be helpful. any update to the sizing there would be helpful Thank you very much. thank you very much

Speaker 2: If you wanna start and then, Kyle take the second part. If you wanna start and then, Kyle take the second part. if you wanna start and then kyle take the second part

Speaker 1: Sure. On the collaborative revenue for this year, the way to think about it is we've raised our revenue guidance for the total year to $875 million-$900 million. That is slightly weighted towards commercial revenue. You can think about that split being slightly more weighted towards commercial revenue versus R&D revenues. Obviously, we've already realized and recognized $95 million in milestones, plus our ongoing collaborative revenue, which put us, you know, well over $100 million, closer to $130 million, $140 million for the first quarter. We've got a host of other milestones that we could potentially earn over the remainder of this year, plus our ongoing collaborative revenue from Waylivra cost share and amortization. Sure. sure On the collaborative revenue for this year, the way to think about it is we've raised our revenue guidance for the total year to $875 million-$900 million. on the collaborative revenue for this year the way to think about it is we've raised our revenue guidance for the total year to $875 million-$900 million That is slightly weighted towards commercial revenue. that is slightly weighted towards commercial revenue You can think about that split being slightly more weighted towards commercial revenue versus R&D revenues. you can think about that split being slightly more weighted towards commercial revenue versus r&d revenues Obviously, we've already realized and recognized $95 million in milestones, plus our ongoing collaborative revenue, which put us, you know, well over $100 million, closer to $130 million, $140 million for the first quarter. obviously we've already realized and recognized $95 million in milestones plus our ongoing collaborative revenue which put us you know well over $100 million closer to $130 million, $140 million for the first quarter We've got a host of other milestones that we could potentially earn over the remainder of this year, plus our ongoing collaborative revenue from Waylivra cost share and amortization. we've got a host of other milestones that we could potentially earn over the remainder of this year plus our ongoing collaborative revenue from waylivra cost share and amortization That is, you know, all the items that really give us confidence in the overall collaborative revenue for this year. For 2027, we've got, think about it this way, there's some very large potential milestones for approvals coming in 2027 with the phase III data that we're expecting to see from pelacarsen, eplontersen in particular. Those milestones are likely gonna drive collaborative revenue in 2027. That is, you know, all the items that really give us confidence in the overall collaborative revenue for this year. that is you know all the items that really give us confidence in the overall collaborative revenue for this year For 2027, we've got, t hink about it this way, there's some very large potential milestones for approvals coming in 2027 with the phase III data that we're expecting to see from pelacarsen, eplontersen in particular. for 2027 we've got, t hink about it this way there's some very large potential milestones for approvals coming in 2027 with the phase iii data that we're expecting to see from pelacarsen eplontersen in particular Those milestones are likely gonna drive collaborative revenue in 2027. those milestones are likely gonna drive collaborative revenue in 2027

Speaker 2: Yeah. The, our launch preparations are going really well, right? Yeah. yeah The, our launch preparations are going really well, right? the our launch preparations are going really well right

