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Operator: Good morning, and welcome to Ionis' Fourth Quarter and Full Year 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.
D. Walke: Thank you, Keith. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We've also posted slides on our website to accompany today's call. With me on the call this morning are Brett Monia, our Chief Executive Officer; Holly Kordasiewicz, Chief Development Officer; Kyle Jenne, Chief Global Product Strategy Officer; and Beth Hougen, Chief Financial Officer. Eugene Schneider, Chief Clinical Development Officer; and Eric Swayze, Executive Vice President of Research will also join us for the Q&A portion of the call. I would like to draw your attention to Slide 3, which contains our forward-looking language statement. During this call, we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail. With that, I'll turn the call over to Brett.
Brett Monia: Thanks, Wade. Good morning, everybody, and thanks for joining us today. 2025 was a defining year for Ionis, marked by the successful execution of our first 2 independent launches and multiple positive data readouts across our rich pipeline. These achievements, together with our expectation for multiple additional value-driving events this year positions Ionis for continued success through 2026 and beyond. TRYNGOLZA, the first FDA-approved treatment for familial chylomicronemia syndrome, or FCS, exceeded expectations in its first year on market. TRYNGOLZA's excellent performance was driven by a compelling clinical profile and strong launch execution. TRYNGOLZA was also launched in Europe late last year, and we're pleased to see our partner, Sobi, bring this transformational medicine to more patients. In August, we kicked off our second independent launch with the FDA approval of DAWNZERA, prophylactic treatment for hereditary angioedema or HAE. As the first and only RNA-targeted medicine for HAE, DAWNZERA offers a compelling profile that is resonating with prescribers and patients. And just last month, DAWNZERA received European approval, enabling our partner Otsuka to bring important medicines to patients across the region. In 2025, we accelerated the strong momentum with the olezarsen pivotal results in severe hypertriglyceridemia, a broad patient population with high unmet need. Further extending our leadership in the development of innovative treatments for diseases associated with high triglycerides. Olezarsen showed highly significant and substantial reductions in triglycerides in an acute pancreatitis attacks establishing olezarsen as the first medicine to demonstrate a benefit in reducing acute pancreatitis risk in this patient population. Based on these groundbreaking Phase III results, we were pleased to receive breakthrough therapy designation from the FDA. Additionally, late last year, we submitted the sNDA and anticipate receiving acceptance very soon. Importantly, we are on track to be launch ready by June. We also delivered positive Phase III results for our innovative medicine, zilganersen, the first to demonstrate a disease-modifying benefit in Alexander's disease, a rare and orphan fatal neurodegenerative disease. We submitted our NDA in January, and we anticipate approval and launch in the second half of this year. Assuming approval, zilganersen will be our first independent launch from our leading neurology franchise. Together, these groundbreaking results meaningfully expand Ionis' commercial opportunity and showcase our commitment to innovation and the power of our platform to deliver first-in-class RNA targeted medicines for patients with serious diseases. Complementing our rich wholly owned pipeline is our partnered pipeline, which targets both rare and highly prevalent life-threatening diseases. We expect multiple Phase III data readouts this year from our partner pipeline. In January, we announced the first of these results with positive top line data for Bepirovirsen, a potential first-in-class medicine for chronic hepatitis B that demonstrated clinically meaningful and unprecedented functional cure rates in the Phase III program. GSK is preparing global regulatory submissions and assuming approval, expects to begin bringing Bepirovirsen to the millions of people living with chronic HBV later this year. Looking ahead, we anticipate results from 2 major cardiovascular outcome trials, the pelacarsen Lp(a) HORIZON trial midyear and the Eplontersen CARDIO-TTRansform trial in the second half of 2026. In addition, sefaxersen for IgA nephropathy and Ulefnersen for FUS-ALS are also positioned for Phase III readouts later this year. If positive, these outcomes position our partner pipeline to deliver 4 key additional launches by the end of next year, driving a meaningful increase in our total revenue through royalties and milestone payments for many years to come. With strong momentum across our business, including our first 2 independent launches and advancing wholly owned pipeline and a robust partner portfolio, Ionis is well positioned to deliver a steady stream of transformational medicines for patients thereby driving substantial value and sustained growth. In addition to our very important recent commercial and pipeline achievements, 2025 was also a strong year of financial performance for Ionis. Revenue increased more than 30% over 2024 with growing contributions from our marketed medicines. This significant revenue growth combined with disciplined investment enabled us to exceed our financial guidance and as Beth will discuss later in the call, this momentum underpins our strong 2026 financial outlook. Importantly, we remain on track to achieve our goal of reaching cash flow breakeven by 2028. Now before I turn it over to Holly, I'd like to take a moment to formally introduce her in her new role as Chief Development Officer. Since joining Ionis, Holly has played a central role in building and expanding our R&D neurology franchise, resulting in the creation of an industry-leading pipeline of RNA-targeted therapies for a broad range of rare and common neurological disorders. Holly has also played a strategic role more broadly in creating Ionis' leading research and development organization and brings a deep understanding of our technology. We are pleased to have Holly in her new role and confident she will continue to drive substantial value and continued success for Ionis and all Ionis stakeholders. Now over to you Holly.
