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

Thank you, Amy. 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 that we will be discussing today, including a reconciliation of our GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We've also posted slides on our website that accompany today's call. With me this morning are Brett Monia, our Chief Executive Officer; Kyle Jenne, Chief Global Product Strategy Officer; and Beth Hougen, Chief Financial Officer. Richard Geary, Chief Development Officer; Eugene Schneider, Chief Clinical Development Officer; Eric Swayze, Executive Vice President of Research; and Jonathan Birchall, Chief Commercial Officer, will also join us for the Q&A portion of our call. I would like to draw your attention to Slide 3, which contains our forward-looking language statement. During this call, we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consider the risk factors contained in our SEC filings for additional detail. And with that, I'll turn the call over to Brett.

Thanks, Wade. Good morning, everyone, and thanks for joining us today. Before we discuss our Q1 earnings and recent progress, I want to take a moment to acknowledge the rapidly evolving environment we're living in today. Recent changes at the FDA and the introduction of new tariff policies have introduced a degree of uncertainty with the potential for a disruption in our industry. Despite these external uncertainties, Ionis remains well positioned to execute on our strategic priorities, including all of our many value-driving catalysts coming up this year and next. We remain focused on our purpose to drive meaningful value for all Ionis stakeholders by successfully bringing better futures to people with serious diseases. We are executing very well against all our strategic priorities. A clear example of our ongoing successes is the completion of two strategic licensing transactions recently which enabled us to substantially increase our 2025 financial guidance. This includes higher expected revenue and cash along with improved operating loss. Raising guidance this early in the year reflects our confidence in our ability to continue executing well, including our ability to deliver transformational medicines to patients even amid the current volatility and our commitment and expectation to drive long-term value for shareholders. We achieved a major milestone for Ionis with our first independent commercial launch now successfully underway. I'm pleased to share that in its first full quarter on the market, TRYNGOLZA, the first and only FDA-approved treatment for familial chylomicronemia syndrome exceeded expectations. This encouraging start reflects our commercial team's thoughtful planning, outstanding execution and highlights the commercial capabilities that we have built. Right behind TRYNGOLZA is our second independent launch, donidalorsen for hereditary angioedema, or HAE, which is rapidly approaching. The team is laser-focused on ensuring success. donidalorsen has the potential to become a preferred treatment for HAE, and we remain on track to launch in the third quarter. These launches are just beginning. We're poised to report data from two Ionis-owned Phase III programs later this year, which, if positive, will enable us to continue delivering a steady cadence of important medicines to even more patients. These are a second indication for olezarsen severe hypertriglyceridemia, or sHTG, a large population with high unmet need; and zilganersen for Alexander's disease, a severe, rare leukodystrophy with no approved therapies. Collectively, these 4 programs represent needed patient breakthroughs and multibillion-dollar revenue potential for Ionis. Additionally, in the next three years, we expect four launches from our late-stage partnered medicines currently in development to treat a range of serious life-threatening diseases. These medicines are poised to significantly increase our revenues by expanding the reach of Ionis discovered medicines to more patients that are in need. With the recent launch of TRYNGOLZA and our upcoming independent and partner launches, Ionis is on a path to bring important medicines to patients for years to come, positioning us to achieve substantial and sustained revenue growth and positive cash flow. With that, I'll turn the call over to Kyle.

