Ionis Pharmaceuticals - Earnings Call - Q1 2025

Executive Summary

• Q1 2025 revenue was $132.0M, up 10% YoY; GAAP EPS was $(0.93). Ionis beat Wall Street consensus on both revenue ($131.6M actual vs $122.5M*) and EPS ($(0.93) actual vs $(1.03)), driven by first-quarter TRYNGOLZA product revenue and stronger partner royalties.
• Management raised FY2025 guidance by more than 20%: revenue to $725–$750M (from >$600M), narrowed non-GAAP operating loss to <$(375)M (from <$(495)M), and year-end cash to ~$1.9B (from ~$1.7B), enabled by licensing (sapablursen $280M upfront) and ex‑U.S. olezarsen rights to Sobi.
• Commercial execution: TRYNGOLZA net product sales >$6M in first full quarter; SPINRAZA and WAINUA royalties strengthened. CFO emphasized path to sustained positive cash flow with growing product and royalty streams.
• Near-term catalysts: donidalorsen PDUFA Aug 21, 2025; ESSENCE (sHTG) data in Q2 and CORE/CORE2 topline in Q3; EU decision for TRYNGOLZA in H2 2025. These events, plus raised guidance, are primary stock reaction drivers.

What Went Well and What Went Wrong

What Went Well

• First independent launch underway with TRYNGOLZA delivering >$6M net product sales; early uptake from converted trial/EAP patients and newly identified FCS patients; favorable coverage (≈60% commercial/≈40% government) and ~90% zero out-of-pocket via Ionis Every Step support.
• Royalty strength: SPINRAZA global sales of $424M (Q1) drove $48M royalties; WAINUA sales of $39M delivered $9M royalties; commercial revenue +28% YoY.
• Management raised FY2025 guidance substantially. CFO: “We are increasing our 2025 financial guidance including raising revenue guidance by more than 20 percent… and now expect to end the year with approximately $1.9 billion in cash”.

What Went Wrong

• Continued GAAP operating losses: Q1 loss from operations $(146)M and GAAP net loss $(147)M; EBIT margin remained deeply negative given heavy launch and pipeline investments.
• SG&A increased to $76M (from $53M YoY) driven by TRYNGOLZA launch and donidalorsen preparation; R&D decreased to $201M as late-stage studies ended, but overall operating expenses ticked up.
• Medicare Part D redesign impacted some WAINUA revenue timing in Q1; however management expects net-positive impact on uptake/compliance going forward.

Transcript

Operator (participant)

Good morning and welcome to the Ionis first quarter 2025 financial results conference call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Please begin.

Wade Walke (SVP of Investor Relations)

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

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

Brett Monia (CEO)

Thanks, Wade. Good morning, everyone, and thanks for joining us today. Before we discuss our Q1 earnings and recent progress, I want to take a moment to acknowledge the rapidly evolving environment we're living in today. Recent changes at the FDA and the introduction of new tariff policies have introduced a degree of uncertainty with the potential for disruption in our industry. Despite these external uncertainties, Ionis remains well-positioned to execute on our strategic priorities, including all of our many value-driving catalysts coming up this year and next. We remain focused on our purpose to drive meaningful value for all Ionis stakeholders by successfully bringing better futures to people with serious diseases. We are executing very well against all our strategic priorities. A clear example of our ongoing successes is the completion of two strategic licensing transactions recently, which enabled us to substantially increase our 2025 financial guidance.

This includes higher expected revenue in cash, along with improved operating loss. Raising guidance this early in the year reflects our confidence in our ability to continue executing well, including our ability to deliver transformational medicines to patients even amid the current volatility and our commitment and expectation to drive long-term value for shareholders. We achieved a major milestone for Ionis with our first independent commercial launch, now successfully underway. I'm pleased to share that in its first full quarter on the market, Tryngolza, the first and only FDA-approved treatment for familial chylomicronemia syndrome, exceeded expectations. This encouraging start reflects our commercial team's thoughtful planning, outstanding execution, and highlights the commercial capabilities that we have built. Right behind Tryngolza is our second independent launch, donidalorsen for hereditary angioedema, or HAE, which is rapidly approaching. The team is laser-focused on ensuring success.

Donidalorsen has the potential to become a preferred treatment for HAE, and we remain on track to launch in the third quarter. These launches are just the beginning. We're poised to report data from two Ionis-owned phase III programs later this year, which, if positive, will enable us to continue delivering a steady cadence of important medicines to even more patients. These are a second indication for olezarsen, severe hypertriglyceridemia, or SHTG, a large population with high intermittent need, and zilganersen for Alexander disease, a severe rare leukodystrophy with no approved therapies. Collectively, these four programs represent needed patient breakthroughs and multi-billion dollar revenue potential for Ionis. Additionally, in the next three years, we expect four launches from our late-stage partnered medicines currently in development to treat a range of serious life-threatening diseases.

These medicines are poised to significantly increase our revenues by expanding the reach of Ionis discovered medicines to more patients that are in need. With the recent launch of Tryngolza and our upcoming independent and partnered launches, Ionis is on a path to bring important medicines to patients for years to come, positioning us to achieve substantial and sustained revenue growth and positive cash flow. With that, I'll turn the call over to Kyle.

Kyle Jenne (Chief Global Product Strategy Officer)

Thank you, Brett. With our first independent launch underway and three additional independent launches planned in the next two years, our commercial team is executing on a focused agenda with substantial growth potential. We're well-positioned to build on the early success of Tryngolza while we prepare for our other upcoming launches.

