Ionis Pharmaceuticals Inc Q4 FY2025 Earnings Call

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.

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.

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. TRYNGOLZA, the first FDA-approved treatment for familial chylomicronemia syndrome, or FCS, exceeded expectations in its first year on the 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 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 two 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 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 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.

Thank you, Brett. I’m honored to lead our exceptional development team, which has recently achieved several important concept data readouts. I’ve been fortunate to work closely with many team members over the years, and I look forward to building on our strong foundation. Our focus will continue to be on innovation and ensuring effective execution to allow Ionis to keep delivering a consistent stream of transformative medicines to those with serious diseases for years to come. Olezarsen exemplifies our expertise in discovering and developing transformative medicines. The groundbreaking Phase III data from the CORE and CORE2 trials positions Olezarsen as a new standard of care for the broad sHTG patient population. As previously presented and published, our pivotal studies assessed Olezarsen in individuals with sHTG who had triglyceride levels significantly exceeding 500 mg per deciliter despite being on standard lowering therapies, putting them at risk for serious acute pancreatitis. In CORE and CORE2, Olezarsen showed highly statistically significant and clinically meaningful mean reductions of up to 72% in placebo-adjusted fasting triglycerides at six months, the primary endpoint. Olezarsen also significantly reduced acute pancreatitis events, making it the first complete treatment to achieve such a positive outcome in those with sHTG. It showed a significant 85% reduction in adjudicated acute pancreatitis events. It’s crucial to remember that the primary goal of triglyceride management in sHTG is to avert AP attacks, and Olezarsen is the first medicine to prove it can do this. The remarkable decline in the rate of AP attacks is also evident in the number of patients needed to treat to prevent a potentially fatal pancreatitis attack. Only four patients need to be treated with Olezarsen for just 12 months to prevent one AP attack in the highest risk group. For comparison, statins used for primary prevention have a number needed to treat ranging from 100 to 500 to prevent one cardiovascular event over five years. We believe these unprecedented results position Olezarsen to address the significant unmet need for individuals with sHTG. We submitted the sNDA at the end of 2025, and it is currently under FDA filing review. We requested priority review and anticipate a decision from the FDA soon. Launch preparations are already well underway, and we look forward to making Olezarsen available to those with sHTG later this year. Alongside Olezarsen, we are also ready for another independent launch this year. We plan to introduce Zilganersen to patients with Alexander disease, a rare leukodystrophy that deeply affects patients and families who currently have no approved disease-modifying therapies. Our positive Phase III results for Zilganersen indicate the first time any therapy has shown a disease-modifying effect in this condition. We recently submitted our NDA based on these groundbreaking results. Meanwhile, we have started an expanded access program to provide eligible patients access to Zilganersen while the review is pending. We expect Zilganersen to be the first of many additional independent launches from our leading neurology pipeline, highlighting Ionis' ability to reliably turn scientific leadership into crucial medicines for our patients. Moving on to our Phase III program for Obudanersen, previously known as ION582, our investigational medicine for Angelman Syndrome. Late last year, we received breakthrough therapy designation from the FDA due to Obudanersen's promising mid-stage data and the significant unmet need in this disorder. Angelman Syndrome is a rare neurodevelopmental disorder that leads to severe lifelong physical and cognitive impairment and is estimated to affect more than 100,000 people worldwide. Obudanersen is progressing 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 robust neurology pipeline in development, including ION464 for multiple system atrophy and ION717 for Prion disease. We are conducting ongoing studies with both investigational medicines in patients. Given the data collected so far, we are encouraged by the level of target engagement and the safety and tolerability profiles. Consequently, we plan to expand the dose cohort studies to fully explore the therapeutic potential of these medicines. With these expansions, we now expect to report data from both programs next year. Looking ahead to key upcoming events, in addition to those highlighted by Brett, we’re eager for the anticipated approval of high-dose SPINRAZA, which has a PDUFA date of April 1. We’re also looking forward to the Phase III study commencement of Salanersen evaluating annual dosing for SMA and Sapablursen for polycythemia vera. We have over three mid-stage partner programs set to announce results this year, along with multiple regulatory milestones, making 2026 another year rich with catalysts. And with that, I’ll turn it over to Kyle.

Thank you, Holly. With a strong first year for TRYNGOLZA, an encouraging start for DAWNZERA 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, TRYNGOLZA continued to gain momentum, generating $50 million in net product sales, reflecting a 56% increase in revenues quarter-over-quarter. 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 their 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. 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 in FCS and DAWNZERA in HAE while preparing to execute two additional launches this year, further expanding Ionis' reach to even more patients in need of our medicines.

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 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 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 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 million to $825 million from numerous sources, this represents an increase of approximately 20% over last year after adjusting for the one-time $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 builds. As we prepare for the sHTG launch, we are establishing a reimbursement strategy designed to achieve broad access while maximizing the value of Olezarsen to 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. 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 one-time 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 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 breakeven 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 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 three additional launches, two of which are independent, including Ionis' first launch in a broad patient population sHTG. We are also on track for five late-stage data readouts across our partnered portfolio with one 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.

And this morning's first question comes from Yaron Werber with TD Cowen.

Congratulations on the solid progress. I have a question for you, Beth, regarding the guidance. It seems that your current guidance does not factor in any sales from sHTG. You also appear to be anticipating minimal new royalty income from potential milestone payments and that TRYNGOLZA will likely see a price adjustment to match REDEMPLO. Is that correct? Additionally, I have a quick follow-up regarding the WAINUA study coming up.