Thank you, Brett. With our first independent launch underway and three additional independent launches planned in the next two years, our commercial team is executing on a focused agenda with substantial growth potential. We're well positioned to build on the early success of TRYNGOLZA while we prepare for our other upcoming launches. Donidalorsen for HAE is on track for anticipated approval in August, followed by olezarsen for sHTG, which is on pace for Phase III data in the third quarter and a potential launch next year. Let's start with TRYNGOLZA which had an encouraging debut in the first quarter. Our commercial team executed seamlessly delivering on all initial launch objectives and exceeding expectations with over $6 million in net product sales in the first quarter. In this first full quarter on the market, we saw strong patient uptake driven by multiple factors. First, we successfully converted nearly all of the U.S. expanded access and clinical trial patients to commercial product. Second, as TRYNGOLZA is the first and only approved FDA treatment for FCS, early uptake benefited from patients who had been previously diagnosed and were waiting for treatment. And third, our patient finding efforts ahead of launch paid off contributing to scripts from newly identified and diagnosed FCS patients. Physician engagement has also gained meaningful traction. We've been encouraged by the initial breadth of physicians prescribing TRYNGOLZA with scripts from a mix of specialists across the country. At the end of Q1, the initial prescriber mix included approximately 50% cardiologists and 25% endocrinologists with lipidologists and internal medicine HCPs comprising the rest. Physicians have also reported positive and deeply moving feedback, including one doctor who shared that he was over the moon that this was the lowest as patient's TG levels have ever been. On the access front, coverage and reimbursement dynamics have been favorable. The coverage split for patients on TRYNGOLZA to date is just over 60% commercial and just under 40% government. Importantly, patients whether clinically diagnosed or genetically confirmed have received timely access with most receiving coverage through the medical exception process based on clinical diagnosis. This underscores both the urgency of the high unmet need and payer willingness to support access ahead of establishing formal policies. As payers establish coverage policies over the next several months, it will be important that these policies support both clinical and genetic diagnosis pathways. To this end, our market access team is actively engaging with payers to enable continued patient access. Through the first quarter, the team had already engaged with payers representing the vast majority of covered lives in the U.S. and are working towards getting additional policies in place. We're also seeing positive trends beyond coverage, including reimbursement timelines that have exceeded our internal benchmarks. And in the first full quarter of launch, nearly 90% of patients had zero out-of-pocket costs highlighting the effectiveness of our Ionis Every Step Support program. Ionis Every Step has been instrumental in delivering high-quality experience for both patients and providers. More than 90% of patients have opted in, receiving support that includes disease and nutrition education, auto-injector administration training, reimbursement support and more. For health care providers, the program streamlines prescribing by handling insurance authorization and coverage assistance as well as coordinating delivery, reauthorizations and refills. We're proud of TRYNGOLZA's early momentum, but we know we're still in the early innings. The vast majority of the estimated 3,000 people living with FCS in the U.S. remain unidentified. To close that gap, we're continuing to focus on our patient finding efforts and HCP education, targeting physicians who treat patients with severe hypertriglyceridemia to increase FCS awareness. At the same time, our payer engagement efforts will continue to focus on establishing broad durable access. Backed by an experienced and high-performing team, we are well positioned to build on our first mover advantage to bring TRYNGOLZA to patients in need and keep them on treatment. Building on our foundation in FCS, we're advancing toward the blockbuster opportunity in sHTG with olezarsen. Like FCS, sHTG is a serious condition defined by triglyceride levels over 500 milligrams per deciliter, well above the normal level of less than 150 milligrams per deciliter. These levels are easily determined through routine fasting blood tests. sHTG affects a broad population with many people unable to adequately manage their triglycerides with currently available treatments. This is particularly true for individuals with high-risk sHTG, defined as triglyceride levels greater than 880 milligrams per deciliter or greater than 500 milligrams per deciliter with a history of acute pancreatitis or other comorbidities. There are more than one million of these especially vulnerable people in the U.S., which represents our initial target population for olezarsen assuming approval. As we heard during our recent KOL panel, sHTG represents a significant unmet medical need and physicians are eager for better treatment options, especially those that can reduce TGs down below pancreatitis risk levels. For example, Dr. Allan Brown, a leading cardiologist focused on lipid management showed that sHTG can be devastating, with patients experiencing recurrent pancreatitis attacks despite best efforts. His primary goal is to reduce the risk of acute pancreatitis, which carries significant mortality and morbidity. Importantly, all three panelists agreed that APOC3 inhibition offers a promising new therapeutic pathway with the potential to help patients dramatically reduce their triglycerides and the associated risk of acute pancreatitis. This view is also shared by other physicians who we've engaged with, including recent discussions at the American Academy of Cardiology Annual Conference with KOLs and community cardiologists. With this conviction to treat, we believe olezarsen is well positioned to meet the needs of people with sHTG and we're making excellent progress across clinical and commercial fronts as we prepare for an anticipated launch next year where we also have first-mover advantage. We expect data from our supportive safety study, ESSENCE, in the second quarter. We then expect to report data in the third quarter from our global pivotal sHTG studies. These pivotal studies, CORE and CORE2, are being conducted in our target sHTG population defined by triglycerides greater than 500 milligrams per deciliter. Baseline characteristics were recently published in the American Heart Journal showing that fasting, median triglycerides at baseline in CORE and CORE2 were 836 and 749 milligrams per deciliter, respectively. And across the two studies, nearly half of participants had baseline TG levels of greater than 880, even though all participants were receiving standard of care therapy. Additionally, 22% and 13% of participants had a history of pancreatitis in the last 10 years prior to enrollment in CORE and CORE2, respectively. Importantly, both studies are well powered to show a significant reduction in triglycerides and it's this reduction that we expect will lead to improvements in clinical outcomes for patients. Assuming positive data, we plan to submit an sNDA before year-end. We're also expanding olezarsen's reach. We recently broadened our partnership with Sobi who will commercialize olezarsen in most markets outside the U.S., including in Europe, which is on pace for an FCS approval decision later this year. This agreement expands the reach of TRYNGOLZA to more patients globally, while providing us the opportunity to earn milestone payments and royalties up to the mid-20% range. This significant first-mover advantage in both FCS and sHTG compelling real-world data and Phase III results in FCS and confidence in the upcoming data for sHTG we believe olezarsen is well positioned to become the standard of care in both indications, transforming treatment for thousands of people and driving long-term growth for Ionis. Turning to donidalorsen, our second anticipated independent launch, we see compelling opportunity to advance the prophylactic treatment for people with hereditary angioedema. We're applying the same discipline and focus that is driving a successful TRYNGOLZA launch as we prepare to bring donidalorsen to market. More than 20,000 people in the U.S. and Europe are estimated to have HAE. In the U.S., most of these patients are on prophylactic treatment. As this market continues to evolve, up to 20% of patients annually have switched treatments in search of more effective and convenient options, signaling that current therapies aren't adequately addressing patients' needs. Additionally, a recent Harris poll found that 9 in 10 HAE patients surveyed are interested in trying new prophylactic therapies and we believe donidalorsen is uniquely positioned to meet that demand if approved. With strong clinical data, a patient-friendly auto-injector and monthly or every other month dosing, we believe donidalorsen checks all the boxes that people with HAE are looking for in a next-generation prophylactic treatment. We're building momentum ahead of launch by drawing on learnings and infrastructure from our ongoing TRYNGOLZA and WAINUA launches. This includes expanding our Ionis every step patient support program to address the unique needs of HAE patients to ensure they have a seamless treatment experience. We've already hired a substantial portion of our field-facing team and remain on track to complete hiring and training ahead of the anticipated approval. Our market access team is actively engaging with payers and our medical affairs team has also been laying the groundwork for a successful launch. Their efforts include showcasing our robust donidalorsen clinical data and Ionis' technology at key medical conferences. For example, at the recent Quad AI meeting, we delivered 11 poster presentations and had robust engagement at our booth, including a dedicated space for unbranded HAE disease awareness campaign. We also capitalized on the conference's San Diego location by welcoming physicians to our campus for deeper in-person education about Ionis' science and technology. Physician feedback continues to be positive, particularly regarding our SWITCH study, which we believe could be a key differentiator in a competitive space. The study showed that people switching to donidalorsen from other prophylactic treatments experienced a further reduction in attacks and 84% of those surveyed said they preferred donidalorsen compared to their previous prophylactic treatment. While we recognize that converting people from existing therapies will take time, we're confident that donidalorsen represents a compelling opportunity to be the preferred prophylactic treatment for many HAE patients. We're excited about the road ahead and well positioned to bring donidalorsen to people who need it, assuming approval. Our highly experienced, efficient and scalable commercial organization is delivering tangible results with the TRYNGOLZA-FCS launch underway. And as we build on these efforts, we're focused on maximizing TRYNGOLZA's full potential while preparing to successfully execute on our three additional launches planned over the next two years with more to follow positioning Ionis for sustained growth and long-term success. With that, I'll now turn the call over to Beth.