Holly Kordasiewicz: Thank you, Brett. I'm honored to lead our world-class development team, which has recently delivered multiple concept data readouts. I've had the privilege of working closely with many members in the development team over the years, and I look forward to building on that strong foundation. Looking ahead, our focus remains on innovation and ensuring strong execution to enable Ionis to continue delivering a steady cadence of transformational medicines to people with serious diseases for years to come. Olezarsen is a clear example of our leadership in discovering and developing transformational medicines. The ground breaking Phase III data generated from the CORE and CORE2 trials position Olezarsen to a new standard of care for the broad sHTG patient population. As previously presented and published, our pivotal studies evaluated Olezarsen and people with sHTG who had triglyceride levels substantially higher than the 500 mg per deciliter despite being on standard of care with the lowering therapies that they find, putting them at risk of life-threatening acute pancreatitis. In CORE and CORE2, olezarsen demonstrated highly statistically significant and clinically meaningful mean reductions of up to 72% and placebo-adjusted fasting triglycerides at 6 months, the primary end point. Olezarsen also significantly reduced acute pancreatitis events, making it the first and fully treatment to achieve this positive outcome in people with sHTG. Olezarsen achieved a highly statistically significant 85% reduction in adjudicated acute pancreatitis events. It's important to remember that the main goal of triglyceride management in sHTG is to prevent AP attacks and olezarsen is the first medicine to demonstrate it can do just that. This remarkable reduction in AP attack rate was also reflected in the number of patients needed to treat to prevent a potentially fatal pancreatitis attack. Just 4 patients needed to be treated with olezarsen for only 12 months to prevent 1 AP attack in the highest risk subgroup. For context, statins used for primary prevention have a number needed to treat in a range of 500 to 100 to prevent 1 cardiovascular event over 5 years. We believe these unprecedented results position olezarsen to meet the substantial unmet need of people with sHTG. We submitted the sNDA at the end of 2025 and it is currently within the FDA filing review period. We requested priority review and expect a decision from the FDA shortly. As Kyle will highlight, launch preparations are already well underway, and we look forward to bringing olezarsen to people with sHTG later this year. In addition to olezarsen, we're poised for another independent launch later this year. We plan to bring to zilganersen to patients with Alexander disease an ultra-rare leukodystrophy that profoundly impacts patients and families who today have no approved disease-modifying therapies. Our positive Phase III results for zilganersen mark the first time any therapy demonstrated a disease-modifying impact in this condition. We recently submitted our NDA based on these groundbreaking data. In the interim, we have initiated an expanded access program to provide eligible patients with access to zilganersen while the review is ongoing. We expect zilganersen to be the first of the numerous additional independent launches from our leading neurology pipeline. Underscoring Ionis' ability to consistently translate scientific leadership into important medicines for our patients. Turning now to our Phase III program for Obudanersen, previously referred to as ION582, our investigational medicine for Angelman Syndrome. Late last year, we received breakthrough therapy designation from the FDA. In recognition of Obudanersen promising mid-stage data and the serious unmet need in this disorder. Angelman Syndrome is a rare neuro developmental disorder that causes profound and lifelong physical and cognitive impairment. Estimated effect more than 100,000 people globally. Obudanersen is advancing in the Phase III REVEAL study with full enrollment expected this year and data next year. In addition to zilganersen and obudanersen, we have a rich neurology pipeline advancing in development, including ION464 for multiple system atrophy and ION717 for Prion disease. We're evaluating both investigational medicines and ongoing studies in patients. Based on the data generated to date, we're encouraged by the level of target engagement in the safety and tolerability profile. As a result, we plan to add additional dose cohort student programs to fully explore the therapeutic potential of these medicines. With these expansions, we now expect to report data from both programs next year. As we look to key upcoming events, in addition to those highlighted by Brett, we're looking forward to the anticipated approval of high-dose SPINRAZA, which has a PDUFA date of April 1. We're also evaluating -- we're also looking forward to the Phase III study start of Salanersen evaluating annual dosing for SMA and Sapablursen for polycythemia vera. We're over 3 mid-stage partner programs are set to read out this year, which in addition to multiple regulatory milestones position 2026 to be another catalyst-rich year. And with that, I'll turn it over to Kyle.
