Ionis Pharmaceuticals, Inc.

Good morning and welcome to IONIS's fourth quarter and full year 2024 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 Wach, Senior Vice President of Investor Relations to lead the call. Please begin.

Thank you, MJ. 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 we will be discussing today, including a reconciliation of gapped to non-gapped financials. We believe non-gapped financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany today's call. With me on the call this morning are Brett Monya, our Chief Executive Officer, Kyle Janay, Chief Global Product Strategy Officer, Richard Gehry, Chief Development Officer, and Beth Haugen, our Chief Financial Officer. Joining us for the Q&A portion of our call will be Eric Swayze, Executive Vice President of Research, and Eugene Schneider, Chief Clinical Development Officer. 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 consult the risk factors contained in our SEC filings for additional detail. With that, I'll turn the call over to Brett. Thanks, Wade.

Good morning, everyone, and thank you for joining us on today's call. As we begin a new year, I am thrilled to share that IONIS has begun a new chapter as a fully integrated commercial-stage biotechnology company with our first independent launch of Tringolza underway. With the FDA approval of Tringolza in late December, adults with familial chylomicronemia syndrome, or FCS, for the first time have access to a treatment that substantially and sustainably reduces triglyceride levels and substantially reduces the risk of life-threatening acute pancreatitis. Our highly experienced team has been executing the launch flawlessly, which enabled Tringolza to be in the hands of patients within a couple of weeks following the December 19th approval. Tringolza is just the beginning. We're on track to deliver three additional independent launches over the next three years. Donnads-Lorsen, a potential treatment, preferred treatment for hereditary angioedema later this year, a second indication for olozarsin and severe hypertriglyceridemia, or SHTG, a large patient population with high end mutiny, and Zoginersen for Alexander disease, a rare leukodystrophy with no approved therapies. These programs collectively provide the opportunity to help tens of thousands of patients and represent multibillion-dollar revenue potential. In addition to our independent launches, we also expect four launches from late-stage partner programs over the next three years. These important medicines are poised to treat a range of serious life-threatening diseases, including several that target broad patient populations. Pellicarsin for Lp-a cardiovascular disease, addressing an independent cardiovascular disease risk factor with high end mutiny with no approved therapies. Eplon-Tursen for ATTR cardiomyopathy, a progressive fatal condition that continues to be underdiagnosed with a significant need for more effective treatments. Bepiriversin for chronic hepatitis B virus, a serious disease that affects hundreds of millions of people globally. Antifaxicin, previously referred to as Ionis FBLRx in development for IgA nephropathy, one of the most common causes of chronic kidney disease and kidney failure. If approved, these important investigational medicines would join our other marketed partnered medicines including Spinraza for SMA and WANUA for hereditary TTR polyneuropathy, which are generating considerable value for patients and revenue for Ionis. Our partnered medicines enable our innovative science to reach even more patients, bolster our strong revenue base and provide substantial growth potential while allowing us to focus our efforts on advancing the medicines we plan to commercialize. Ionis is on a path to bring important medicines to patients for years to come, and in turn we are positioned to achieve substantial and sustained revenue growth and positive cash flow. Our recent accomplishments and ongoing investments position us well to drive accelerating value for all Ionis stakeholders. And with that, I'll turn the call over to Kyle.

