Logo of jester cap with thought bubble.

Image source: The Motley Fool.

DATE

Wednesday, April 29, 2026 at 11:30 a.m. ET

CALL PARTICIPANTS

  • Chief Executive Officer — Brett P. Monia
  • Chief Financial Officer — Elizabeth L. Hougen
  • Chief Medical Officer — Eugene Schneider

Need a quote from a Motley Fool analyst? Email [email protected]

TAKEAWAYS

  • Total Revenue -- $246 million, up 87% year over year, led by both commercial and R&D revenues.
  • Commercial Revenue Growth -- Increased over 42% year over year, driven by Trangolza and Donzara sales.
  • Trangolza Product Sales -- over $27 million, reflecting continued demand; offset by an expected decline in net price.
  • Donzara Product Sales -- $16 million, representing a 125% increase versus the prior quarter.
  • Milestone Revenue -- Approximately $95 million from partnerships recognized during the quarter.
  • Operating Expenses -- Increased 29% year over year, mainly due to investments in launches for Trangolza, Donzara, ozarsen, and zilgarnirsen.
  • Cash Balance -- Ended the quarter with approximately $1.9 billion, after repaying $633 million in 0% convertible notes due April 1.
  • 2026 Total Revenue Guidance -- Raised to $875 million–$900 million, an increase of $75 million from previous guidance and moderately more weighted toward commercial revenue.
  • Trangolza Full-Year Sales Outlook -- Now projected between $100 million–$110 million; management expects a significant decline in Q2 following a price reset, with growth resuming post anticipated SHTG approval.
  • Donzara Full-Year Sales Outlook -- Projected between $110 million–$120 million; guidance assumes revenue growth as the launch advances.
  • Non-GAAP Operating Loss Guidance -- Now expected at $425 million–$475 million, reflecting a $75 million improvement versus prior expectations.
  • Year-End 2026 Cash Projection -- Forecasted at greater than $1.6 billion, reflecting strategic investments and recent debt repayment.
  • Peak Sales Estimate for Ozarsen -- Management raised peak annual sales forecast from>$2 billion to>$3 billion based on payer research and pricing decisions.
  • Wholesale Acquisition Cost for Trangolza/Ozarsen -- Set at $40,000 annually effective April 1; applies to both FCS and SHTG indications, aiming for consistent access and payer alignment.
  • PDUFA Dates for New Launches -- Ozarsen in SHTG: June 30; Zilgarnirsen in Alexander disease: September 22, both under priority review by FDA.
  • Epiravirsen Update -- Granted Breakthrough Therapy designation and FDA priority review, with a PDUFA date of October 26; partner GSK to present phase 3 data showing “statistically significant and clinically meaningful functional cure rates” at EASL.
  • Upcoming Partner-Led Launches -- Five launches expected by the end of 2027, including epiravirsen, pelacarsen, and eplontersen, supporting recurring royalty and milestone streams.
  • Phase 3 Efficacy Data -- Ozarsen phase 3 showed “85% reduction in acute pancreatitis” and “72% reduction in triglycerides on top of standard of care.”
  • Donzara Uptake -- Strong “conversion-to-paid-therapy rate” from a free-trial program, with repeat prescribers emerging rapidly.
  • Salinersen Update -- First patient in phase 3 triggered a $45 million milestone payment to be recognized in Q2.

SUMMARY

Ionis Pharmaceuticals (IONS +4.25%) delivered a sharp 87% revenue increase for the quarter, leveraging both commercial uptake of new medicines and significant partnership milestone receipts. Management revealed enhanced strategic visibility by raising 2026 total revenue and non-GAAP operating loss guidance, initiating specific annual sales targets for Trangolza and Donzara, and substantially lifting the peak sales estimate for ozarsen to over $3 billion. Product launches remain central, with two independent pipeline launches on track for FDA decisions under priority review in the next two quarters, and the company implemented a broad pricing strategy designed to accelerate payer adoption and integrate major therapies into the forthcoming annual cycles. The steady expansion of the partnered pipeline, marked by regulatory advances and projected five launches by next year, further augments the company’s growing stream of recurring revenue. With a robust $1.9 billion cash reserve and prudent capital allocation, Ionis Pharmaceuticals continues to drive toward operational leverage and targets cash flow breakeven by 2028.

