Note: This is an earnings call transcript. Content may contain errors.

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DATE

Oct. 29, 2025, at 11:30 a.m. ET

CALL PARTICIPANTS

  • Chief Executive Officer — Brett Monia
  • Chief Operating Officer — Richard Geary
  • Chief Commercial Officer — Kyle Jenne
  • Chief Financial Officer — Beth Hougen

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TAKEAWAYS

  • Total revenue -- $157 million in revenue, reflecting a 17% year-over-year increase, with $740 million in revenue for the first nine months, marking 55% year-over-year growth.
  • Royalty revenue -- $76 million in royalty revenue, increasing approximately 13% year over year, driven by SPINRAZA and WAINUA.
  • 2025 revenue guidance -- A $50 million increase from prior full-year 2025 guidance.
  • Tringolsa full-year sales guidance -- Up from earlier expectations.
  • Operating loss guidance -- Full-year operating loss forecast improved to a range of $275 million to $300 million.
  • Projected year-end cash balance -- Now expected to exceed $2.1 billion.
  • Tringolsa prescriber base -- Nearly 70% of prescribers in Q3 2025 are cardiologists and endocrinologists; provider reach continues expanding through omni-channel efforts targeting over 30,000 HCPs.
  • Tringolsa payer mix -- Coverage for Tringolsa patients is approximately 60% commercial and 40% government as of Q3 2025.
  • European approval -- Tringolsa approved in Europe with commercial launch by partner Sobi expected in the fourth quarter.
  • Donzara launch status -- Shipped first prescriptions within ten days of FDA approval; early adoption reported from both switch and naive patients.
  • Donzara market opportunity -- Prophylactic HAE market in the U.S. estimated at 7,000 patients, with about 75% on prophylaxis; peak sales for Donzara projected to exceed $500 million.
  • Olezarsen Phase III core studies -- Achieved up to 72% mean reduction in placebo-adjusted fasting triglycerides at six months and recorded an 85% reduction in adjudicated acute pancreatitis events.
  • Olezarsen regulatory plans -- U.S. supplemental NDA submission on track for year-end, with additional global filings next year.
  • Olezarsen market size -- High-risk SHTG population in the U.S. exceeds 1 million, with commercial focus aimed at approximately 20,000 HCPs treating about 360,000 high-risk patients.
  • Olezarsen peak sales guidance -- Management expects over $1 billion, with dosing flexibility planned for both 50 mg and 80 mg formulations.
  • Zilgarnirsen Phase III data -- Demonstrated a 33% mean gait speed benefit versus control at week 61 in the Phase III study for Alexander disease; new drug application scheduled for 2026.
  • Zilgarnirsen market estimate -- Peak sales for Alexander disease are projected to exceed $100 million.
  • ION 582 developments -- Granted FDA Breakthrough Therapy designation for Angelman syndrome, with Phase III REVEAL study enrollment on track for full completion next year and data expected in 2027.
  • Pipeline expansion -- Four partnered launches anticipated by 2027 are expected to contribute to total revenue growth.
  • Guidance on cash flow -- Still targeting company-wide cash flow breakeven by 2028.

SUMMARY

Ionis Pharmaceuticals (IONS +2.59%) reported accelerating commercial momentum, including dual independent launches and the expansion of its approved portfolio. Management raised guidance for both full-year revenue and Tringolsa sales, citing robust quarter-over-quarter growth and broadening prescriber adoption. The company spotlighted groundbreaking clinical results for olezarsen and zilgarnirsen, characterized by pronounced efficacy and differentiated clinical impact in severe hypertriglyceridemia and Alexander disease, respectively. Multiple pipeline milestones and additional launches, including expansion into Europe and continued late-stage trial advancements, frame a forward-looking growth strategy based on scientific validation and ongoing commercial execution.

  • Management stated that early Donzara uptake includes transitions from all existing prophylactic therapies, expansion into on-demand treatment users, and new patient starts.
  • Jenne said, "Our current target population of HCPs is about 3,000 that we're reaching with our existing Salesforce. We're going to expand that to reach approximately 20,000 HCPs. Those 20,000 HCPs are covering approximately 360,000 patients that have SHTG."
  • Geary confirmed, "the dropout rate was about half what we expected from the beginning" in the CORE and CORE II studies for SHTG, citing no unifying cause for discontinuations.
  • Beth Hougen clarified that capital allocation remains weighted toward internal pipeline growth, stating, "Our capital our top priority for capital allocation is for internal growth."
  • Management projected that Donzara will provide "a modest revenue contribution" in 2025, according to Hougen, with greater impact in the following year due to launch timing.

INDUSTRY GLOSSARY

  • FCS (Familial Chylomicronemia Syndrome): A rare genetic disorder causing extremely high triglycerides, leading to pancreatitis risk.
  • SHTG (Severe Hypertriglyceridemia): A condition of very elevated triglyceride levels, increasing the risk of acute pancreatitis.
  • Alexander disease: A rare, progressive neurological disorder with no approved disease-modifying treatments prior to this pipeline.
  • Breakthrough Therapy Designation: An FDA status granted to expedite development and review of drugs showing substantial improvement over existing therapies for serious conditions.
  • Acute pancreatitis events (AP events): Sudden inflammation of the pancreas, often life-threatening in high triglyceride patients.
  • HCP (Healthcare Provider): Medical professionals authorized to prescribe and manage therapies.
  • NNT (Number Needed to Treat): The number of patients who need to be treated to prevent one additional adverse outcome.
  • sNDA (Supplemental New Drug Application): A regulatory filing for approval of new indications or formulations for an already approved drug.