Thank you, Brett. As we start this important new chapter as a fully integrated commercial stage biotech, I cannot be prouder of our team. Their seamless execution of initial launch activities ensured that our first independently launched medicine, Tringolza, got to FCS patients quickly. Following the approval of Tringolza, the first prescription was written within 24 hours. The team got drug in channel within one week, and the first patient self-administered Tringolza within two weeks of approval. And today we are encouraged by seeing both genetically confirmed and clinically diagnosed patients on drug. While it's early in the launch, we are encouraged by the positive response in several key areas. The breadth of physicians identifying FCS patients and prescribing Tringolza. The mix of prescribers, including endocrinologists and cardiologists with an interest in lipids. And that we're already seeing numerous repeat prescribers. The rapid time from prescription to patients receiving Tringolza. And coverage by payers for both commercial and Medicare patients. Our experience team is laser focused on continuing this momentum. As the first ever treatment in the US, we are capitalizing on our first mover advantage that is enabling us to develop the market, identify and onboard patients early, and create positive treatment experience that encourages long-term adherence. Additionally, it has enabled us to establish a strong presence in the patient community. All of which we expect will drive long-term success for Tringolza. The total addressable US FCS patient population is estimated to be up to approximately 3,000 people. And currently, the vast majority of the FCS population remains unidentified and undiagnosed. As a result, there are multiple critical steps that we are taking to get patients identified and on Tringolza. First, our team is focused on patient finding efforts, working to identify FCS patients who are not yet diagnosed. Building on these efforts, our team is working to increase FCS awareness through HCP education to drive increased diagnosis, and our commercial field team is actively engaging with HCPs who treat patients with high triglycerides. Once patients are identified and diagnosed, the team works closely with prescribers and patients to obtain coverage and initiate treatment for Tringolza. We have deployed a suite of services to accomplish this, anchored by our innovative IONIS Every Step patient support program. As part of this program, dedicated patient education managers provide patient disease and nutrition education, auto injector administration training, reimbursement support, and more. For HCPs, IONIS Every Step streamlines the Tringolza prescribing process by offering insurance authorization and coverage assistance, as well as coordinating delivery, reauthorizations, and refills. To date, we have had very high engagement with patients, sharing their excitement as they now have a treatment in the services that they are experiencing from the program. Our market access and reimbursement teams have been actively engaged with a broad set of U.S. payers, representing the vast majority of covered lives. And through these efforts, payers have recognized the significant burden FCS places on patients. With this recognition, we are pleased to report that in the early days of the launch, patients have received timely access to Tringolza. Finally, our omni-channel capabilities extend the reach of our commercial team and amplify our efforts with patients and physicians. Our launch trajectory will reflect the time it takes to execute on these efforts, which we fully expect will gain momentum as the year unfolds. To realize the full blockbuster potential of Olisarsin, we plan to further scale our commercial organization and infrastructure to address the much larger SHTG patient population, where we have substantial first mover advantage. SHTG is comprised of people with triglycerides over 500 milligrams per deciliter and is a symptomatic disease where people can suffer debilitating chronic symptoms that impact all aspects of their life, including severe abdominal pain and cognitive impairment. In