Kyle Jenne: Thank you, Holly. With a strong first year for TRYNGOLZA, an encouraging start for DAWNZERA and 2 more anticipated independent launches this year, our commercial team remains focused on flawless execution to continue bringing our important medicines to patients. In the fourth quarter, TRYNGOLZA continued to gain momentum, generating $50 million in net product sales, reflecting a 56% increase in revenues quarter-over-quarter. And notably, December was our strongest month of 2025 underscoring continued growing demand. This performance drove full year revenue to $108 million. The efforts of our team, together with our innovative initiatives to identify patients continue to deliver positive results. We saw quarter-over-quarter expansion in both the breadth and depth of physicians prescribing TRYNGOLZA reflecting positive experiences among clinicians and patients. Q4 was a strong quarter of adding new prescribers who span a broad mix of specialties, including cardiologists, endocrinologists and lipidologists. Overall, approximately 75% of prescriptions came from these specialists. This provider mix and growing prescriber base positions us well as we prepare to expand into the broader sHTG population. Our leadership in establishing FCS access and coverage continues to benefit FCS patients and elevate TRYNGOLZA performance. Patients are gaining access to TRYNGOLZA quickly with time from prescription to first fill consistently exceeding our aggressive expectations. The current payer mix is approximately 60% commercial and 40% government and both clinically diagnosed and genetically confirmed patients continued to secure coverage. All the strong momentum we saw from TRYNGOLZA in 2025 has carried into the first part of 2026. There has been no meaningful impact on cancellation or discontinuation rates following a new market entrant. In fact, TRYNGOLZA continues to deliver strong growth in referrals and patient starts. Physicians continue to report very high satisfaction with both their prescribing experience and TRYNGOLZA's overall product profile, including efficacy, safety, tolerability and convenience. At the same time, pricing dynamics in the market are evolving. We are effectively managing these changes and preserving broad access and coverage for FCS patients. We are building on our leadership position in FCS as we prepare for the anticipated sHTG approval and launch later this year. Many people with sHTG struggle to manage to triglyceride levels with current treatments. In the U.S. alone, more than 1 million people have high-risk sHTG, defined as individuals with triglyceride levels above 880 milligrams per deciliter or above 500 milligrams per deciliter with a history of acute pancreatitis, or other high-risk comorbidities, including progressive cardiovascular disease and type 2 diabetes. Following our groundbreaking Phase III results, we conducted robust HCP demand research that confirmed strong enthusiasm for olezarsen and its potential to address patient unmet needs. HCPs found the low number needed to treat to prevent one potentially fatal acute pancreatitis attack, especially compelling. With the anticipated upcoming sHTG launch, we are continuing to engage with payers ahead of our planned price adjustment for the broader sHTG patient population. This work is anchored in olezarsen's compelling clinical profile and includes educating on the clinical and economic burden of disease and associated budget impact considerations. Ultimately, our goal is to provide the broadest access possible to patients and maximize the value of olezarsen. I am pleased to share that we now have our full field organization in place with approximately 200 field team members hired, trained and deployed. Our field team expansion materially increases share of voice and expands our reach to HCPs. Today, the team is actively supporting access to TRYNGOLZA for people with FCS. With our expanded team, we are positioned to effectively engage approximately 20,000 high-volume sHTG prescribers across the U.S., providing the scale and reach required for a successful launch in the larger indication. As we shared last month, based on the positive Phase III data and strength of olezarsen's product profile, we increased our annual fee revenue estimates for olezarsen to more than $2 billion. And today, we're even more confident in the blockbuster opportunity of olezarsen. Our groundbreaking data, strong HCP enthusiasm and first-mover advantage position olezarsen to realize its full potential as the new standard of care for people with severe hypertriglyceridemia. Turning to DAWNZERA. The launch is off to an encouraging start. We're seeing early adoption across all patient segments, including patients switching from prior prophylactic therapies patients previously using on-demand therapy only and treatment-naive patients. And we have seen strong participation in our free trial program with 100% conversion to paid therapy to date. Initial feedback from both physicians and patients shows high enthusiasm for DAWNZERA's differentiated mechanism of action, strong efficacy and patient-friendly profile, including a self-administered auto-injector and potential for the longest dosing interval, which is translating into increasing demand. Notably, we are also seeing a growing number of repeat prescribers due to the positive experience prescribers and patients are having with DAWNZERA. Additionally, we are seeing an extremely high conversion from referral to patient start. While it will take time to transition patients from other HAE therapies as we educate patients and physicians about the attractive profile DAWNZERA offers, we are confident we have the right drug, the right strategy and the right team to successfully bring DAWNZERA to people with HAE. Importantly, with strong launch fundamentals today, we expect DAWNZERA to meaningfully contribute to our growing commercial revenue this year and we reaffirm annual peak sales potential in excess of $500 million. Turning now to zilganersen for Alexander disease. We expect it to be the first independent launch from our neurology portfolio. Based on the Phase III results, zilganersen offers a potentially meaningful advance for patients and caregivers in a disease with no approved disease-modifying treatments. With the NDA submitted and acceptance expected soon, we are preparing to launch in the second half of this year. Ahead of launch, we are leveraging our strong relationships with the neurology community and patient advocacy groups to support awareness and diagnosis. Our medical affairs team is working with top leukodystrophy centers. Our marketing team is in place, and we will bring the customer-facing team on board ahead of approval. At launch, our priorities will include ensuring continued access for clinical trial participants, facilitating timely access for diagnosed patients, improving patient identification and ensuring availability. Importantly, we believe zilganersen could be the first of many first-in-class disease-modifying treatments from Ionis' industry-leading neurology pipeline. 2025 was marked by strong commercial execution. Looking ahead to 2026, the commercial organization is well positioned to build on this momentum. We remain focused on maximizing the full potential of TRYNGOLZA's in FCS, and DAWNZERA in HAE while preparing to execute 2 additional launches this year, further expanding Ionis' reach to even more patients in need of our medicines. With that, I'll now turn it over to Beth.