  • Trangolza demand growth was described as delivering “Q1 was our strongest quarter in terms of demand, with patient starts increasing significantly versus prior quarters.”
  • Updated clinical guidelines in the U.S. explicitly single out ozarsen as the recommended therapy for lowering triglycerides and reducing pancreatitis risk in FCS.
  • Initial launch of Trangolza in Europe is underway via partner Sobi, broadening geographic revenue potential.
  • Donzara’s U.S. launch is gaining “significant momentum” across new, switch, and treatment-naive patient segments, with a majority starting on four-week dosing before progressing to eight-week intervals as experience accumulates.
  • Physician and patient feedback on Donzara has been “consistently positive,” emphasizing efficacy, tolerability, and convenience of the self-administered auto-injector.
  • Open-label extension studies on ozarsen show “increases in hepatic fat that we saw were relatively minor, and there were no clinical sequelae associated with these small increases.”; long-term data indicate return to baseline.
  • Priority review and PDUFA acceptance for zilgarnirsen in Alexander disease set the stage for the company's inaugural neurology program launch.
  • Management stated payer access for SHTG will ramp gradually, with some payers waiting six to nine months for final coverage reviews post-approval, but early steps are underway via current pricing actions and contract cycles.
  • No comment was offered on gross-to-net expectations for Trangolza following the price reset.

INDUSTRY GLOSSARY

  • FCS: Familial chylomicronemia syndrome, a rare genetic disorder causing severe hypertriglyceridemia.
  • SHTG: Severe hypertriglyceridemia, abnormally high triglyceride levels posing pancreatitis risk.
  • PDUFA date: The date by which FDA commits to complete review of a new drug application under the Prescription Drug User Fee Act.
  • WAC: Wholesale Acquisition Cost, the manufacturer’s list price for distributors.
  • Breakthrough Therapy designation: FDA pathway expediting review for drugs with substantial improvement over current standards.
  • Auto-injector: Self-administered device enabling patients to deliver subcutaneous injections outside a clinical setting.
  • HCP: Healthcare Professional, referring to prescribing clinicians.
  • Open-label extension (OLE): A continuation phase of clinical studies where all patients receive the investigational drug to assess long-term effects.

Full Conference Call Transcript

Ionis Pharmaceuticals, Inc. entered 2026 with significant momentum, which continued to accelerate through the first quarter of this year. Our performance to date highlights our strong execution across the business, which positions us to fuel substantial growth for years to come. We are very pleased with the continued success of Trangolza. Demand continues to grow, reflecting both the compelling clinical profile and strong launch execution by our team. The launch of Trangolza is now also underway in Europe through our partner Sobi, expanding access to this transformational therapy for people with FCS. We also continue to advance our launch of Donzara. We are very encouraged by the strong early trajectory and the breadth of prescribers across patient segments. Outside the U.S., Donzara received European approval earlier this year and our partner, Otsuka, has now initiated launch activities across the region. Together, Trangolza and Donzara give us a strong foundation of successful commercial execution as we look ahead to two additional independent launches this year, with more to come. We are on track for the launch of ozarsen in severe triglyceridemia, which represents our first independent launch in a broad patient population. We are pleased to have received priority review by the FDA with a PDUFA date of June 30, reflecting the significant unmet need in SHTG and the groundbreaking results from our landmark CORE and CORE 2 studies. In these studies, we demonstrated profound and highly statistically significant reductions in triglycerides and acute pancreatitis events, along with favorable safety and tolerability. Today, based on HCP demand and payer research, we are increasing our annual peak sales estimate for ozarsen from greater than $2 billion to now greater than $3 billion, positioning ozarsen to become Ionis Pharmaceuticals, Inc.’s first wholly owned multibillion-dollar medicine as the new standard of care for treating patients with severe hypertriglyceridemia. Dilganersen for Alexander disease is our second planned independent launch this year, the first from our industry-leading neurology pipeline. Gilganersen is the first and only medicine to demonstrate clinically meaningful and disease-modifying benefit in Alexander disease, a devastating and often fatal leukodystrophy with no approved treatments today. We submitted our NDA in January. Based on the results of our pivotal study, the FDA accepted our NDA with priority review and a PDUFA date of September 22. Overall, we are on track to have three independent medicines for four indications on the market in 2026: Trangolza for FCS and SHTG, Donzara for HAE, and Zilgarnersen for Alexander disease. This marks a major step in Ionis Pharmaceuticals, Inc.’s evolution as a fully integrated commercial biotech company. Complementing our wholly owned portfolio is our partner pipeline, a rich pipeline that continues to advance toward multiple value-driving events this year. Epiravirsen, our potential first-in-class medicine for chronic hepatitis B, is on track to launch in the U.S. and Japan this year by our partner GSK. And just this week, epiravirsen was granted Breakthrough Therapy designation and accepted for priority review by FDA with a PDUFA date of October 26.