Donidalorsen for HAE is on track for anticipated approval in August, followed by olezarsen for SHTG, which is on pace for phase III data in the third quarter and a potential launch next year. Let's start with Tryngolza, which had an encouraging debut in the first quarter. Our commercial team executed seamlessly, delivering on all initial launch objectives and exceeding expectations with over $6 million in net product sales in the first quarter. In this first full quarter on the market, we saw strong patient uptake driven by multiple factors. First, we successfully converted nearly all of the U.S. expanded access and clinical trial patients to commercial product. Second, as Tryngolza is the first and only approved FDA treatment for FCS, early uptake benefited from patients who had been previously diagnosed and were waiting for treatment.

Our patient-finding efforts ahead of launch paid off, contributing to scripts from newly identified and diagnosed FCS patients. Physician engagement has also gained meaningful traction. We've been encouraged by the initial breadth of physicians prescribing Tryngolza with scripts from a mix of specialists across the country. At the end of Q1, the initial prescriber mix included approximately 50% cardiologists and 25% endocrinologists, with lipidologists and internal medicine HCPs comprising the rest. Physicians have also reported positive and deeply moving feedback, including one doctor who shared that he was, quote, "over the moon," that this was the lowest his patients' TG levels have ever been. On the access front, coverage and reimbursement dynamics have been favorable. The coverage split for patients on Tryngolza to date is just over 60% commercial and just under 40% government.

Importantly, patients, whether clinically diagnosed or genetically confirmed, have received timely access, with most receiving coverage through the medical exception process based on clinical diagnosis. This underscores both the urgency of the high unmet need and payer willingness to support access ahead of establishing formal policies. As payers establish coverage policies over the next several months, it will be important that these policies support both clinical and genetic diagnosis pathways. To this end, our market access team is actively engaging with payers to enable continued patient access. Through the first quarter, the team had already engaged with payers representing the vast majority of covered lives in the U.S. and are working toward getting additional policies in place. We're also seeing positive trends beyond coverage, including reimbursement timelines that have exceeded our internal benchmarks.

In the first full quarter of launch, nearly 90% of patients had zero out-of-pocket costs, highlighting the effectiveness of our Ionis Every Step support program. Ionis Every Step has been instrumental in delivering high-quality experience for both patients and providers. More than 90% of patients have opted in, receiving support that includes disease and nutrition education, autoinjector administration training, reimbursement support, and more. For healthcare providers, the program streamlines prescribing by handling insurance authorization and coverage assistance, as well as coordinating delivery, reauthorizations, and refills. We're proud of Tryngolza'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 U.S. remain unidentified. To close that gap, we're continuing to focus on our patient-finding efforts and HCP education, targeting physicians who treat patients with severe hypertriglyceridemia to increase FCS awareness.

At the same time, our payer engagement efforts will continue to focus on establishing broad, durable access. Backed by an experienced and high-performing team, we are well-positioned to build on our first-mover advantage to bring Tryngolza to patients in need and keep them on treatment. Building on our foundation in FCS, we're advancing toward the blockbuster opportunity in SHTG with olezarsen. Like FCS, SHTG is a serious condition defined by triglyceride levels over 500 mg per dL, well above the normal level of less than 150. These levels are easily determined through routine fasting blood tests. SHTG affects a broad population, with many people unable to adequately manage their triglycerides with currently available treatments. This is particularly true for individuals with high-risk SHTG, defined as triglyceride levels greater than 880 mg per dL or greater than 500 with a history of acute pancreatitis or other comorbidities.

There are more than 1 million of these especially vulnerable people in the U.S., which represents our initial target population for Olezarsen, assuming approval. As we heard during our recent KOL panel, SHTG represents a significant unmet medical need, and physicians are eager for better treatment options, especially those that can reduce TGs down below pancreatitis risk levels. For example, Dr. Alan Brown, a leading cardiologist focused on lipid management, shared that SHTG can be devastating, with patients experiencing recurrent pancreatitis attacks despite best efforts. His primary goal is to reduce the risk of acute pancreatitis, which carries significant mortality and morbidity. Importantly, all three panelists agreed that ApoC3 inhibition offers a promising new therapeutic pathway with the potential to help patients dramatically reduce their triglycerides and the associated risk of acute pancreatitis.

This view is also shared by other physicians who we've engaged with, including recent discussions at the American Academy of Cardiology annual conference with KOLs and community cardiologists. With this conviction to treat, we believe olezarsen is well-positioned to meet the needs of people with SHTG, and we're making excellent progress across clinical and commercial fronts as we prepare for an anticipated launch next year, where we also have first-mover advantage. We expect data from our supportive safety study, Essence, in the second quarter. We then expect to report data in the third quarter from our global pivotal SHTG studies. These pivotal studies, Core and Core II, are being conducted in our target SHTG population defined by triglycerides greater than 500 mg per dL.

Baseline characteristics were recently published in the American Heart Journal, showing that fasting median triglycerides at baseline in Core and Core II were 836 and 749 mg per dL, respectively. Across the two studies, nearly half of participants had baseline TG levels of greater than 880, even though all participants were receiving standard-of-care therapy. Additionally, 22% and 13% of participants had a history of pancreatitis in the last 10 years prior to enrollment in Core and Core II, respectively. Importantly, both studies are well-powered to show a significant reduction in triglycerides, and it's this reduction that we expect will lead to improvements in clinical outcomes for patients. Assuming positive data, we plan to submit an sNDA before year-end. We're also expanding olezarsen's reach.

