Q4 2025 Ionis Pharmaceuticals Inc Earnings Call

February 25, 2026

Operator: Good morning. Welcome to Ionis's Q4 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.

Speaker #1: 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'd like to turn the call over to Wade Walk, Senior Vice President of Investor Relations, to lead off the call.

Speaker #1: Please begin.

Speaker #2: 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.

Wade Walke: Thank you, Keith. Before we begin, I encourage everyone to go to the investors section of the Ionis website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We've also posted slides on our website that accompany today's call. With me on the call this morning are Brett P. Monia, our Chief Executive Officer, Holly Kordasiewicz, Chief Development Officer, Kyle Jenne, Chief Global Product Strategy Officer, and Elizabeth L. Hougen, Chief Financial Officer. Eugene Schneider, Chief Clinical Development Officer, and Eric E. Swayze, Executive Vice President of Research, will also join us for the Q&A portion of the call. I would like to draw your attention to slide three, which contains our forward-looking language statement.

Speaker #2: Including a reconciliation of gap to non-gap financials. We believe non-gap financial results better represent the economics of our business and how we manage our business.

Speaker #2: 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 Kordasevic, Chief Development Officer; Kyle Jenne, Chief Global Product Strategy Officer; and Beth Hougen, Chief Financial Officer.

Speaker #2: 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.

Speaker #2: I would like to draw your attention to slide three, which contains our forward-looking language statement. During this call, we will be making forward-looking statements that are based on our current expectations and beliefs.

Wade Walke: 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.

Speaker #2: 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.

Speaker #2: With that, I'll turn the call over to Brett.

Speaker #3: 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.

Speaker #3: These achievements, together with our expectation for multiple, additional value-driving events this year, position IONIS for continued success through 2026 and beyond. During goals of the first FDA-approved treatment for familial chylomicronemia syndrome, or FCS, exceeded expectations in its first year on the market.

Speaker #3: During goals of excellent performance was driven by a compelling clinical profile and strong launch execution. During goals, it was also launched in Europe late last year, and we're pleased to see our partner, Soby, bring this transformational medicine to more patients.

Wade Walke: 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, 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.

Speaker #3: In August, we kicked off our second independent launch with the FDA approval of Donzera prophylactic treatment for hereditary angioedema, or HAE. As the first and only RNA-targeted medicine for HAE, Donzera offers a compelling profile that has resonated with prescribers and patients.

Speaker #3: In just last month, Donzera received European approval, enabling our partner Atsuka to bring this important medicine to patients across the region. In 2025, we accelerated this strong momentum with the Olazars and Pivotal results in severe hypertriglyceridemia, a broad patient population with high unmet need.

Speaker #3: Further extending our leadership in the development of innovative treatments for diseases associated with high triglycerides. Olazarsen showed highly significant and substantial reductions in triglycerides and in acute pancreatitis attacks.

Wade Walke: 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, 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...

Speaker #3: Establishing Olazarsen as the first medicine to demonstrate a benefit in reducing acute pancreatitis risk in this patient population. Based on these groundbreaking phase three results, we were pleased to receive breakthrough therapy designation from the FDA.

Speaker #3: Additionally, late last year, we submitted the SMDA, an anticipate receiving acceptance very soon. Importantly, we are on track to be launch ready by June.

Speaker #3: We also delivered positive phase three results for our innovative medicine, Zilga Nursing, the first to demonstrate a disease-modifying benefit in Alexander disease, a rare and often fatal neurodegenerative disease.

Speaker #3: We submitted our NDA in January, and we anticipate approval and launch in the second half of this year. Assuming approval, Zilga Nursing will be our first independent launch from our leading neurology franchise.

Speaker #3: 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.

Wade Walke: 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 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 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.

Speaker #3: Complementing our rich whole-yarn pipeline is our partnered pipeline, which targets both rare and highly prevalent life-threatening diseases. We expect multiple phase three data readouts this year from our partnered pipeline.

Speaker #3: In January, we announced the first of these results with positive top-line data for Bepi-Aversin. A potential first-in-class medicine for chronic hepatitis B that demonstrated clinically meaningful and unprecedented functional cure rates in the phase three program.

Speaker #3: GSK is preparing global regulatory submissions, and assuming approval, expects to begin bringing Bepi-Aversin to the millions of people living with chronic HPV later this year.

Speaker #3: Looking ahead, we anticipate results from two major cardiovascular outcome trials. The Pelicarson Lp(a) Horizon trial mid-year and the Eplin-Turson Cardiotransformer trial in the second half of 2026.

Wade Walke: Looking ahead, we anticipate results from 2 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, IONIS-FB-LRx 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 pipelines to deliver 4 key additional launches by the end of next year, driving a meaningful increase in our total revenue through royalties and milestone payments for many years to come. With strong momentum across our business, including our first 2 independent launches, 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.

Speaker #3: In addition, Cefaximib for IgA nephropathy and Neuleprosin for FUS ALS are also positioned for Phase 3 readouts later this year. If positive, these outcomes position our partnered 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.

Speaker #3: With strong momentum across our business, including our first two independent launches and advancing wholly owned pipeline and a robust partnered portfolio, Ionis is well positioned to deliver a steady stream of transformational medicines for patients.

Speaker #3: 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.

Wade Walke: 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.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: 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.

Wade Walke: 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, 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.

Speaker #3: Holly has also played a strategic role more broadly, in creating Ionis' leading research and development organization, and brings a deep, deep understanding of our technology.

Speaker #3: We are pleased to have Holly in our new role, and confident she will continue to drive substantial value and continue to success for IONIS and all IONIS stakeholders.

Speaker #3: Now over to you, Holly.

Speaker #2: Thank you, Rhett. 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.

Holly Kordasiewicz: Thank you, Brad. 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.

Speaker #2: 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.

Speaker #2: Olazarsen is a clear example of our leadership in discovering and developing transformational medicines. The groundbreaking phase three data generated from the CORE and CORE 2 trials position Olazarsen to be the new standard of care for the broad FHTG patient population.

