Good morning, and welcome to IONIS's fourth quarter and full year 2025 financial results conference call. As a reminder, this call is being recorded. At this time, we'd like to turn the call over to Wade Walk, Senior Vice President of Investor Relations, to lead off the call. Please begin.

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, today, including a reconciliation of GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We've also posted slides on our website that accompany today's call. With me on the call this morning are Brett Monja, our Chief Executive Officer, Holly Kordesiewicz, Chief Development Officer, Kyle Jenae, Chief Global Product Strategy Officer, and Beth Haugen, 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 three, which contains our forward-looking language statement. During this call, we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail. So with that, I'll turn the call over to Bray.

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 two 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. Tringolza, the first FDA-approved treatment for familial chylomicronemia syndrome, or FCS, exceeded expectations in its first year on the market. Tringolza's excellent performance was driven by a compelling clinical profile and strong launch execution. Tringolza was also launched in Europe late last year, and we're pleased to see our partner Sobe bring this transformational medicine to more patients. In August, we kicked off our second independent launch with the FDA approval of Donzera, a prophylactic treatment for hereditary angioedema, or HAE. As the first and only RNA-targeted medicine for HAE, Donzera offers a compelling profile that is resonating with prescribers and patients. In just last month, Donzera received European approval, enabling our partner, Atzuka, to bring this important medicine to patients across the region. In 2025, we accelerated this strong momentum with the Olazarsin 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. Olazarsin showed highly significant and substantial reductions in triglycerides in acute pancreatitis attacks, establishing Olazarsin 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. I also delivered positive Phase III results for our innovative medicine, Zilgenersen, the first to demonstrate a disease-modifying benefit in Alexander disease, a rare and often fatal neurodegenerative disease. We submitted our NDA in January, and we anticipate approval and launch in the second half of this year. Assuming approval, Zilga Nursen 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. 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 partnered pipeline. In January, we announced the first of these results with positive top-line data for Bethair Versin, 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 Beperaversin to the millions of people living with chronic HPV later this year. Looking ahead, we anticipate results from two major cardiovascular outcome trials, the Pellicarsin-LP-A-Horizon trial mid-year and the Eplon-Tersin-CardioTransform trial in the second half of 2026. In addition, Cifaxosin for IJ Nephropathy and Uefnusin for FUS ALS are also positioned for phase three readouts later this year. If positive, these outcomes position our partner pipelines to deliver four 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 two independent launches, an advancing wholly owned pipeline and a robust partner portfolio, IONUS 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 IONUS. 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's leading research and development organization and brings a deep, 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.

Thank you, Rhett. I'm honored to lead our world-class development team because we recently delivered a hopeful positive data readout. I've had the privilege of working closely with many members of 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 medicine to people with serious diseases for years to come. Olazarsin is a clear example of our leadership in discovering and developing transformational medicine. The groundbreaking Phase III data generated from the CORE and CORE II trials position Olazarsin to be the new theater of care for the broad FHTG patient population. As previously presented and published, our pivotal studies evaluated olidarsen in people with SHTG who had triglyceride levels substantially higher than the 500 mg per deciliter, despite being on standard of triglycerides and lowering therapies at baseline, putting them at risk of life-threatening acute pancreatitis. In core and core two, olidarsen demonstrated highly statistically significant and clinically meaningful mean reductions of up to 72% in placebo-adjusted fasting triglycerides at six the primary endpoint. Olizarsen also significantly reduced acute pancreatitis events, making it the first and only treatment to achieve this positive outcome in people with health. Olizarsen achieved a highly statistically significant 85% reduction in adjudicated acute pancreatitis. It's important to remember that the main goal of triglyceride management in SACG is to prevent AP attacks. And Olizarsen 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 four patients needed to be treated with holozarsin for only 12 months to prevent one AP attack. These unprecedented results were the substantial unmet need of people with FHTG. We submitted the SNDA at the end of 2025 and it is currently within the FDA. We requested priority review and based on these grounds, we have initiated an expanded access program or send what review is ongoing we expect ovidinersen to be the first of numerous additional independent launches from our leading neurology pipeline underscoring ios's ability to consistently translate scientific leadership into important medicines for our patients turning now to our phase three program for ovidinersen previously referred to as ion 5a2 our investigational medicine for angel therapy designation from the fda in recognition of Zoganursin is advancing in the Phase III Reveal study with folic enrollment expected this year and data next year. In addition to Zoganursin and Ovidinursin, we have a rich neurology pipeline advancing in development, including ION464 for multiple systems atrophy and ION717 for pre-end 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 profiles. 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 U.S. approval of high-dose FINRAZA, which has a PDUFA date of April 1st. We're also looking forward to the Phase III study start of style and nursing, evaluating annual dosing for SMA, and SAP O'Gorison for Polyphenia Vera. More over three 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.