the most severe manifestation, SHTG patients can suffer from life-threatening pancreatitis events that require intensive hospital care. As a result, physicians recognize the importance of lowering severely elevated triglycerides with established guidelines already in place. Many people with SHTG are severely underserved by current treatment options and in many cases are unable to reduce triglyceride levels to current recommended guidelines with available options. This is why we are excited about the potential Olisarsin could offer to people with SHTG. Today, the team is focused on pre-commercialization activities ahead of an anticipated launch next year. WANUA, our co-commercialized medicine with AstraZeneca for hereditary ATTR polyneuropathy, has now been on the market for about a year and we couldn't be more pleased with the strong progress of the launch. WANUA delivered accelerating sequential growth throughout last year, including strong demand in the fourth quarter, with product sales nearly doubling compared to the third quarter. Uptake continues to be strong with the majority of top centers of excellence prescribing WANUA and broadening use into the community setting. Patient growth continued to come from patients new to treatment, as well as switches and patients adding WANUA to their existing therapy. We consistently receive positive feedback from physicians about their patients' experience with WANUA, including patients' quality of life improvements, their ability to rapidly access WANUA, and patients' ability to easily self-administer WANUA. And we are pleased with the reimbursement and affordability dynamics we saw in 2024. The vast majority of patients who initiated WANUA treatment, regardless of insurance type, paid $0 out of pocket. We in AstraZeneca are confident WANUA will continue to provide a differentiated experience for patients. The growing global ATTR polyneuropathy launch sets the foundation for our efforts to address ATTR cardiomyopathy, a substantial opportunity with 300,000 to 500,000 people estimated worldwide. Switching gears to Donnie deLorson with the potential approval just six months away, the team is preparing for our second independent launch. In fact, we recently hired the head of Donnie deLorson sales and plan to add the customer team soon, ensuring that they will be ready to bring Donnie deLorson to patients quickly after anticipated approval. Our team is also leveraging and building upon the WANUA entering goals of launches. For example, we will expand our innovative IONIS Every Step patient support program to include the needs of HEE patients. Our medical affairs team has been in the field meeting with physicians. This includes ensuring high visibility at key medical conferences, building awareness of IONIS' platform technology, and presenting the positive clinical data generated from our robust Phase III program ahead of our anticipated launch. More than 20,000 people are estimated to have HEE in the U.S. and Europe. In the U.S., while the HEE market is well-defined, prophylactic treatment continues to grow with a meaningful segment of patients switching treatment in search of a better option. Based on Donnie deLorson's strong clinical data, including the positive data in patients switching from current prophylactic treatments to Donnie deLorson, and the simplicity of monthly or every two months self-administration via an auto-injector, we believe Donnie deLorson offers the attributes that many people with HEE are looking for. And while we expect the Donnie deLorson launch ramp to take time as we work to convert patients from existing treatment, we believe Donnie deLorson has the potential to be a preferred prophylactic treatment for many HEE patients. We have built a highly experienced, efficient, and scalable commercial organization. With the Tringolza FCS launch underway, we are focused on delivering its full potential while preparing to successfully execute our three additional launches planned over the next three years with more to follow, positioning IONIS for sustained growth and long-term success. With that, I'll now turn it over to Richard.

