Ionis Pharmaceuticals - Q4 2025

Transcript

Operator (participant)

Morning, 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, I'd like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Please begin.

Wade Walke (SVP)

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 that accompany today's call. With me on the call this morning are Brett Monia, our Chief Executive Officer, Holly Kordasiewicz, Chief Development Officer, Kyle Jenne, Chief Global Product Strategy Officer, and Beth Hougen, Chief Financial Officer. Eugene Schneider, Chief Clinical Development Officer, and Eric Swayze, Executive Vice President of Research, will also join us for the Q&A portion of the call. I would like to draw your attention to slide 3, which contains our forward-looking language statement.

During this call, we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail. With that, I'll turn the call over to Brett.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

Thanks, Wade. Good morning, everybody, and thanks for joining us today. 2025 was a defining year for Ionis, marked by the successful execution of our first 2 independent launches and multiple positive data readouts across our rich pipeline. These achievements, together with our expectation for multiple additional value-driving events this year, positions Ionis for continued success through 2026 and beyond. TRYNGOLZA, the first FDA-approved treatment for familial chylomicronemia syndrome, or FCS, exceeded expectations in its first year on 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. 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, a 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. Just last month, DAWNZERA received European approval, enabling our partner, Otsuka, to bring this important medicine to patients across the region. In 2025, we accelerated this 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 and 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 3 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 3 results for our innovative medicine, zilganersen, the first to demonstrate a disease-modifying benefit in Alexander disease, a rare and often fatal neurodegenerative disease. We submitted our NDA in January. 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 whole-gene pipeline is our partnered pipeline, which targets both rare and highly prevalent life-threatening diseases. We expect multiple phase 3 data readouts this year from our partnered 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 3 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 mid-year and the Eplontersen CARDIO-TTRansform trial in the second half of 2026. In addition, Sofosersen for IgA nephropathy and Ulefnersen for FUS-ALS are also positioned for phase 3 readouts later this year.

If positive, these outcomes position our partner pipeline to deliver 4 key additional launches by the end of next year, driving a meaningful increase in our total revenue through royalties and milestone paying, 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 partnered 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.

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 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. Over to you, Holly.

Holly Kordasiewicz (Executive VP and Chief Development Officer)

Thank you, Brett. I'm honored to lead our world-class development team, which has recently delivered multiple positive data readouts. 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 medicines to people with serious diseases for years to come. Olezarsen is a clear example of our leadership in discovering and developing transformational medicines. The groundbreaking Phase 3 data generated from the CORE and CORE2 trials position Olezarsen to be the new standard of care for the broad sHTG patient population.

As previously presented and published, our pivotal studies evaluated Olezarsen in people with sHTG who had triglyceride levels substantially higher than the 500 mgs per deciliter, despite being on standard of care with the lowering therapy that they find, putting them at risk of life-threatening acute pancreatitis. In CORE and CORE2, Olezarsen demonstrated highly statistically significant and clinically meaningful mean reductions of up to 72% in placebo-adjusted fasting triglycerides at six months, the primary endpoint. Olezarsen also significantly reduced acute pancreatitis events, making it the first and only treatment to achieve this positive outcome in people with sHTG. Olezarsen achieved a highly statistically significant 85% reduction in adjudicated acute pancreatitis events. It's important to remember that the main goal of triglyceride management in sHTG is to prevent AP attacks, and Olezarsen is the first medicine to demonstrate it can do just that.

This remarkable reduction in AP attack rates was also reflected in the number of patients needed to treat to prevent a potentially fatal pancreatitis attack. Just 4 patients needed to be treated with Olezarsen for only 12 months to prevent 1 AP attack in the highest risk subgroup. For context, statins used for primary prevention have a number needed to treat in the range of 500 to 100 to prevent 1 cardiovascular event over 5 years. We believe these unprecedented results position Olezarsen to meet the substantial unmet need of people with sHTG. We submitted the sNDA at the end of 2025 and is currently within the FDA's filing review period. We've requested priority review and expect a decision from the FDA shortly. As Kyle will highlight, launch preparations are already well underway, and we look forward to bringing Olezarsen to people with sHTG later this year.