Full Conference Call Transcript

Brett Monia: With that, I'll turn the call over to Brett. Thanks, Wade. Good morning, everyone, and thank you for joining us on today's call. The third quarter was a watershed moment for Ionis Pharmaceuticals, Inc. as we made important progress advancing first and best-in-class medicines for several serious diseases, including in our core focus areas of neurology and cardiometabolic diseases. Our first independent launch for Tringolsa, the only FDA-approved treatment for familial chylomicronemia syndrome, or FCS, continues to build strong momentum. This performance reflects Tringolsa's compelling clinical profile, strong launch execution, and the significant unmet need that we are addressing.

Based on this performance and confidence in our continued success across the business, we are raising our 2025 financial guidance, including Tringolsa revenues, which Beth will review in more detail shortly. Tringolsa also recently received European approval, and we are pleased that our partner Sobi expects to begin bringing this transformative medicine to patients across Europe in the fourth quarter. In August, the FDA approved Donzara for Hereditary Angioedema, or HAE, marking our second independent launch. This is an important milestone for people living with HAE and for Ionis Pharmaceuticals, Inc. I am especially proud of the launch execution by our commercial team, which Kyle will further highlight in a few moments.

In September, we reported positive top-line results from two pivotal programs from our wholly-owned pipeline, both of which were groundbreaking in their own right. Olazarsen in severe hypertriglyceridemia, or SHTG, showed highly significant reductions in triglycerides and became the first medicine ever to show a reduction in acute pancreatitis in this population. And in neurology, Zilgarnason showed the first-ever disease-modifying effect in Alexander disease, a rare and often fatal neurologic disease. These results reinforce the strength of our science and position Ionis Pharmaceuticals, Inc. for two additional independent launches next year. Together, these two programs, along with Tringolsa and Donzara, represent significant breakthroughs for patients and the potential for multibillion-dollar revenue for Ionis Pharmaceuticals, Inc.

Complementing our rich wholly-owned pipeline is our partner pipeline, which continues to progress very well. By 2027, we anticipate four key launches from our partner pipeline targeting both rare and highly prevalent life-threatening diseases. We expect these partnered programs will further expand the impact of Ionis Pharmaceuticals, Inc. discovered medicines and meaningfully increase total revenue for Ionis Pharmaceuticals, Inc. With the strong momentum across our business, including our first two independent launches underway, an advancing wholly-owned late-stage pipeline, and a robust partnered portfolio, Ionis Pharmaceuticals, Inc. is well-positioned to deliver transformative medicines for patients year after year, driving sustained growth. And with that, I'll turn the call over to Richard.

Richard Geary: Well, thank you, Brett. We are making excellent progress across our pipeline, reinforcing Ionis Pharmaceuticals, Inc.'s ability to deliver on our mission of bringing transformational medicines to patients for years to come. Just last month, we reported positive top-line results from the Phase III CORE and CORE II studies of olisarcin in people with SHTG who had triglyceride levels substantially higher than 500 milligrams per deciliter despite being on standard of care lipid-lowering therapies at baseline, putting them at risk of life-threatening acute pancreatitis. In these pivotal studies, olesarsen demonstrated highly statistically significant and clinically meaningful mean reductions of up to 72% in placebo-adjusted fasting triglycerides at six months, the primary endpoint of these studies.

In these studies, olesarsen also significantly reduced acute pancreatitis events, making it the first and only treatment to achieve this positive outcome in people with SHTG. Olisarcin 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 these AP events, and olicersin is the first medicine to demonstrate it can do just that. We believe these unprecedented results position olicarsen to meet the substantial unmet needs of people with SHTG, a large patient population in great need for more effective triglyceride lowering to reduce the risk of potentially fatal acute pancreatitis.

In terms of next steps, we're looking forward to presenting additional data from the CORE and CORE II studies on November 8. Following that, we are on track to submit our sNDA in the US by the end of the year, with additional global filings expected next year. And as Kyle will highlight, launch preparations are already underway, and we are moving with urgency as we look to deliver olicarsen to people with SHTG next year. Turning our attention to zilgarnirsen, our medicine to treat Alexander disease, an ultra-rare leukodystrophy that profoundly impacts patients and families who today have no approved disease-modifying therapies.

With the positive phase three results in hand, we are on track for another independent launch next year, and we expect this to be the first of numerous additional independent launches from our leading neurology pipeline. In our phase three study, zilgarnirsen achieved statistically significant and clinically meaningful stabilization on the primary endpoint of gait speed. This is an assessment of gross motor function, as measured by the 10-meter walk test. At week sixty-one, zilgarnirsen showed a 33% mean benefit in gait speed versus control, with a favorable safety and tolerability profile. Zilgrenosen also demonstrated consistent benefit across key secondary endpoints. These results represent the first time an investigational medicine has shown a positive disease-modifying impact in Alexander disease.

We plan to submit a new drug application to the FDA in 2026, and we are also initiating an expanded access program in the US. Turning to ION 582, our investigational medicine for Angelman syndrome, the newest addition to our late-stage pipeline. Angelman syndrome is a serious, rare, neurodevelopmental disorder that causes profound and lifelong physical and cognitive impairments estimated to affect more than 100,000 people. Earlier this month, at our innovation day, we shared additional twelve and eighteen-month data from the long-term extension portion of the HALO study. Results from this study showed consistent and durable improvement in expressive communication over eighteen months, exceeding what is seen in natural history, while maintaining a favorable safety and tolerability profile.