Speaker #2: As previously presented and published, our pivotal studies evaluated Olazarsen in people with FHTG who had triglyceride levels substantially higher than 500 mg per deciliter, despite being on standard of care with lipid-lowering therapies at baseline.

Holly Kordasiewicz: As previously presented and published, our pivotal studies evaluated olezarsen in people with sHTG who had triglyceride levels substantially higher than 500 mg/dL, despite being on standard of care lipid-lowering therapy at baseline, 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 6 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, olezarsen is the first medicine to demonstrate it can do just that.

Speaker #2: Putting them at risk of life-threatening acute pancreatitis. In core and core two, Olazarsen demonstrated highly statistically significant and clinically meaningful mean reductions of up to 72% in placebo-adjusted fasting triglycerides at six months, the primary endpoint.

Speaker #2: Olazarsen also significantly reduced acute pancreatitis events. Making it the first and only treatment to achieve this positive outcome in people with FHTG. Olazarsen achieved a highly statistically significant 85% reduction in adjudicated acute pancreatitis events.

Speaker #2: It's important to remember that the main goal of triglyceride management in FHTG is to prevent AP attacks. In Olazarsen, it is the first medicine to demonstrate it can do just that.

Holly Kordasiewicz: 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 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.

Speaker #2: 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.

Speaker #2: Just four patients needed to be treated with Olazarsen for only 12 months to prevent one AP attack and 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 one cardiovascular event over five years.

Speaker #2: We believe these unprecedented results position Olazarsen to meet the substantial unmet need of people with FHTG. We submitted the FNDA at the end of 2025, and it is currently within the FDA's filing review period.

Speaker #2: We've ve requested priority review and expected decision from the FDA shortly. As Kyle will highlight, launch preparations are already well underway, and we look forward to bringing Olazarsen to people with FHTG later this year.

Speaker #2: In addition to Olazarsen, we're poised for another independent launch later this year. We plan to bring Vildanursin to patients with Alexander disease, an ultra-rare leukodystrophy that profoundly impacts patients and families who today have no approved disease-modifying therapies.

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

Speaker #2: Our positive Phase 3 results for Vildanursin marked the first time any therapy demonstrated a disease-modifying impact in this condition. We recently submitted our NDA based on these groundbreaking data.

Speaker #2: In the interim, we have initiated an expanded access program to provide eligible patients with access to Vildanursin, while review is ongoing. We expect Vildanursin to be the first of numerous additional independent launches from our leading neurology pipeline.

Speaker #2: Underscoring IONIS' ability to consistently translate scientific leadership into important medicines for our patients. Turning now to our phase three program for Obedinursin, previously referred to as ION 5A2, our investigational medicine for Angelman syndrome.

Speaker #2: Late last year, we received breakthrough therapy designation from the FDA. In recognition of Obedinursin's promising mid-stage data and the serious unmet need in this disorder.

Holly Kordasiewicz: Late last year, we received Breakthrough Therapy designation from the FDA in recognition of obinursin'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. Obinursin is advancing in the Phase 3 REVEAL study, with full enrollment expected this year and data next year. In addition to Zolgensma and obinursin, we have a rich neurology pipeline advancing in development, including ION464 for multiple system atrophy and ION717 for prion disease. We're evaluating both investigational medicines and ongoing studies in patients. Based on the data generated to date, we're encouraged by the level of target engagement 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.

Speaker #2: Angelman syndrome is a rare neurodevelopmental disorder that causes profound and lifelong physical and cognitive impairment. Estimated effect more than 100,000 people globally. Obedinursin is advancing in the phase three reveal study with full enrollment expected this year and data next year.

Speaker #2: In addition to Vildanursin and Obedinursin, we have a rich neurology pipeline advancing in development, including ION 464 for multiple systems atrophy and ION 717 for prion disease.

Speaker #2: 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.

Speaker #2: 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.

Holly Kordasiewicz: 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 US approval of high-dose SPINRAZA, which has a PDUFA date of 3 April. We're also looking forward to the Phase 3 study start of salanersen, evaluating annual dosing for SMA and sapablursen for polycythemia vera. Moreover, 3 mid-stage partner programs are set to read out this year, which in addition to multiple regulatory milestones, position 2026 to be another catalyst-rich year. With that, I'll turn it over to Kyle.

Speaker #2: As we look to key upcoming events, in addition to those highlighted by Brett, we're looking forward to the anticipated US approval of high-dose spinraza, which has a PDUFA date of April 3rd.

Speaker #2: We're also evaluating, we're also looking forward to the Phase 3 study start of salinursin, evaluating annual dosing for FMA, and sapaglursin for polycythemia vera.

Speaker #2: 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.

Speaker #2: And with that, I'll turn it over to Kyle.

Speaker #1: Thank you, Holly. With a strong first year for Tringolza and an encouraging start for Donzera, and with two more anticipated independent launches this year, our commercial team remains focused on flawless execution to continue bringing our important medicines to patients.

Kyle Jenne: Thank you, Holly. With a strong first year for TRYNGOLZA, an encouraging start for DAWNZERA, two more anticipated independent launches this year, our commercial team remains focused on flawless execution to continue bringing our important medicines to patients. In Q4, 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.

Speaker #1: In the fourth quarter, Tringolza continued to gain momentum, generating $50 million in net product sales reflecting a 56% increase in revenues quarter over quarter.

Speaker #1: And notably, December was our strongest month of 2025. Underscoring continued growing demand. This performance drove full-year revenue to $108 million. The efforts of our team, together with our innovative initiatives to identify patients, continue to deliver positive results.

Speaker #1: We saw quarter over quarter expansion in both the breadth and depth of physicians prescribing Tringolza. Reflecting positive experiences among clinicians and patients. Q4 was a strong quarter of adding new prescribers who span a broad mix of specialties, including cardiologists, endocrinologists, and lipidologists.

Kyle Jenne: 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. 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.

Speaker #1: Overall, approximately 75% of prescriptions came from these specialists. This provider mix and growing prescriber base positions as well as we prepare to expand into the broader SHTG population.

Speaker #1: Our leadership and establishing FCS access and coverage continues to benefit FCS patients and elevate Tringolza performance. Patients are gaining access to Tringolza quickly with time from prescription to first fill consistently exceeding our aggressive expectations.