In addition to Olezarsen, we're poised for another independent launch later this year. We plan to bring zilganersen to patients with Alexander disease, an ultra-rare leukodystrophy that profoundly impacts patients and families who today have no approved disease-modifying therapies. Our positive Phase 3 results for zilganersen marked the first time any therapy demonstrated a disease-modifying impact on this condition. We recently submitted our NDA based on these groundbreaking data. In the interim, we have initiated an expanded access program to provide eligible patients with access to zilganersen while the review is ongoing. We expect zilganersen to be the first of numerous additional independent launches from our leading neurology pipeline, underscoring Ionis's ability to consistently translate scientific leadership into important medicines for our patients. Turning now to our Phase 3 program for Obidutersen, previously referred to as ION582, our investigational medicine for Angelman syndrome.

Late last year, we received breakthrough therapy designation from the FDA in recognition of Obidutersen's promising mid-stage data and the serious unmet need in this disorder. Angelman syndrome is a rare neurodevelopmental disorder that causes profound and lifelong physical and cognitive impairment, estimated to affect more than 100,000 people globally. Obidutersen is advancing in the phase 3 REVEAL study, with full enrollment expected this year and data next year. In addition to Zolgensma and Obidutersen, we have a rich neurology pipeline advancing in development, including ION 四六四 for multiple system atrophy and ION 七一七 for Prion disease. We're evaluating both investigational medicines and ongoing studies in patients. Based on the data generated to date, we're encouraged by the level of target engagement and the safety and tolerability profiles.

As a result, we plan to add additional dose cohorts to these 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 Spinraza, which has a PDUFA date of April 3rd. We're also looking forward to the phase 3 study start of salanersen, evaluating annual dosing for SMA and Sapagluclin for polycythemia vera. Moreover, 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. With that, I'll turn it over to Kyle.

Kyle Jenne (Executive VP and Chief Global Product Strategy Officer)

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 continue 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 3 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 3 data and strength of olezarsen's product profile, we increased our annual peak revenue estimates for olezarsen to more than $2 billion. 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 3 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, 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. With that, I'll now turn it over to Beth.

Beth Hougen (Executive VP and CFO)

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, anchored by meaningful contributions from Spinraza and growing royalties from Waylivra. 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 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-$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. Today, we will share some high-level perspectives 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 multi-billion 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 from 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. 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 3 initiations of salinersen 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 % 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 our 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 million-$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. With that, I'll turn the call back over to Brett.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

Thank you, Beth. 2025 was indeed a defining year for Ionis. We successfully transitioned into a fully integrated commercial stage company. Our first 2 independent launches were initiated, highlighted by TRYNGOLZA for FCS, which drove significant revenue growth. Importantly, we delivered multiple landmark data readouts that position us to continue driving accelerating value. We expect growth in 2026 to be driven by several key catalysts this year, some of which we've already achieved. Notably, we are on track for 3 additional launches, 2 of which are independent, including Ionis's first launch in a broad patient population, sHTG. We are also on track for 5 late-stage data readouts across our partnered portfolio, with 1 positive readout already achieved.

With strong commercial momentum and advancing high-value pipeline, and a clear path to cash flow breakeven by 2028, we believe Ionis is exceptionally well-positioned to deliver transformational medicines for patients and accelerating value for shareholders for years and years to come. With that, we'll open the call up for questions.

Operator (participant)

Yes, thank you. We will now begin the question-and-answer session. To ask a question, you may press star, then 1 on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. If anytime your question has been addressed and you would like to withdraw it, please press star then 2. At this time, we will pause momentarily to assemble the roster. This morning's first question comes from Yaron Gerber with TD Cowen.

Yaron Gerber (Senior Biotechnology Analyst)

Great. Thanks so much and congrats, really, on a lot of solid progress. Maybe, just, one question back to you on the guidance. I mean, so it sounds like 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 the TRYNGOLZA will get impacted. It sounds like you're potentially matching the price of Rydemplo. Is that correct? If you don't mind, I have a quick follow-up more on the WAINUA, on the study coming up.