Next month at EASL, GSK will present the unprecedented results of the phase 3 program in which epiravirsen achieves statistically significant and clinically meaningful functional cure rates in patients with chronic hepatitis B. We also remain on track for data from two major cardiovascular outcome trials from our partner pipeline this year: the pelacarsen LP(a) HORIZON trial in patients with elevated Lp(a) and cardiovascular disease, and the eplontersen CardioTransform trial in transthyretin-mediated cardiomyopathy. Including these programs along with epiravirsen, we expect five partner-led launches by the end of next year, creating a diversified stream of royalties and milestones for Ionis Pharmaceuticals, Inc. with multibillion-dollar potential well into the next decade.

In addition to our commercial and pipeline achievements, we also delivered strong financial results in the first quarter. As a result of this strong Q1 performance and outlook for the balance of the year, today we are announcing a significant improvement to our financial guidance, which Beth will cover in detail in a few moments. Ionis Pharmaceuticals, Inc. has achieved a great deal of late. Our pipeline and our launches are delivering tremendous value. And we continue to strengthen our financial position. But even more importantly, we are well positioned and committed to build on this success to drive far greater value for patients and our shareholders. And with that, I will turn the call over to Kyle.

Thank you, Brett. As we enter 2026, Ionis Pharmaceuticals, Inc. is capitalizing on the exceptional launch momentum we generated in 2025 to drive even greater impact. We are set up for continued success with our independent launches. Trangolza demand is accelerating. Donzara early launch metrics are tracking extremely well. And enthusiasm continues to build for our upcoming ozarsen launch in SHTG and zilgarnirsen launch in Alexander disease. Trangolza continues to build on the strong performance from last year. Q1 was our strongest quarter in terms of demand, with patient starts increasing significantly versus prior quarters. Patients on treatment are doing extremely well.

Our patient-finding initiatives continue to identify appropriate FCS patients, and we are successfully converting prescriptions to patients on treatment. We are seeing ongoing expansion in both breadth and depth of prescribing, with more clinicians initiating Trangolza and existing prescribers writing additional scripts. Prescribers span a broad mix of specialties, including cardiology, endocrinology, and lipidology, which is exactly the prescriber base we want as we prepare for the broader SHTG population. Physicians remain highly satisfied with Trangolza’s overall profile—efficacy, safety, tolerability, and the patient experience—and that is translating into an accelerating rate for new patient starts.

Additionally, we are highly encouraged by the updated ACC and clinical practice guidelines which single out ozarsen as the recommended treatment to lower triglycerides and reduce pancreatitis risk in patients with FCS. Outside the U.S., our partner Sobi is now in the early stages of launching Trangolza for FCS in Europe. This is expanding access for FCS patients and will bring in additional revenue over time. Following the groundbreaking CORE and CORE 2 data in SHTG, we conducted extensive market research with high-volume lipid specialists, cardiologists, and endocrinologists.