Elizabeth L. Hougen: Thank you, Kyle. 2025 was a defining year for Ionis across our business, resulting in our impressive financial performance. We exceeded our guidance across all metrics through exceptional execution and disciplined financial management. This performance was underpinned by accelerating revenue growth from our marketed medicines, alongside sustained progress across our pipeline. We generated $944 million in revenue in 2025, representing a 34% increase year-over-year. Revenue was split between commercial products, which generated $436 million or 46% of our total revenue and R&D collaborations, which generated $508 million or 54% of our total revenue. These results underscore the value of our diversified revenue streams. Our marketed medicines provide growing recurring revenue and increasing operating leverage. While revenue from R&D collaborations acts as a financial accelerator. Together, our diversified revenue streams mitigate risk, enhance financial flexibility and create multiple pathways to sustained growth. 2025 was a strong first year for the TRYNGOLZA launch in which we earned $108 million in product sales with quarter-over-quarter growth throughout the year. This included $50 million of product sales in the fourth quarter, representing a 56% increase over the third quarter. We earned $8 million in DAWNZERA product sales in 2025 from the initial few months of launch. Since launch, we have been offering a free trial program, which has seen strong participation and 100% conversion to paid therapy to date. While still early, this provides encouraging visibility into anticipated DAWNZERA revenue growth. Royalty revenues increased 11% to $285 million in 2025. And anchored by meaningful contributions from SPINRAZA and growing royalties from WAINUA. Our R&D revenue also increased generating more than 20% growth year-over-year. driven by progress across multiple partner programs. The largest contributor was the Sapablursen license fee, underscoring our ability to monetize noncore assets to support our ongoing and planned launches and our pipeline. As planned, total non-GAAP operating expenses increased modestly year-over-year, highlighting our commitment to disciplined investment. The increase was primarily driven by investments related to the U.S. launch of TRYNGOLZA and DAWNZERA and accelerated investments to prepare for the sHTG launch following the groundbreaking Phase III data. Our excellent progress last year, coupled with disciplined financial management positions us well for accelerating growth and value creating. Our financial guidance for this year reflects Ionis' evolution to a commercial stage biotechnology company launching multiple medicines while remaining steadfast in our commitment to drive operating leverage as we advance our high-value pipeline. We project to earn revenue in the range of $800 million to $825 million from numerous sources, this represents an increase of approximately 20% over last year after adjusting for the onetime $280 million Sapablursen license fee. We expect the year-over-year increase to be driven by commercial revenue growth. As Holly mentioned, the sNDA is still within the review period. As a result, our guidance assumes a standard review for olezarsen which sets us up for anticipated sHTG approval in the fourth quarter. If we achieve priority review, we expect our guidance to improve. Since we are awaiting acceptance of the sNDA for olezarsen, we plan to provide TRYNGOLZA and DAWNZERA product level revenue guidance at our first quarter earnings call. So today, we will share some high-level perspective and directional insights to help frame expectations. We continue to see strong demand for TRYNGOLZA with FCS patients, and we expect continued patient growth this year. At the same time, we have been actively engaging with payers to ensure FCS patients continue to have broad access to TRYNGOLZA ahead of the anticipated sHTG approval. As a result, we expect a meaningful decline in TRYNGOLZA revenues throughout the year ahead of the sHTG launch, followed by accelerating growth as uptake build. As we prepare for the sHTG launch, we are establishing a reimbursement strategy designed to achieve broad access while maximizing the value of olezarsen drive sustainable long-term growth. Following anticipated approval, we expect to launch quickly with momentum building as we begin to bring olezarsen to this much larger patient population. And importantly, as Kyle highlighted, we are more confident than ever in the multibillion dollar opportunity for olezarsen. For DAWNZERA, we expect product sales to meaningfully contribute to total commercial revenue growth and to grow steadily as the launch progresses throughout the year. Given that HAE is primarily a switch market, and we remain in the early stages of launch, we expect patient conversion from existing therapies to take some time. That said, with strong launch fundamentals, including increasing demand, a high referral to start conversion rate positive patient-reported outcomes and rapid uptake of our free trial program, we are confident we have the elements in place to drive substantial growth. from our partnered commercial programs, we anticipate earning substantial royalties for medicines on the market today. We expect SPINRAZA to remain resilient and WAINUA to continue its upward trajectory this 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. Our R&D revenue from existing collaborations remains a meaningful contributor to our total revenue guidance. As such, it's an important financial accelerator. With a rich pipeline and many partnered programs advancing, we have the potential to earn numerous milestone payments throughout the year. So far this quarter, we've already earned $65 million including $15 million for the EU approval of DAWNZERA and $50 million when Roche initiated a Phase I trial for an investigational medicine for Alzheimer's disease. Additionally, we are eligible to earn milestone payments for the Phase III initiations of Salanersen and Sapablursen as well as numerous regulatory milestone payments for Bepirovirsen and pelacarsen. Overall, our 2026 revenue outlook reflects the strength of our unique financial profile which includes numerous commercial and R&D revenue streams that enable us to achieve growing revenue through multiple pathways. We project our 2026 operating expenses to increase in the low-teen percentage range compared to last year, with revenue growing faster than expenses, driving improved operating leverage. This modest increase reflects our commitment to financial discipline as we bring multiple medicines directly to patients and advance their pipeline. Our planned expense growth will continue to be driven by our sales and marketing expenses as we invest to support the success of our multiple ongoing and planned launches. 