Speaker 8: Yeah. For zilganersen, I just, I want to, you know, just reinforce the excitement that we've got around this program. You know, this is gonna be our first anticipated neurology launch program. To be able to potentially bring this therapy to patients living with Alexander disease, I think is really an exciting opportunity for the community and also exciting for Ionis. In terms of the approach here, we're really gonna be focused on the patients that are currently on the clinical trial and helping get those patients moved over so that they can maintain treatment. The second area that we'll focus on are patients that are going to be enrolled in our expanded access program, which is ongoing and going very well. Yeah. yeah For zilganersen, I just, I want to, you know, just reinforce the excitement that we've got around this program. for zilganersen i just i want to you know just reinforce the excitement that we've got around this program You know, this is gonna be our first anticipated neurology launch program. you know this is gonna be our first anticipated neurology launch program To be able to potentially bring this therapy to patients living with Alexander disease, I think is really an exciting opportunity for the community and also exciting for Ionis. to be able to potentially bring this therapy to patients living with alexander disease i think is really an exciting opportunity for the community and also exciting for ionis In terms of the approach here, we're really gonna be focused on the patients that are currently on the clinical trial and helping get those patients moved over so that they can maintain treatment. in terms of the approach here we're really gonna be focused on the patients that are currently on the clinical trial and helping get those patients moved over so that they can maintain treatment The second area that we'll focus on are patients that are going to be enrolled in our expanded access program, which is ongoing and going very well. the second area that we'll focus on are patients that are going to be enrolled in our expanded access program which is ongoing and going very well As, as you asked, what about the patients that are currently being identified and how do we help get those patients on treatment? We believe that there are approximately 300 or so Alexander disease patients in the United States. About 50% of those have been identified thus far. Some of them are on therapy that I just referenced. But we are doing some expanded work through our omni-channel and through our non-personal promotion campaigns to help identify more and more of these patients. Really what we want to make sure of is that they have the opportunity to experience zilganersen as the patients in the clinical trial did to potentially have the positive outcomes that were seen in that trial. As, as you asked, what about the patients that are currently being identified and how do we help get those patients on treatment? as as you asked what about the patients that are currently being identified and how do we help get those patients on treatment We believe that there are approximately 300 or so Alexander disease patients in the United States. we believe that there are approximately 300 or so alexander disease patients in the united states About 50% of those have been identified thus far. about 50% of those have been identified thus far Some of them are on therapy that I just referenced. some of them are on therapy that i just referenced But we are doing some expanded work through our omni-channel and through our non-personal promotion campaigns to help identify more and more of these patients. but we are doing some expanded work through our omni-channel and through our non-personal promotion campaigns to help identify more and more of these patients Really what we want to make sure of is that they have the opportunity to experience zilganersen as the patients in the clinical trial did to potentially have the positive outcomes that were seen in that trial. really what we want to make sure of is that they have the opportunity to experience zilganersen as the patients in the clinical trial did to potentially have the positive outcomes that were seen in that trial Patient identification will be a key area of focus, and we're doing that while we're really making sure that we're gonna take care of the patients that are on treatment today and those that are awaiting treatment that have already been identified. Patient identification will be a key area of focus, and we're doing that while we're really making sure that we're gonna take care of the patients that are on treatment today and those that are awaiting treatment that have already been identified. patient identification will be a key area of focus and we're doing that while we're really making sure that we're gonna take care of the patients that are on treatment today and those that are awaiting treatment that have already been identified

Speaker 12: The next question comes from Luca Issi of RBC Capital Markets. Please go ahead. The next question comes from Luca Issi of RBC Capital Markets. the next question comes from luca issi of rbc capital markets Please go ahead. please go ahead

Speaker 17: Thank you. Thanks so much for taking our questions. This is Kasian for Luca. Good morning, team. Quick question on WAINUA. What happened to WAINUA for the quarter? Drug is actually down 35% versus the fourth quarter. What drove the weakness here? It looks like AstraZeneca is flagging the availability of the drug now as a prefilled syringe to be administered by healthcare provider. Did that have a negative impact on growth to net? Any color there is much appreciated. Thank you so much. Thank you. thank you Thanks so much for taking our questions. thanks so much for taking our questions This is Kasian for Luca. this is kasian for luca Good morning, team. good morning team Quick question on WAINUA. quick question on wainua What happened to WAINUA for the quarter? what happened to wainua for the quarter Drug is actually down 35% versus the fourth quarter. drug is actually down 35% versus the fourth quarter What drove the weakness here? what drove the weakness here It looks like AstraZeneca is flagging the availability of the drug now as a prefilled syringe to be administered by healthcare provider. it looks like astrazeneca is flagging the availability of the drug now as a prefilled syringe to be administered by healthcare provider Did that have a negative impact on growth to net? did that have a negative impact on growth to net Any color there is much appreciated. any color there is much appreciated Thank you so much. thank you so much