We recently broadened our partnership with Sobi, who will commercialize olezarsen in most markets outside the U.S., including in Europe, which is on pace for an FCS approval decision later this year. This agreement expands the reach of Tryngolza to more patients globally while providing us the opportunity to earn milestone payments and royalties up to the mid-20% range. With significant first-mover advantage in both FCS and SHTG, compelling real-world data and phase III results in FCS, and confidence in the upcoming data for SHTG, we believe olezarsen is well-positioned to become the standard-of-care in both indications, transforming treatments for thousands of people and driving long-term growth for Ionis. Turning to donidalorsen, our second anticipated independent launch, we see compelling opportunity to advance the prophylactic treatment for people with hereditary angioedema.

We're applying the same discipline and focus that is driving a successful Tryngolza launch as we prepare to bring donidalorsen to market. More than 20,000 people in the U.S. and Europe are estimated to have HAE. In the U.S., most of these patients are on prophylactic treatment. As this market continues to evolve, up to 20% of patients annually have switched treatments in search of more effective and convenient options, signaling that current therapies aren't adequately addressing patients' needs. Additionally, a recent Harris poll found that 9 in 10 HAE patients surveyed are interested in trying new prophylactic therapies, and we believe donidalorsen is uniquely positioned to meet that demand if approved. With strong clinical data, a patient-friendly autoinjector, and monthly or every other month dosing, we believe donidalorsen checks all the boxes that people with HAE are looking for in a next-generation prophylactic treatment.

We're building momentum ahead of launch by drawing on learnings and infrastructure from our ongoing Tryngolza and WAINUA launches. This includes expanding our Ionis Every Step patient support program to address the unique needs of HAE patients to ensure they have a seamless treatment experience. We've already hired a substantial portion of our field-facing team and remain on track to complete hiring and training ahead of the anticipated approval. Our market access team is actively engaging with payers, and our medical affairs team has also been laying the groundwork for a successful launch. Their efforts include showcasing our robust donidalorsen clinical data and Ionis' technology at key medical conferences. For example, at the recent Quad AI meeting, we delivered 11 poster presentations and had robust engagement at our booth, including a dedicated space for unbranded HAE disease awareness campaign.

We also capitalized on the conference's San Diego location by welcoming physicians to our campus for deeper in-person education about Ionis' science and technology. Physician feedback continues to be positive, particularly regarding our switch study, which we believe could be a key differentiator in a competitive space. The study showed that people switching to donidalorsen from other prophylactic treatments experienced a further reduction in attacks, and 84% of those surveyed said they preferred donidalorsen compared to their previous prophylactic treatment. While we recognize that converting people from existing therapies will take time, we're confident that donidalorsen represents a compelling opportunity to be the preferred prophylactic treatment for many HAE patients. We're excited about the road ahead and well-positioned to bring donidalorsen to people who need it, assuming approval. Our highly experienced, efficient, and scalable commercial organization is delivering tangible results with the Tryngolza FCS launch underway.

As we build on these efforts, we're focused on maximizing Tryngolza's full potential while preparing to successfully execute on our three additional launches planned over the next two years, with more to follow, positioning Ionis for sustained growth and long-term success. With that, I'll now turn the call over to Beth.

Beth Hougen (CFO)

Thank you, Kyle. I am pleased to share today that we are increasing our 2025 financial guidance across all metrics, including raising revenue by more than 20% due to our strong first-quarter results and recent successful licensing transactions. We earned $132 million of revenue in the first quarter, which increased 10% year-over-year. More than half of our revenue came from commercial products, which grew 28% compared to the same period last year. Our increasing revenue reflected the encouraging early performance of the Tryngolza launch, marking the first time in our company's history we've reported product revenue.

In the first full quarter of the launch, Tryngolza generated over $6 million in product sales, exceeding expectations. As Kyle discussed, we saw good uptake from patients awaiting treatment and from newly identified patients. Our commercial revenue also included $48 million in SPINRAZA royalties from substantial SPINRAZA product sales, which increased 25% year-over-year. Additionally, we earned $9 million in WAINUA royalties. We and our partner, AstraZeneca, expect WAINUA revenue to grow this year, driven by strong U.S. demand and an expanding global footprint following the recent EU approval. The remainder of our revenue came from programs under our R&D collaborations, underscoring the important financial contributions of our partnered pipeline. You may have noticed we've streamlined the revenue section of our P&L. We did this to reflect our new chapter as a commercial-stage biotech and to plan for numerous independent launches in the coming years.

Total non-GAAP operating expenses increased less than 5%, reflecting our commitment to disciplined investment and driving operating leverage. As planned, our sales and marketing expenses increased year-over-year, reflecting our investments in the U.S. launch of Tryngolza and preparations for the upcoming launch of donidalorsen. Our SG&A expenses also included our minority portion of WAINUA's sales and marketing expenses. R&D expenses decreased year-over-year, as several of our late-stage studies recently concluded. Importantly, we continue to appropriately fund our advancing pipeline, with a large majority of our total R&D expenses funding our late-stage programs. Building on our strong first-quarter results, we recently completed licensing transactions for Sapablursen and ex-U.S. commercialization rights for olezarsen that meaningfully enhanced our financial outlook. This is the reason we are substantially increasing our 2025 guidance.

Last week, we finalized the licensing of Sapablursen, a medicine outside of our core disease areas of cardiology and neurology, and generating $280 million. This transaction enables us to remain focused on realizing the potential of the medicines that we plan to independently bring to patients while further strengthening our financial position. Additionally, we are eligible to earn significant milestone payments as Sapablursen advances, together with royalties up to the mid-teen % range on future product sales. As a result of the substantial license fees, which exceeded the probableized revenue included in our original guidance, we are increasing our revenue guidance by more than 20%. We now expect to earn revenue in the $725 million-$750 million range for the year. Our revenue guidance also includes sizable commercial revenue anchored by stable SPINRAZA royalties and growing WAINUA royalties.