2026 will be an important year of disciplined commercial investment as we prepare for our first launch in a broad indication with annual peak sales projected to exceed $2 billion. We expect our R&D expenses to remain steady this year, similar to last year. As late-stage studies reach completion, we are redeploying our resources for the drugs in our pipeline that we expect to fuel our next phase of growth. With sizable revenues and modest expense growth, we are projecting a non-GAAP operating loss between $500 million and $550 million. This represents a similar level compared to 2025, excluding the onetime sapablursen license fee last year and assuming a standard review for olezarsen. Importantly, we project to end the year with a well-capitalized balance sheet, including cash and investments of approximately $1.6 billion. The projected year-over-year change in cash reflects the use of $433 million earmarked to repay the remaining 2026 convertible notes. In addition, it reflects our prudent fiscal management as we make strategic investments to bring our medicines directly to patients, including inventory build for the anticipated sHTG launch and continued advancement of our wholly owned medicines in development. Looking beyond this year with 2 launches underway and more planned for this year and next, Ionis remains well positioned to achieve our goal of accelerating revenue growth and achieving cash flow breakeven by 2028, driving long-term value creation. And with that, I'll turn the call back over to Brett.
Brett Monia: Thank you, Beth. 2025 was indeed a defining year for Ionis. We successfully transitioned into a fully integrated commercial stage company. Our first 2 independent launches were initiated, highlighted by TRYNGOLZA for FCS, which drove significant revenue growth. Importantly, we delivered multiple landmark data readouts that position us to continue driving accelerating value. We expect growth in 2026 to be driven by several key catalysts this year, some of which we've already achieved. Notably, we are on track for 3 additional launches, 2 of which are independent, including Ionis' first launch in a broad patient population sHTG. We are also on track for 5 late-stage data readouts across our partnered portfolio with 1 positive readout already achieved. With strong commercial momentum and advancing high-value pipeline and a clear path to cash flow breakeven by 2028, we believe Ionis is exceptionally well positioned to deliver transformational medicines for patients and accelerating value for shareholders for years and years to come. And with that, we'll open the call up for questions.
Operator: [Operator Instructions] And this morning's first question comes from Yaron Werber with TD Cowen.
Yaron Werber: Congrats really a lot of solid progress. Maybe just one question, Beth, for you on the guidance. I mean, so it sounds like you're not -- your guidance right now is not assuming any sHTG sales. You're assuming really not a lot of new royalty income from all the potential milestone payments and you're expecting that TRYNGOLZA will get impacted, it sounds like you're potentially matching the price of REDEMPLO. Is that correct? And then if you don't mind, I have a quick follow-up more on WAINUA on the study coming up.
Elizabeth L. Hougen: So let me kind of -- there were a few things in there, so let me see if I can break it all down. So we are assuming sales and revenue from olezarsen in the sHTG patient population. But with the assumption of standard review, that would be in really just the fourth quarter of the year. So it will be a FCS driven revenues for TRYNGOLZA between now and the launch of SHTG after approval. Obviously, priority review would improve that guidance we expect. We do anticipate that WAINUA will continue to grow. We do anticipate that there could be revenues from bepirovirsen for example, once it were to get to market. Right now, that's going to be late in the year most likely. So there's not a lot of contribution in that in our guidance. We're really focused on the regulatory initiatives, the acceptance of the NDA as well as the approvals to drive R&D revenues for bepirovirsen as well as the potential NDA acceptance for pelacarsen assuming positive Phase III data. So I think overall, looking at a really strong guidance given that we're assuming standard review. It's a 20% or so increase year-over-year on a like-for-like basis by taking the sapablursen out of the equation. That puts us on an apples-to-apples basis. And I think that 20% increase is really strong.
Kyle Jenne: And as it relates to pricing for this year, we are continuing to actively engage with payers. Obviously, those are confidential discussions. But really, what we want to make sure first and foremost is that we continue to ensure broad access for TRYNGOLZA prior to the sHTG approval. Those discussions are going very well. Based on those discussions, we do expect a meaningful decline in TRYNGOLZA revenues throughout the year ahead of the sHTG launch, as Beth reflected in her comments. But post the approval in sHTG, we expect accelerating growth, as you would expect, right, as that launch progresses throughout the balance of the year. Really, our focus remains on balancing the broad patient access with long-term value realization for this program. And so we're continuing to do that work. We're on track to deliver on that work, and we'll announce price when we conclude that work later this year.