Speaker #1: The current payer mix is approximately 60% commercial and 40% government. And both clinically diagnosed and genetically confirmed patients continue to secure coverage. All of the strong momentum we saw from Tringolza in 2025 has carried into the first part of 2026.

Speaker #1: There has been no meaningful impact on cancellation or discontinuation rates following a new market entrant. In fact, Tringolza continues to deliver strong growth in referrals and patient starts.

Kyle Jenne: 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 US alone, more than 1 million people have high-risk sHTG, defined as individuals with triglyceride levels above 880 mg/dL or above 500 mg/dL with a history of acute pancreatitis or other high-risk comorbidities, including progressive cardiovascular disease and type 2 diabetes.

Speaker #1: Physicians continue to report very high satisfaction with both their prescribing experience and Tringolza’s overall product profile, including efficacy, safety, tolerability, and convenience. At the same time, pricing dynamics in the market are evolving.

Speaker #1: 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.

Speaker #1: Many people with SHTG struggle to manage their triglyceride levels with current treatments. And US 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.

Speaker #1: Including progressive cardiovascular disease and type 2 diabetes. Following our groundbreaking phase three results, we conducted robust HCP demand research that confirmed strong enthusiasm for olisarsen and its potential to address patient unmet needs.

Kyle Jenne: 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.

Speaker #1: 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.

Speaker #1: This work is anchored in olisarsen's compelling clinical profile and includes educating on the clinical and economic burden of disease, and associated budget impact considerations.

Speaker #1: Ultimately, our goal is to provide the broadest access possible to patients and maximize the value of olisarsen. 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.

Speaker #1: Our field team expansion materially increases share of voice and expands our reach to HCPs. Today, the team is actively supporting access to Tringolza for people with FCS.

Kyle Jenne: 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 US, 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.

Speaker #1: With our expanded team, we are positioned to effectively engage approximately 20,000 high-volume SHTG prescribers across the US, providing the scale and reach required for a successful launch in the larger indication.

Speaker #1: As we shared last month, based on the positive phase three data, and strength of olisarsen's product profile, we increased our annual peak revenue estimates for olisarsen to more than $2 billion.

Speaker #1: And today, we're even more confident in the blockbuster opportunity of olisarsen. Our groundbreaking data, strong HCP enthusiasm, and first-mover advantage position olisarsen to realize its full potential as the new standard of care for people with severe hypertriglyceridemia.

Speaker #1: Turning to Donzera, 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.

Kyle Jenne: 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.

Speaker #1: And we have seen strong participation in our free trial program, with 100% conversion to paid therapy to date. Initial feedback from both physicians and patients shows high enthusiasm for Donzera's differentiated mechanism of action, strong efficacy, and patient-friendly profile, including a self-administered autoinjector and potential for the longest dosing interval, which is translating into increasing demand.

Speaker #1: Notably, we are also seeing a growing number of repeat prescribers due to the positive experience prescribers and patients are having with Donzera. Additionally, we are seeing an extremely high conversion from referral to patient start.

Speaker #1: While it will take time to transition patients from other HAE therapies, as we educate patients and physicians about the attractive profile Donzera offers, we are confident we have the right drug, the right strategy, and the right team to successfully bring Donzera to people with HAE.

Kyle Jenne: 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 zolgensma for Alexander disease. We expect it to be the first independent launch from our neurology portfolio. Based on the Phase 3 results, zolgensma 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.

Speaker #1: Importantly, with strong launch fundamentals today, we expect Donzera to meaningfully contribute to our growing commercial revenue this year, and we reaffirm annual peak sales potential in excess of $500 million.

Speaker #1: Turning now to Zilga Nursen for Alexander disease. We expect it to be the first independent launch from our neurology portfolio. Based on the phase three results, Zilga Nursen offers a potentially meaningful advance for patients and caregivers in a disease with no approved disease-modifying treatments.

Speaker #1: 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.

Kyle Jenne: 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.

Speaker #1: 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.

Speaker #1: 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.

Speaker #1: Importantly, we believe Zilga Nursen could be the first of many first-in-class disease-modifying treatments from IONIS's industry-leading neurology pipeline. 2025 was marked by strong commercial execution.

Speaker #1: Looking ahead to 2026, the commercial organization is well positioned to build on this momentum. We remain focused on maximizing the full potential of Tringolza and FCS and Donzera and HAE, while preparing to execute two additional launches this year, further expanding IONIS's reach to even more patients in need of our medicines.

Kyle Jenne: We remain focused on maximizing the full potential of TRYNGOLZA and FCS and DAWNZERA and 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.

Speaker #1: With that, I'll now turn it over to Beth.

Speaker #2: 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.

Elizabeth L. Hougen: Thank you, Kyle. 2025 was a defining year for Ionis across our business, resulting in our impressive financial performance. We exceeded our guidance across all metrics through exceptional execution and disciplined financial management. This performance was underpinned by accelerating revenue growth from our marketed medicines, alongside sustained progress across our pipeline. We generated $944 million in revenue in 2025, representing a 34% increase year-over-year. Revenue was split between commercial products, which generated $436 million, or 46% of our total revenue, and R&D collaborations, which generated $508 million, or 54% of our total revenue. These results underscore the value of our diversified revenue streams. Our marketed medicines provide growing, recurring revenue and increasing operating leverage, while revenue from R&D collaborations acts as a financial accelerator.

Speaker #2: 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.

Speaker #2: 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.

Speaker #2: These result 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.

Speaker #2: Together, our diversified revenue streams mitigate risk, enhance financial flexibility, and create multiple pathways to sustain growth. 2025 was a strong first year for the Tringolza launch, in which we earned $108 million in product sales, with quarter-over-quarter growth throughout the year.

Elizabeth L. Hougen: 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 Q4, representing a 56% increase over Q3. 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.

Speaker #2: This included $50 million of product sales in the fourth quarter, representing a 56% increase over the third quarter. We earned $8 million in Donzera product sales in 2025 from the initial few months of launch.