Thank you, Holly. With a strong first year for Tringolza, an encouraging start for Donzera, and two 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, Tringolza 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 tringolza, 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 as 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 Tringolza performance. Patients are gaining access to Tringolza 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 continue to secure coverage. All the strong momentum we saw from Tringolza 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 In fact, Tringolza continues to deliver strong growth in referrals and patient starts. Physicians continue to report very high satisfaction with both their prescribing experience and Tringolza'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 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 their triglyceride levels with current treatments. In the U.S. alone, more than one 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 olazarsin and its potential to address patient-unmet HCPs found the low number needed to treat to prevent one potentially fatal acute pancreatitis of the TAC, 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 Olazarsen'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 Olazarsin. 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 Tringolza 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 Olazarsen's product profile, we increased our annual peak revenue estimates for Olazarsen to more than $2 billion. And today, we're even more confident in the blockbuster opportunity of Olazarsin. Our groundbreaking data, strong HCP enthusiasm, and first-mover advantage position Olazarsin to realize its full potential as the new standard of care for people with severe hypertriglyceridemia. Turning to Don Zera, the launch is off to an encouraging start. We're seeing early adoption across all patient segments, including patient 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 percent conversion to paid therapy to date. Initial feedback from both physicians and patients shows high enthusiasm for Don Zara'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 Donzera. 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 Donzera offers, we are confident we have the right drug, the right strategy, and the right team to successfully bring Donzera to people with HAE. Importantly, with strong launch fundamentals today, we expect Donzera to meaningfully contribute to our growing commercial revenue this year, and we reaffirm annual peak sales, essential in excess of $500 million. Turning now to Zilga-Nursen for Alexander Disease, we expect it to be the first independent launch from our neurology portfolio. Based on the Phase III results, Zilga-Nursen 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 Zilga-Nursen could be the first of many first-in-class disease-modifying treatments from IONIS's 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 Trindles in FCS and Donzera in HAE while preparing to execute two additional launches this year, further expanding IONUS's reach to even more patients in need of our medicines. With that, I'll now turn it over to Beth.