With our first independent launch underway, we expect increasing product revenues as the year progresses. As the Tryngolza launch progresses, it is important to remember that FCS is a rare disease with most patients still unidentified and undiagnosed. Therefore, our focus remains on disease education and patient identification, both of which will take time. We are also on track to add initial product revenue from our second launch with the FDA action date for donidalorsen set for August 21. In addition to the Sapablursen revenue we will recognize in Q2, we expect to earn additional R&D revenue from partnered programs later this year. We continue to project our full year 2025 operating expenses to increase in the high-single-digit % range compared to last year. This increase will be driven by SG&A expenses as we invest to support the success of our multiple ongoing and planned launches.

We project our R&D expenses to remain steady this year, similar to last year. As several of our late-stage studies have recently concluded or are wrapping up this year, we are able to reallocate our resources toward our next wave of opportunities, including Ion 582 for Angelman syndrome, which we expect to start phase III development shortly. Since our license fee revenue drops entirely to our bottom line, we are improving our non-GAAP operating loss guidance by nearly 25% to less than $375 million. We now expect to end the year with $1.9 billion in cash. Our strengthened BALANCE sheet and commitment to drive operating leverage positions us well to advance our strategic priorities in this dynamic macroeconomic environment. Looking beyond 2025, we are confident in our ability to deliver sustained revenue growth.

The late-stage programs we have in our pipeline today represent a significant opportunity, with combined peak sales potential in the multi-billion dollar range. We expect our Ionis-owned medicines to generate more than $3 billion in peak annual product sales. This, of course, means that we will continue making investments to bring these medicines to patients. On top of our substantial product revenue opportunity, our late-stage partnered medicines could contribute over $2 billion annually in peak royalties. Notably, nearly all of these medicines are on track to deliver phase III data either this year or next year, setting the stage for potential launches soon after. Together, these upcoming launches are poised to reach hundreds of thousands of patients worldwide and, in turn, position Ionis to deliver significant top-line growth and reach sustainable positive cash flow, turning scientific innovation into long-term value for shareholders.

With that, I'll turn the call back over to Brett.

Brett Monia (CEO)

Thank you, Beth. We've accomplished a great deal to get us where we are today, a fully integrated commercial-stage biotech company with our first independent launch well underway. 2025 is off to an excellent start, including the U.S. Tryngolza launch. With additional upcoming launches anticipated, including donidalorsen for HAE and a deep commitment to innovation, we're well-positioned to drive accelerating value. It's through Ionis' innovation that we've established a proven discovery and development engine, which has provided us with a pipeline of medicines with transformational potential. Our pipeline continues to deliver. We are on track for olezarsen and zilganersen phase III data later this year that, if positive, would expand the reach of our medicines to even more patients.

With many additional phase III data readouts expected next year, we're well-positioned to continue bringing a steady cadence of medicines to patients. Our scalable and experienced commercial organization is executing well, as demonstrated by the encouraging start to the Tryngolza launch. Furthermore, our commercial organization has established a solid foundation to support multiple planned product launches in the future. Based on recent successful licensing transactions, along with our first-quarter results and disciplined financial management, we significantly increased our 2025 financial guidance. Importantly, the progress we've made puts us on a clear path to achieving positive cash flow, supported by our expectations for substantial top-line revenue growth. With that, we'll now open the call up for questions.

Operator (participant)

Thank you. To ask a question, you may press star then one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys.

Please limit yourself to one question and one follow-up. If you have further questions, you may re-enter the question queue. To withdraw your question, you may press star then two. At this time, we'll pause momentarily to summon our roster. Actually, we'll just go straight to Jay Olson from Oppenheimer.

Jay Olson (Managing Director and Senior Analyst)

Oh, hey. Congrats on all the progress. And thank you for taking our question. We're curious about Olezarsen and any overlap between physician prescribers for FCS and SHTG and how you plan to leverage that. Then related to that, would approximately 20% pancreatitis history for the patients enrolled in your pivotal SHTG studies provide sufficient power to show AP reduction? What level of AP reduction are you targeting? Thank you.

Brett Monia (CEO)

Thanks, Jay. Kyle will take the overlap of prescribers for FCS, SHTG, and I'll touch on the AP question you had.

Kyle Jenne (Chief Global Product Strategy Officer)

Yeah. Thanks, Jay.

First, I mean, the Tryngolza launch is really off to an encouraging start. The execution by the commercial team has been very strong. I'm very pleased with where we're at right now. As we discussed, we've been able to convert the EAP and OLE patients. Those that have been waiting for a therapy have begun getting treatment, and we're also identifying new patients. The current targets that we have are a few thousand physicians, as you would expect, based on the type that are treating FCS today. These are cardiologists and endocrinologists, and they're seeing SHTG patients, but they're also seeing FCS patients. That's kind of the runway to get us to SHTG. When you get to SHTG, the population expands, obviously, upwards of north of a million patients. As we go there, the overlap is quite significant. There are still cardiologists, endocrinologists, and lipidologists treating these patients.

They're currently being treated with suboptimal therapies and not getting the goal. What we're hearing, and we heard this from the KOL panel that we did on April 14th, is that there's the realization that reducing triglycerides is directly correlated to AP. Physicians are well aware of that, and they're looking for a better treatment option. We're looking forward to potentially having positive data and an approval for olezarsen to be able to help those patients.