Thank you, Kyle. I am pleased to share today that we are increasing our 2025 financial guidance across all metrics, including raising revenue by more than 20% due to our strong first quarter results and recent successful licensing transactions. We earned $132 million of revenue in the first quarter, which increased 10% year-over-year. More than half of our revenue came from commercial products which grew 28% compared to the same period last year. Our increasing revenue reflected the encouraging early performance of the TRYNGOLZA launch marking the first time in our company's history, we've reported product revenue. In the first full quarter of the launch, TRYNGOLZA generated over $6 million in product sales exceeding expectations. As Kyle discussed, we saw a good uptake from patients awaiting treatment and from newly identified patients. Our commercial revenue also included $48 million in SPINRAZA royalties from substantial SPINRAZA product sales, which increased 25% year-over-year. Additionally, we earned $9 million in WAINUA royalties. We and our partner, AstraZeneca, expect WAINUA revenue to grow this year, driven by strong U.S. demand and an expanding global footprint following the recent EU approval. The remainder of our revenue came from programs under our R&D collaborations underscoring the important financial contributions of our partnered pipeline. You may have noticed we've streamlined the revenue section of our P&L. We did this to reflect our new chapter as a commercial stage biotech and to plan for numerous independent launches in the coming years. Total non-GAAP operating expenses increased less than 5%, reflecting our commitment to disciplined investment and driving operating leverage. As planned, our sales and marketing expenses increased year-over-year, reflecting our investments in the U.S. launch of TRYNGOLZA and preparations for the upcoming launch of donidalorsen. Our SG&A expenses also included our minority portion of WAINUA's sales and marketing expenses. R&D expenses decreased year-over-year as several of our late-stage studies recently concluded. Importantly, we continue to appropriately fund our advancing pipeline with a large majority of our total R&D expenses funding our late-stage programs. Building on our strong first quarter results, we recently completed licensing transactions for sapablursen and ex U.S. commercialization rights for olezarsen that meaningfully enhanced our financial outlook. This is the reason we are substantially increasing our 2025 guidance. Last week, we finalized the licensing of sapablursen, a medicine outside of our core disease areas of cardiology and neurology and generating $280 million. This transaction enables us to remain focused on realizing the potential of the medicines that we plan to independently bring to patients while further strengthening our financial position. Additionally, we are eligible to earn significant milestone payments as sapablursen advances together with royalties up to the mid-teen percentage range on future product sales. As a result of the substantial license fees, which exceeded the probabilized revenue included in our original guidance, we are increasing our revenue guidance by more than 20%. We now expect to earn revenue in the $725 million to $750 million range for the year. Our revenue guidance also includes sizable commercial revenue anchored by stable SPINRAZA royalties and growing WAINUA royalties. And with our first independent launch underway, we expect increasing product revenues as the year progresses. As the TRYNGOLZA launch progresses, it's important to remember that FCS is a rare disease with most patients still unidentified and undiagnosed. Therefore, our focus remains on disease education and patient identification, both of which will take time. We're also on track to add initial product revenue from our second launch with the FDA action date for donidalorsen set for August 21. In addition to the sapablursen revenue, we will recognize in Q2, we expect to earn additional R&D revenue from partnered programs later this year. We continue to project our full year 2025 operating expenses to increase in the high single-digit percentage range compared to last year. This increase will be driven by SG&A expenses as we invest to support the success of our multiple ongoing and planned launches. We project our R&D expenses to remain steady this year similar to last year. As several of our late-stage studies have recently concluded or are wrapping up this year, we are able to reallocate our resources toward our next wave of opportunities, including ION582 for Angelman syndrome, which we expect to start Phase III development shortly. Since our license fee revenue drops entirely to our bottom line, we are improving our non-GAAP operating loss guidance by nearly 25% to less than $375 million. And we now expect to end the year with $1.9 billion in cash. Our strength in balance sheet and commitment to drive operating leverage positions us well to advance our strategic priorities in this dynamic macroeconomic environment. Looking beyond 2025, we are confident in our ability to deliver sustained revenue growth. The late-stage programs we have in our pipeline today represent a significant opportunity with combined peak sales potential in the multibillion-dollar range. We expect our Ionis-owned medicines to generate more than $3 billion in peak annual product sales. This, of course, means that we will continue making investments to bring these medicines to patients. On top of our substantial product revenue opportunity, our late-stage partner of medicines could contribute over $2 billion annually in peak royalties. Notably, nearly all of these medicines are on track to deliver Phase III data either this year or next year, setting the stage for potential launches soon after. Together, these upcoming launches are poised to reach hundreds of thousands of patients worldwide and in turn, position Ionis to deliver significant top line growth and reach sustainable positive cash flow, turning scientific innovation into long-term value for shareholders. And with that, I'll turn the call back over to Brett.