Beth Hougen (Executive VP and CFO)

Let me kind of... There were a few things in there, let me see if I can break it all down. We are assuming sales and revenue from Olezarsen in the sHTG patient population. With this assumption of standard review, that would be in really just the 4th quarter of the year. It will be an FCS driven revenues for TRYNGOLZA between now and the launch of sHTG after approval. Obviously, priority review would improve that guidance we expect. We do anticipate that WAINUA will continue to grow. We do anticipate that there could be revenues from that Bepirovirsen, for example, once it were to get to market.

Right now, that's gonna be late in the year, most likely, there's not a lot of contribution that in our guidance. We're really focused on the regulatory initiatives, the acceptance of the NDA, as well as the approvals to drive R&D revenues for Bepirovirsen, as well as the potential NDA acceptance for Pelacarsen, assuming positive Phase 3 data. I think overall, we're looking at a really strong guidance, given that we're assuming standard review. It's a 20% or so increase year-over-year on a like-for-like basis by taking the sapablursen out of the equation. That puts us on an apples-to-apples basis, and I think that 20% increase is really strong.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

As it relates to pricing for this year, you know, we are continuing to actively engage with payers. Obviously, those are confidential discussions. Really what we want to make sure of, 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. 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. 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 Gerber (Senior Biotechnology Analyst)

Thanks.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

Yaron, you had a question about?

Yaron Gerber (Senior Biotechnology Analyst)

Yeah, just on the CARDIO-TTRansform, as we're now beginning to really kind of focus on that next, everybody, can you give us a sense, what % of patients are on a stabilizer at baseline? Because it was mostly an add-on strategy. And maybe what % will only be on that WAINUA alone, essentially head-to-head against placebo, if you can, any color? Thank you.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

I'll start. Eugene, please jump in if you want to add anything. Yaron, 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 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.

That's where we ended up. We have had some drop-ins during the course of the study. It's not meaningful. It hasn't been that many. We are working on a baseline presentation. We don't know the timing of that presentation yet. We are working on it, and we'll be able to share that data hopefully at some point soon. Eugene, anything more to add?

Eugene Schneider (Executive VP, Chief Clinical Development and Operations Officer)

No, not really, Brett. Thank you.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

Thank you, Yaron.

Operator (participant)

Thank you. The next question comes from Salveen Richter with Goldman Sachs.

Salveen Richter (Managing Director and Lead Analyst for the U.S. Biotechnology)

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

Kyle Jenne (Executive VP and Chief Global Product Strategy Officer)

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. 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 is, 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. 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, 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.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

I'll just add to that, Salveen, that, again, as Kyle mentioned in his prepared remarks, we've had no meaningful impact of a new market entrant on the demand for TRYNGOLZA. The demand for TRYNGOLZA continues to be very, very strong. Patients are doing very well on the medicine, and we're seeing reauthorizations over and over and over again. We're very pleased with the performance of TRYNGOLZA, but we're in that period right now, which, in which we're preparing to transition for the sHTG launch.

Salveen Richter (Managing Director and Lead Analyst for the U.S. Biotechnology)

Thank you.

Operator (participant)

Thank you. The next question comes from Jason Gerberry with Bank of America.

Speaker 14

Hey, guys, this is Chi. I'm for Jason. Thanks for taking our question. I want to go back to a comment that you made, Kyle. You said you know, obviously you guys have recently increased the peak revenue for olezarsen to over $2 billion, and I recall this based on higher volume assumption. Today, Kyle, you mentioned you're even more confident in the blockbuster opportunity. Is it more confident in hitting that $2 billion number, or is it more confident in hitting a potentially higher peak number? What drove the higher confidence? Is it based on any recent research, and is it high assumption on price or volume? If I may squeeze in a quick one on a second question, want to ask about ION532 which was licensed to AstraZeneca for APOL1-mediated kidney disease.

Curious your thoughts about the market opportunity there, target profile of the S as well as the competitions. Lastly, when might we see phase 2 data? Thanks so much.

Kyle Jenne (Executive VP and Chief Global Product Strategy Officer)

Yeah, on the $2 billion, Chi, you know, when 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 3 data. In addition to that, we've done extensive prescriber demand research, and that's what drove us to increase to greater than $2 billion. I think what's increasing our confidence is the strong underlying demand trends that we're seeing that I just explained, not only ending last year, but also that are continuing here early in 2026.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

Your second question, Chi, I'll take, is really best asked for AstraZeneca. It's a program that we've been working on for quite some time. We published on preclinical data for targeting APOL1 for FSGS, particularly for people with mutations in the APOL1 gene, of course, 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 APOL1 carriers, if the APOL1 carrier data is strong enough to go in that direction. It's a significant market opportunity for renal disease.