Brett Monia (CEO)

Thanks, Kyle. Jay, obviously, you're referring to the AP baseline event data that we reported in our baseline demographics clinical trial design study that we published last month or earlier this month, where we had 22% in core and 13% in Core II patients with a history of AP over the last 10 years.

I want to emphasize, before I get into expectations for AP data from those studies, that this is a substantial unmet medical need, large patient population that HCPs, healthcare providers are ready to treat patients with SHTG even without AP data in hand. This is a large market opportunity, large unmet need. What we heard in our HCP panel, and we've heard from other HCPs, is that they are looking for a medicine that will substantially reduce triglycerides on top of standard of care, which is exactly how our trial is designed. That is the opportunity there. Now, with that said, AP is, of course, a secondary endpoint in our study. As a secondary endpoint, it's not powered for AP, but we're doing everything we can to increase the powering for the study.

For example, we are combining Core and Core II in our secondary analysis of AP events, and we're looking at AP events at 12 months, whereas the triglyceride primary endpoint is at 6 months. We're looking at the maximum amount of time and patients to look at AP data. Of course, the FCS data is also encouraging for Tryngolza, where we reported statistically significant reductions in acute pancreatitis events in our BALANCE study. Take all that into account. What we are laser-focused on is to demonstrate substantial reductions of triglycerides in SHTG patients, which is what HCPs are looking for to prescribe a medicine like olezarsen.

Operator (participant)

The next question comes from Gary Nachman at Raymond James.

Gary Nachman (Managing Director)

Hey, thanks for taking the questions and nice quarter.

On donidalorsen, just talk a bit more about what you're doing ahead of the PDUFA date internally to prepare for that launch. For patients that are going to be switching, how you're thinking about that transition, I guess, in the first year of launch. In terms of access, how long you think that process is going to take. Just as a follow-up, Brett, on the macro dynamics, you just highlighted it briefly, but just talk a bit more. What do you think the expected impact from tariffs is going to be to the overall business, just based on the current trade policy? In terms of your conversations with FDA, if you're seeing any sort of signs of potential delays, whether with PDUFA dates or starting clinical studies? Thank you.

Brett Monia (CEO)

Great. Kyle, donidalorsen launch? Yeah.

Kyle Jenne (Chief Global Product Strategy Officer)

What we know about the HAE market is this is largely an unsatisfied market. We see approximately 20% of patients that are moving between prophylactic treatments in the U.S. on an annual basis. We also recently released the Harris poll that showed that 9 out of 10 patients are interested in trying new therapies in this space. There is definitely an opportunity here. The donidalorsen profile, in terms of efficacy, tolerability, and convenience, is offered all in one single treatment. When we start talking about switching patients and the dynamic of why patients want to switch, it is one of those three reasons that they are looking for something new and different. We are going to be able to provide donidalorsen in a way that demonstrates reductions in attacks, improved tolerability, and they are only going to have to take the treatment every four or every eight weeks.

The profile is very, very strong there. In terms of switching patients, what we need to do is we need patients to advocate for themselves, and we need physicians to understand what these patients are experiencing. That is the work that we're doing right now. We're being informed by patients, and we're also beginning to communicate directly with HCPs what the need is in this market and setting ourselves up to be able to talk about how and why to switch these patients and why it's important for that to happen. This is a switch market. We will begin the ramp, hopefully, in Q4. We anticipate peak sales being greater than $500 million for donidalorsen.

With a concentrated prescriber base, we can have a very targeted sales force to go out and do that, which is currently being hired and trained and going to be deployed well in advance of the PDUFA date.

Brett Monia (CEO)

Thanks, Kyle. To your other question, Gary, we are obviously carefully monitoring changes that the new administration is bringing, both at the FDA and at the macro level on tariffs, etc. At the FDA, today, we're pleased to report that we've had no changes in any of the programs that we've been discussing with the FDA. Everything is on track. As mentioned earlier, donidalorsen's PDUFA is on track for August 21st. The discussions we're having are the exact discussions we should be having at this stage of the review process. The same is true for our other discussions with the FDA, INDs, and so on.

Everything appears to be going well with the FDA at this time, despite the changes that are occurring. We'll, of course, keep on monitoring that. With respect to other changes, tariffs, etc., that too, we have not seen any meaningful impact on our business to date. That includes costs that we have to potentially absorb for drugs that are already launched or future drugs. With respect to commercial supply and clinical supply, that is also going very well. We have sufficient supplies in place to support the Tryngolza launch and the donidalorsen launch, and they're ready to go and to support those launches for the near term. For our clinical trials, we make drug here at Ionis as well as with some CMOs, but we have a lot of redundancies in the supply chain to support our clinical trial studies with respect to supply.

It's obviously a fluid situation that we're monitoring very carefully and building contingencies to manage. However, to date, we have not had any impact with respect to tariffs or with the FDA on our business.

The next question comes from Debjit Chattopadhyay at Guggenheim.

Debjit Chattopadhyay (Senior Managing Director and Equity Research Analyst)

Hey, good morning, and thanks for taking my question. On the FCS launch, how confident is the team on the 2,000+ FCS patient estimate, and how quickly can you convert these patients to commercial therapy before you have significant price erosion with a launch in SHTG? Thank you.

Brett Monia (CEO)

Jonathan, take that, please.

Jonathan Birchall (Chief Commercial Officer)

Yeah, happy to take that. I think while the epidemiology varies between 1 and 13 per million, we're fairly confident in those 3,000s. The genesis of your question, though, really is how quickly can we identify them?