Thank you, Beth. We've accomplished a great deal to get us where we are today, a fully integrated, commercial-stage biotech company with our first independent launch well underway. Slide 25 is off to an excellent start, including the U.S. TRYNGOLZA launch. With additional upcoming launches anticipated, including donidalorsen for HAE and a deep commitment to innovation, we're well positioned to drive accelerating value. It's through Ionis' innovation that we've established a proven discovery and development engine, which has provided us with a pipeline of medicines with transformational potential. Our pipeline continues to deliver. We are on track for olezarsen and zilganersen Phase III data later this year that if positive would expand the reach of our medicines to even more patients. And with many additional Phase III data readouts expected next year, we're well positioned to continue bringing a steady cadence of medicines to patients. Our scalable and experienced commercial organization is executing well, as demonstrated by the encouraging start to the TRYNGOLZA launch. Furthermore, our commercial organization has established a solid foundation to support multiple planned product launches in the future. And based on recent successful licensing transactions, along with our first quarter results and disciplined financial management, we significantly increased our 2025 financial guidance. Importantly, the progress we've made puts us on a clear path to achieving positive cash flow supported by our expectations for substantial top line revenue growth. And with that, we'll now open the call up for questions.

We'll now take questions from analysts, starting with Jay Olson from Oppenheimer.

We're curious about olezarsen and any overlap between physician prescribers for FCS and sHTG and how you plan to leverage that? And then related to that, would approximately 20% pancreatitis history for the patients enrolled in your pivotal sHTG studies provide sufficient power to show AP reduction and what level of AP reduction are you targeting?

Thanks, Jay. Kyle will take the overlap of prescribers for FCS, sHTG, and I'll touch on the AP question you had.