The decision by at AZ to go to phase 2, after we licensed it to them, was based on data they conducted in phase 1 that showed strong target engagement, and of course, with good safety. They advanced it to phase 2, and as for timing of data, that's a question for AZ.

Speaker 14

Thanks so much.

Operator (participant)

Thank you. The next question comes from Michael Ulz with Morgan Stanley.

Michael Ulz (Executive Director of Biotechnology Equity Research)

Good morning. Thanks for taking the question. 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. Secondly, you know, has your thinking on the potential for a priority review, you know, changed at all recently? Thanks.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

I'll start the second one, and I'll ask Eugene to talk about, you know, how things are going. For priority review, you know, 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. We're in that window, we're in that evaluation window right now. Of course, again, I will remind you, we did receive breakthrough therapy designation. As far as regulatory interaction, it's been on track, right?

Eugene Schneider (Executive VP, Chief Clinical Development and Operations Officer)

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

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

Yeah.

Michael Ulz (Executive Director of Biotechnology Equity Research)

Great, thank you.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

We're within that window, Mike.

Michael Ulz (Executive Director of Biotechnology Equity Research)

Yep. Thanks.

Operator (participant)

Thank you. The next question comes from Luca Issi with RBC Capital.

Luca Issi (Senior Biotechnology Research Analyst)

Great. Thanks so much for taking my question. Congrats on the progress. I do wanna 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. I just wondering if kind of anything has changed or maybe this is just kind of standard conservatism, like, any thoughts there, I think much appreciated. Maybe on Angelman, Holly, I think when I go on ClinicalTrials.gov, I don't see any European sites there for your program, I think, except for the U.K. Versus I think your competitor, Progenics, has many European sites.

Is that because the European regulators prefer sham control trials instead of placebo-controlled trials, or is that kind of more complex than that? Any thoughts, much appreciated. Thank you.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

I'll have Holly address the Angelman in a moment, Luca, but as far as priority review, there's not really much more to add than beyond the answer that we just provided 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, you know, usually takes the time that they need to draw a conclusion, and I think we'll just leave it there. As far as assuming standard review for guidance, we think that's the responsible thing to do at this stage. As Beth mentioned, we will adjust guidance if we receive priority review, and we'll inform everybody. Holly?

Holly Kordasiewicz (Executive VP and Chief Development Officer)

Yep. For Angelman, you've hit on it. We have submitted to Europe. We're waiting to hear back from them for that, and we need that approval then to move forward with those sites. We do plan to open up sites in Europe as soon as that approval comes through.

Luca Issi (Senior Biotechnology Research Analyst)

Got it. Thanks so much.

Operator (participant)

Thank you. The next question comes from Maurice Riario with Guggenheim Securities.

Speaker 15

Hi, this is Maurice Riario for Debjit. Thanks so much for taking my question. 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? 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. Yeah, we will provide those details once we finalize everything and get that out. $20,000 net is what we had assumed in the greater than $2 billion peak sales revenue number that we've been using.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

That's still consistent. We haven't updated that at this point in time. 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 VHH BBB molecule. Although we have not laid out definitive plans yet, I expect you'll get an update by this, in the second half of this year on where we are with our BBB strategy.

Speaker 15

Thank you so much.

Operator (participant)

Thank you. The next question comes from Joseph Stringer with Needham & Company.

Joseph Stringer (Senior Analyst)

Hi, thanks for taking our questions. A quick one on the GSK partnered HBV program. When could we see functional cure rates from the phase 3 program? What are your and GSK's expectations for potential peak sales as a functional cure? Maybe more directly, what net revenue assumptions to Ionis are baked into your projected peak royalty revenues from this partner program? Thank you.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

Yeah, sure. Beth will take the peak sales estimates because I can't keep them all straight from our partners and the revenue, what they're projecting. 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 unmet medical needs, millions of people. GSK plans to present the data at EASL in May, the European Association for the Study of the Liver. What they've said is that the functional cure rates are clinically meaningful. Beth?