I think, as Kyle outlined, we obviously had clinical trial patients that we've been able to convert onto covered product very quickly. In the pre-launch phase, we were definitely very successful in engaging with our target audience and identifying FCS patients, and that's helped drive our initial uptake in the product. Every month, as more and more physicians become aware, we're finding more and more patients. That is very encouraging for the outlook that we've got for FCS. I definitely think this is an underserved community with a very debilitating disease. As that awareness grows, both amongst HCPs, but importantly, through a lot of the work we're doing with Omnichannel, we're going to find more and more patients in the next 18 months prior to the SHTG launch, obviously with positive data and potential approval from the FDA.

As soon as that indication expands, we'll be addressing the far larger population. The specifics of FCS become less apparent.

Brett Monia (CEO)

Price? Price erosion?

Kyle Jenne (Chief Global Product Strategy Officer)

Yeah. In terms of price, we priced at the FCS launch appropriately with the 3,000 patient population out there, right? That's how we ended up at the price point that we did and the value that Tryngolza brings to that patient population. As we think about moving forward for SHTG, that population is going to be exponentially higher, right? A million-plus addressable in terms of the population. If we look at the marketplace, typically, drugs that have a million or so patients addressable are in the specialty pricing range of $10,000-$20,000, for example.

We've got some work to do to figure out what the pricing will be ultimately in this category based on the data that supports the program itself, which we'll know later this year. We will go back and do some more research and then, obviously, announce the price when we receive approval for the SHTG indication.

Brett Monia (CEO)

Yeah. Again, we're very encouraged by the Tryngolza launch to date. It is early days, of course, but we expect to be commercializing Tryngolza in FCS for a year and a half to two years before SHTG commercialization will kick in.

Operator (participant)

The next question is from Jessica Frey at JPMorgan.

Jessica Frey (Head of Privacy)

Hey, guys. Good morning. Thanks for taking my questions. I just had a couple. Forgive me if I missed this, but was there any channel stocking for Tryngolza captured in that one Q number? If so, can you quantify that?

Second one, can you just elaborate a little bit more on the sources of upside to the revenue guidance and how much of that's driven by commercial product performance versus the licensing deal? Lastly, you kind of touched on this, but maybe just a little more specifics. Can you just talk about the manufacturing footprint for Tryngolza, donidalorsen, and how you think about possible exposure to tariffs? Thanks.

Brett Monia (CEO)

Sure. Channel stocking, Kyle, for Tryngolza?

Kyle Jenne (Chief Global Product Strategy Officer)

Yeah. The Tryngolza sales is currently directly correlated to demand. There was not a large stock end of inventory. It's adequately being managed for the contract that we have in place with the specialty pharmacy, and it's really reflected by demand.

Brett Monia (CEO)

Do you want to add anything to that, Beth, as well as then talk about the revenue guidance?

Beth Hougen (CFO)

Sure. I would just second what Kyle said, that the team has done a wonderful job at managing inventories. Of course, with a rare disease drug like Olezarsen, you want to make sure that you're keeping those inventory levels as low as you possibly can and driving inventory in the channel from demand, which is exactly what the team is doing. On the revenue guidance, it's based on, obviously, a strong Q1, but the vast majority of that raise is related to the licensing transactions we did for Sapablursen with Ono and the OUS commercial licensing to Sobi for Olezarsen. Those transactions were, as you can imagine, probabilized in our initial guidance of more than $600 million in revenue.

With the now completion of those transactions, we're increasing our guidance to reflect 100% probability and flowing that through not only revenue, but to our operating loss and to our cash guidance as well.

Brett Monia (CEO)

Yeah. Regarding manufacturing, Jess, we have a number of sources for supplying our drugs for both clinical trials as well as for the commercial launches, including South Korea, Europe, and the U.S. As I mentioned earlier to one of the other questions, we're well stocked in supply already to support the Tryngolza launches as well as the anticipated launch for donidalorsen. All that's in place. We're continuing to monitor any potential impact, but right now, there has not been any. That includes on tariffs as well. Really, we're watching it very carefully, but we have not experienced any meaningful impacts. Our guidance stays the same.

We just improved our guidance, and that's also factoring in any potential impact of tariffs.

Operator (participant)

The next question is from Jason Gerberry at Bank of America.

Chi Fong (Equity Research VP)

Hey, this is Chi for Jason. Thanks for taking our question. Maybe just on a follow-up on Tryngolza, can you unpack a little bit between the conversion that you see from your expanded access and newly identified patients that were previously not enrolled in any of the prior clinical trials and understood that this is a market that requires a market building? Are you seeing a steady case enough new starts? And just a quick follow-up on your angelment. You guys have it on track for a 2Q phase III start. Are there any outstanding staff needed to execute before the phase III start? Thanks so much.

Brett Monia (CEO)

Okay. Thanks, Chi.

I'll take the Angelman's question as a brief answer, and then Kyle will take the question with respect to conversion of EAP, OLE patients, and so on, and new starts. The Angelman phase III study is on track for on-time initiation. As a reminder, we had excellent discussions and completion of conversations with the FDA last year. We aligned on our phase III trial design. We think we have the right trial design. We have the right drug, the right chemical platform to get the study started in the first half of this year, which means it'll get started in this quarter. Very soon, we're well on our way. What we've also said is that our expectation is to complete enrollment in 2026. We expect to enroll fairly quickly.

Kyle Jenne (Chief Global Product Strategy Officer)

Yeah. Thanks, Brett.