That work consistently showed a clear understanding that preventing pancreatitis is the key treatment goal in SHTG, and that current options fall short; strong recognition of ozarsen’s differentiated clinical profile, especially the acute pancreatitis data and the very low number needed to treat; and HCPs have stated a high intent to prescribe across a range of patient types, with initial use expected for 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. In line with our commitment to patient access, and to a successful transition into the broader SHTG market, we recently announced an important pricing decision for Trangolza.

Effective April 1, we set the new annual wholesale acquisition cost to $40,000, which applies to the current FCS indication and will be maintained for the anticipated SHTG indication across both doses. Importantly, by establishing a new price ahead of the June 30 PDUFA date, we are integrating ozarsen into 2027 payer contracting cycles, positioning us for accelerating access following approval. From a go-to-market standpoint, our full U.S. field organization is now in place, trained, and deployed. Today, that team is focused on supporting Trangolza for FCS and deepening our relationships with the key specialists who also treat SHTG. With this expanded footprint, we are positioned to engage 20,000 high-volume SHTG prescribers across the country.

The Donzara launch is gaining significant momentum in what is largely a switch market in the U.S. We are seeing increasing adoption across all patient segments: patients switching from existing prophylactic therapies, patients who were previously using on-demand treatment, and treatment-naive patients. Our free-trial program has been very successful, with a high conversion-to-paid-therapy rate to date. Just as importantly, feedback from both physicians and patients has been consistently positive, highlighting Donzara’s strong efficacy, its differentiated RNA-targeted mechanism, the positive switch data—which HCPs describe as “differentiating and motivating”—and Donzara’s patient-friendly profile that includes a self-administered auto-injector that can be stored at room temperature for up to six weeks.

We are also seeing a growing base of repeat prescribers, which is a key indicator that Donzara is providing a substantial benefit for patients. While it will take time to fully transition appropriate patients off legacy therapies, especially in a well-established market like HAE, the launch fundamentals give us confidence that Donzara will contribute significantly to the increase in our commercial revenue in 2026 and beyond. Outside the U.S., Donzara is now approved in the EU, and our partner Otsuka has initiated launch activities. Over time, we expect ex-U.S. markets to become an important contributor to the global Donzara franchise. Finally, we are preparing for our first independent launch from our neurology portfolio with zilgarnirsen for Alexander disease.

On the back of the positive phase 3 results, we now have FDA priority review with the PDUFA date set for September 22, and our expanded access program is underway. On the commercial side, our focus has been on continuing to strengthen current relationships and build new relationships with the highly specialized community of leukodystrophy and rare neurology HCPs, further advancing partnerships with patient advocacy groups, and ensuring the right support infrastructure is in place for diagnosis, treatment, and ongoing care. Our medical affairs team has been engaging with top leukodystrophy centers, sharing data, and helping to build awareness of Alexander disease. Our marketing and access teams are finalizing the launch strategy.

We will hire the customer-facing team closer to approval. Zilgarnirsen is not only an important medicine for people living with Alexander disease, but it is also a template for how we will commercialize future rare, first-in-class neurology therapies emerging from our pipeline. With two independent launches building momentum, two additional launches anticipated this year, and a strong pipeline behind them, we believe Ionis Pharmaceuticals, Inc. is well positioned to change the lives of patients around the world. With that, I will turn the call over to Beth. Thank you, Kyle.

Elizabeth L. Hougen: The strong operational execution you have heard about this morning translated into very strong first quarter financial results. We delivered year-over-year revenue growth and maintained disciplined expense management, while continuing to invest in our current and upcoming independent launches. First quarter total revenues were $246 million, an increase of 87% compared to 2025. This increase was driven by year-over-year commercial revenue growth from Trangolza and Donzara and substantial R&D revenue, including approximately $95 million of milestone payments from multiple partnerships. Commercial revenue increased over 42% year over year in the first quarter, driven in large part by Trangolza and Donzara growth.