Thank you, Kyle. 2025 was a defining year for IONUS 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 percent increase year-over-year. Revenue was split between commercial products, which generated $436 million, or 46 percent 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 sustain growth. 2025 was a strong first year for the Tringosa 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 Donzera 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 Donzera revenue growth. Royalty revenues increased 11% to $285 million in 2025, anchored by meaningful contributions from Spinraza and growing royalties from Wayne Nua. Our R&D revenue also increased, generating more than 20% growth year-over-year, driven by progress across multiple partnered programs. The largest contributor was the SAP of Lurston license fee, underscoring our ability to monetize non-core 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 Tringolza and Dunzera 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 creation. 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 to $825 million from numerous sources. This represents an increase of approximately 20% over last year after adjusting for the one-time $280 million SAPA-Borson 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 Olozarsen, 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 S-NDA for Olozarsen, we plan to provide Tringolza and Donzera product-level revenue guidance at our first quarter earnings call. So today, we will share some high-level perspectives and directional insights to help frame expectations. We continue to see strong demand for Tringolza 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 Tringolza ahead of the anticipated SHDG approval. As a result, we expect a meaningful decline in Tringolza revenues throughout the year ahead of the SHTG launch, followed by accelerating growth as uptake builds. As we prepare for the SHTG launch, we are establishing a reimbursement strategy designed to achieve broad access while maximizing the value of Olo's arson to drive sustainable long-term growth. Following anticipated approval, we expect to launch quickly with momentum building as we begin to bring Olazarsen to this much larger patient population. And importantly, as Kyle highlighted, we are more confident than ever in the multi-billion dollar opportunity for Olazarsen. For Danzera, 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, program, we are confident we have the elements in place to drive substantial growth. From our partnered commercial programs, we anticipate earning substantial royalties from medicines on the market today. We expect Spinraza to remain resilient and WENUA to continue its upward trajectory this 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 Donzera 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 salinersin and sapoblursin, as well as numerous regulatory milestone payments for bepiraversin and Powell Carson. 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 is 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 toward 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 and $550 million. This represents a similar level compared to 2025, excluding the one-time SAPPA-Blurson license fee last year and assuming a standard review for Ola's arson. Importantly, we project to end the year with a well-capitalized balance sheet, including in 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 bills for the anticipated SHTG launch and continued advancement of our wholly owned medicines and development. Looking beyond this year, with two 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 break-even by 2028, driving long-term value creation. And with that, I'll turn the call back over to Brett.

Thank you, Beth. 2025 was indeed a defining year for Ionis. We successfully transitioned into a fully integrated commercial stage company. Our first two independent launches were initiated, highlighted by Tringolza for FCS, which drove significant revenue growth. Importantly, we delivered multiple landmark data readouts that position us to continue driving and 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 three additional launches, two of which are independent, including Ionis' first launch in a broad patient population, SHTT. We are also on track for five late-stage data readouts across our partner portfolio, with one positive readout already achieved. With strong commercial momentum and advancing high-value pipeline and a clear path to cash flow break-even 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.

We will now begin the question and answer session. To ask a question, you may press star, then want on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. If any time your question has been addressed and you would like to withdraw it, please press star then zero. This time we will pause momentarily to assemble the roster. This morning's question comes from Euron River with T.D. Gallen.

Thanks so much, and congrats, Julian. A lot of solid progress. Maybe just one question back to 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 your goals will get impacted. It sounds like you're potentially matching the price of Redempla. Is that correct? And then, if you don't mind, I have a quick follow-up more on the Anway Nua, on the study coming up.

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 Olizarsin and the SHTG patient population, but with this assumption of standard review, that would be in really just the fourth quarter of the year. So, it will be an FCS-driven revenues for Tringolza between now and the launch of SHTG after approval. Obviously, priority review would improve that guidance we expect. We do anticipate that Wayne Newell will continue to grow. We do anticipate that there could be revenues from that peer reversion, 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 Bacteraversin, as well as the potential NDA acceptance for pellet-carsin assuming positive Phase III data. So, you know, I think overall we're looking at our, you know, really strong guidance given that we're assuming standard review, it's a 20 percent or so increase year-over-year on a like-for-like basis by taking the SAPA-Borson out of the equation. That puts us on an apples-to-apples basis, and I think that 20 percent increase is really strong.

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 of first and foremost is that we continue to ensure broad access for Tringolza prior to the SHTG approval. Those discussions are going very well. Based on those discussions, we do expect a meaningful decline in Tringolza 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.

Yaron, I had a question about. Yeah, just on the cardio transform, you know, as we're now beginning to really kind of focus on that next, everybody, can you give us a sense what percentage of patients are on a stabilizer at baseline? Because it was mostly an add-on strategy, and maybe what percent will only be on that way new or alone, essentially, head-to-head against placebo, if you can, any color.

I'll start. Eugene, please jump in. So, Jeroen, what we've been saying and, you know, is playing out very nicely is that we have a good balance at baseline of patients not on stabilizer tefamidus versus patients on tefamidus at baseline. It's not quite 50-50. We have more patients on tefamidus 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 droppings 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? No, not very good, Brad. Thank you, Ron.