Yes. Thanks, Jay. First, I mean, the TRYNGOLZA launch is really off to an encouraging start. The execution by the commercial team has been very strong. I'm very pleased with where we're at right now. As we discussed, we've been able to convert the EAP and OLE patients, those that have been waiting for a therapy have begun getting treatment, and we are also identifying new patients. The current targets that we have are a few thousand physicians, as you would expect, based on the type that are treating FCS today. These are our cardiologists and endocrinologists and they're seeing sHTG patients, but they're also seeing FCS patients. So that's kind of the runway to get us to sHTG. When you get to sHTG, the population expands, obviously, upwards of north of a million patients and as we go there, the overlap is quite significant. They're still cardiologists, endocrinologists and lipidologists treating these patients. They are currently being treated with suboptimal therapies and not getting the goal. And what we're hearing, and we heard this from the KOL panel that we did on April 14 is that there is the realization that reducing triglycerides is directly correlated to and physicians are well aware of that, and they're looking for a better treatment option and we're looking forward to potentially having positive data and an approval for olezarsen to be able to help those patients.

Thank you, Kyle. Jay, you are referring to the AP baseline event data we reported in our baseline demographics clinical trial design study that we published earlier this month, where we observed 22% in CORE and 13% in CORE2 patients with a history of AP over the last 10 years. I want to emphasize before discussing expectations for AP data from those studies that there is a significant unmet medical need and a large patient population that healthcare providers are prepared to treat for sHTG even without AP data available. This represents a substantial market opportunity, and from our discussions with healthcare professionals, we understand that they are seeking a medication that will significantly reduce triglycerides in addition to standard care, which aligns perfectly with our trial design. With that said, AP is a secondary endpoint in our study, and it is not powered to focus on AP. However, we are making every effort to enhance the power of the study. For instance, we are combining CORE and CORE2 for our secondary analysis of AP events and investigating AP events at 12 months, while the primary endpoint for triglycerides is at 6 months. We are maximizing the duration of observation in patients to analyze AP data. Additionally, the results from the FCS data are promising for TRYNGOLZA, where we reported significant reductions in acute pancreatitis events in our BALANCE study. We are fully dedicated to demonstrating substantial reductions in triglycerides in sHTG patients, which is what physicians look for when prescribing a medicine like olezarsen.

The next question comes from Gary Nachman at Raymond James.

So on donidalorsen, just talk a bit more about what you're doing ahead of the PDUFA date internally to prepare for that launch. For patients that are going to be switching, how you're thinking about that transition, I guess, in the first year of launch? And just in terms of access, how long do you think that process is going to take? And then just as a follow-up here, Brett, on the macro dynamics. You just highlighted it briefly, but just talk a bit more what you think the expected impact from tariffs is going to be to the overall business just based on the current trade policy? And just in terms of your conversations with FDA, if you're seeing any sort of signs of potential delays, whether with PDUFA dates or starting clinical studies?

Great. Kyle, donidalorsen launch?

Yes. What we know about the HAE market is this is largely an unsatisfied market. We see approximately 20% of patients that are moving between prophylactic treatments in the U.S. on an annual basis. We also recently released the Harris Poll that showed that 9 out of 10 patients are interested in trying new therapies in this space. So there's definitely an opportunity here in the donidalorsen profile in terms of efficacy, tolerability and convenience is offered all in one single treatment. And when we start talking about switching patients and the dynamic of why patients want to switch, it's one of those three reasons that they're looking for something new and different. We're going to be able to provide donidalorsen in a way that demonstrates reductions in attacks, improve tolerability, and they're only going to have to take the treatment every 4 or every 8 weeks. So the profile is very, very strong there. In terms of switching patients, what we need to do is we need patients to advocate for themselves and we need physicians to understand what these patients are experiencing. And that's the work that we're doing right now. we're being informed by patients, and we're also beginning to communicate directly with HCPs what the need is in this market and setting ourselves up to be able to talk about how and why to switch these patients and why it's important for that to happen. But this is a switch market. We will begin the ramp, hopefully, in Q4, and we anticipate peak sales being greater than $500 million for donidalorsen. And with the concentrated prescriber base, we can have a very targeted sales force to go out and do that, which is currently being hired and trained and going to be deployed well in advance of the PDUFA date.

Thanks, Kyle. Regarding your other question, Gary, we are closely observing the changes the new administration is implementing at both the FDA and the macro level concerning tariffs, among other things. Currently, we are pleased to confirm that there have been no alterations to any of the programs we've been discussing with the FDA. Everything is progressing as planned. As previously mentioned, donidalorsen's PDUFA date is set for August 21, and our discussions are proceeding as they should at this stage of the review process. The same applies to our other conversations with the FDA regarding INDs and related matters. Overall, it seems that everything is on track with the FDA, despite the ongoing changes, which we will continue to monitor closely. In terms of other changes, including tariffs, we have not observed any significant impact on our business thus far. This includes costs that we might have to absorb for already launched drugs or those planned for the future. As for our commercial and clinical supply, everything is progressing smoothly. We have adequate supplies to support the launches of TRYNGOLZA and donidalorsen, and we are well-prepared for these launches in the near future. For our clinical trials, we produce drugs in-house at Ionis as well as with some contract manufacturing organizations, and we have numerous redundancies in our supply chain to ensure the smooth continuation of our clinical studies. While we are carefully monitoring the situation and creating contingencies to manage potential challenges, we have not experienced any impacts related to tariffs or the FDA on our business at this time.