Eugene Schneider: Yaron you had a question about...
Yaron Werber: Yes. Just on the cardio transform as we're now beginning to really kind of focus on that next everybody. Can you give us a sense of what percentage of patients are honest, a stabilizer at baseline because it was mostly an add-on strategy? And maybe what percent will only be on WAINUA alone essentially head-to-head against placebo, if you can, any color.
Brett Monia: I'll start. Eugene, please jump in if you want to add anything. So Yaron what we've been saying and is playing out very nicely is that we have a good balance at baseline of patients not on stabilizer tafamidis versus patients on tafamidis at baseline. It's not quite 50-50, we have more patients on tafamidis than naive at baseline, but it's well balanced. It's not capped, but we do not have -- but that's where we ended up. We have had some drop-ins during the course of the study, but it's not meaningful. It hasn't been that many. And we are working on a baseline presentation. We don't know the timing of that presentation yet. But we are working on it, and we'll be able to share that data hopefully at some point soon. Eugene, anything more to add?
Eugene Schneider: No, great one Brett.
Operator: And the next question comes from Salveen Richter with Goldman Sachs.
Salveen Richter: Just maybe help us understand what you're seeing for reimbursement in FCS given the competitors' lower price. And then just help us understand kind of this end pricing dynamic between the competitor and yourselves for sHTG and how that would essentially provide broader population access for yourselves. But I'm just trying to understand how to think about the differential there.
Kyle Jenne: Yes. So let me first say, again, what a strong year that we had last year, $108 million in total, $50 million in Q4, a 56% increase quarter-over-quarter. We continue to see very, very strong patient demand, even as we kick off 2026. So there's been no meaningful impact from a competitive standpoint, and we continue to have very broad access for our patients in FCS today. The work is ongoing. The goal that we have, as I mentioned, is to maximize the value, so the highest price possible, but also provide the broadest access possible when we get to sHTG. So we're having the right conversations today. We're leading the way with payers in those engagements. We did a great job in 2025 to execute that. We're doing the same in 2026. But it will take us a little bit more time before we complete the conversations and our research with the payers so that we come to a final decision on pricing.
Brett Monia: And I'll just add to that, Salveen, again, as Kyle mentioned in his prepared remarks, we've had no meaningful impact of a new market entrant on the demand for TRYNGOLZA. The demand for TRYNGOLZA continues to be very, very strong. Patients are doing very well on the medicine and we're seeing reauthorizations over and over and over again. So we're very pleased with the performance of TRYNGOLZA, but we're in that period right now in which we -- we're preparing to transition for the sHTG launch.
Operator: And the next question comes from Jason Gerberry with Bank of America.
Chi Meng Fong: This is Chi on for Jason. I want to go back to a comment that you made, Kyle. You said you -- obviously, you guys have recently increased the peak revenue for olezarsen to over $2 billion. And I recall is based on higher volume assumption. And today, Kyle, you mentioned you're even more confident in the blockbuster opportunity. Is it more confident in hitting that $2 billion number? Or is it more confident in hitting a potentially higher peak number? What drove the higher confidence? Is it based on any reason research? And is it high assumption on price or volume? And if I may squeeze in a quick one on the second question. I wanted to ask about ION532, which was licensed to AstraZeneca for APOL1-mediated kidney disease. Curious your thoughts about the market opportunity there, target profile of PS relative to competition? And lastly, when might we see Phase II data?
Kyle Jenne: Yes. On the $2 billion, Chi, we shared this last month, we had these conversations. That $2 billion is really based on the strength of the product profile and the positive Phase III data. In addition to that, we've done extensive prescriber demand research, and that's what drove us to increase to greater than $2 billion. I think what's increasing our confidence is the strong underlying demand trends that we're seeing that I just explained, not only ending last year, but also that are continuing here early in 2026.
Brett Monia: And your second question, Chi, I'll take is really best ask for AstraZeneca. It's a program that we've been working on for quite some time. We published on preclinical data for targeting APOL1 for FSG, particularly for people with mutations in the APOL1 gene across kidney disease. The preclinical data is very strong. The unmet need is very significant. There's a potential to go after patient populations that do not have -- that are not APOL1 carriers if the APOL1 carrier data is strong enough to go in that direction. So it's a significant market opportunity for renal disease. The decision by AZ to go to Phase II after we licensed it to them was based on day-to-day conducted in Phase I that showed strong target engagement and, of course, with good safety. So they advance it to Phase II. And as for time of data, that's a question for AZ.
Operator: And the next question comes from Michael Ulz with Morgan Stanley.
Michael Ulz: Congratulations on all the progress as well. Maybe just one related to the sHTG filing. Just wondering if you can give us any color on any recent FDA interactions there? And then secondly, has your thinking on the potential for a priority review changed at all recently?
Brett Monia: I'll start with the second one and I'll ask Eugene to talk about how things are going. So for priority review, we can't speak for the FDA, but we believe that based on the unmet medical need and the compelling product profile, for olezarsen and sHTG that it deserves priority review designation, but we're in that window, we're in that evaluation window right now. And of course, again, I will remind you, we did receive breakthrough therapy designation. As far as regulatory interactions been on track, right?