In terms of the Tryngolza launch, very strong patient uptake in Q1, as we were referencing, and it's demand-driven. The conversion of EAP and OLE patients was obviously a main focus here in moving those patients on to commercial drug. As we mentioned, the majority of those patients converted over, which was exactly what we expected to have happen. The second area of patient population we talked about are those that were waiting for treatment, right? This was kind of the pent-up patients that have been treated for years and, unfortunately, didn't have a therapeutic option available. Those have also, many of them have started on treatment as well. The identification of new patients is really what we're going to be focused on moving forward. That's the main focus of our work.

In Q1, we had patients from all three of those buckets, but the predominant patient populations were coming from the EAP, OLE, and the pent-up demand patients that had already been identified. Our focus really is getting new patients diagnosed, new patients treated, and working them through the payer channel, which we're doing very effectively right now. Jonathan, maybe you can add a little bit.

Jonathan Birchall (Chief Commercial Officer)

Yeah. Perhaps a little bit of color. We're definitely having success engaging with HCPs to actually find both patients that were identified prior to launch and converting them to covered product, number one. Also, number two, as the awareness gets out there, finding new patients and becoming aware of patients that we weren't aware of at launch. That's super encouraging in the first quarter of our launch.

Chi Fong (Equity Research VP)

Thanks so much.

Brett Monia (CEO)

Thanks, Chi.

Operator (participant)

The next question comes from Yaron Werber at TD Cowen.

Yaron Werber (Managing Director and Senior Biotechnology Analyst)

All right. Thanks so much. Congrats on nice progress. Maybe just a couple of questions for me. The first one in WAINUA, can you give us a little bit of a sense? The Part D redesign, now that it's in effect and it's capping patients at $2,000 out-of-pocket, how is that going to, do you think, sort of impact uptake under Part D? And then on Tryngolza, do you have any sense? I mean, the $6 million was really a great number. That sounds like it's a good baseline from here onwards. From here on, do you already have patients that you think are going to come on board pretty quickly that are diagnosed?

As we kind of think ahead about growth and patient identification, maybe give us some qualitative view on how fast that can be.

Kyle Jenne (Chief Global Product Strategy Officer)

Yeah. Let me touch on WAINUA first. AstraZeneca continued to see very strong U.S. demand for WAINUA. The redesign of Medicare Part D impacted some of the Q1 revenue, but there are a lot of positives that you just emphasized in terms of the out-of-pocket change that's happening. First of all, I think you're going to see an increased volume from new patient starts because of this. We're seeing cardiologists and neurologists prescribe WAINUA. What they're telling us is that it's going to, number one, increase the number of patients they can treat because of affordability.

Number two, they feel like it's going to increase the compliance rates for those patients as well because they're going to be able to afford their medication moving forward. I think that has a significant advantage and opportunity for patients overall and WAINUA specifically to be able to demonstrate revenue growth quarter-over-quarter as we move forward in 2025. I think we're very optimistic about that. In terms of the Tryngolza question, again, greater than $6 million in the first quarter. We just talked about the three patient buckets that that came from. We do have additional patients that are being identified currently that are potentially going to go on to Tryngolza. This takes a lot of work, right? 3,000 potential patients in the U.S.

We're doing a lot of work not only with our customer-facing teams, but also with our omnichannel efforts and the education that we're doing with our medical affairs groups at congresses and in different meetings. Those are the things that we're doing to get the word out about the new treatment option available, how to diagnose FCS patients. It's going to take some time and some work, but we are encouraged by the number of patients that are coming forward, and we'll work to get them on treatment this quarter and moving forward throughout the year.

Brett Monia (CEO)

Thanks, Kyle. Remember, Yaron, that WAINUA is now launched outside the U.S. and Europe as well. We're expecting continued revenue growth based on strong patient demand, not only in the U.S., but also in other geographies as well in 2025 and going forward.

Operator (participant)

The next question is from Luca Issi at RBC Capital Markets.

Cassie Yuan (Equity Research Associate)

Okay. Hi. Good morning, team. This is Cassie on for Luca. Thanks so much for taking our question and congrats on the impressive launch today for Tryngolza. This question will be on ATTR cardiomyopathy. We appreciate still early days as CardioTransform has yet to read out. Were you surprised by Amvuttra not lowering pricing when they got label expansion for cardiomyopathy? Are you planning to follow the same playbook, or is there a scenario where you compete with them by lowering the price? Any color there would be much appreciated. Thank you.

Kyle Jenne (Chief Global Product Strategy Officer)

Yeah. In terms of our Alnylam strategy, I was not too surprised by that.

I believe they've got a balance of patients that are hereditary polyneuropathy patients, and I think they're trying to maintain a price in order to manage their revenues now and moving forward. It's up to them kind of how that market evolves, I think, and what they're able to get coverage on for cardiomyopathy. I think that's yet to be determined. In terms of the strategy for WAINUA, that's ultimately AstraZeneca's decision in terms of how they navigate that. I'm sure there are a lot of learnings in this market. As the market continues to evolve, we'll take a look in terms of reimbursement and coverage and physician and patient feedback and figure out what the right price point is for WAINUA based on the benefit and value that it delivers.

Operator (participant)

The next question comes from David Lebowitz at Citi. Thank you very much for taking my question.

David Lebowitz (Senior Research Analyst)

When you look at the core trials and the baseline AP data, I'm curious as to how the analysis and the trials will actually be carried out. Is it going to be strictly based on baseline for the overall population relative to reductions? Will there be additional studies or analyses on patients that actually had baseline AP events to reduce? Over the smaller denominator, I'm curious to what's pre-specified and what could possibly be accepted by the FDA for labeling consideration.