Thank you, Kyle. We had many important pipeline achievements in 2024 that position us well for success in 2025. These included numerous positive late-stage data readouts, which resulted in multiple regulatory submissions and our first independent launch. Additionally, as our pipeline advances, we are on track for multiple late-stage data readouts and regulatory actions this year and next, positioning IONIS to bring transformational medicines to people with serious diseases for years to come. Starting with Tringolza, the first ever approved treatment for adults with FCS in the U.S., the positive data from the Phase III Balance Study formed the basis for Tringolza's approval. In the Balance Study, Tringolza 80 milligrams demonstrated substantial and sustained triglyceride reductions, clinically meaningful reductions in acute pancreatitis, a substantial reduction in all-cause hospitalization and days spent in the hospital, and a favorable safety and tolerability profile in people with FCS. We believe these positive data underscore the tremendous benefit Tringolza can bring to adults with FCS. And while we are starting with FCS, we expect to quickly expand to a second broader indication, SHTG. Many SHTG patients are unable to manage their triglycerides with currently available treatments and physicians are eager for a more effective treatment. As a reminder, we have three separate studies. We expect to report top-line results from ESSENSE, our Supported Safety Exposure Study first, with data expected in mid-this year. ESSENSE is being conducted primarily in patients with triglyceride levels between 150 and 500 mics per deciliter who are not at high risk for acute pancreatitis. This is not the patient population we're targeting commercially. Rather, the ESSENSE study was designed to satisfy the regulatory requirements for a safety database to support a highly prevalent disease. We look forward to data from our pivotal studies, CORE and CORE2, to truly understand the OlaSarsen profile in SHTG. These studies are evaluating OlaSarsen in our target patient population who have triglycerides greater than 500 milligrams per deciliter. We are on track for data from CORE and CORE2 in the second half of this year. And once we have data in hand for both of these studies, we will report the results. And assuming these data are positive, we plan to submit our SNDA before year end. With significant first mover advantage in both FCS and SHTG and compelling results already demonstrated in FCS, coupled with our expectation for similarly positive data in SHTG, we believe OlaSarsen could be the standard of care for both diseases. Following closely behind Trinvulsa is Donny deLorsen, a potential advance for patients with hereditary angioedema. We're pleased that Donny deLorsen is now under regulatory review in both the U.S. and the EU. Our regulatory submissions were based on positive data generated from our Phase 2 and Phase 3 studies, including a separate switch study. In the Phase 3 program, long-term Donny deLorsen treatment demonstrated substantial reductions in HAE attack rates of more than 90% with both monthly and bimonthly dosing and a favorable safety and tolerability profile. These reductions translated to a high level of disease control and clinically meaningful improvements in quality of life measures. In the switch study, patients who switched to Donny deLorsen from prior prophylactic treatment showed a further reduction in HAE attack rates from baseline with nearly 85% of the patients surveyed preferring Donny deLorsen. With a PDUFA date of August 21st, we look forward to bringing this potential preferred prophylactic treatment to HAE patients later this year, assuming approval. Rounding out our Ionisone late stage pipeline is Zilgenursen, our medicine to treat Alexander disease, an ultra-rare leukodystrophy that profoundly impacts patients and families and has no approved disease modifying treatments. Last year, Zilgenursen was granted fast-track designation by the FDA, reflecting the serious unmet need that exists for this rare disease. We are looking forward to reporting Phase III data for this program late this year. The rest of our rich pipeline is also making excellent progress. This includes Ion 582, our wholly-owned investigational medicine for Angelman syndrome, which we believe has transformational potential for the tens of thousands of patients living with this serious rare disorder. Last year, based on the positive early results from the HALOS study of Ion 582 in children and adults with Angelman syndrome, we reached alignment with FDA to conduct the most robust and comprehensive Phase III study in this patient population to date. Our study will focus on clinical endpoints that reflect the most pressing and meaningful outcomes for people living with Angelman syndrome, endpoints that showed positive results in our HALOS study. We remain on track to start Ion 582 Phase III study in the first half of this year. As we look to our key value-driving events, we have already made excellent progress. In addition to launching Tringulsa, we are pleased that higher dose Nusenursen is one step closer to the market with the recent FDA and EMA acceptances of Biogen's regulatory submissions. With the well-characterized profile of Spinraza established over the past 10-plus years and the positive data from the higher dose Spinraza, we believe Spinraza is well positioned to continue to bring benefit to SMA patients around the world. To summarize, key near-term value-driving events, we anticipate many late-stage data readouts, significant regulatory actions, and numerous product launches. By the end of 2026, we expect seven Phase III data readouts, including two Ionis-owned medicines. This year, Ola Sarsen for the broad SHTG indication and Zilgenersen for Alexander disease. Next, five Ionis-discovered medicines are on track for Phase III data, most of which are for very broad patient populations. If positive, these groundbreaking medicines could start to reach patients as soon as next year, and we expect to have five launches underway, including four independent launches. All of this sets us up to bring a steady cadence of new Ionis medicines to patients for years to come. With that, I'll turn it over to Beth.