Beth Hougen (Executive VP and CFO)

GSK has talked about peak sales in the about $2.5 billion range. We've got a royalty, tiered royalties that go from 10%-12% in addition to the regulatory milestones, many of which we anticipate earning this year as they move through the regulatory filing, acceptance, and approval process in multiple countries. We've baked their peak sales and our royalties into our estimated peak royalties, which are about, I think, several billion dollars.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

Next question.

Operator (participant)

Yes, thank you. Next question comes from Andy Chan with Wolfe Research.

Andy Chan (Managing Director and Senior Equity Research Analyst)

Hey, thank you for taking the question. I know you talked about Alexander quite a bit today. Just curious how fast that ramp would be or how big the eventual opportunity would be. If you can compare the opportunity to other rare diseases, such as DAWNZERA or FCS, that'd be great. Thank you.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

Thanks, Andy. I'd like Holly to just talk about what she's hearing from the community first with, for zilganersen. It's really exciting, and that, of course, affects the ramp, what we're hearing. Kyle to take on how he anticipates expectations for the launch.

Holly Kordasiewicz (Executive VP and Chief Development Officer)

Just quick to remind everybody, last year, we read out our phase 3 study. We hit statistically significant clinical meaningful differences on our primary endpoint, which is a motor functional test. We also, in key secondary endpoints, had favorable, 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 in for that as well. It's very encouraging to see how the response has been from the community, that they're just waiting for this medicine.

Kyle Jenne (Executive VP and Chief Global Product Strategy Officer)

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, 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 in. It'll be modest this year and then grow into 2027.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

The zilganersen opportunity, of course, is incredibly meaningful for the patient community. It's gonna provide, you know, a meaningful revenue for Ionis once we get there. 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 gonna deliver to patients, commercialize ourselves. Behind that is our Angelman's program, 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. It really gets us started.

Operator (participant)

Thank you. The next question comes from Akash Tewari with Jefferies.

Speaker 16

Hey, this is Manoj on for Akash Tewari. Just one from our end. Can you provide some color on your expectations around the upcoming HORIZON Lp(a) 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-term Lp(a) readouts could change the commercial outlook for Pelacarsen? Also, can you comment on the current status of your next-gen or, like, follow-on Lp(a) targeting asset? Thank you.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

Like, 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 Ionis tradition. It's in our DNA to be first. We've done it so many times, and for Lp, we'll be the first to test the Lp CVD hypothesis. Based on the epidemiology, based on the conduct of the 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 Lp levels in this study have been reported already. I believe they're, 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%, 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 gonna give the answer to the Lp hypothesis. As far as competition goes, you know, it's pelacarsen has a meaningful first mover advantage in this massive market opportunity.

We've seen no drug profile out there that we believe will be superior to the Lp(a) lowering effects that we're seeing for Pelacarsen. Stay tuned. Midyear this year, we'll get an answer. Eric, what about the follow-on?

Eric Swayze (Executive VP of Research)

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. 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, it's an siRNA that extends dosing frequency in for lowering ApoC-III and triglycerides in humans. We've been making equal or better progress on Lp(a) with our siRNA platform. Goal is to get it to 6-month 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. Hopefully we can demonstrate that in humans soon.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

Yeah, we have several programs coming forward into the clinic that are, you know, that are offering strong durability, twice a year, once a year dosing. ION775, of course, is the Olezarsen follow-on for ApoC-III. We reported data last year in phase 1. It looked excellent. We're gonna be in sHTG patients in phase 2 this year. We believe that will be replicated with the Pelacarsen follow-on, which is now in IND-supporting toxicology studies.

Speaker 16

Yep, thanks.

Operator (participant)

Thank you. The last question comes from Jay Olson with Oppenheimer. We've got Oppenheimer. Okay, Oppenheimer has dropped off the line. That does conclude the question session, so I would like to turn the floor back over to Brett Monia for any closing comments.

Brett Monia (CEO, Member of the Board of Directors and Founding Scientist)

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. 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.

Holly Kordasiewicz (Executive VP and Chief Development Officer)

Goodbye.

Operator (participant)

Thank you. As mentioned, the conference is now concluded. Thank you for attending today's presentation. You may now disconnect your line.