Trangolza delivered over $27 million in product sales, reflecting continued strong demand that was offset by an anticipated decline in net price. Donzara contributed meaningfully to commercial revenue, delivering $16 million in the first quarter, an increase of 125% compared to the prior quarter. 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. Operating expenses for the quarter were in line with expectations and increased 29% year over year, primarily driven by commercial investments supporting Trangolza and Donzara, and launch-readiness activities for ozarsen in SHTG and zilgarnirsen in Alexander disease. We ended the quarter with cash of approximately $1.9 billion.

The change in cash from year-end 2025 was primarily related to $633 million we used to repay our 0% convertible notes, which were due on April 1. The strength of our balance sheet is the result of our prudent fiscal management, which enables us to make strategic investments as we advance and launch our wholly owned medicines. Our Q1 performance underscores the value of our diversified revenue model, which combines growing commercial revenue with substantial and recurring R&D revenue from partnered programs. Based on our strong year-to-date financial results, accelerating launch momentum, and positive outlook for the rest of the year, we are improving our 2026 financial guidance.

We now expect total revenue in the range of $875 million to $900 million, an increase of $75 million versus prior guidance, with total revenue weighted slightly more toward commercial revenues. For the first time this year, we are also providing product-level guidance for Trangolza and Donzara. We expect Trangolza product sales to be between $100 million and $110 million for the full year, and generally in line with 2025 full-year Trangolza revenue. Our guidance assumes a significant decline in second-quarter Trangolza revenue based on the updated price effective April 1, and a steady return to growth after the June 30 approval for SHTG.

We are projecting Donzara product sales to be between $110 million and $120 million for the full year. Our guidance assumes Donzara will continue to be a significant contributor to year-over-year growth in 2026, with revenue steadily increasing as the launch advances. We also anticipate significant R&D revenue from existing collaborations, including potential development and regulatory milestones across our partnered portfolio, demonstrating that R&D revenue is indeed an important financial accelerator. In fact, we recently learned that the first patient initiated treatment in the phase 3 program for salinersen triggered a $45 million payment we will recognize in the second quarter.

Over the balance of the year, we are also eligible to earn additional milestones tied to favoplersen, epiravirsen, pelacarsen, and other partnered programs as they advance. We expect our 2026 operating expenses to increase in the low-teens percentage range compared to last year. This modest increase reflects our commitment to financial discipline as we bring multiple medicines directly to patients and advance our pipeline. The key drivers of expense growth will be sales and marketing investments to support Trangolza and Donzara and to ensure successful launches for ozarsen in SHTG and zilgarnirsen in Alexander disease, assuming approvals. We anticipate 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. Our focus on improving operating leverage is enabling us to drop the full increase in revenue guidance to the bottom line. As a result, we expect a non-GAAP operating loss between $425 million and $475 million, a $75 million improvement over our previous guidance. This is similar to our 2025 operating loss after adjusting for the one-time sapablurson license fee we earned last year. We are projecting a 2026 year-end cash balance of greater than $1.6 billion. This reflects the repayment of the 0% convertible notes, which were due on April 1.

The strength of our balance sheet, combined with our diversified revenue streams, supports our continued strategic investments in ongoing and planned launches as we advance our wholly owned pipeline. Our financial outlook reflects accelerating commercial launches, a progressing pipeline, and a diversified revenue base, positioning us for continued growth and keeping us on track for cash flow breakeven in 2028. And with that, I will turn the call back over to Brett.

Brett P. Monia: Thank you, Beth. The first quarter and our outlook for 2026 underscore the strength of Ionis Pharmaceuticals, Inc. today, with two successful independent launches underway, two more independent launches anticipated this year, a robust pipeline advancing toward multiple near- and mid-term catalysts, and a solid financial position that supports the continued investments we are making to maximize the value of our commercial medicines and pipeline. With all these key elements in place, we are confident in our ability to accelerate revenue growth and deliver increasing value for patients and for all Ionis Pharmaceuticals, Inc. stakeholders.