Eugene Schneider: So far, so good. It's early days, of course, as you said.
Brett Monia: Yes. We're within that window, Mike.
Operator: And the next question comes from Luca Issi with RBC Capital.
Luca Issi: I don't want to maybe just double down here on this prior review versus standard review. I think in the past, you came across as pretty confident about prior overview, but obviously, you're now guiding assuming a standard review. So just wondering kind of hinting has changed? Or maybe this is just kind of standard conservatism? Like any thoughts there, I'd be much appreciated. And then maybe on Angelman, Holly, I think when I go on clinicaltrial.gov, I don't see any European sites there for your program, I think, except for the U.K., so versus, I think, your competitor Ultragenyx has many European sites. So is that because the European regulators prefer sham controlled trials? Is that a placebo-controlled trial? Or is that kind of more complex than that? Any thoughts much appreciated.
Brett Monia: I'll let Holly address the Angelman in a moment, Luca. But as far as priority review, there's not really much more to add beyond the answer that we described from the previous question. We're in the evaluation period by the FDA. We submitted our supplemental NDA late last year. We're in that window. We believe the medicine deserves priority review, but we can't speak for the FDA. And the FDA usually takes the time that they need to draw a conclusion and I think we'll just leave it there. And as far as assuming standard review for guidance, we think that's the responsible thing to do at this stage. As Beth mentioned, we will adjust guidance if we receive priority review, and we'll inform everybody. Holly?
Holly Kordasiewicz: For Angelman, you hit on it. So we have submitted to Europe. We're waiting to hear back from them for that and we need that approval of spending forward with those sites. But we do plan to open up sites in Europe as soon as that approval comes through.
Operator: And the next question comes from [indiscernible] with Guggenheim Securities.
Moritz Reiterer: This is Moritz on for Debjit. First, a quick follow-up on TRYNGOLZA sHTG pricing. You previously said that you're expecting to price TRYNGOLZA at approximately 20,000 net price should that still be our base case assumption at this point? And then secondly, a question on the blood brain barrier penetrating platforms. During your Innovation Day, you highlighted both the VHH and the bicycle delivery systems to potentially cross the blood-brain barrier. When can we expect updates on those platforms?
Kyle Jenne: On the pricing question, we're finalizing the payer research. We'll provide those details once we finalize everything and get that out. But 20,000 net is what we had assumed in the greater than $2 billion peak sales revenue number that we've been using. So that's still consistent. We haven't updated that at this point in time.
Brett Monia: And as far as the BBB work, it continues to go exceptionally well. I think as we mentioned previously, we selected our first BBB wholly owned molecule that's now in manufacturing. It does utilize the VHH technology. We're making great progress on bicycle as well for BBB overcoming the BBB for CNS diseases. We anticipate initiating IND supporting toxicology studies later this year for the VHH BBB molecule. And although we have not laid out definitive plans yet, I expect you'll get an update in the second half of this year on where we are with our BBB strategy.
Operator: And the next question comes from Joseph Stringer with Needham & Company.
Joseph Stringer: A quick one on the GSK partnered HBV program. When can we see functional cure rates from the Phase III program? And what are your GSK's expectations for potential peak sales as a functional cure? And maybe more directly, what net revenue assumptions to Ionis are baked into your projected peak royalty revenues from this partner program.
Brett Monia: Yes. Sure. Beth will take the peak sales estimates because I can't keep them all straight from our partners and the revenue what they're projecting. But as far as the presentation, yes, the data is will impress. The data shows it's unprecedented functional cure rates in this massive patient population with very high unmet medical need, millions of people. And GSK plans to present the data at EASL in May, the European Association for the Study of the Liver. And what they've said is that the functional cure rates are clinically meaningful. Beth?
Elizabeth L. Hougen: So GSK has talked about peak sales in the about USD 2.5 billion range. We've got a royalties that go from 10% to 12% in addition to the regulatory milestones, many of which we anticipate earnings this year as they move through the regulatory filing acceptance and approval process in multiple countries. So we've baked their peak sales estimate with our royalty tiers 10% to 12% into our overall peak royalties from -- from sorry. We've baked their peak sales and our royalties into our estimated peak royalties, which are about, I think, several billion dollars.
Operator: Next question comes from Andy Chen with Wolfe Research.
Andy Chen: So I know you talked about Alexander quite a bit today. So just curious how fast that ramp would be or how big the eventual opportunity would be? And if you can compare the opportunity to other rare diseases, such as DAWNZERA or FCS, that would be great.
Brett Monia: I'd let Holly just talk about what she's hearing from the community first with Zilganersen. It's really exciting. And that, of course, affects the ramp like what we're hearing. And then Kyle to take on how he anticipates expectations for the launch.
Holly Kordasiewicz: Just quick to remind everybody, last year, we read out our Phase III study, and we hit statistical significant clinical meaningful differences on our primary endpoint, which is a motor functional test. And then we also, in key secondary endpoints had favorable results all favoring Zilganersen. The community, of course, has been overwhelmingly positive. They are excited for the drug. We've opened up an early access program. We already have folks coming into that as well. And so it's very encouraging to see how the response has been from the community that they're just waiting for that medicine.