Speaker #2: Since launch, we have been offering a free trial program, which has seen strong participation and 100% conversion to paid therapy to date. While still early, this provides encouraging visibility into anticipated Donzera revenue growth.

Speaker #2: Royalty revenues increased 11% to $285 million in 2025, anchored by meaningful contributions from Spinraza and growing royalties from Winua. Our R&D revenue also increased, generating more than 20% growth year over year.

Elizabeth L. Hougen: Royalty revenues increased 11% to $285 million in 2025, 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 partnered programs. The largest contributor was the sapoplersen 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 US launch of TRYNGOLZA and DAWNZERA, and accelerated investments to prepare for the sHTG launch following the groundbreaking Phase 3 data. Our excellent progress last year, coupled with disciplined financial management, positions us well for accelerating growth and value creation.

Speaker #2: Driven by progress across multiple partnered programs. The largest contributor was the SAPA Blurston license fee, underscoring our ability to monetize non-core assets to support our ongoing and planned launches, and our pipeline.

Speaker #2: As planned, total non-gap operating expenses increased modestly year over year, highlighting our commitment to disciplined investment. The increase was primarily driven by investments related to the US launch of Tringolza and Donzera and accelerated investments to prepare for the SHTG launch, following the groundbreaking phase three data.

Speaker #2: 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's 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.

Elizabeth L. Hougen: Our financial guidance for this year reflects Ionis' evolution to a commercial-stage biotechnology company, launching multiple medicines while remaining steadfast in our commitment to drive operating leverage as we advance our high-value pipeline. We project to earn revenue in the range of $800 to 825 million from numerous sources. This represents an increase of approximately 20% over last year, after adjusting for the one-time $280 million sapoplersen 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 Q4. If we achieve Priority Review, we expect our guidance to improve.

Speaker #2: 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 SAPA Blurston license fee.

Speaker #2: 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 olazarsen.

Speaker #2: 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 Olazarsen, we plan to provide Tringolza and Donzera product-level revenue guidance at our first-quarter earnings call.

Elizabeth L. Hougen: Since we are awaiting acceptance of the sNDA for olezarsen, we plan to provide TRYNGOLZA and DAWNZERA product-level revenue guidance at our Q1 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.

Speaker #2: So today, we will share some high-level perspectives and directional insights to help frame expectations. We continue to see strong demand for Tringolza with FCS patients, and we expect continued patient growth this year.

Speaker #2: At the same time, we have been actively engaging with payers to ensure FCS patients continue to have broad access to Tringolza, ahead of the anticipated SHTG approval.

Speaker #2: As a result, we expect a meaningful decline in Tringolza revenues throughout the year ahead of the SHTG launch, followed by accelerating growth as uptake builds.

Speaker #2: As we prepare for the SHTG launch, we are establishing a reimbursement strategy designed to achieve broad access while maximizing the value of Olazarsen to drive sustainable, long-term growth.

Elizabeth L. Hougen: 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 partners' commercial programs, we anticipate earning substantial royalties from medicines on the market today.

Speaker #2: Following anticipated approval, we expect to launch quickly with momentum building as we begin to bring Olazarsen to this much larger patient population, and importantly, as Kyle highlighted, we are more confident than ever in the multibillion-dollar opportunity for Olazarsen.

Speaker #2: For Donzera, we expect product sales to meaningfully contribute to total commercial revenue growth and to grow steadily as the launch progresses throughout the year.

Speaker #2: 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.

Speaker #2: 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.

Speaker #2: From our partnered commercial programs, we anticipate earning substantial royalties from medicines on the market today. We expect Spinraza to remain resilient and WINREVA to continue its upward trajectory this year.

Elizabeth L. Hougen: 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.

Speaker #2: 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.

Speaker #2: 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.

Speaker #2: So far this quarter, we've already earned $65 million including $15 million for the EU approval of Donzera, and $50 million when Roche initiated a phase one trial for an investigational medicine for Alzheimer's disease.

Speaker #2: Additionally, we are eligible to earn milestone payments for the phase three initiations of Salonursin and SAPA Blurston as well as numerous regulatory milestone payments for Bepiroversin and Palikarsen.

Elizabeth L. Hougen: Additionally, we are eligible to earn milestone payments for the Phase 3 initiations of salanersen and sapoplersen, 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 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.

Speaker #2: 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.

Speaker #2: 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.

Speaker #2: 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.

Elizabeth L. Hougen: 2026 will be an important year of disciplined commercial investment as we prepare for our first launch in a broad indication, with annual peak sales projected to exceed $2 billion. We expect our R&D expenses to remain steady this year, similar to last year. As late-stage studies reach completion, we are redeploying our resources toward the drugs in our pipeline that we expect to fuel our next phase of growth. With sizable revenues and modest expense growth, we are projecting a non-GAAP operating loss between $500 and $550 million. This represents a similar level compared to 2025, excluding the one-time sapoplersen 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.

Speaker #2: 2026 will be an important year of discipline, commercial investment, as we prepare for our first launch in a broad indication with annual peak sales projected to exceed $2 billion.

Speaker #2: 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.

Speaker #2: With sizable revenues and modest expense growth, we are projecting a non-GAAP operating loss between $500 and $550 million. This represents a similar level compared to 2025, excluding the one-time SAPA Blurston license fee last year, and assuming a standard review for Olazarsen.

Speaker #2: 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.

Elizabeth L. Hougen: 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 builds 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.

Speaker #2: In addition, it reflects our prudent fiscal management as we make strategic investments to bring our medicines directly to patients, including inventory builds for the anticipated SHTG launch.

Speaker #2: And continued advancement of our wholly owned medicines and development. Looking beyond this year, with two launches underway and more planned for this year and next, IONIS remains well positioned to achieve our goal of accelerating revenue growth and achieving cash flow break-even by 2028, driving long-term value creation.

Speaker #2: And with that, I'll turn the call back over to Brett.

Speaker #1: 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 trend goals for FCS, which drove significant revenue growth.

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

Speaker #1: 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.

Speaker #1: 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.

Speaker #1: 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, an advancing high-value pipeline, and a clear path to cash flow break-even by 2028, we believe Ionis is exceptionally well-positioned to deliver transformational medicines for patients.