Speaker 8: At Q1, we continued to see very strong demand in terms of patients on therapy as well as new patient starts. Demand is still there. Oftentimes you see some January, February pressure as it relates to reauthorizations and the timing of those reauthorizations, which drove some of the pressure early in the quarter. We expect to see that pick up in subsequent quarters and in return to revenue growth as we move into Q2 and beyond in the U.S. You asked about the prefilled syringe. Really that's been put out there for optionality, right? At Q1, we continued to see very strong demand in terms of patients on therapy as well as new patient starts. at q1 we continued to see very strong demand in terms of patients on therapy as well as new patient starts Demand is still there. demand is still there Oftentimes you see some January, February pressure as it relates to reauthorizations and the timing of those reauthorizations, which drove some of the pressure early in the quarter. oftentimes you see some january february pressure as it relates to reauthorizations and the timing of those reauthorizations which drove some of the pressure early in the quarter We expect to see that pick up in subsequent quarters and in return to revenue growth as we move into Q2 and beyond in the U.S. we expect to see that pick up in subsequent quarters and in return to revenue growth as we move into q2 and beyond in the u.s You asked about the prefilled syringe. you asked about the prefilled syringe Really that's been put out there for optionality, right? really that's been put out there for optionality right It's flexibility of dosing, and it's to allow HCPs to determine if they want to use the auto-injector or if they want to be able to treat these patients in some of the major centers with a prefilled syringe. It's really optionality for the program. That is not impacting the gross to net at this point. It's way too early to see any impact of that. You know, I would just keep an eye towards future quarters. Again, this is the hereditary polyneuropathy space. The market is growing rapidly on the cardiomyopathy space and the eye towards CARDIO-TTRansform readout and getting ready for that launch is definitely where the line of sight is. It's flexibility of dosing, and it's to allow HCPs to determine if they want to use the auto-injector or if they want to be able to treat these patients in some of the major centers with a prefilled syringe. it's flexibility of dosing and it's to allow hcps to determine if they want to use the auto-injector or if they want to be able to treat these patients in some of the major centers with a prefilled syringe It's really optionality for the program. it's really optionality for the program That is not impacting the gross to net at this point. that is not impacting the gross to net at this point It's way too early to see any impact of that. it's way too early to see any impact of that You know, I would just keep an eye towards future quarters. you know i would just keep an eye towards future quarters Again, this is the hereditary polyneuropathy space. again this is the hereditary polyneuropathy space The market is growing rapidly on the cardiomyopathy space and the eye towards CARDIO-TTRansform readout and getting ready for that launch is definitely where the line of sight is. the market is growing rapidly on the cardiomyopathy space and the eye towards cardio-ttransform readout and getting ready for that launch is definitely where the line of sight is

Speaker 17: Got it. Thank you. Got it. got it Thank you. thank you

Speaker 12: The next question is from Yanan Zhu with Wells Fargo Securities. Please go ahead. The next question is from Yanan Zhu with Wells Fargo Securities. the next question is from yanan zhu with wells fargo securities Please go ahead. please go ahead

Speaker 14: Great. Thanks for taking our questions. Wondering for the FCS, you mentioned a great continued growth in demand. Could you help quantify that a little bit in terms of percent growth, given that, you know, the price change making it difficult for us to appreciate? And then, can you talk about how to think about sHTG in 2027? What kind of growth could we expect from, you know, the initial launch quarters in 2026? Obviously, you guided for peak revenue at $3 billion. Any sense that how long that might take? Any color would be super helpful. Thank you. Great. great Thanks for taking our questions. thanks for taking our questions Wondering for the FCS, you mentioned a great continued growth in demand. wondering for the fcs you mentioned a great continued growth in demand Could you help quantify that a little bit in terms of percent growth, given that, you know, the price change making it difficult for us to appreciate? And then, c an you talk about how to think about sHTG in 2027? could you help quantify that a little bit in terms of percent growth given that you know the price change making it difficult for us to appreciate? and then, c an you talk about how to think about shtg in 2027 What kind of growth could we expect from, you know, the initial launch quarters in 2026? what kind of growth could we expect from you know the initial launch quarters in 2026 Obviously, you guided for peak revenue at $3 billion. obviously you guided for peak revenue at $3 billion Any sense that how long that might take? any sense that how long that might take Any color would be super helpful. any color would be super helpful Thank you. thank you