Kyle Jenne: Yes. And related to the launch, there are approximately 300 people living with Alexander disease in the United States today. We believe that about 50% of those have been identified. There are about a dozen or so major leukodystrophy centers that we'll focus on at the launch. So we can do that with a very modest-sized team. Our medical affairs group is already out. We have a neurology-focused group that's been working in this area for quite some time, that and on other programs that we have. We'll add some account specialists and then some of our patient education managers to help the reimbursement and transition on to treatment and keep patients taken care of, et cetera, through the process. We have guided to greater than $100 million in peak revenue for this program. And we'll work on that launch later this year with an expected approval sometime towards the fourth quarter. We'll get the team in place and get launched. And so it will be modest this year and then grow into 2027.
Brett Monia: The Zilganersen opportunity, of course, is incredibly meaningful for the patient community. It's going to provide meaningful revenue for Ionis once we get there. But also, it's really important to understand and recognize the strategic value for our neurology wholly owned pipeline Zilganersen is the first coming from Ionis that we're going to deliver to patients, commercialize ourselves. Behind that is our Angelman's program and then we have a rich pipeline of medicines that are wholly owned for neurology, not just for rare diseases, but also from broad disease indications. So it really gets us started.
Operator: And the next question comes from Akash Tewari with Jefferies.
Manoj Eradath: This is Manoj on for Akash. Just one from our end. Can you provide some color on your expectations around the upcoming HORIZON Lp(a) Phase III? What could be a commercial viable risk reduction bar in the setting do you consider any potential deeper risk reduction in the other near-term Lp(a) readouts could change the commercial outlook for pelacarsen? And also, can you comment on the current status of your next-gen or like full on Lp(a) targeting asset.
Brett Monia: Yes. I'll let Eric talk about the next gen and why we're so excited about its profile. With respect to the HORIZON trial, I mean we remain quite confident in the outcome, recognizing the risk of doing something for the first time, it's Ionis tradition. It's in our DNA to be first. We've done it so many times and for Lp(a) will be the first to test the Lp(a) CBD hypothesis. But based on the epidemiology based on the conduct of the study, based on the clearance of 2 interim analyses very positively already and based on everything we're seeing from our partner, Novartis, in the trial, we remain confident. Of course, the risk is that no one's ever done this before. But that's an enormous opportunity as well. The patient -- the mean Lp(a) levels in the study have been reported already. I believe they're the median, I should say, 109 milligrams per deciliter. So it's quite a sick patient population. The vast majority of patients with prior cardiovascular disease, more than 80% have had myocardial infarction. The rest are stroke or serious peripheral artery disease to be qualified for the study. It's a very well-conducted study. It's going to give the answer to the Lp(a) hypothesis. And as far as competition goes, it's -- pelacarsen has a meaningful first-mover advantage in this massive market opportunity. And we've seen no drug profile out there that we believe will be superior to the Lp(a) lowering effects that we saw -- that we're seeing for pelacarsen. So stay tuned, midyear this year, we'll get an answer. Eric, what about the follow on?
Eric Swayze: Yes, sure. Because we believe in the market opportunity and the indication and that lowering LP(a) can give value for patients with cardiovascular disease. Some years ago, we started looking for drugs that extend the dosing interval. And that really was the goal of our program was to extend the interval of dosing. We've been working with siRNA technology for some time now. We recently reported some nice positive data on ION775 with siRNA that extends dosing frequency in -- for lowering ApoC-III and triglycerides in humans. And we've been making equal better progress on LP(a) with our siRNA platform. Goal is to get it to 6 months extended dosing or perhaps a year depending on how the drugs perform. We're very encouraged by the ION775 performance. And preclinically, the LP(a) siRNA looks better. So hopefully, we can demonstrate that in humans soon.
Brett Monia: We have several programs coming forward into the clinic that are offering strong durability twice a year, once a year dosing 775, of course, is the olezarsen follow-on for ApoC-III, we reported data last year in Phase I. It looked excellent, and we're going to be in sHTG patients in Phase II this year. And we believe that, that will be replicated with the pelacarsen follow-on, which is now in IND supporting toxicology studies.
Operator: And the last question comes from Jay Olson with Oppenheimer. Oppenheimer has dropped off the line. That does conclude the question session. So I would like to turn the floor back over to Brett Monia for any closing comments.
Brett Monia: Great. Thank you for all the great questions. Thanks for everybody's participation. Obviously, we are incredibly proud of the pivotal year we had in 2025 for Ionis, and we're building on that momentum to set us up for an even more pivotal, more exciting year for Ionis in 2026. We've already achieved a great deal and we're well positioned to achieve a great deal more. And with that, we'll close the call. Thank you again for your participation. We look forward to providing further updates throughout the year. Goodbye for now.
Operator: Thank you. And as much the conference has now concluded. Thank you for attending today's presentation. You may now disconnect your lines.