Now in closing, I want to highlight that this week at Ionis Pharmaceuticals, Inc., we are holding our annual “Why Week.” It is a time when our employees come together to hear directly from patients and caregivers about their personal stories and to reinforce our purpose, which is bringing better futures to people in need. I have never been prouder of the impact we are having on patient lives and clinical medicine, and I am even more excited about the greater impact we are positioned to make in the near term and sustainably well into the future. And with that, we will now open the call for questions. Sabrina?

Operator: Thank you. We will now begin the question and answer session.

Operator: If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then 2. At this time, we will pause momentarily to assemble our roster. The first question comes from Jessica Fye of JPMorgan. Please go ahead.

Jessica Fye: Hey, guys. Good morning. Thanks for taking my question. So you once again raised peak expectations for Trangolza. Can you just spend a little time elaborating on what enabled you to increase it from at least $2 billion at JPMorgan to now at least $3 billion? And can you also talk about your expectation for gross-to-nets for Trangolza following this price reset?

Brett P. Monia: Yes, Jessica, thank you for the question. Our increase in peak product sales for Trangolza in SHTG and FCS combined, in the U.S., to $3 billion was based on several factors. As you recall, we increased the peak sales to $2 billion in January based really solely on the phase 3 data and the HCP demand research that we had conducted. The demand was very high. Since then, we have completed our HCP demand research, but more importantly, we completed our payer research, which landed on our $40,000 annual WAC price. Price, as well as priority review, were the biggest drivers of the increase in peak sales that we have put out today.

As far as gross-to-net, we are not commenting on that at this time.

Operator: Thank you. The next question comes from Michael Eric Ulz of Morgan Stanley. Please go ahead.

Brett P. Monia: Good morning. Thanks for taking the question, and congratulations on the progress. Maybe just a question on the Trangolza trajectory for the year. You mentioned return to growth in the second half really driven by the SHTG launch. Just curious in some of your market research, are you picking up on maybe any pent-up demand? Could we anticipate a bolus early in the launch here, given the groundbreaking data? Thanks. Kyle, would you take that, please? Yes, Michael, I appreciate that. And I think what is important first is the strong performance that we saw in Q1 in terms of demand.

It is the best quarter that we have had in terms of the FCS patient population—the number of scripts that were received and the number of patients that are starting on therapy. So that actually lends us a lot of confidence not only in the FCS space, but also as we get closer to the June 30 PDUFA date in SHTG. I think it is indicating that there is a lot of interest in using ozarsen very broadly in this patient population.

In terms of the launch in SHTG, we do know that there are a number of patients that are waiting, especially the patients that have a history of acute pancreatitis, patients that are above 880, and those are really the patients that we are going to focus on out of the gate. The trajectory, I think, is going to be modest at the beginning here in 2026. I think the revenue guidance that Beth shared, of $100 million to $110 million, is consistent with that expectation, and we will see it steadily grow over time, with that focus being in the highest-risk patient population.

But some of the dynamics here, as typically seen, are that it takes some time for the HCPs to be educated on the label. We have to get those patients into those centers in order to get the prescriptions and then get the execution of the scripts to turn into patients on treatment. So it will be a build over time, and it will accumulate, and we expect modest and steady growth throughout the back half of this year. Great. Thank you.

Operator: The next question comes from Gary Jay Nachman with Canaccord Genuity. Please go ahead.

Brett P. Monia: Hi, guys. Good morning, and congrats on the progress. So again, on SHTG, just talk about how you expect the payer access to ramp up, the timing of that, when you think it will really kick in. And you got updated guidelines for FCS. Will you be able to get that for SHTG as well? And how long before you think you could expand to a less severe patient population over time? Thanks. Kyle, do you want to start, and I can touch on the guidelines? Sure. On the payer access piece, Gary, part of the price change—the decision that we made on April 1 to change the WAC price to $40,000—is directly in line with working with those payers.