Thank you, Richard. We've made excellent progress advancing our strategic growth priorities, including executing our first independent launch while simultaneously upholding our commitment to drive operating leverage. This important progress is reflected in our strong financial results for last year and our outlook for this year, both of which I am happy to share with you today. We delivered a non-GAAP operating loss of $345 million, a significant improvement compared to our 2024 guidance. We also substantially exceeded our 2024 revenue guidance by more than $130 million, earning revenues of $705 million last year. During 2024, Spinraza remained the primary source of commercial revenue with $216 million of royalties for the year. We were encouraged by Spinraza's performance and look forward to the anticipated launch of the higher dose option. WANUA product revenue achieved accelerating sequential growth throughout last year, driven by strong underlying demand. Notably, WANUA product revenue increased 84% in the fourth quarter compared to the third quarter. WANUA product sales were $85 million for last year, for which we earned $20 million in royalties. As planned, our non-GAAP operating expenses increased slightly for 2024 over 2023. The 12% increase year over year in sales and marketing expenses reflected our investments in the U.S. launch of Tringosa and preparations for the upcoming launch of Donnie DeLorsen. Our SG&A expenses also included our minority portion of WANUA's sales and marketing costs, which are in the high teens to low 20% range. In line with our plan, we kept R&D expenses stable year over year while appropriately funding our rich pipeline. Our excellent progress last year coupled with our disciplined financial management positions as well for continued growth and value creation. Our financial guidance for this year reflects our evolution to a fully integrated commercial company focused on maximizing the value of our innovative medicines while remaining steadfast in our commitment to deliver strong operating leverage. We project to earn more than $600 million in revenue from numerous sources, including a shift toward commercial revenue with the addition of Tringosa product revenues and initial Donnie DeLorsen product revenues, assuming approval. With Tringosa, it's important to remember that FCS is a rare and under-recognized disease, and we anticipate an initial gradual buildup of launch momentum, especially in the first few quarters. As our efforts aimed at driving physician awareness and patient identification progress, we expect the number of new patients diagnosed with FCS to increase, which in turn will translate to an acceleration of our launch progress. We're also looking forward to adding Donnie DeLorsen product revenues beginning in late Q3, assuming approval in August. And since this is primarily a Swinch market, we expect the launch to reflect the time it takes to convert patients from their existing therapy to Donnie DeLorsen. From our partnered programs, we anticipate earning substantial royalties from medicines on the market today. These include Spinraza, which continues to be our largest commercial revenue source. We expect the resilience Spinraza has demonstrated to continue and our royalties to reflect that. And this also includes WANUA, which we expect will continue its upward trajectory this year. With these expected launch dynamics, coupled with the resetting of the royalty rate for Spinraza at the beginning of each year, we anticipate that our commercial revenue will increase as the year progresses. Our R&D revenue remains a meaningful contributor to our total revenue guidance, although we expect it to be lower this year than it was last year. With a rich pipeline and many partnered programs advancing, we have the potential to earn numerous milestone payments. Based on the timing of anticipated milestones, we expect to earn much of our R&D revenue in the second half of the year. Additionally, as we continue to conduct the CardioTransform study, we will continue to earn revenue from AstraZeneca for its 55% share of the study costs. We project our 2025 operating expenses to increase in the high single-digit percentage range compared to last year. This modest increase reflects our commitment to bring our medicines directly to patients and advance our pipeline while also continuing to exercise sound fiscal stewardship. This is in 2024, our planned expense growth will come from increases in our sales and marketing expenses and as we invest to support the success of our multiple ongoing and planned launches. We expect our R&D expenses to remain steady in 2025, similar to last year. As several of our late-stage studies have recently concluded or are on track to wrap up this year, we are able to reallocate our resources toward our next wave of opportunities, just as we have done for the Phase III development of ION 582 for Angelman syndrome. With sizable revenues and modest expense growth, we are projecting a non-GAAP operating loss of less than $495 million. We project to end the year with cash and investments of approximately $1.7 billion. Our projected -over-year change in cash reflects our investments to bring our medicines directly to patients in addition to advancing our wholly-owned medicines in development while exercising prudent fiscal responsibility. Looking beyond 2025, with the numerous opportunities before us, we are on track to deliver substantial and sustained revenue growth. This revenue growth, combined with our commitment to drive operating leverage, positions us well to also generate positive cash flow. To achieve our goal, we expect to continue making significant investments to advance our pipeline and bring our growing portfolio of medicines directly to patients. We estimate that the programs in our pipeline today have a combined -billion-dollar peak revenue potential. This includes estimated annual peak sales of more than $3 billion from our IONIS-owned medicines, including Olisarsin and ION 582. Additionally, based on our partners' peak sales estimates, we could earn more than $2 billion annually in royalties from our late-stage partnered medicines. So as you can see, with robust revenue growth potential, we have a clear path to achieve positive cash flow. With that, I'll turn the call back to Brett.