Wade Walke: 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.

Speaker #1: And accelerating value for shareholders, for years and years to come. And with that, we'll open the call up for questions.

Speaker #3: 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.

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

Speaker #3: If at any time 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.

Speaker #3: And this morning's first question comes from Your Honor Robert with a TD Collins.

Yaron Werber: 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, 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 that TRYNGOLZA will get impacted. It sounds like you're potentially matching the price of Amvuttra. Is that correct? If you don't mind, I have a quick follow-up more on the WAINUA on the study coming up.

Speaker #4: Great. Thanks so much and congrats really on a lot of solid progress. Maybe just one question, Beth, for you on the guidance. I mean, so it sounds like you're not your guidance right now is not assuming any SHTG sales; you're assuming really not a lot of new royalty income from all the potential milestone payments.

Speaker #4: And you're expecting the trend goals that we'll get impacted it sounds like you're potentially matching the price of Redemplo. Is that correct? And then if you don't mind, I have a quick follow-up more on the unwaited new on the study coming up.

Elizabeth L. Hougen: There were a few things in there, so 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 Q4 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 bepirovirsen, for example, once it were to get to market.

Speaker #5: So let me kind of there were a few things in there. So let me see if I can break it all down. So we are assuming sales and revenue from Olazarsen and the SHTG patient population.

Speaker #5: But with this assumption of standard review, that would be in really just the fourth quarter of the year. So it will be an FCS-driven revenues for trend goals of between now and the launch of SHTG after approval.

Speaker #5: Obviously, priority review would improve that guidance, we expect. We do anticipate that Waylivra will continue to grow; we do anticipate that there could be revenues from that peer version, for example, once it were to get to market.

Elizabeth L. Hougen: Right now, that's going to be late in the year, most likely, so 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. You know, I think overall, we're looking at a, you know, 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 sapoplersen out of the equation. That puts us on an apples-to-apples basis, and I think that 20% increase is really strong.

Speaker #5: Right now, that's going to be late in the year most likely, so there's not a lot of contribution in that in our guidance. We're really focused on the regulatory initiatives, the acceptance of the NDA, as well as the approvals to drive R&D revenues for that peer aversion as well as the potential NDA acceptance for pelvic carcinoma assuming positive phase three data.

Speaker #5: So 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 SAPA Blurston out of the equation.

Speaker #5: That puts us on an apples-to-apples basis, and I think that 20% increase is really strong.

Kyle Jenne: 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.

Speaker #1: And as it relates to pricing for this year, we are continuing to actively engage with payers. Obviously, those are confidential discussions. But really what we want to make sure of first and foremost is that we continue to ensure broad access for trend goals of prior to the SHTG approval.

Speaker #1: Those discussions are going very well. Based on those discussions, we do expect a meaningful decline in trend goals of revenues throughout the year ahead of the SHTG launch as Beth reflected in her comments.

Speaker #1: 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.

Speaker #1: 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.

Speaker #1: We're on track to deliver on that work, and we'll announce price when we conclude that work later this year.

Kyle Jenne: We're on track to deliver on that work, and we'll announce price when we conclude that work later this year.

Speaker #3: Thanks.

Wade Walke: Thanks. Yaron, you had a question.

Speaker #1: Your Honor, you had a question about.

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

Speaker #4: Yeah. 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 what percentage of patients are on a stabilizer at baseline?

Speaker #4: Because it was mostly an add-on strategy and maybe what percent will only be on way newer alone, essentially head to head against placebo if you count any color.

Speaker #4: Thank you.

Speaker #1: I'll start, Eugene. Please jump in if you want to add anything. So Your Honor, what we've been saying and is playing out very nicely is that we have a good balance at baseline of patients not on stabilizer to famotus.

Kyle Jenne: I'll start. Eugene, please jump in if you want to add anything. Yaron, what we've been saying, 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, but that's where we ended up. We have had some drop-ins during the course of the study, but it's not meaningful. It hasn't been that many. We are working on a baseline presentation.

Speaker #1: Versus patients on to famotus at baseline. It's not quite 50/50. We have more patients on to famotus than naive at baseline, but it's well balanced.

Speaker #1: It's not capped. But we do not have but that's where we ended up. We have had some drop-in during the course of the study, but it's not meaningful.

Speaker #1: It hasn't been that many. And we are working on a baseline presentation. We don't know the timing of that presentation yet. But we are working on it, and we'll be able to share that data hopefully at some point soon.

Kyle Jenne: We don't know the timing of that presentation yet, but we are working on it, and we'll be able to share that data hopefully at some point soon. Eugene, anything more to add?

Speaker #1: Eugene, anything more to add?

Speaker #4: No, not really, Beth.

Luca Issi: No, not really, Beth.

Eugene Schneider: No, not really, Beth.

Speaker #1: Thank you. Thanks, Your Honor.

Yaron Werber: Thank you.

Kyle Jenne: Thank you, Yaron.

Speaker #3: Thank you. And the next question comes from Sabine Richter with Goldman Sachs.

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

Speaker #6: Good morning. Thanks for taking my question. Could you help us understand what you're seeing for reimbursement in FCS, given the competitor's lower price? And then just help us understand this end-pricing dynamic between the competitor and yourselves for SHTG, and how that would essentially provide broader population access for yourselves.

Salveen Richter: 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. 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.

Speaker #6: But I'm just trying to understand how to think about a differential there.

Speaker #1: Yeah. So let me first say, again, what a strong year that we had last year, 108 million dollars in total, 50 million dollars in Q4, a 56% increase quarter over quarter.

Kyle Jenne: Yeah. 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.

Speaker #1: 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.

Speaker #1: 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.

Speaker #1: But also provide the broadest access possible when we get to SHTG. So we're having the right conversations today. We're leading the way with payers and those engagements.

Speaker #1: We did a great job in 2025 to execute that. We're doing the same in 2026. But it'll take us a little bit more time before we complete the conversations and our research with the payers so that we come to a final decision on pricing.

Kyle Jenne: 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.