The next question comes from Debjit Chattopadhyay at Guggenheim.

On the FCS launch, how confident is the team on the 2,000-plus FCS patient estimate and how quickly can you convert these patients to commercial therapy before you have significant price erosion with the launch in sHTG?

Can someone take that, please?

Yes. Happy to take that. I think while the epidemiology varies between 1 and 13 per million, we're fairly confident in those 3,000 that genesis of your question, though, really is how quickly can we identify them. I think as Kyle outlined, we obviously had clinical trial patients that we've been able to convert on to cover product very quickly. In the prelaunch phase, we were definitely very successfully engaging with our target audience and identifying FCS patients, and that's helped drive our initial uptake in the product. But in every month as more and more physicians become aware, we're finding more and more patients. And that's very encouraging for the outlook that we've got for FCS. I definitely think this is an underserved community with a very debilitated disease. And as that awareness grows, both amongst HCPs, but importantly, through a lot of the work we're doing with omnichannel, we're going to find more and more patients in the next 18 months prior to the sHTG launch. Obviously, with positive data and potential approval from the FDA. As soon as that indication expands, we'll be addressing the far larger population. The specifics of FCS become less apparent.

And price erosion?

Yes. In terms of price, we priced at the FCS launch appropriately with the 3,000 patient population out there, right? And that's how we ended up at the price point that we did and the value that TRYNGOLZA brings to that patient population. As we think about moving forward for sHTG that population is going to be exponentially higher, right, 1 million plus addressable in terms of the population. If we look at the marketplace, typically, drugs that have 1 million or so patients addressable are in the specialty pricing range of $10,000 to $20,000, for example, we've got some work to do to figure out what the pricing will be ultimately in this category based on the data that supports the program itself, which we'll know later this year. and we'll go back and do some more research and then obviously announce the price when we receive approval for the sHTG indication.

Yes. Again, we're very encouraged by the TRYNGOLZA launch to date. It is early days, of course, but we expect to be commercializing TRYNGOLZA in FCS for 1.5 years to 2 years before sHTG commercialization will kick in.

The next question is from Jessica Fye at JPMorgan.

I just had a couple. Forgive me if I missed this, but was there any channel stocking for TRYNGOLZA captured in that 1Q number? And if so, can you quantify that? Second one, can you just elaborate a little bit more on the sources of upside to the revenue guidance and how much of that is driven by commercial product performance versus the licensing deal? And lastly, you kind of touched on this, but maybe just a little more specific. Can you just talk about the manufacturing footprint for TRYNGOLZA, donidalorsen and how you think about possible exposure to tariffs?

Sure. So channel stocking, Kyle, for TRYNGOLZA?

Yes. The TRYNGOLZA sales is currently directly correlated to demand. There was not a large stock end of inventory. It's actually being managed for the contract that we have in place with the specialty pharmacy, and it's really reflected by demand.

You want to add anything to that, Beth, as well as then talk about the revenue guidance?

Sure. I would agree with what Kyle mentioned about the team effectively managing inventories. For a rare disease drug like TRYNGOLZA, it's crucial to keep inventory levels as low as possible while ensuring it is driven by demand, which the team is successfully achieving. Regarding revenue guidance, it is based on a strong first quarter, but the primary reason for the increase is the licensing transactions we completed for sapablursen and the OUS commercial licensing to Sobi for olezarsen. Those transactions, which were factored into our initial guidance exceeding $600 million in revenue, are now being reflected with a 100% probability in our updated guidance, impacting not only revenue but also our operating loss and cash projections.

Yes. Regarding manufacturing, we have several sources for supplying our drugs for clinical trials and commercial launches, including South Korea, Europe, and the U.S. We are well stocked to support the TRYNGOLZA launches and the expected launch for donidalorsen. We are monitoring any potential impacts, but so far, there hasn't been any, including from tariffs. We are keeping a close eye on it, but we are not experiencing any significant effects. Our guidance remains unchanged; we just improved it, taking into account any potential tariff impacts.

The next question is from Jason Gerberry at Bank of America Merrill Lynch.

This is Chi on for Jason. Maybe just on a follow-up on TRYNGOLZA, can you unpack a little bit between the conversion that you see from your expanded access and newly identified patients that were previously not enrolled in any of the prior clinical trials and understood that this is a market that requires some market building. Are you seeing a steady case and enough new starts? And just a quick follow-up on your Angelman, you guys have it on track for 2Q Phase III start. Are there any outstanding needed to execute before the Phase III start?