Thank you, Beth. Becoming a fully integrated commercial-stage biotechnology company required the commitment and hard work for all IONIS employees, and we expect to continue our great progress as we enter this next exciting chapter for IONIS. Innovation has always been a key differentiator for IONIS, and through innovation, we've established a proven and prolific discovery and development engine that has provided us with a rich pipeline of medicines with transformational potential, and this will continue. Our pipeline is consistently delivering, with three important FDA drug approvals in just under two years, CalSaudi for SOG1ALS, WANUA for ATTR polyneuropathy, and now Tringosa for FCS, and a fourth FDA approval anticipated later this year, Donnadal-Lorson for HAE. We've also achieved several important approvals outside the U.S., and we expect a great deal more this year and in coming years. And with an advancing late-stage pipeline, we've delivered several positive phase 3 data readouts with more expected this year and next that are being developed to treat both rare and broad patient populations. And today, we have a scalable, highly experienced, innovative commercial organization in place, currently launching Tringosa for FCS, and positioned for three additional launches over the next three years. This progress provides us with a clear path to achieve positive cash flow driven by our expectations for substantial outlying revenue growth. This sets us up to deliver accelerating value for all IONIS stakeholders. And with that, we'll now open the call up for questions. MJ?

Thank you. We will now begin our question and answer session. To ask a question, you may press star then 1 on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then 2. In the interest of time, we ask that analysts limit themselves to one question, then they may return to the queue. We will pause momentarily to assemble our roster. Today's first question comes from Mike Ols with Morgan Stanley. Please go ahead.

Hey, guys. Thanks for taking the question, and congratulations on all the progress. Maybe just one on Olsarsen and SHTG, just given the Essence study is supposed to read out sort of mid-year ahead of the core studies, and I realize it's more of a safety study and you're enrolling a different population. But what kind of read-through could we make from Essence to your core studies? Thanks.

Thank you, Mike. The Essence study, just as a reminder, is a patient population, as Richard described before, that is not our target commercial patient population. It's mildly elevated triglycerides 150 to 500. Our target patient population is SHTG 500 milligrams per deciliter of triglycerides and a plus. So it is a safety study, as you say, Mike. As for read-through, safety will certainly be a key read-through. We are going to be looking at triglyceride reductions in that study. That, as a predictor of what we'll see in SHTG, is somewhat less direct, but we still think it will be a safe study. It's still an indicator of what to expect in SHTG to some extent, a lesser extent, because it is a slightly different patient population. But we're really focused on the safety in that study and the target engagement as a read-through to

SHTG. Helpful. Thank you.

The next question comes from Jessica Five with JP Morgan. Please go ahead.

Hey, guys. Good afternoon. Thanks for taking my question. I was hoping you could talk a little bit about what you're seeing in the TTR polyneuropathy market. For example, what portion of New Starts do you think you're capturing there? Thank you.

Yeah. Thanks, Jess. As Beth communicated earlier, we're so excited about the continued progress here with the launch of WANUWA and HATTR polyneuropathy, the growth quarter over quarter of an increase of 84% and $42 million in Q4 and $85 million on the year. I think what that speaks to is the strong demand and the continued growth that's within that category right now. Currently, the new to brand share is about 40% for WANUWA, so we are continuing to capture, in terms of new patient starts, a significant portion of those, and we expect that to continue to grow over time. We're seeing not only centers of excellence, but also community physicians begin prescribing, so the expansion, and neuros and cardiologists are both prescribing, and we're still seeing a mix of naive switches as well as combination treatment for WANUWA. So 2025 is really setting up, I think, to be a very strong year for WANUWA to see the continued growth that we saw in 2024 quarter over quarter.

Thank

you. The next question is from Akash Tewari with Jeffries. Please go ahead.

Hey, thanks so much. Can you talk a little more about your design for SHCG, the Phase III? I mean, you've mentioned previously the enrollment rate in that trial is 10x that of FCS. What does that imply for the effect size you've powered for, particularly on acute pancreatitis and severe abdominal pain? And really, how does your event rate assumption maybe differ versus FCS, but also that essence study that you mentioned isn't necessarily representative of your other trials? And then any feedback from KOLs on what would be a clinically meaningful reduction would be very helpful as well. Thank you.

Thank you, Akash. Let me take a stab at that. There were a few things there to unpack, very important questions, but then also Eugene can jump in. So our study, our SHCG Phase III study core and core two are powered, of course, well powered for triglyceride reductions, which is our primary endpoint. As far as acute pancreatitis, impact on acute pancreatitis events in the SHCG core studies, you know, this has really never been studied before. We did not believe we were well powered for a positive AP outcome in FCS, and we were pleasantly surprised to see what a tremendous impact we had at reducing AP events in that patient population, even though it was a very small study. The higher the triglycerides in patients, the greater the risk of acute pancreatitis. That's obvious and well established. The SHCG population has somewhat milder triglycerides on average compared to FCS, so you might expect a lower rate of acute pancreatitis in that study, in that patient population. Nevertheless, we have more than 10 times the number of patients in our core studies, which, which, of course, allows us to accumulate potentially more events. So, you know, although we're not necessarily powered, and no one's ever studied this before, so it would be difficult to power a study on reduction of AP in SHCG. Certainly the balanced FCS data lends us some confidence that we'll see a significant or a meaningful signal in acute pancreatitis in SHCG.

Would you like to add anything to that, Eugene? Not really. There was another question about clinical meaningfulness of reduction. Of course, as Brad said, it's not really clear. There is no particular threshold that is considered to be clinically meaningful in terms of AP reduction. So what we're hoping to see is really any significant reduction overall. But as Brad said, of course, the powering of the study is not something that we were able to model based on

any existing data. The next

question comes from Yanan Zhu with Wells Fargo Security. Please go ahead.