Speaker #1: And I'll just add to that, Sabine, that again, as Kyle mentioned, is prepared remarks. We've had no meaningful impact of the new market entry on the demand for trend goals.

Wade Walke: 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 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 in which we're preparing to transition for the sHTG launch.

Speaker #1: The demand for trend goals 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.

Speaker #1: So, we're very pleased with the performance of trend goals. But we're in that period right now in which we're preparing to transition for the SHTG launch.

Speaker #6: Thank you.

Salveen Richter: Thank you.

Speaker #3: Thank you. And the next question comes from Jason Garvery with Bank of America.

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

Speaker #7: Hey, guys. This is Chi on for Jason. Thanks for taking our question. I want to go back to a comment that you made, Kyle.

Qi Wang: Hey, guys. This is Qi Wang for Jason. Thanks for taking our questions. 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 olaparib to over $2 billion, and I recall this based on a 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 higher 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.

Speaker #7: You said you obviously, you guys have recently increased the peak revenue for olosartan to over 2 billion. And I recall this based on higher volume assumption.

Speaker #7: And today, Kyle, you mentioned you're even more confident in the blockbuster opportunity. Is it more confident in hitting that 2 billion number, or is it more confident in hitting a potentially higher peak number?

Speaker #7: What drove the higher confidence? Is it based on any recent research? And is it a high assumption on price or volume? And if I may squeeze in a quick one on a second question, I wanted to ask about ION 532, which was licensed to AstraZeneca.

Speaker #7: For April, it was mediated kidney disease. Curious your thoughts about the market opportunity there. Target profile of the S relative to competitions. And lastly, when might we see phase two data?

Qi Wang: 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.

Speaker #7: Thanks so much.

Speaker #1: Yeah. On the 2 billion dollars, Chi, when we shared this last month, we had these conversations. That 2 billion is really based on the strength of the product profile.

Wade Walke: ... Yeah, on the $2 billion, Chi, you know, 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. 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.

Kyle Jenne: ... Yeah, on the $2 billion, Chi, you know, 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. 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.

Speaker #1: 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.

Speaker #1: 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 continuing here early in 2026.

Speaker #1: And your second question, Chi, I'll take. It's really best asked for AstraZeneca. It's a program that we've been working on for quite some time.

Speaker #1: We published on preclinical data for targeting April L1 for FSG, particularly for people with mutations in the April L1 gene. Of course, kidney disease.

Wade Walke: We published on preclinical data for targeting APOL1 for FSGS, particularly for people with mutations in the APOL1 gene, across kidney disease. The preclinical data is very strong. The unmet need is very significant. There's a potential to go after patient populations that do not have an APOL1 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 AstraZeneca to go to phase two, after we licensed it to them, was based on data they conducted in phase one that showed strong target engagement and of course, with good safety. They advanced it to phase two, and as for timing of data, that's a question for AstraZeneca.

Kyle Jenne: We published on preclinical data for targeting APOL1 for FSGS, particularly for people with mutations in the APOL1 gene, across kidney disease. The preclinical data is very strong. The unmet need is very significant. There's a potential to go after patient populations that do not have an APOL1 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 AstraZeneca to go to phase two, after we licensed it to them, was based on data they conducted in phase one that showed strong target engagement and of course, with good safety. They advanced it to phase two, and as for timing of data, that's a question for AstraZeneca.

Speaker #1: The preclinical data is very strong. The unmet need is very significant. There's the potential to go after patient populations that do not have an April that are not April L1 carriers if the April L1 carrier data is strong enough to go in that direction.

Speaker #1: So it's a significant market opportunity for renal disease. The decision by AZ to go to phase two, after we licensed it to them, was based on data they conducted in phase one that showed strong target engagement.

Speaker #1: And of course, with good safety. So they advanced it to phase two. And as for timing of data, that's a question for AZ.

Speaker #7: Thanks so much.

[Analyst] (Guggenheim Securities): Thanks so much.

Qi Wang: Thanks so much.

Speaker #3: Thank you. And the next question comes from Michael. With Morgan Stanley.

Operator: Thank you. The next question comes from Michael Yee with Morgan Stanley.

Speaker #8: Good morning. Thanks for taking the question and 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.

Michael Yee: Good morning. Thanks for taking the question, and congratulations on all the progress as well. Maybe just one related to the sHTG filing. You know, just wondering if you can give us any color on any recent FDA interactions there. Secondly, you know, has your thinking on the potential for a Priority Review, you know, changed at all recently? Thanks.

Speaker #8: And then secondly, has your thinking on the potential for a priority review changed at all recently? Thanks.

Speaker #1: I'll start with the second one I asked Eugene to talk about how things are going. So for priority review, we can't speak for the FDA.

Wade Walke: I'll start with 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 interactions, it's been on track, right?

Speaker #1: But we believe that based on the unmet medical need and the compelling product profile, for olosartan and SHTG, that it deserves priority review designation.

Speaker #1: But we're in that window. We're in that evaluation window right now. And of course, again, I want to remind you, we did receive breakthrough therapy designation.

Speaker #1: As far as regulatory interactions, it's been on track, right?

Speaker #8: So far, so good. It's early days, of course. As you said.

Eugene Schneider: So far, so good. It's early days, of course.

Wade Walke: Yeah.

Eugene Schneider: as you said.

Speaker #1: Yeah.

Wade Walke: Yeah.

Speaker #3: Great. Thank you.

Michael Yee: Great. Thank you.

Wade Walke: We're within that window, Mike.

Speaker #1: We're within that window, Mike.

Wade Walke: We're within that window, Mike.

Speaker #3: Yep. Thanks. Thank you. And the next question comes from Luca Esse with RBC Capital.

Michael Yee: Yep. Thanks.

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

Speaker #9: Oh, great. Thanks so much for taking my question. Congrats on the progress. I do want to maybe just double down here on just priority review versus standard review.

Luca Issi: Oh, great! Thanks so much for taking my question. Congrats on the progress. I do want to maybe just double down here on this, you know, priority review versus standard review. I think in the past, you came across as pretty confident about priority review. 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 UK. Versus I think your competitor, Progenics, has many European sites.