Thank you. And the next question comes to Savine Richter with Goldman Sachs.

Good morning. Thanks for taking my question. Just maybe help us understand what you're seeing for reimbursement in FCS, given the competitor's 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, you know, broader population access for yourselves.

But I'm just trying to understand how to think about a differential there.

Yeah, so let me first say, you know, 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 and those engagements. We did a great job in 2025 to execute that. We're doing the same in 2026. But it'll 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.

And I'll just add to that, Salveen, that, again, as Kyle mentioned in his prepared remarks, We've had no meaningful impact of our new market entry on the demand for Tringolza. The demand for Tringolza 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 Tringolza, but we're in that period right now in which we're preparing to transition for the SHTG launch.

Thank you.

And the next question comes from Jason Gowry with Bank of America.

Hey, guys. This is Chi on first, Jason. Thanks for taking our question. I want to go back to a comment that you made, Kyle. You said you have, you know, obviously you guys have recently increased the peak revenue for oil absorption to over $2 billion. And I recall that's 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? With drill to higher confidence, is it based on any recent research, and is it a high assumption on price or volume? And if I may squeeze in a quick one on a second question, I want to ask about IR532, which was licensed to AstraZeneca for a poor-alware mediator kidney disease. Here's your thoughts about the market opportunity there, target profile of the ASA relative to competition, And lastly, when might we see Phase II data? Thanks so much.

Yeah, on the $2 billion sheet, you know, and 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.

And your second question, Chi, I'll take, is really best to ask for AstraZeneca. It's a program that we've been working on for quite some time. We published on preclinical data for targeting APOL-L1 for FST, particularly for people with mutations in the APOL-L1 gene that cause kidney disease. The preclinical data is very strong. The unmet need is very significant. There's the potential to go after patient populations that are not APOL-L1 carriers if the APOL-L1 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 data they conducted in Phase I that showed strong target engagement. And, of course, with good safety, so they advance it to phase two. And as for timing of data, that's a question for AZ.

And the next question comes from Mike Orles with Morgan Stanley.

Good morning. Thanks for taking the question, and congratulations on all the progress as well. Maybe just one related to the SHTG filing, you know, just wondering if you can give us any color on any recent FDA interactions there. And then secondly, you know, has your thinking on the potential for a priority review, you know, change at all recently?

So the second one I'll ask Eugene to talk about, you know, how things are going. So for priority review, you know, we can't speak for the FDA, but we believe that based on the unmet medical need in a compelling product profile for Olizarsen and SHCG that it deserves a prior review designation, but we're in that window, we're in that evaluation window right now. And we did receive breakthrough therapy designation. As far as regular three interactions, it's been on track, right? So far, so good. It's early days, of course, as you said. Great, thank you. We're within that window, Mike.

Thank you. And the next question comes from LUCA EC with RBC Capital.

Oh, great. Thanks so much for taking a question. Congrats on the progress. I do want to maybe just double down here on this, you know, priority review versus standard review. I think in the past you came across as pretty confident about priority review, but obviously you're now guiding assuming standard review. So I'm just wondering if kind of anything has changed or maybe this is just kind of standard conservatism. Like any thought there, I'd be much appreciated. And maybe on Angelman, Ali, I think when I go on clickotry.gov, I don't see any European sites there for your program, I think except for the U.K., so versus I think your Conceptor Ultrogenics has many European sites. So is that because the European regulators prefer sham-controlled trials instead of placebo-controlled trials, or is that kind of more complex than that? Much appreciated.

I'll have Holly addressed the angel ones in a moment, Luca, but as far as prior to review, there's not really much more to add than 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, you know, 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.

Yep, for Angela and 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 to then move forward with those sites. But we do plan to open up sites in Europe for sure that approval comes through.

And that's Chris Gronson from Allich Radio with the Guggenheim Securities.

Hi, this is Morrison for the budget. Thanks so much for taking my question. First, a quick follow-up on Tringolsa's HDE pricing. You previously said that you're expecting to price Tringolsa 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? Thank you.