Let me break it down. We are assuming sales and revenue from Olezarsen in the sHTG patient population, but with a standard review assumption, those sales would likely come in the fourth quarter. Therefore, revenues for TRYNGOLZA will be primarily driven by FCS until the launch of sHTG after approval. A priority review could improve that guidance. We expect WAINUA to continue growing and anticipate potential revenues from Bepirovirsen once it reaches the market, likely late this year, so it doesn’t contribute significantly to our current guidance. Our focus is on regulatory initiatives, including the acceptance of the NDA and approvals to drive R&D revenues for Bepirovirsen, along with the potential NDA acceptance for pelacarsen if we receive positive Phase III data. Overall, considering standard review, we’re looking at strong guidance, with about a 20% year-over-year increase on a comparable basis, excluding Sapablursen from the equation. This represents a robust 20% increase when looking at the figures apples-to-apples.

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.

Yaron you had a question about...

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 on 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.

I'll start. Eugene, please jump in if you want to add anything. Yaron, what we've been saying 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 that's where we ended up. We have had some drop-ins during the course of the study, but it's not meaningful, and it hasn't been that many. We are working on a baseline presentation, but we don't know the timing of that presentation yet. We are actively working on it and will be able to share that data hopefully at some point soon. Eugene, anything more to add?

No, great one Brett.

And the next question comes from Salveen Richter with Goldman Sachs.

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.

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.

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 again. So we're very pleased with the performance of TRYNGOLZA, but we're in that period right now in which we're preparing to transition for the sHTG launch.

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

This is Chi on for Jason. I want to revisit a comment you made, Kyle. You mentioned that you recently increased the peak revenue estimate for Olezarsen to over $2 billion, which I believe is based on higher volume assumptions. Today, you expressed even greater confidence in the blockbuster potential. Are you more confident in achieving the $2 billion figure, or do you foresee a possibly higher peak? What has contributed to this increased confidence? Is it based on specific research, or is it tied to assumptions about price or volume? Additionally, I have a quick follow-up question regarding ION532, which was licensed to AstraZeneca for APOL1-mediated kidney disease. What are your thoughts on the market opportunity and the target profile compared to the competition? Lastly, when can we expect to see Phase II data?

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.

Regarding your second question, Chi, that is best directed to AstraZeneca. It's a program we've been developing for quite some time. We have published preclinical data on targeting APOL1 for FSG, especially for individuals with mutations in the APOL1 gene related to kidney disease. The preclinical data is robust, and there is a significant unmet need. There is potential to pursue patient populations that are not APOL1 carriers if the data for APOL1 carriers is compelling enough to support that direction. This represents a substantial market opportunity for renal disease. AstraZeneca’s decision to progress to Phase II after we licensed it to them was informed by the strong target engagement and good safety demonstrated in Phase I. Therefore, they have advanced to Phase II. As for the timeline for data, that is a question for AstraZeneca.

And the next question comes from Michael Ulz with Morgan Stanley.

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?

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?

So far, so good. It's early days, of course, as you said.

Yes. We're within that window, Mike.

And the next question comes from Luca Issi with RBC Capital.

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 review, 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.

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. 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?

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.

The next question comes from indiscernible with Guggenheim Securities.

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?

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.

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.

And the next question comes from Joseph Stringer with Needham & Company.

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.

Yes. Sure. Beth will take the peak sales estimates because I can't keep them all straight from our partners and the revenue projections. But as far as the presentation, yes, the data 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. 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?

GSK has indicated that peak sales are expected to be around 2.5 billion USD. We will receive royalties ranging from 10% to 12%, in addition to regulatory milestones, many of which we expect to achieve this year as they progress through the regulatory approval process in several countries. We have incorporated their peak sales estimate along with our royalty tiers into our overall peak royalty projections, which we estimate to be several billion dollars.

Next question comes from Andy Chen with Wolfe Research.

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.

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.

Just quick to remind everybody, last year, we read out our Phase III study, and we hit statistically 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.

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 and 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 onto treatment and keep patients taken care of, etc., 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.

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.

And the next question comes from Akash Tewari with Jefferies.

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 full-on Lp(a) targeting asset?

Yes. I'll let Eric discuss the next generation and why we are excited about its profile. Regarding the HORIZON trial, we remain quite confident in the outcome, acknowledging the risks associated with undertaking something for the first time, which is part of Ionis's tradition. Being first is in our DNA. We have accomplished this many times, and for Lp(a), we will be the first to test the Lp(a) CBD hypothesis. Based on the epidemiology, how the study is conducted, the positive results from two interim analyses, and everything we are observing from our partner, Novartis, in the trial, we maintain our confidence. Naturally, there is a risk because no one has done this before, but that also presents a tremendous opportunity. The mean Lp(a) levels in the study have been reported, and I believe the median is 109 milligrams per deciliter. This indicates a significantly ill patient population, with a large majority having a history of cardiovascular disease; over 80% have experienced a myocardial infarction, while the rest qualify due to strokes or serious peripheral artery disease. It is a well-conducted study that will provide answers to the Lp(a) hypothesis. In terms of competition, Pelacarsen has a significant first-mover advantage in this vast market opportunity, and we have seen no drug profile that we think could surpass the Lp(a) lowering effects offered by Pelacarsen. So stay tuned, we will have an answer midyear this year. Eric, what about the follow-on?

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 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 six 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.

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 will be replicated with the Pelacarsen follow-on, which is now in IND supporting toxicology studies.

And the last question comes from Jay Olson with Oppenheimer.

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.

Thank you. And as much the conference has now concluded. Thank you for attending today's presentation. You may now disconnect your lines.