Improvements were also observed across multiple other functional domains, including cognition and motor function, suggesting meaningful disease-modifying potential for ION 582. As a reminder, the primary endpoint in our Phase III REVEAL study is expressive communication, reflecting what families have reported matters most to them. And just last month, the FDA granted ION 582 breakthrough therapy designation, recognizing the encouraging results from the phase one two HALO study and the significant unmet need. Enrollment in the phase three registration study is progressing well, and we remain on track to be fully enrolled next year, with data in 2027.

With multiple data readouts and regulatory milestones expected this year and next, our advancing pipeline underscores the strength of our science and our commitment to addressing unmet needs in people with serious diseases. With that, I'll turn the call over to Kyle.

Kyle Jenne: Thank you, Richard. With our first independent launch gaining momentum, a second now underway, and two more anticipated next year, our commercial team is focused on flawless execution to bring these important medicines to patients. In the third quarter, Tringolsa continued to exhibit strong momentum as we reported $32 million in net product sales, reflecting a nearly 70% increase in revenues quarter over quarter. Our patient identification initiatives are proving effective. The breadth and depth of unique physicians prescribing Tringolsa continue to expand through the third quarter, underscoring the positive experience of both clinicians and patients.

This demand also spans a broad mix of specialties, with cardiologists and endocrinologists representing nearly 70% of prescribers and lipidologists and internal medicine providers making up the balance. This favorable provider mix will support awareness and familiarity when we expand into the broader SHTG patient population next year, assuming approval. Access and coverage have also remained strong. To date, the coverage mix for patients on Tringolsa is approximately 60% commercial and 40% government. Importantly, both clinically diagnosed and genetically confirmed patients have continued to obtain coverage through a growing number of formal policies or via the medical exception process. We're proud of Tringolsa's early momentum, but we know we're still in the early innings.

The vast majority of the estimated 3,000 people living with FCS in the US remain unidentified. As a result, we're continuing to focus on our patient-finding efforts and HCP education. Our customer-facing team has reached over 3,000 physicians, and over 30,000 HCPs have been targeted through our omni-channel capabilities, further increasing awareness of FCS, expanding patient identification, and educating on the potential benefits of Tringolsa treatment. Backed by an experienced and high-performing team, we are well-positioned to continue to take advantage of our first-mover position to bring Tringolsa to patients in need. Building on our early success in FCS, we are preparing for a launch in the severe hypertriglyceridemia patient population.

SHTG represents a large patient population, many of whom struggle to manage their triglyceride levels with current treatments. In the US alone, more than one million people have high-risk SHTG, defined as individuals with triglyceride levels above 880 milligrams per deciliter, or above 500 milligrams per deciliter with a history of acute pancreatitis or other comorbidities. With a significant first-mover advantage and groundbreaking positive Phase III data in hand, as Richard just outlined, we believe olezarsen is well-positioned to address the unmet needs of patients with severe hypertriglyceridemia. Our commercial team is making excellent progress as we prepare for an expected launch next year.

To unlock the potential of olezarsen in SHTG, we plan to initially target approximately 20,000 HCPs in the US who are high-volume treaters of high-risk SHTG patients and expand this outreach even further via our omni-channel capabilities. Our commercial strategy leverages the strong foundation we have built with healthcare providers already prescribing Tringolsa, many of whom manage SHTG patients. At the same time, we are broadening our reach to additional prescribers who treat SHTG patients. To support this effort, we are expanding awareness through targeted disease education and continued investment in our commercial infrastructure. With key field leadership now in place, we plan to scale the Tringolsa field force to approximately 200 representatives ahead of launch.

At the same time, we have begun engaging payers to ensure broad patient access at launch. We believe there is strong recognition of the value in treating SHTG, given the potential to reduce the risk of life-threatening triglyceride-induced acute pancreatitis and the cost associated with treating these patients. Now turning to Donzara. The approval of Donzara marked a major milestone for Ionis Pharmaceuticals, Inc. And our team is energized and focused on executing a successful launch. We've built a top-tier commercial organization with deep experience in allergy and immunology, including in HAE. Within ten days of approval, we shipped our first prescriptions, and the first patient self-administered their initial dose.

We're pleased to see strong early adoption of Donzara, with patients switching from prior prophylactic or on-demand therapies, as well as treatment-naive patients starting on Donzara. And the initial feedback from both physicians and patients has been very encouraging, with clear early excitement around Donzara. Notably, we are already seeing repeat prescribers. The US prophylactic HAE market is well established, yet many patients remain dissatisfied with their current therapies. Approximately twenty percent of patients switch treatments each year, highlighting the ongoing need for better treatment options. While educating patients and physicians and supporting switches from existing therapies will take time, we believe Donzara, with its differentiated profile and focused launch strategy, is well-positioned to meet this unmet need.

As with Tringolsa and FCS, we are committed to providing appropriate and comprehensive support to the HAE community, including ensuring broad and timely access for patients who need Donzara. We have established differentiated patient assistance and financial support programs. We are offering a free trial program, which allows patients, in collaboration with their healthcare providers, to determine if Donzara is the right fit for them. For eligible commercially insured patients, out-of-pocket costs can be reduced to as little as $0. With this foundation in place, we are confident in the anticipated trajectory of Donzara as we work to transform the treatment landscape for patients with HAE. Now turning to zilganeursen for Alexander disease.

Zilganeursen could deliver the first meaningful advance for patients and caregivers, as there are currently no approved disease-modifying treatments. This program represents another important opportunity to extend our commercial capabilities. We will build on Ionis Pharmaceuticals, Inc.'s long-standing partnerships with the neurology community and patient advocacy groups to support awareness, diagnosis, and access. At launch, our focus will be on ensuring continued access for clinical trial participants to zilganeursen, expediting access for diagnosed patients, and improving identification of new patients, including enhanced genetic screening. Additionally, we will be working to ensure treatment availability at appropriately equipped centers.