It fits into the annual review cycle as they are getting ready for their 2027 decisions to be made. So we believe that it will help us get ahead of SHTG a little bit, not only in 2026, but also in anticipation of 2027. That being said, all payers will actually wait for the final label before they make any payer coverage decisions, because they want to see what the indication statement is, they want to see what information is in the label—including acute pancreatitis and some of the other clinical study data that will be included in the label. So it will take a little bit of time.

Some payers will say, “We are not going to review anything for six to nine months,” for example. That is standard policy with some payers. But we hope that we will be able to get ahead of that with the payers that do review earlier by making that price change and also with our current interactions that we are having leading up to the SHTG approval. So we are going to work quickly, and I think we are in a good spot right now in terms of the way that we are approaching the payers.

And, Gary, to your other question, we were very pleased by the fact that the cardiovascular treatment guidelines for FCS singled out Trangolza as the treatment of choice for this disease indication, and we applaud the aggressiveness that they are taking to update their guidelines for treatments. We believe that SHTG will be part of that in the future, and we believe Trangolza will be a treatment of choice for severe hypertriglyceridemia. They have been very supportive of the new treatments that are coming out, and we think that they will move pretty quickly.

We are also pleased by the fact that they have updated their guidelines on Lp(a) testing, which bodes well for a potential positive phase 3 readout for pelacarsen and the subsequent launch. So it is great news for patients, and it is great news for our pipeline. And in terms of the less severe patient population, we will start with the over-880 and over-500 with history of AP. However, those same physicians that are treating that patient population also have patients that are 500 to 880, for example. So the education will be ongoing.

We are in the right segment of HCPs in terms of our targets—focused on cardiology, endocrinology, and lipid specialists—so they will see a mix of those patients. I think some of those patients will already be picked up, especially if they have comorbidities—type 2 diabetes and/or ASCVD. But the broader population will take a little bit of time, just awareness and for more of the data and information to come out and more experience using ozarsen in the SHTG population.

There is a lot of optimism and a lot of excitement around the category and around the use of a product like this because they have never seen the triglyceride-lowering effects that they are going to see on top of standard of care, and they have never seen the outcomes in acute pancreatitis like they have seen with the CORE and CORE 2 data. Great. Thank you very much.

Operator: The next question comes from Jason Gerberry with Bank of America. Please go ahead.

Chi Meng Fong: Hey. Good morning. This is Chi on for Jason. Thanks for taking our question. On ozarsen in SHTG, could you give us an update on the levels of liver fat you have observed in the CORE open-label extension studies? To what extent have those open-label extension study data been incorporated into the NDA as the FDA reviews the totality of the safety data? And when would you present the updated OLE data later this year? Thanks so much.

Brett P. Monia: Yes, let me start, Chi—thank you for the question—and then I will pass it on to Eugene. Maybe you could comment on where we are in the regulatory process for SHTG briefly. We are very pleased with the ongoing open-label extension data that we are continuing to accumulate with respect to MRI assessment of hepatic fat fraction. As you recall, the increases in hepatic fat that we saw were relatively minor, and there were no clinical sequelae associated with these small increases. We strongly believe this is a non-target effect.

It is consistent with other modalities that have taken the silencing approach in lowering APOC3 in this patient population, and it is completely logical based on the mechanism of inhibition of APOC3, which leads to a rapid and substantial clearance of triglycerides, in large part through the liver. We have always felt that the observations in liver fat that we have seen here—again, with no clinical sequelae associated—would be transient, based on the liver just needing to have a little bit more time to clear out the lipid that is being shunted through the liver. And that is what we are seeing in the long-term extension data. We are seeing a return to baseline in liver fat.

Again, no clinical sequelae associated with anything in the long-term extension, and we look forward to presenting the data in the second half of the year at a major medical congress. So stay tuned for that. Eugene, do you want to provide an update on regulatory?

Eugene Schneider: Yes. The application is under review. Everything is going as planned. Of course, the new emerging safety data has been provided to the agency as part of routine Day 90 safety updates. That is under review now with no questions asked so far. I will also add that the discontinuations in the long-term extension are extremely low. We are seeing excellent compliance with long-term treatment in the open-label extension. So stay tuned. We are very much looking forward to presenting the results.