Okay. Thanks, Chi. I'll take the Angelman's question as it's a brief answer, and then Kyle will take the question with respect to conversion of EAP, OLE patients and so I'll start. So the Angelman Phase III study is on track for a timely initiation. As a reminder, we had excellent discussions and completion of conversations with the FDA last year. We aligned on our Phase III trial design. We think we have the right trial design. We have the right drug, the right chemical platform to get the study started in the first half of this year, which means it will get started in this quarter. So very soon. We're well on our way. And what we've also said is that our expectation is to complete enrollment in 2026. So we expect to enroll fairly quickly.

Thank you, Brett. Regarding the TRYNGOLZA launch, we saw a strong uptake from patients in Q1, which was driven by demand. Our main focus was on converting EAP and OLE patients to the commercial drug, and I’m pleased to say the majority successfully made the transition, which was in line with our expectations. We also had a significant number of long-standing patients who were previously without treatment options begin their therapy. Moving forward, our attention will be on identifying new patients, as that will be our key area of focus. In Q1, we had patients from all three groups, but predominantly from the EAP OLE and those with pent-up demand. Our main goal is to get new patients diagnosed, treated, and efficiently navigate them through the payer process, which we are currently doing successfully. Jonathan, would you like to add anything?

Yes. Perhaps a little bit of color. We're definitely having success engaging with HCPs to actually find both patients that were identified prior to launch and converting them to cover product, number one. But also number two is the awareness gets out there finding new patients and becoming aware of patients that we weren't aware of at launch. So that's super encouraging in the first quarter of our launch.

The next question comes from Yaron Werber at TD Cowen.

I have a couple of questions. First, regarding WAINUA, can you provide some insight into how the Part D redesign, now that it's implemented and limits patients' out-of-pocket expenses to $2,000, might impact its uptake? Secondly, about TRYNGOLZA, the $6 million is a really impressive figure. It seems like a solid baseline going forward. Do you already have patients who you expect will start using it quickly after being diagnosed? As we look forward to growth in patient identification, could you share some qualitative insights on how rapidly that might occur?

Yes. Let me touch on WAINUA first. AstraZeneca continues to see very strong U.S. demand for WAINUA. The redesign of Medicare Part D impacted some of the Q1 revenue, but there are a lot of positives that you just emphasized in terms of the out-of-pocket change that's happening. First of all, I think you're going to see an increased volume from new patient starts because of this. We're seeing cardiologists and neurologists prescribe WAINUA and what they're telling us is that it's going to, number one, increase the number of patients they can treat because of affordability; and number two, they feel like it's going to increase the compliance rates for those patients as well because they're going to be able to afford their medication moving forward. So I think that has a significant advantage and opportunity for patients overall, and we knew us specifically to be able to demonstrate revenue growth quarter-over-quarter as we move forward in 2025. I think we're very optimistic about that. In terms of the TRYNGOLZA question, again, greater than $6 million in the first quarter. We just talked about the three patient buckets that, that came from. But we do have additional patients that are being identified currently that are potentially going to go on to TRYNGOLZA. This takes a lot of work, right, 3,000 potential patients in the U.S. We're doing a lot of work, not only with our customer-facing teams but also with our omnichannel efforts and the education that we're doing with our medical affairs groups at congresses in different meetings. So those are the things that we're doing to get the word out about the new treatment option available, how to diagnose FCS patients. But it's going to take some time and some work, but we are encouraged by the number of patients that are coming forward, and we'll work them on treatment this quarter and moving forward throughout the year.

Thanks, Kyle. I want to point out that WAINUA has been launched outside the U.S. and Europe as well. We are anticipating ongoing revenue growth, driven by strong patient demand not only in the U.S. but also in other regions for 2025 and beyond.

Our next question is from Luca Issi at RBC Capital Markets.

This is Cassie on for Luca. And this question will be on TTR cardiomyopathy. We appreciate the early days as cardio transform has yet to read out. But were you surprised by an item not lowering pricing when they got label expansion for cardiomyopathy. And are you planning to follow the same playbook? Or is there a scenario where you compete with them by lowering the price? Any color there would be much appreciated.

Yes. In terms of strategy, I wasn't too surprised by that. I believe they've got a balance of patients that are hereditary polyneuropathy patients. And I think they're trying to maintain a price in order to manage their revenues now and moving forward. And it's up to them kind of how that market evolves, I think, and what they're able to get coverage on for cardiomyopathy, I think that's yet to be determined. In terms of the strategy for WAINUA, that's ultimately AstraZeneca's decision in terms of how they navigate that. I'm sure there are a lot of learnings in this market. And as the market continues to evolve, we'll take a look in terms of reimbursement and coverage and physician and patient feedback and figure out what the right price point is for WAINUA based on the benefit and value that it delivers.

The next question comes from David Lebowitz at Citi.