With preparations well underway, we are confident that zilganeursen can provide a first-in-class disease-modifying treatment option for patients and caregivers and opens the door to further strengthen our foundation as we advance our leading neurology pipeline. Our experienced commercial organization is already delivering strong results, as reflected in the early momentum of both Tringolsa and Donzara. Building on this success, we remain focused on maximizing the full potential of these therapies while preparing to execute two additional launches by the end of next year, expanding Ionis Pharmaceuticals, Inc.'s reach to even more patients in need of our medicines. With that, I will now turn it over to Beth.

Beth Hougen: We delivered another strong quarter driven by continued commercial execution and disciplined financial management, which enables us to raise our financial guidance once again. Our results reflect accelerating revenue growth, with strong contributions from our marketed medicines and sustained progress across our pipeline. We remain focused on executing our strategy, advancing our late-stage portfolio, and maintaining the financial strength that enables us to invest in future growth. In the third quarter, we generated $157 million in revenue, representing a 17% increase year over year. For the first nine months of this year, revenue totaled $740 million, an increase of 55% compared with the prior year.

As you heard from Kyle, the Tringolsa launch continues to perform exceptionally well, earning $32 million in product sales, representing a nearly 70% increase over the second quarter. Royalty revenues increased by approximately 13% to $76 million in the third quarter, anchored by meaningful contributions from both SPINRAZA and WAINUA. As planned, total non-GAAP operating expenses year to date increased 9% year over year, highlighting our commitment to disciplined investment and driving operating leverage. Our sales and marketing expenses increased year over year, driven by our investments in the US launch of Tringolsa and Donzara. R&D expenses decreased year over year as several of our late-stage studies recently concluded.

Importantly, we continued to strategically fund our advancing pipeline, with more than two-thirds of our total R&D expenses funding our late-stage programs. Based on this continued strong performance and fourth-quarter outlook, we are once again increasing our 2025 financial guidance, our third consecutive increase this year. We now expect to generate between $875 million and $900 million in total revenue for the year, an increase of $50 million versus our prior guidance. Our guidance reflects meaningful contributions from our commercial portfolio, including continued strong performance of Tringolsa. We now anticipate Tringolsa product sales between $85 and $95 million for the full year, also an increase from prior guidance.

Given the timing of approval, we expect Donzara will provide a modest revenue contribution this year, with a greater impact beginning next year. We now expect an operating loss between $275 million and $300 million for the full year. This improvement includes our planned acceleration in investments to support commercial preparations for olanzarcen and zilganeursen following the strong Phase III data and anticipated launches next year. Additionally, we now expect to end the year with a cash balance of more than $2.1 billion, highlighting our strong balance sheet that will support continued to drive accelerating growth. Our third-quarter results demonstrate strong execution across our business.

With two product launches now underway and more on the horizon, Ionis Pharmaceuticals, Inc. is well-positioned to deliver transformative medicines to patients in need and achieve our goal of cash flow breakeven by 2028, driving long-term value creation. With that, I'll turn the call back over to Brett.

Brett Monia: Thanks, Beth. The third quarter was marked by strong execution and accelerating momentum across our business. With two independent launches underway, continued pipeline progress, and key regulatory milestones achieved, we are delivering on our strategy. The commercial organization continues to perform very well. The Tringolsa launch is strong, and the approval of Donzara for HAE marked another important milestone, with encouraging early feedback from physicians and patients. And positive phase three results for olanzarcen in SHTG and zilgarnirsen in Alexander disease are paving the way for two additional independent launches next year. Together, these achievements strengthen our foundation for long-term growth.

With a deep pipeline, outstanding execution, and a clear path to achieve cash flow breakeven in 2028, Ionis Pharmaceuticals, Inc. is well-positioned to deliver transformative medicines for patients and accelerating value creation for shareholders. Now before we move to the Q&A, I'd like to take a moment to recognize and thank Richard Geary for his tremendous impact on Ionis Pharmaceuticals, Inc. over the past thirty years. With his retirement at the end of this year, this will be his last earnings call with us. Richard has been a driving force behind our innovation, leading dozens of development programs and guiding six transformative medicines through regulatory approvals and to patients.

His leadership, vision, and unwavering commitment to patients have been instrumental in shaping Ionis Pharmaceuticals, Inc. into the company we are today. On behalf of the entire Ionis Pharmaceuticals, Inc. team, I want to thank Richard for his remarkable contributions and his dedication to improving the lives of patients around the world. And with that, we'll now open the call up for questions. Chuck?

Operator: Thank you. We will now begin the question and answer session. To ask a question, you may press star then 1 on your touch-tone phone. If you are using a speakerphone, please pick up your handset before pressing the key. If at any time your question has been addressed, and you would like to withdraw your question, please press star then 2. And at this time, we'll take our first question. Excuse me. Will come from Miss Jessica Fye with JPMorgan. Please go ahead.

Jessica Fye: Hey, guys. Good morning. Thanks for taking our question. Was hoping you could talk a little bit about how we should best think about the shape of the launch curve for olanzarzan in SHTG. And I guess what I mean by that is kind of like in terms of the, you know, physicians you're targeting and the number of patients they cover, you know, do you perceive that there's, you know, pent-up demand or almost like a warehouse effect where you see rapid adoption the way we have in this obviously, much, much smaller FCS setting. Or if not, you know, what is the right way to think about the shape of that ramp? Thank you.