On the pricing question, we're finalizing the payer research. We will 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.

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, you know, overcoming the BBB for CNS diseases. We anticipate initiating IND-supporting toxicology studies later this year for the EVHH 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.

Thank you so much.

Thank you. And the next question is Joseph Stringer with Needham & Company.

Hi, thanks for taking our questions. A quick one on the GSK-partnered HPV program. When can we see functional cure rates from the Phase III program, and what are your and 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? Thank you.

Yeah, sure. That will take the peak sales, as I can't keep them all straight from our partners and the revenue, what they're projecting. But as far as the presentation, yeah, the data is well impressed. It's unprecedented functional cure rates in this massive patient population with very high medical needs, millions of people. And GSK plans to present the data at ESIL 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.

So GSK has talked about peak sales in the about $2.5 billion U.S. dollar range. We've got a royalty – tiered royalties that go from 10 to 12 percent 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 percent, into our overall peak royalties from – we've baked their peak sales and our royalties into our estimated peak royalties, which are about, I think, several billion dollars.

Next question. Yes, thank you. And next question goes from Andy Chan with Wolf Research.

Hey, thank you for taking the question. 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 Donsera or FCS, that would be great.

Thanks, Andy. I'd like, Holly, to just talk about what she's hearing from the community first with Brazilian nurses. 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.

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 all favoring boganersin 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 in for 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 this medicine Yeah, 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, you know, 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, you know, we'll work on that launch later this year with an expected approval, you know, sometime towards the fourth quarter, we'll get the team in place and get launched. And so it'll be modest this year and then grow into 2027.

The Sylvan Urson opportunity, of course, is incredibly meaningful for the patient community. It's going to provide, you know, meaningful revenue for IONIS once we get there. But also it's really important to understand and recognize the strategic value for our neurology fully-owned pipeline. So the nurses first that we're going to deliver to patients, commercialize our cells. 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 for broad disease indications. So it really gets us started.

Thank you. And the next question comes from Awash Tiwari with Jeffries.

Hey, this is Manojwan Faragas, just one from our end. Can you provide some color on your expectations around the upcoming Horizon LpL phase 3? What could be a commercially viable risk reduction bar in the setting? Do you consider any potential deeper risk reduction in the other near-time LpL readouts could change the commercial outlook for Pelikarsen? And also, can you comment on the current status of your next-gen or, like, follow-on LpL targeting assets?

Yeah, like Eric talked about the next-gen and why we're so excited about its profile. With respect to the Horizon trial, I mean, you know, we remain quite confident in the outcome. You know, recognizing the risk of doing something for the first time, you know, it's Sionis tradition. It's in our DNA to be first. We've done it so many times, and for Lp. little a, we'll be the first to test the Lp. little a CVD hypothesis. But based on the epidemiology, based on the conduct of this study, based on the clearance of two 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. You know, the patient, the mean healthy little levels in the study have been reported already. I believe the median, I should say, is 109 milligrams per deciliter, so it's quite a sick patient population. The vast majority of patients with prior cardiovascular disease, more than 80 percent, 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-little-A hypothesis. And as far as competition goes, you know, Pellicarsin 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-little-A lowering effects that we're seeing for Pellicarsin. So stay tuned. Mid-year this year, we'll get an answer. Eric, what about the follow-on?

Yeah, sure. Because we believe in the market opportunity and the indication and that lowering LPA 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. We've been working with sRNA technology for some time now. We recently reported some nice positive data on IN-775 with an SNS-RNA that extends dosing glycerides in humans. And we've been making progress on LPA programs coming forward into the clinic that are going on.

Jay Olson with Oppenheimer. Please go ahead, Oppenheimer.

Hey, Oppenheimer has dropped off the line. That does conclude the question session, so I would like to turn the floor back over to Greg and Ronia for any closing comments.

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.

Goodbye. Thank you. And as mentioned, the conference is now concluded. Thank you for attending today's presentation. May now disconnect your lines.