Speaker 2: Yeah. Yanan, let me start, and then I'll. Kyle already touched on what expectations are for 2026 launch in sHTG. He could cover that again, maybe comment on 2027. For FCS, as Kyle mentioned earlier, our first quarter of this year is our strongest quarter to date on patient demand and gaining access to TRYNGOLZA for FCS. That's purely a product of patient finding and the great experiences the HCPs and patients are having with TRYNGOLZA in managing their disease from an efficacy standpoint and from a tolerability standpoint. Demand has never been higher. We're thrilled with what we're seeing, and we think that that's gonna bode quite well for the sHTG launch. Yeah. yeah Yanan, let me start, and then I'll. yanan let me start and then i'll Kyle already touched on what expectations are for 2026 launch in sHTG. kyle already touched on what expectations are for 2026 launch in shtg He could cover that again, maybe comment on 2027. he could cover that again maybe comment on 2027 For FCS, as Kyle mentioned earlier, our first quarter of this year is our strongest quarter to date on patient demand and gaining access to TRYNGOLZA for FCS. for fcs as kyle mentioned earlier our first quarter of this year is our strongest quarter to date on patient demand and gaining access to tryngolza for fcs That's purely a product of patient finding and the great experiences the HCPs and patients are having with TRYNGOLZA in managing their disease from an efficacy standpoint and from a tolerability standpoint. that's purely a product of patient finding and the great experiences the hcps and patients are having with tryngolza in managing their disease from an efficacy standpoint and from a tolerability standpoint Demand has never been higher. demand has never been higher We're thrilled with what we're seeing, and we think that that's gonna bode quite well for the sHTG launch. we're thrilled with what we're seeing and we think that that's gonna bode quite well for the shtg launch Launch trajectory? Launch trajectory? launch trajectory

Speaker 8: Yeah, I think what's important again is to mention that in 2026, the revenue guidance is $100 million-$110 million for olezarsen this year. We expect that to grow steadily over time. As I also described, the focus initially is gonna be on the high risk sHTG patient population over 880 mg/dL or over 500 mg/dL with history of AP. As we get into 2027, I would expect that more and more patients will start to come on board that are broader than that, Type 2 diabetes, ASCVD, et cetera, as I described. The launch momentum will build, and so will the patient base. Yeah, I think what's important again is to mention that in 2026, the revenue guidance is $100 million-$110 million for olezarsen this year. yeah i think what's important again is to mention that in 2026 the revenue guidance is $100 million-$110 million for olezarsen this year We expect that to grow steadily over time. we expect that to grow steadily over time As I also described, the focus initially is gonna be on the high risk sHTG patient population over 880 mg/dL or over 500 mg/dL with history of AP. as i also described the focus initially is gonna be on the high risk shtg patient population over 880 mg/dl or over 500 mg/dl with history of ap As we get into 2027, I would expect that more and more patients will start to come on board that are broader than that, Type 2 diabetes, ASCVD, et cetera, as I described. as we get into 2027 i would expect that more and more patients will start to come on board that are broader than that type 2 diabetes ascvd et cetera as i described The launch momentum will build, and so will the patient base. the launch momentum will build and so will the patient base As we get these patients on, as HCPs get experience in seeing the triglyceride-lowering levels and seeing the reduction in acute pancreatitis, that were demonstrated in CORE and CORE2. I think that experience and that evidence ultimately, will help us drive the trajectory into next year. As we get these patients on, as HCPs get experience in seeing the triglyceride-lowering levels and seeing the reduction in acute pancreatitis, that were demonstrated in CORE and CORE2. as we get these patients on as hcps get experience in seeing the triglyceride-lowering levels and seeing the reduction in acute pancreatitis that were demonstrated in core and core2 I think that experience and that evidence ultimately, will help us drive the trajectory into next year. i think that experience and that evidence ultimately will help us drive the trajectory into next year

Speaker 14: Great. Thanks. Very helpful. Great. great Thanks. thanks Very helpful. very helpful

Speaker 12: The next question comes from Salveen Richter of Goldman Sachs. Please go ahead. The next question comes from Salveen Richter of Goldman Sachs. the next question comes from salveen richter of goldman sachs Please go ahead. please go ahead