When you look at the core trials and the baseline AP data, I'm curious as to how the analysis in the trials will actually be carried out. Is it going to be strictly based on baseline for the overall population relative to reductions, whether it be additional studies or analysis on patients that actually had baseline AP events to reduce but over the smaller denominator. I'm curious to what's prespecified and what could possibly be accepted by the FDA for labeling consideration?

Eugene?

Yes. Thanks for the question. So certainly, the analysis of AP events, the prespecified analysis, we'll look at all events happening during the 12 months exposure in a trial and obviously comparing the active arm versus placebo. We will look at the population that had a baseline or at baseline reported historical events, but that's a much smaller subgroup. So I guess, the answer is that the overall analysis will look at all events happening during the trial comparing the olezarsen patients.

And I believe, if I recall, Eugene, we'll also be looking at AP in patients above and below 80 in the analysis as well.

Right. Yes.

So we'll be carving up the AP data based on history of AP and without and so on. As far as the labeling discussions and getting AP in the label, I mean that's a data-driven outcome that we'll have to talk about with the FDA. But again, as I emphasized earlier, we believe that this is a very substantial unmet need and a very sizable market opportunity for Ionis based on triglyceride lowering. But these patients are suffering from acute pancreatitis, and we have a substantial number of patients with a history of AP enrolled in our study. So we think we have the right trial design that if we can see it, we have a potential to see it.

Yes, I'll just add, we have AP in the label now for TRYNGOLZA, which is in the FCS population but that's very beneficial. And then the read-through in terms of the connection between triglycerides and lowering of acute pancreatitis, we know from the recent KOL panel that we just had that's well understood, as Brett and Eugene just described.

The next question comes from Mani Foroohar from Leerink.

This is Lily Young on for Mani. First question, digging a little more into the patients and the scripts for TRYNGOLZA. So you mentioned that the majority of patients were from the open-label extension as well as the EAP program. But in terms of the remaining patients with the newly diagnosed and previously diagnosed patients, could you give a little more color on the distribution there between newly diagnosed and previously diagnosed as well as your expectations on how it will evolve quarter-to-quarter?

I don't have too much additional color to add. We're not going to disclose the exact patient numbers or the percentages at this point in time. But we are encouraged the patient finding work that we've done, the identification of new patients so far, and we believe we'll be able to add incremental patients quarter-over-quarter as we move forward throughout the year. The launch is going very well, as we talked about, strong patient uptake and strong demand and good payer coverage. So I think we're in a great place.

Yes. To clarify, we didn’t imply that most patients are from the open-label extension. We mentioned that there are patients in the open-label extension study from the Phase III trial, which had an equal number of 66 patients. In the U.S., we focused on this segment, and most of those patients have transitioned to commercial status, but that doesn’t fully reflect the entire patient population using TRYNGOLZA commercially at this time. Moving forward, we will concentrate on identifying new patients, which we have emphasized. While we've successfully converted patients diagnosed previously and those from clinical trials, the priority now is on patient identification, and there’s still much work ahead.

Yes. One thing I'll add is we're definitely finding new patients just to be transparent around that. I mean it's very difficult to seek a diagnosis for a condition where it doesn't ultimately change the treatment. So as awareness builds, clinical experience builds, there's far more motivation to see these patients, and they're definitely out there, they definitely exist.

I think we have time for one more question.

The last question comes from Mike Ulz at Morgan Stanley.

Maybe just a follow-up on olezarsen and sHTG. It looks like you narrowed the timing of that data slightly for the CORE and CORE2 studies, the 3Q from the second half previously. Just curious. Any reason behind that? And then secondly, maybe just clarify, will that initial update from those studies include the 12-month AP data?

Thanks, Mike. There's nothing specific behind the change; as we approach the data readouts and manage all the necessary details to present the top line data, we can provide greater clarity. We have indeed given more precision regarding the Q2 ESSENCE data, as well as the Q3 CORE and CORE2 top line data. Regarding the AP readouts, we don’t anticipate AP results from the ESSENCE study, just to confirm. These patients have slightly elevated triglyceride levels and don’t experience many AP events. This study is focused on safety to support the exposure database needed for such a common disease from the FDA's perspective. Our main concern in this study is the reduction of triglycerides and safety. I also want to stress that the expected percentage reductions in triglycerides in ESSENCE do not represent what we would anticipate in CORE sHTG, since those patients are only mildly elevated. We are expecting significant reductions in triglycerides, but not to the same extent as we would expect in CORE. For the top line data in CORE and CORE2, we are still determining whether the AP data will be available in time for that announcement, but our main emphasis will be on triglyceride reductions and safety for those studies. If we do have the AP data by then, we will certainly include it in our top line announcement later this year. Thank you for the question, Mike, and thanks to everyone for their participation and great questions. Looking ahead, we are excited about building on our momentum throughout the year and sharing our progress with you all. Thank you once again, and we’ll talk soon. Have a great day.

Goodbye.