Speaker #9: I think in the past, you came across as pretty confident about priority review. But obviously, you're now guiding, assuming standard review. So I'm just wondering kind of how anything has changed or maybe this is just kind of standard conservatism.

Speaker #9: Any thoughts there? I think much appreciated. And then maybe on Angelman, all the I think when I go in clinic and try to gov, I don't see any European sites there.

Speaker #9: For your program, I think except for the UK, so versus I think your competitor, Ultragenics, has many European sites. So is that because the European regulators prefer sham control trials instead of placebo control trials?

Luca Issi: 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.

Speaker #9: Or is that kind of more complex than that? Any thoughts? Much appreciated. Thank you.

Speaker #1: I'll probably address the Angelman's 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.

Wade Walke: I'll probably address the Angelman's 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. 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.

Speaker #1: 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.

Speaker #1: But we can't speak for the FDA. And the FDA usually takes the time that they need to draw a conclusion. And I think we'll just leave it there.

Speaker #1: 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.

Speaker #1: And we'll inform everybody. Holly?

Speaker #10: Yep. 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 sending forward with those sites.

Wade Walke: Holly?

Holly Kordasiewicz: Yep. For Angelman, you 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.

Speaker #10: But we do plan to open up sites in Europe as soon as that approval comes through.

Speaker #3: Got it. Thanks so much. Thank you. And the next question comes from Rich Radio with the Guggenheim Securities.

Luca Issi: Got it. Thanks so much.

Operator: Thank you. The next question comes from Yatin Suneja with Guggenheim Securities.

Speaker #11: Hi. This is Morris. I'm for DebJet. Thanks so much for taking my question. First, a quick follow-up on Trincosa, SHDD pricing. You previously said that you're expecting to price Trincosa at approximately 20,000 net price.

[Analyst] (Guggenheim Securities): Hi, this is Maurice I'm 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.

Speaker #11: Should that still be our base case assumption at this point? And then, secondly, a question on the brain barrier-penetrating platforms during your Innovation Day.

Speaker #11: 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.

Speaker #1: On the pricing question, we're finalizing the payer research. We will provide those details once we finalize everything and get that out. But 20,000 net is what we had assumed in the greater than $2 billion peak sales revenue.

Wade Walke: On the pricing question, we're finalizing the payer research. You know, 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. 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.

Speaker #1: 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.

Speaker #1: 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.

Speaker #1: 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.

Wade Walke: I, 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.

Speaker #1: With our BBB strategy.

Speaker #11: Thank you so much.

Holly Kordasiewicz: Thank you so much.

[Analyst] (Guggenheim Securities): Thank you so much.

Speaker #3: Thank you. And the next question comes from Joseph Stringer with Needham & Company.

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

Speaker #12: Hi. Thanks for taking our questions. Quick one on the GSK partnered HBV program. When can we see functional cure rates from the phase three program?

Joseph Stringer: Hi, thanks for taking our questions. Quick one on the GSK partnered HBV program. When can 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.

Speaker #12: And what are your and GSK's expectations for potential peak sales as a functional cure? And maybe more directly, what net revenue assumptions to Ionis are baked into your projected peak royalty revenues from this partner program?

Speaker #12: Thank you.

Speaker #1: Yeah. Sure. Beth will take the peak sales as soon as I can keep them all straight from our partners. And the revenue, what they're projecting.

Wade Walke: Yeah, sure. Beth will take the peak sales, as this is 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 need, 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?

Speaker #1: But as far as the presentation, yeah, the data is, we'll impress. It's unprecedented functional cure rates in this massive patient population with very high unmet medical need—millions of people.

Speaker #1: And GSK plans to present the data at EASL in May. The European Association for the Study of the Liver, and what they've said is that the functional cure rates are clinically meaningful.

Speaker #1: Beth?

Speaker #12: So GSK has talked about peak sales in the about two and a half billion dollar US dollar range. We've got a royalty tiered royalties that go from 10 to 12 percent in addition to the regulatory milestones.

Elizabeth L. Hougen: GSK has talked about peak sales in the about $2.5 billion US dollar range. We've got a royalty, tiered royalties that go from 10% to 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 estimate with our royalty tiers, 10% to 12%, into our overall peak royalties. Sorry. We've baked their peak sales and our royalties into our estimated peak royalties, which are about, I think, several billion dollars.

Speaker #12: Many of which we anticipate earning this year as they move through the regulatory filing, acceptance, and approval process in multiple countries. So we've baked their peak sales estimate, with our royalty tiers—10 to 12 percent—into our overall peak royalties from, sorry.

Speaker #12: We've baked their peak sales and our royalties into our estimated peak royalties which are about, I think, several billion dollars.

Speaker #11: Next question.

Speaker #3: Yes. Thank you. And the next question comes from Andy Chan with Wolfe Research.

Wade Walke: Next question.

Operator: Yes, thank you. Next question comes from Andy Chen with Wolfe Research.

Speaker #13: Hey. Thank you for taking the question. So I know you talked about Alexander quite a bit. Today. So just curious how fast that ramp would be or how big the eventual opportunity would be.

Andy Chen: 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.

Andy Hsieh: 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.

Speaker #13: And if you can compare the opportunity to other rare diseases, such as Donzera or FCS, that'd be great. Thank you.

Speaker #1: Thanks, Andy. I'd like Holly to just talk about what she's hearing from the community first for Zilga nurses. It's really exciting. And that, of course, affects the ramp.

Wade Walke: 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, that, of course, affects the ramp, like, what, how, what we're hearing. Then Kyle to take on what he, how he anticipates expectations for the launch.

Speaker #1: What we're hearing. And then Kyle to take on how he anticipates expectations for the launch.

Speaker #10: Just quick to remind everybody: last year, we read out our Phase 3 study, and we hit statistically significant, clinically meaningful differences on our primary endpoint, which is a motor functional test.

Holly Kordasiewicz: Just quick to remind everybody, last year, we read out our Phase 3 study. We hit statistical 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.

Speaker #10: And then we also in key secondary endpoints had favorable all-favoring Zilga nursing. The community, of course, has been overwhelmingly positive. They are excited for the drug.