Kyle Jenne: Yeah. Thanks, Jess. This is Kyle. It's a great question. First, I'll just mention that there's strong interest in trying to expand the use of Tringolsa and interest in olanzarcen in the SHTG patient population. An ongoing question that we get from HCPs as we're interacting with them today. Our current target population of HCPs is about 3,000 that we're reaching with our existing Salesforce. We're going to expand that to reach approximately 20,000 HCPs. Those 20,000 HCPs are covering approximately 360,000 patients that have SHTG. Some of those are high-risk patients, meaning above 880 or above 500 with a history of AP. Many of those patients are currently on standard of care treatments.

So they're on fibrates and fish oils and statins and PCSK9s and other background therapies. So what we are expecting is that if those patients are on standard of care treatment and they're not getting to goal today, that there will be interest in using olanzarcen in that population, you know, based on the phase three data that we generated in CORE and CORE II. So that will be the beachhead in which we will approach this. And, you know, we expect strong uptake based on the interest and what we've learned about the market thus far.

Jessica Fye: Thank you.

Operator: The next question will come from Gena Wang with Barclays. Please go ahead.

Gena Wang: Thank you for taking my questions. So maybe I will also ask one is olefsacen, CORE and CORE II data. Since you have updated you we already have a top-line data. Anything that will be concerning regarding, say, the acute pancreatitis events? You know, if it's I know the rate ratio is super impressive, but, you know, you did have approved two studies. Would that be anything will be you know, we should pay attention to? Would that be well balanced between the CORE and the CORE II? Regarding the acute pancreatitis events and also any other things we should pay attention to. So that was one question.

And the second, high level, I know you give peak revenue potential for Donzara over $500 million. Do you have a view regarding, say, Alassane and also Alexander disease?

Richard Geary: Okay. Let's try those three questions, you know. Let's try to go through them quickly. But thank you. So I'll start with the then I'll turn it over to Kyle for Donzara and Alexander disease. So we're very much looking forward to presenting the detailed data at the American Heart Association in a prestigious late-breaking clinical trial session on November 8. Nothing to be concerned about. The AP data is groundbreaking. And I think that people are gonna really be impressed when we share the detailed data on the AP outcome, including how rapid protection is against acute pancreatitis and how durable those effects are.

Remember, this was a pre-specified statistical plan analysis of CORE and CORE II purposefully because we want to ensure the maximum powering for a positive outcome, which was proven to be a very, very smart thing to do. CORE and CORE II have been published on their baseline demographics. And what you see in the baseline demographics is that there's a higher triglyceride median amount in CORE versus CORE II, and that will reflect acute pancreatitis events in the study too. But you'll see all that data at the and there's nothing else to be concerned about. We're very much looking forward to it. Again, groundbreaking results, and the will be a great venue.

We're also encouraged that with where we are in the review process for publication, no guarantees. But we're hoping for a simultaneous publication with the presentation. If we can get that done, then all the deep that we can't get to in the presentation will be in the publication. So stay tuned for all that. Looking forward to it. Touch on Donzara and Alexander?

Kyle Jenne: Yeah. I'll just touch on peak sales for each of the programs. Peak sales for Donzara, as you referenced, are expected to be greater than $500 million. For olezarsen, our first anticipated blockbuster launch, we are expecting to be greater than $1 billion. And for Alexander's disease, it is greater than $100 million are the expectations.

Gena Wang: Thank you very much.

Operator: The next question will come from Mike Ulz with Morgan Stanley. Please go ahead.

Mike Ulz: Good morning, and thanks for taking the question. Maybe just a follow-up on ozarsen and SHTG. Just curious if you have any updated thoughts on pricing. I know this is an area where you're doing some extra work, so just curious if there's anything there to share or if not, you know, when we might expect a little bit more clarity on the pricing question. Thank you.

Kyle Jenne: Yeah. Thanks, Mike. This is Kyle again. The work is ongoing. We do have the CORE and CORE II data, the s data, and we've got a lot of work to go through with our information related to ER visits, hospitalization rates, number needed to treat, which is some information that will come out at as well. So there's still a lot for us to pull together. The research will kick off, and we expect to have additional information next year for us to be able to make some decisions in terms of final pricing recommendation.

I think what some early signals continue to tell us and is consistent with the research that we've done in the past, is that this is a market of greater than 3 million patients and that payers are going to look at this market in terms of their total exposure to potentially covering olazarsen in an SHTG indication of greater than 500 milligrams per deciliter patient population. So we're still doing that work, and we will announce the final price upon the approval of the SHCG indication, similar to how we've done with the FCS indication as well as the HAE indication for Donzara.

Mike Ulz: Great. Thank you.

Operator: The next question will come from Yaron Werber with TD Cowen. Please go ahead.

Yaron Werber: Great. Thanks so much. Congrats on a really nice quarter and hopefully, it should be very good next year as well. Couple of questions. Number one, just for when you're looking at when we're looking at the data, should we be expecting that it's the reduction in AP is gonna be principally in patients with a history of AP, is there a chance that you're gonna show potentially a prevention of new events in patients that did not have AP events in the past? Then secondly, you know, some of the other companies in the HAE space are actually beginning to talk that there's considerably more patients in the US market.

They're think some are mentioning as many as eleven thousand patients, and seventy-five percent on prophylaxis. I know you're mentioning seven thousand. Maybe can you help us kinda maybe understand the difference a little bit? Thank you.