Brett Monia (CEO)

Eugene?

Eugene Schneider (Chief Clinical Development Officer)

Yeah. Thanks for the question. Certainly, the analysis of AP events, the pre-specified analysis, will look at all events happening during the 12-month exposure in a trial and obviously comparing the active arm versus placebo. We will look at population that had a baseline or at baseline reported historical events, but that's a much smaller subgroup.

I guess the answer is the overall analysis will look at all events happening during the trial, comparing all those arson patients.

Brett Monia (CEO)

I believe, if I recall, Eugene, we'll also be looking at AP in patients above and below 80 in the analysis as well. Right. Yeah. We'll be carving up the AP data based on history of AP and without, and so on. As far as the labeling discussions and getting AP in the label, I mean, that's a data-driven outcome that we'll have to talk about with the FDA. Again, as I emphasized earlier, we believe that this is a very substantial unmet need and a very sizable market opportunity for Ionis based on triglyceride lowering. These patients are suffering from acute pancreatitis, and we have a substantial number of patients with a history of AP enrolled in our study.

We think we have the right trial design that if we can see it, we have the potential to see it.

David Lebowitz (Senior Research Analyst)

I'll just add that we have AP in the label now for Tryngolza, which is in the FCS population, but that's very beneficial. The read-through in terms of the connection between triglycerides and lowering of acute pancreatitis, we know from the recent KOL panel that we just had that that's well understood, as Brett and Eugene just described.

Brett Monia (CEO)

Thanks, David.

Operator (participant)

Question comes from Mani Foroohar at Leerink.

Lili Nsongo (Biotechnology Equity Research VP)

Hi. This is Lili on for Mani. First question, digging a little more into the patients and the scripts for Tryngolza. You mentioned that the majority of patients were from the open label extension as well as the AP program.

Brett Monia (CEO)

In terms of the remaining patients, so the newly diagnosed and previously diagnosed patients, could you give a little more color on the distribution there between newly diagnosed and previously diagnosed, as well as your expectations as to how it will evolve quarter to quarter?

Kyle Jenne (Chief Global Product Strategy Officer)

I do not have too much additional color to add. We are not going to disclose the exact patient numbers or the percentages at this point in time. We are encouraged at the patient-finding work that we have done, the identification of new patients so far, and we believe we will be able to add incremental patients quarter-over-quarter as we move forward throughout the year. The launch is going very well, as we talked about, strong patient uptake and strong demand, and good payer coverage. I think we are in a great place. Yeah.

Brett Monia (CEO)

Just to clarify, I don't think we said that the majority of patients are from the open label extension. What we said was that we have, obviously, patients in the open label extension study from the phase III trial, which had 66 patients in BALANCE. Of course, we're focused on the U.S. segment of that. Many of those patients, the majority of those patients, have converted over to commercial, but that doesn't necessarily represent the overall patient population that is on Tryngolza commercially today. Going forward, it's going to be newly identified patients. That's what we've emphasized because those patients that were already diagnosed, as well as the clinical trial patients, we did a good job. We are doing a good job converting those patients, but going forward, it's all about patient identification. We have a lot of work to do.

Jonathan Birchall (Chief Commercial Officer)

Yeah. One thing I'll add is we're definitely finding new patients, just to be transparent around that. I mean, it's very difficult to seek a diagnosis for a condition where it doesn't ultimately change the treatment. As awareness builds, clinical experience builds, there's far more motivation to see these patients, and they're definitely out there. They definitely exist.

Brett Monia (CEO)

I think we have time for one more question.

Jonathan Birchall (Chief Commercial Officer)

The last question comes from Mike Ulz at Morgan Stanley.

Mike Ulz (Executive Director of Biotechnology Equity Research)

Hey, guys. Thanks for taking the question and for squeezing me in. Maybe just to follow up on Olezarsen and SHTG. Looks like you narrowed the timing of that data slightly for the Core and Core II studies, the third quarter from the second half previously. Just curious. Any reason behind that? And then secondly, maybe just to clarify, will that initial update from those studies include the 12-month AP data? Thanks.

Brett Monia (CEO)

Thanks, Mike. No, nothing really behind it. Just as we get closer to the data readouts and we get through everything we need to get through, all the blocking and tackling to read out the top-line data, we provide more clarity. Yes, we have provided more precision. Q2 Essence data, Q3 Core and Core II top-line data. With respect to AP readouts, we do not expect AP in the Essence study, of course, just to confirm that. These are mildly elevated patients with triglycerides. They do not have many AP events. This is a safety study to support the exposure database that is necessary for a highly prevalent disease in the eyes of the FDA. We are focused on triglyceride lowering in that study and safety.

I just also want to emphasize that the % reductions in triglycerides that we expect in Essence is not a reflection of what we would expect in Core SHTG. That's because these patients are only mildly elevated. We're expecting good substantial reductions in TGs, but not to the magnitude of what we would expect in Core. In the top-line data for Core and Core II, we're still working that out, whether we will have the AP data in time for that top-line data, but we'll be focused on there principally, the triglyceride reductions and safety for Core and Core II. If we have the AP data at that time, we will certainly share it in our top-line announcement later this year. Thanks for the question, Mike. Thanks, everybody, for participating and all the great questions.

I'd like to really emphasize that looking forward, we're excited about building on our momentum throughout the year and sharing our additional achievements with all of you along the way. Thanks again for participating, and we'll talk soon. Have a great day.