Speaker #10: We've opened up an early access program. We already have folks coming in for that as well, and so it's very encouraging to see how the response has been from the community—that they're just waiting for this medicine.

Speaker #13: Yeah. And related to the launch, there are approximately 300 people living with Alexander disease in the United States today. We believe that about 50% of those have been identified.

Kyle Jenne: Yeah, 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.

Speaker #13: 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.

Speaker #13: 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.

Speaker #13: We'll add some account specialists, and then some of our patient education managers to help with reimbursement and the transition onto treatment, and to keep patients taken care of, etc., throughout the process.

Speaker #13: We have guided to greater than 100 million dollars 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'll be modest this year and then grow into 2027.

Kyle Jenne: 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 Q4. We'll get the team in place and get launched in. It'll be modest this year and then grow into 2027.

Speaker #1: The Zilga nursing opportunity, of course, is incredibly meaningful for the patient community. It's going to provide a meaningful revenue for Ionis once we get there.

Wade Walke: The Zolgensma 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. Zolgensma is first, coming from Ionis, that we're gonna 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 for broad disease indications. It really gets us started.

Speaker #1: But also, it's really important to understand and recognize the strategic value for our neurology fully owned pipeline. Zilga nursing is the first coming from Ionis.

Speaker #1: That we're going to deliver to patients and 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 for broad disease indications.

Speaker #1: So it really gets us started.

Speaker #3: Thank you. And the next question comes from Raj Tawari with Jefferies.

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

Speaker #14: Hey. This is Manoj on four others. Just one from our end. Can you provide some color on your expectations around the upcoming Horizon LPLA phase three?

[Analyst] (Jefferies): Hey, this is Manoj on for Akash. Just one from our end. Can you provide some color on your expectations around the upcoming Horizon Lp 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 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 targeting asset? Thank you.

Speaker #14: What would be a commercially viable risk reduction bar in the setting? Do you consider any potential deeper risk reduction in the other near-term LPLA readouts could change the commercial outlook for Pelicarsen?

Speaker #14: And also, can you comment on the current status of your next-gen or follow-on LPLA targeting asset? Thank you.

Speaker #1: Yeah. Like Eric talked about the next-gen, and why we're so excited about its profile. With respect to the Horizon trial, I mean, we remain quite confident in the outcome.

Wade Walke: Yeah, like Eric talked about the next gen, and why we're so excited about it, 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(a), we'll be the first to test the Lp(a) 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, and in the trial, we remain confident.

Speaker #1: Recognizing the risk of doing something for the first time it's Ionis tradition. It's in our DNA to be first. We've done it so many times.

Speaker #1: And for LPLA, we'll be the first to test the LPLA CBD hypothesis. But 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 and in the trial, we remain confident.

Speaker #1: Of course, the risk is that no one's ever done this before. But that's an enormous opportunity as well. The mean LPLA levels in the study have been reported already.

Wade Walke: 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.

Speaker #1: 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.

Speaker #1: The rest are stroke or serious peripheral artery disease to be qualified for the study. It's a very well-conducted study. It's going to give the answer to the LPLA hypothesis.

Speaker #1: And as far as competition goes, it's Pelicarsen has a meaningful first-mover advantage in this massive market opportunity. And we've seen no drug profile out there that we believe will be superior to the LPLA lowering effects that we saw that we're seeing for Pelicarsen.

Wade Walke: As far as competition goes, you know, it's pelacarsen has a meaningful first mover advantage in this massive market opportunity, and we've seen no drug profile out there that we believe will be superior to the Lp(a) lowering effects that we're seeing for pelacarsen. Stay tuned. Midyear this year, we'll get an answer. Eric, what about the follow-on?

Speaker #1: So stay tuned. Mid-year this year, we'll get an answer. Eric, what about the follow-on?

Speaker #13: Yeah, 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.

Eugene Schneider: 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 it's an siRNA that extends dosing frequency for lowering APOC3 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.

Speaker #13: 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.

Speaker #13: We recently reported some nice positive data on IN775 with an siRNA that extends dosing frequency in for lowering APOC3 and triglycerides in humans. And we've been making better progress on LPA with our siRNA platform.

Speaker #13: The goal is to get it to six-month extended dosing or perhaps a year, depending on how the drugs perform. We're very encouraged by the IN775 performance.

Speaker #13: And preclinically, the LPA siRNA looks better. So hopefully, we can demonstrate that in humans soon. Yeah. We have several programs coming forward into the clinic that are offering strong durability.

Eugene Schneider: Hopefully we can demonstrate that in humans soon.

Wade Walke: Yeah, we have several programs coming forward into the clinic that are, you know, offering strong durability, twice a year, once a year dosing. 775, of course, is the olezarsen follow-on for APOC3. We reported data last year in phase 1, it looked excellent, and we're gonna be in FCS 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 #13: Twice a year, once-a-year dosing, 775, of course, is the old Larsen follow-on for APOC3. We reported data last year in Phase I.

Speaker #13: It looked excellent. And we're going to be in SHCG patients in Phase 2 this year, and we believe that that will be replicated. With the Pelacarsen follow-on, which is now in IND-supporting toxicology studies.

Speaker #1: Yeah. Thanks.

Eugene Schneider: Yep. Thanks.

Speaker #3: Thank you. And the last question comes from Jay Olson with Oppenheimer. Please go ahead, Oppenheimer. You're welcome. Hey, Oppenheimer, as I dropped off the line, that does conclude the question session.

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

Speaker #3: So I would like to turn the floor back over to Brett Monia for any closing comments.

Speaker #1: 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.

Wade Walke: 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.

Speaker #1: 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.

Speaker #1: 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.

Speaker #1: Goodbye for now.

Speaker #15: Goodbye.

Speaker #3: Thank you as mentioned. Thank you. And as mentioned, the conference is now concluded. Thank you for attending today's presentation. You may now disconnect your lines.

[Company Representative] (Ionis Pharmaceuticals): Goodbye.

Holly Kordasiewicz: Goodbye.

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

Q4 2025 Ionis Pharmaceuticals Inc Earnings Call

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