Richard Geary: Sure, Yaron. Thank you for the question. I'll Kyle will address the, you know, market research and the prevalence in HAE in the US. Regarding a HAE, mean, Ah heart association meeting, So, again, I wanna get ahead of details, Yaron, but what I'll what I can say is this. You know, all of the research has been done over the decades has indicated that the higher the triglycerides, the more AP events that you're gonna get. In a study, and that's exactly what we've seen in our study. So the higher the triglycerides, the more AP events you're gonna get. In the study.

And that, you know, will correspond to the data that we present at or just gonna be in the in the patient's not only with a AP above 880, also consistent with research, if you've had an AP prior event, your chances of having another one is higher. So that is consistent with the data that we will present at So you're gonna see a lot of you're gonna see more events in the high-risk patient population as you would expect. So there's no surprises there. That's actually very comforting because that means that all the work that we've done, all the research we've done is holding up. And triglycerides are driving these AP events.

Kyle Jenne: Yeah. In terms of the prevalence in the United States, we're still working off of the seven thousand estimated patients in the US. That's the information that we've documented and been able to work from up to this point. You referenced that about seventy-five percent of those patients are on a current prophylactic therapy today. And so this is a switch market, that's really the market that we're focused on is moving patients over that could be doing potentially do better on a therapy with a profile like Donzara? And there are some patients that were on demand therapy patients only that have added Donzara up to this point. And we'll also get newly diagnosed patients as your reference.

But, yeah, we're not I'm not aware of an 11,000 number. We're still working off of the 7,000 population that has been addressable up to this point.

Richard Geary: And, Yaron, I'd like to come back to your first question too. You know, at one point I didn't make that I think is very important is to remember that the AP data that we have generated in CORE and CORE II is after only twelve months of treatment. Right? So, you know, when you think about a cardiovascular outcome trial, when you're looking at outcome data, it's years of treatment. This is only twelve months, so, we expect there to be even more AP events eventually in all segments of the SHCG population. With longer-term observation, longer-term treatment. So this is a relatively short study, which makes our results even more remarkable.

Operator: The next question will come from Gary Nachman with Raymond James. Please go ahead.

Gary Nachman: Thanks and congrats on all the progress. So Tringolsa accelerated really nicely in the third quarter. Are most of those additional FCS patients coming from? So how many physicians are prescribing right now? And maybe describe the percent genetic versus clinical that are diagnosed. And based on your full-year guidance, you have that acceleration slowing a bit in the fourth quarter. Is there any good reason for that? Could you explain that? And then just on the olanzarcen filing, for severe high trigs. Any chance you can get a priority review for it, especially if it's gonna be lowering the cost of the drug significantly? I mean, you're still working through that, but it would be a significant drop.

So I don't know if that's an argument that could be made to get it on the market sooner. Thank you.

Richard Geary: Gary, I'll take the second question first, and Kyle could address the, you know, your question about Tringolsa. So our assumptions right now are as a standard review. Supplemental NDA by the end of the year, ten-month review. However, we will do, we will pursue all avenues to potentially bring this medicine to the market as quickly as possible. So stay tuned for that, but right now, we're assuming a ten-month review. We don't see any reason why it couldn't be considered for other, you know, other paths forward with regulators.

Kyle Jenne: Yeah. In terms of the FCS patient population, there are a couple of things that we've been doing. Number one is identification of patients and you move them through the diagnosis and then, the prescription. We focused on those highest prescribing, SHTG physicians, the first 3,000, right, that we've been working through throughout the balance of this year. I mean, we've also supplemented that with some of our marketing and our omni-channel capabilities to drive more disease state awareness and an understanding about the need to treat patients with high triglycerides, and specifically how to assess and diagnose FCS.

The clinical scoring tools, either the North America FCS scoring tool or the Mulan criteria, are also driving the clinical diagnosis ability for these HCPs. So they're looking for these patients. They know these patients are in need. They wanna get them out of harm's way of acute pancreatitis. And they're using the available tools and resources to either, you know, clinically confirm or genetically confirm these patients. The other thing I'll mention is on the payer dynamics, the policies are getting put in place to where it's a streamlined process for HCPs to be able to prescribe once they've made the diagnosis for FCS.

So I won't get into specific numbers around age or the split between genetic and clinical confirmation, but, you know, what's going well is disease education is improving, the awareness of the need to treat continues to go up. And Tringolsa is performing very well when HCPs are using it, and they're looking for more appropriate patients in order to treat with Tringolsa because of the performance of the drug. Oh, for Q4, it's I don't wanna say it's Q4? a slowdown. We took a look at a couple of things. One thing is duration. It's ten weeks as opposed to thirteen weeks because we've got the holidays in there.

And then also, don't know the seasonality yet, if there's some implications here at the end of the year because this is our first full year of the Tringolsa launch. So, you know, we're just making sure that we're taking into account some of the unknowns as we're considering the guidance for the quarter.

Gary Nachman: Alright, great. Thank you, and best of luck to you, Richard, on your retirement.

Richard Geary: Thank you.

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

Jason Gerberry: Hey, guys. Thanks for taking my questions. Just two for me. Ahead of Cardio Transform next year, I just wonder get your latest thoughts. How do you maybe maximize the benefit of the data in combination with tafamidis if it hits stats to the disproportionate benefit of epilentersen, and that there isn't sort of a free-riding effect that happens for your competitor, as it pertains to sort of the validated, you know, benefit of silencers and stabilizers together. And so that's question one.

And then just question two, into and the update on NNT, Just wondering if you can contextualize as we think about the NNT both in the all-comer and the high-risk group, you know, if obviously the NNT is more compelling in the high-risk group, that's a small proportion of the overall population, how important that is? Is that to the overall kind of value proposition in the eyes of payers from your perspective?