Speaker 16: Hi, this is Mark on for Salveen. Thank you guys so much for taking our question. Congrats on the quarter. You kind of touched on the DAWNZERA quarterly dynamics. We were wondering, what are the specific drivers for the quarter-over-quarter jump? Are there quarterly dynamics we should be aware of for the rest of 2026? How are you thinking of these dynamics going into 2027 and beyond? Hi, this is Mark on for Salveen . hi this is mark on for salveen Thank you guys so much for taking our question. thank you guys so much for taking our question Congrats on the quarter. congrats on the quarter You kind of touched on the DAWNZERA quarterly dynamics. you kind of touched on the dawnzera quarterly dynamics We were wondering, what are the specific drivers for the quarter-over-quarter jump? we were wondering what are the specific drivers for the quarter-over-quarter jump Are there quarterly dynamics we should be aware of for the rest of 2026? are there quarterly dynamics we should be aware of for the rest of 2026 How are you thinking of these dynamics going into 2027 and beyond? how are you thinking of these dynamics going into 2027 and beyond

Speaker 8: Yeah, the real quarter-over-quarter growth is coming from the switch cadence that we are expecting to see, right? This being a switch market. We expect that to continue throughout the course of this year. That's the big driver, right? We know that, you know, that there's a need. We know that the profile of DAWNZERA meets the need of many of those patients, being efficacy, tolerability and convenience. We've got the data with the switch data to help support how to move those patients over from existing prophylactic treatments over to DAWNZERA. Yeah, the real quarter-over-quarter growth is coming from the switch cadence that we are expecting to see, right? yeah the real quarter-over-quarter growth is coming from the switch cadence that we are expecting to see right This being a switch market. this being a switch market We expect that to continue throughout the course of this year. we expect that to continue throughout the course of this year That's the big driver, right? that's the big driver right We know that, you know, that there's a need. we know that you know that there's a need We know that the profile of DAWNZERA meets the need of many of those patients, being efficacy, tolerability and convenience. we know that the profile of dawnzera meets the need of many of those patients being efficacy tolerability and convenience We've got the data with the switch data to help support how to move those patients over from existing prophylactic treatments over to DAWNZERA. we've got the data with the switch data to help support how to move those patients over from existing prophylactic treatments over to dawnzera As HCPs are gaining experience, we're seeing more and more HCPs not only prescribe for the first time, but we're also seeing those that have used the treatment before use it again and again. I think that plus payer coverage tells us that we've got an optimistic outlook in terms of what 2026 looks like. I think the $110 million-$120 million guidance is in line with that expectation. As HCPs are gaining experience, we're seeing more and more HCPs not only prescribe for the first time, but we're also seeing those that have used the treatment before use it again and again. as hcps are gaining experience we're seeing more and more hcps not only prescribe for the first time but we're also seeing those that have used the treatment before use it again and again I think that plus payer coverage tells us that we've got an optimistic outlook in terms of what 2026 looks like. i think that plus payer coverage tells us that we've got an optimistic outlook in terms of what 2026 looks like I think the $110 million-$120 million guidance is in line with that expectation. i think the $110 million-$120 million guidance is in line with that expectation

Speaker 2: We have time for one more question, please. We have time for one more question, please. we have time for one more question please

Speaker 12: The last question comes from Myles Minter with William Blair. Please go ahead. The last question comes from Myles Minter with William Blair. the last question comes from myles minter with william blair Please go ahead. please go ahead