Operator: The next question comes from Elie Merle of Barclays. Please go ahead.

Analyst: Hi. This is Tejas on for Elie. Thanks for taking our question. In SHTG, you have a set of readouts coming up later this year. Curious how you would frame those data in the context of the space and if any outcomes there would impact your peak sales view.

Brett P. Monia: We would rather not comment on competitor data that does not even exist yet today. We are looking forward to seeing any additional data that comes out this year, next year, and in years to come in SHTG from other programs. All I will say is that the phase 3 data that we presented at the American Heart Association in the late-breaking clinical trials session last year is incredibly compelling. It is a very high bar to meet with respect to efficacy, safety, and tolerability: 85% reduction in acute pancreatitis, which has resonated very well in the HCP community, as Kyle highlighted earlier in his prepared remarks, and 72% reduction in triglycerides on top of standard of care.

We are focused on our program. We are ready to launch in June, and I will just leave it there. I will just add: this is a large market—greater than 3 million patients that are potentially addressable here. We have a lot of confidence in the greater-than-$3 billion peak that we have put out there. That is really based on the phase 3 clinical trial outcomes that we have, our HCP demand research, the comprehensive payer research that we have done, and also the final pricing decision that we made. So we stand behind the increase, and we are excited about launching this program and getting it to as many patients as possible after the June 30 PDUFA date.

Operator: The next question comes from Jay Olson with Oppenheimer. Please go ahead.

Jay Olson: Hey, congrats on the quarter, and thank you for this update. Maybe I will shift gears to Donzara. Can you talk about how you expect the competitive landscape to evolve in HAE and any feedback that you are getting from patients and physicians on Donzara, and any color that you are getting on what percent of patients are currently on every-eight-week dosing?

Brett P. Monia: Yes, happy to, Jay. Thanks for the question. The competitive landscape obviously is evolving, with some recent announcements as late as this week related to some of the dynamics in the marketplace. Keep in mind that in the United States, over 75% of the patients are currently on a prophylactic treatment. This is a switch market as we understand the dynamics to be, and we are really pleased with the momentum that we are seeing in terms of the interest in using Donzara, which is the first RNA-targeted therapy modality in order to treat these patients.

The patient and HCP feedback has been extremely positive when they have been able to transition over to Donzara or start Donzara as a naive patient. What led into this, in terms of our market research, is consistently being played out in the market. Really, this is about efficacy, tolerability, and convenience. All three of those things are stacking up very nicely with the profile of Donzara, and patients are responding very positively to the therapy. Now, the majority of patients start on a four-week dosing schedule.

This is to make sure that they get transitioned over, that they are well controlled, and then they have the option, per the labeled indication, to move over to every eight weeks if they choose to do so. So as early in the launch as we are right now, you would anticipate that the majority of patients would be on a four-week regimen, and we will expect over time that they will be able to progress to an eight-week schedule as they are doing well on therapy, and we saw that in the clinical trial as well. So patients are doing great.

Momentum is very strong, and we are encouraged by what we are seeing in terms of the metrics with the launch at this point.

Jay Olson: Great. Thank you.

Operator: The next question comes from Moritz Reiterer with Guggenheim Securities. Please go ahead.

Analyst: Hi. This is Martin on for Debjit. Thanks for taking our questions. I will continue on Donzara. Your 2026 guidance for Donzara is essentially above what consensus was going into the quarter. So just trying to understand a little bit better what data drove this guidance number. And also, if you could comment a little bit more on the current mix between new patient starts versus switches and how you expect this to evolve through the end of the year? Thank you.

Brett P. Monia: Yes, I would be happy to touch on that. Thanks for the question. We had a very strong first quarter—$16 million in net product sales. This is a 128% increase over Q4. And I just spoke about the momentum that we are seeing in this market and the dynamics, and also the receptivity by both HCPs and patients as they get started and gain experience.