Richard Geary: Thanks. Thanks, Jason. You know, on Cardio Transform, as you know, it's the largest study ever conducted in TTR cardiomyopathy, I mean, by far. And we will have the largest amount of data for combination usage as well as monotherapy usage in the study. And, you know, the combination usage is a key secondary endpoint in the statistical plan of Cardio Transform and, as well. So know, how important, how valuable that will be once we launch eflandersen in TTR cardiomyopathy is to be seen, to be determined. Obviously, the mechanisms are highly complementary in theory. And we expect to see added benefit over monotherapy in the study, but that remains to be seen and proven.

But if anyone is gonna be able to show a benefit of combination usage, and for that to drive value and resulting in driving value for, you know, the commercial opportunity for Ephrontera, and it'll be it'll be this program. I don't wanna comment on whether that provides, you know, tailwinds for other competitor programs and those sorts of things. We're focused on EfwamTersen, and we think we have the right trial design. We have the right drug. And we're very much looking forward to the data in the second half of next year. We will be sharing some data on NNT in different subgroup populations in SHTG at and if we can get a simultaneous publication as well.

I think the results are gonna be strikingly positive in both groups or in all the subgroups that we've looked at. But I don't wanna get ahead of that data at this time, Jason. As far as the value for payers, I'll leave it to Kyle to comment on that.

Kyle Jenne: Yeah. I comment on the totality of the data and how the evidence is stacking up for CORE and CORE II and how that will be interpreted by the payers. Reductions in triglyceride levels to the magnitude that we're seeing of up to 72%, for example, on top of standard of care. So these are patients that are being treated already that aren't getting to goal, that aren't getting out of harm's way of AP on the current standard, and by adding olazarcin, you're seeing significant reductions in triglycerides. An eighty-five percent reduction in acute pancreatitis is, you know, really incredible to see. And payers, I think will react accordingly when they see that data.

Hospitalizations and ER visit data, the NNT data will just add value and will complement that. It'll talk about some of the subpopulations, but overall, I think that the quality and the totality of the data here is what's gonna drive payer engagement and, you know, effective reimbursement here. Keep in mind that the focus here is to prevent a first AP attack from ever occurring. And HCPs understand that, the guidelines represent that, and HCPs are trying to treat the goal, and they just can't with the current existing therapies that are out there. The other thing that I'll mention is these are fasting triglyceride levels.

And you're gonna have postprandial spikes in these patients, you know, even if they are between five hundred and eight eighty. That increases their risk of having an acute pancreatitis event. So that whole story and the comprehensive nature of the data that I just talked through, I think, is gonna be the value proposition for the payers.

Jason Gerberry: Thanks, guys.

Operator: The next question will come from Yanan Zhu with Wells Fargo Securities. Please go ahead.

Yanan Zhu: Great. Thanks for taking our questions and congrats on the quarter. Maybe a couple of questions, one on Donzara launch. One on Winua. Can you give more color a little more color on the early prescription for Donzara? Are these from switching patients or newly diagnosed patients? And if it's switching patients, any pattern of the previous therapy. For Winua, there's also a sizable bump in the polyneuropathy revenue. Looks like twenty-five percent. Is that due to the growing of the market via newly diagnosed patients, or is that reflecting you taking share? And any updated metrics, like, new to brand numbers? Thank you.

Kyle Jenne: Yeah. I'll start with the Donzara launch. First, it's going very well as were highlighted in the opening comments. Both HCPs and payers, the feedback has been very positive. The commercial team has executed extremely well. Getting product into the channel, getting the first prescriptions in, getting those patients onto treatment and patients self-administering with Donzara. So the launch is going very well. It's very early. Right? I mean, the PDUFA was August 21. You know, we're a month or so into this launch. So I don't wanna provide too many details or specifics at this point in time, but I'll just share with you that the receptivity by HCPs has been very strong.

The profile of the drug, the data to support it, the label, and specifically the switch data has been very valuable so that they can understand that they can move these patients over safely and effectively and get them started on Donzara and have a positive experience there using our Ionis Every Step patient support program. So I think all signals are very positive. We are seeing switches from all of the currently approved prophylactic treatments. We're seeing Donzara added to on-demand treatments where patients weren't on a prophylactic treatment. And then, you know, we're seeing newly diagnosed patients as well.

So I won't get into the details on the splits, but all signals are very positive so far with the early signs of the launch.

Richard Geary: And then the bump in Winua? Revenue?

Kyle Jenne: Yeah. The bump in Winua revenue. Again, so this is a growth market. And, you know, as we've said all along, it's about new patient identification and that's predominantly where the demand is coming from in the third quarter for Winua. The product's performing very well, in terms of quality of life improvements. Access is going very strong in terms of coverage. The majority of patients paying $0 out of pocket. You know, we do expect continued growth with the identification of new patients, especially in the centers of excellence. Where these amyloidosis centers are using Winua very broadly for the polyneuropathy indication.

And, I think we just continue to be encouraged by AstraZeneca's execution around the launch and their focus on the program.

Yanan Zhu: Great. Thank you.

Operator: The next question will come from Miles Minter with William Blair. Please go ahead.

Miles Minter: Hi, thanks for taking the question. First off, Richard on his retirement. Thoroughly deserved. The question is on hepatic fat fraction data in the core studies, and if you can comment on that and if we'll see it. I've just been getting some questions considering you've got, you know, robust serum triglyceride reductions there, whether you're shunting, you know, maybe too much to deliver at any one time and it's accumulating there. You know, also acutely aware that you have the wait live for a day to presented that actually showed reductions in hepatic fat fraction. So any sort of color on that, metric would be helpful.