Speaker 11: Hey, thanks for sending me in and congrats on the quarter. Just on the TTR cardiomyopathy market, you know, Pfizer did settle for a potential generic entry from VYNDAMAX in mid-2031 versus something like, you know, in 2035. Does that change the way you or AstraZeneca are thinking about the cardiomyopathy market moving forward? How much emphasis you're gonna place on that stabilizer background therapy subgroup in CARDIO-TTRansform? Thanks very much. Hey, thanks for sending me in and congrats on the quarter. hey thanks for sending me in and congrats on the quarter Just on the TTR cardiomyopathy market, you know, Pfizer did settle for a potential generic entry from VYNDAMAX in mid- 2031 versus something like, you know, in 2035. just on the ttr cardiomyopathy market you know pfizer did settle for a potential generic entry from vyndamax in mid- 2031 versus something like you know in 2035 Does that change the way you or AstraZeneca are thinking about the cardiomyopathy market moving forward? does that change the way you or astrazeneca are thinking about the cardiomyopathy market moving forward How much emphasis you're gonna place on that stabilizer background therapy subgroup in CARDIO-TTRansform? how much emphasis you're gonna place on that stabilizer background therapy subgroup in cardio-ttransform Thanks very much. thanks very much

Speaker 2: Thank you, Myles. You know, the news that has been emerging this past week or so on genericizing tafamidis versus brand pricing has not come terribly surprising to us. It's consistent with our product sales guidance that we've put out there with AstraZeneca previously. We believe, we remain completely and believe that the silencer class will end up being the mechanism of choice for TTR amyloidosis. We believe that the silencer class will be utilized as first-line treatment, as well as in those patients that inevitably progress on stabilizers. Thank you, Myles. thank you myles You know, the news that has been emerging this past week or so on genericizing tafamidis versus brand pricing has not come terribly surprising to us. you know the news that has been emerging this past week or so on genericizing tafamidis versus brand pricing has not come terribly surprising to us It's consistent with our product sales guidance that we've put out there with AstraZeneca previously. it's consistent with our product sales guidance that we've put out there with astrazeneca previously We believe, we remain completely and believe that the silencer class will end up being the mechanism of choice for TTR amyloidosis. we believe we remain completely and believe that the silencer class will end up being the mechanism of choice for ttr amyloidosis We believe that the silencer class will be utilized as first- line treatment, as well as in those patients that inevitably progress on stabilizers. we believe that the silencer class will be utilized as first- line treatment as well as in those patients that inevitably progress on stabilizers Combination usage, to your question, will also be utilized very, very, you know, robustly, especially if there's data supporting that combination usage will add further benefit to these patients that inevitably are progressing on current treatments. Our study is designed to actually generate the data that we believe could be convincing to HCPs who are asking the question whether or not combination of a stabilizer with a silencer will add further benefit to these patients. It's the largest study ever conducted in ATTR cardiomyopathy, and the combination subgroup is quite sizable. We're looking forward to the data in the second half of this year. Combination usage, to your question, will also be utilized very, very, you know, robustly, especially if there's data supporting that combination usage will add further benefit to these patients that inevitably are progressing on current treatments. combination usage to your question will also be utilized very very you know robustly especially if there's data supporting that combination usage will add further benefit to these patients that inevitably are progressing on current treatments Our study is designed to actually generate the data that we believe could be convincing to HCPs who are asking the question whether or not combination of a stabilizer with a silencer will add further benefit to these patients. our study is designed to actually generate the data that we believe could be convincing to hcps who are asking the question whether or not combination of a stabilizer with a silencer will add further benefit to these patients It's the largest study ever conducted in ATTR cardiomyopathy, and the combination subgroup is quite sizable. it's the largest study ever conducted in attr cardiomyopathy and the combination subgroup is quite sizable We're looking forward to the data in the second half of this year. we're looking forward to the data in the second half of this year We're prepared to submit the NDA by the end of this year and to launch next year. Thank you, Myles, for that. Thank you for the question, Myles. Thank you everybody who joined us today and participated on our call. We're looking forward to an outstanding year and sharing our progress along the way. Until then, thank you and have a great day, everybody. We're prepared to submit the NDA by the end of this year and to launch next year. we're prepared to submit the nda by the end of this year and to launch next year Thank you, Myles, for that. thank you myles for that Thank you for the question, Myles. thank you for the question myles Thank you everybody who joined us today and participated on our call. thank you everybody who joined us today and participated on our call We're looking forward to an outstanding year and sharing our progress along the way. we're looking forward to an outstanding year and sharing our progress along the way Until then, thank you and have a great day, everybody. until then thank you and have a great day everybody

Speaker 12: Goodbye. Goodbye. goodbye