Richard Geary: Yeah. Miles, I don't wanna get ahead of the presentation because you know, that is a secondary endpoint, so it'll be it will be covered in the presentation. And publication. So, yeah, we're gonna present we're gonna do a deep dive at on the primary endpoint of triglyceride lowering, including both doses through twelve months, time courses, no that kind of thing. You'll see the durability of triglyceride reductions, You'll see, details on the acute pancreatitis, which is secondary endpoint, and you'll see all the data, you know, listed out on all the secondary endpoints, including hepatic fat fraction. We'll also talk a little bit about the NNT that we touched on in the earlier question.

So I don't wanna get ahead of that. Let's we'll sit we're just a couple of weeks away from and let's just leave it there.

Miles Minter: No worries. Thanks.

Operator: The next question will come from Luca Issi with RBC. Please go ahead.

Luca Issi: Great. Thanks so much for taking my question and then Richard, congrats on a fantastic run, and all the best on your next chapter there. If maybe if I can circle back on severe hypoglycemia, Kyle and Beth, you have obviously a billion-dollar plus peak revenue opportunity for the drug. Is that conservative? The reason why I'm asking is because if the TAM is truly a million patients, the price is $20,000 patients, which seem consistent with your commentary, that all implies, like, 5% penetration at peak, which, again, feels a little conservative to me. So would love to hear you talk about some of the assumptions that went into that $1 billion plus number that you have articulated.

Then maybe sticking on severe hyperglycemia, what's the latest thinking on whether you're gonna file just the eighty milligram, which is obviously same bill as approved in FCS versus filing both the 50 and the eighty milligram. To give, you know, docs more options to kind of tailor the dose based on the need of the patient's call there, much appreciated. Thanks so much.

Richard Geary: Yeah. Thanks, Luca. I'll take the easy question. We're filing on both doses. Both doses look great. And, we believe that dosing flexibility in the hands of cardiologists, endocrinologists, lipid specialists will be very well received. Once we get to the market. So that's that. And, with respect to peak sales,

Kyle Jenne: Yeah. Luca, I mean, you know, I keep referencing that this is a it's a prevalent patient population. Right? Greater than three million patients. The high-risk SHTG patients, you've got approximately a million of that you were just referencing as well. I think we still have some unknowns here around, the payer dynamics. We also have some unknowns around pricing dynamics. In order to factor into these, these assumptions. You know, what we felt comfortable with, I think, going into this, and have been consistent all along is greater than a billion in peak sales is where we've landed up to this point. We're continuing to assess the market.

We've got a lot of good learnings from FCS as well in terms of how the launch trajectory has gone here. We're doing more market research to understand, HCP and payer and patient perceptions, around the SHTG marketplace. And, you know, we will provide, you know, updated information as we learn more and feel more comfortable and confident with, the way the information comes together. But, it's greater than a billion dollars is where we feel comfortable today.

Luca Issi: Nice. Thanks so much, guys.

Operator: Your next question will come from Jay Olson with Oppenheimer. Please go ahead.

Jay Olson: Congrats on all the progress. I'll add my best wishes to Richard as well. Beth, I know you commented a little bit about this on your opening remarks, but with your strong balance sheet, could you share your priorities for capital allocation, especially with regards to any external versus internal investments. Thank you.

Beth Hougen: We're happy to. We do have a strong balance sheet, very healthy cash balance, and expect with the increased guidance that we'll maintain that. As we go into next year. Continue to execute on these launches as well as the oligosarcen s a and zilgarnirsen launches next year. Our capital our top priority for capital allocation is for internal growth. We think that there's tremendous opportunity in our pipeline and behind these existing marketed products and the ones coming to market here shortly. So we will continue to prioritize growth for capital allocation. We'll do that with discipline as we've done historically, but that's what you where you should expect to see us using our balance sheet.

Jay Olson: Great. Thank you. I think we have time for one more question.

Operator: Our last questions for the day will come from Mitchell Kapoor with H. C. Wainwright. Please go ahead.

Mitchell Kapoor: Hey, for taking the questions. Just wanted to ask with an impressive 90% rolling into the open-label extension in the SHTG trials, can you name some of the more prevalent dropout reasons and whether there's any reasons that we should be cautious going into a launch. Because of some of those?

Richard Geary: Thanks, Mitch. And I'm going to let Rich answer the final question of this earnings call. Any reasons to be concerned with dropouts in the CORE II studies? Richard, anything you wanna highlight?

Richard Geary: Yeah. So first, I would say the dropout rate was about half what we expected from the beginning. Very well-tolerated medicine. I would there isn't actually any one issue that led to discontinuations. They varied across the study. Some of them had to do with personal reasons, moves, vacations, different things that needed to be taken care of. Pregnancies, etcetera. But there were and so I can't point to, like, a main reason. And for that reason, I'm very bullish on this medicine in terms of its tolerability and safety.

Mitchell Kapoor: Excellent. Thank you all very much, and congrats, Richard.

Brett Monia: Thanks, Richard. Thanks, Mitch. Thanks, everybody, for joining us and participating in our call today. We really do look forward to building on the remarkable momentum that we've achieved this year so far and for years to come. And sharing additional updates along the way. Just as a reminder, the detailed data from the Landmark phase three CORE and CORE II studies for olanzarcen, will be presented in s h for SHTG will be presented during a late-breaking session on November eighth. At We encourage you to listen in. To our webcast. Until then, thanks for participating, and everybody have a great day.

Operator: The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.