Oh, great. Thanks for taking our questions, and congrats on the quarter. First, I wanted to have a quick follow-up to a prior question on the, we knew polyneuropathy, 84% quarter over quarter growth. How much of that growth is driven by switching? Because I did hear they're both naive patient and switching patient, but wondering how much of a force is the switch from siRNA? Okay. And my main question, I think Biogen announced a couple of updates to some neurology collaboration programs. Could you provide a little more color, and what's the plan for those programs? Thank you.

Sure. Kyle, please take the question on quarter over quarter growth, what's driving that, and I'll be happy to comment on Biogen. Yeah,

the growth, as we know in this market, you know, less than 20% of the patients are currently being treated in the polyneuropathy space with the therapy today. So the opportunity here remains to grow this market, and that's really what we're seeing, and that's the focus that AstraZeneca and our teams have in terms of identifying newly diagnosed patients and getting those naive patients started on treatment. What we are hearing consistently from physicians is that there is improvement in quality of life. The safety profile and the tolerability of WANUA is very strong, and access to treatment is extremely strong. The majority of patients, as I highlighted, have a zero dollar out of pocket expense. That's regardless if they are commercial or Medicare patients. So to be able to afford the medication on top of the profile and the ability to self-administer WANUA at a place of their choosing continues to resonate extremely well. So as the market expands, physicians are choosing WANUA over some of these other treatments. Now, in the instances where there are switches from other therapies, the main driver for that really is the ability to self-administer. We're seeing very good access and very good coverage, and if patients are able to do this on their own and not have some of the challenges associated with side of care, and they can do this at a place of their choosing, physicians and patients are choosing WANUA. So with a very highly performing medication combined with the ability to self-administer, it's really making a differentiation possible, you know, quarter over quarter, and we're seeing that growth due to that.

And then regarding the other part of your question, Yannan, we couldn't be more pleased to retain global rights for both of these programs. These programs that you're referring to are our Alpha Synuclein program that is in development, Phase II development for multiple system atrophy, and the LARC II program, which is indicated for Parkinson's disease. We couldn't be more thrilled to retain full control of these programs. Just a little color to add to these, the Alpha Synuclein program required a decision by Biogen to opt in on this based on partial data. It's a study that's ongoing, and in fact, they really only had access to the low-dose cohort at the time. This was based on a contract with Biogen for this particular program, and like I said, we were thrilled to have the full control of this very important drug going forward. The LARC II program was a very small study, 12 weeks of treatment. Obviously, you're not going to have any clinical data, meaningful data in a 12-week study in PD patients. The study was designed for safety and target engagement, and we're very pleased with what we saw in safety. We're very pleased with the magnitude of our LARC II reductions we saw in the study. This drug definitely deserves to be further developed, and we're looking forward to forging a path forward for both programs, LARC II and Alpha Synuclein. We're expecting to have data in MSA later this year. Our partnership with Biogen remains very strong, and this was essentially a R&D prioritization decision by

Biogen. Great. Thanks for all the cover.

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

Oh, hey, congrats on all the progress, and thank you for taking the question. For Tringosa, I think you mentioned 3,000 patients in the U.S. Can you just talk about how many of those patients are currently diagnosed and available for treatment? And if it's not too early, how many of those patients are on treatment or any other important metrics you could share to help track the launch of Tringosa? Thank you.

Yeah, thanks, Jay. I can't be more excited to kind of talk about Tringosa. You know, obviously a rare disease population, we're doing a lot of work right now to, number one, identify, number two, diagnose, and then finally get prescriptions written and get these patients on drug. The launch is going very, very well. When you look at the label that we received, it's a very broad label. It's a clean label. It allows the physicians to prescribe Tringosa for clinically or genetically diagnosed patients. We have AP in the label demonstrating substantial reductions in acute pancreatitis, and we've got first mover advantage, which allows us to develop this market and to take the patients that you're asking about and move them on to Tringosa very quickly. The feedback that we're receiving already is that all of the stakeholders, be it patients, HCPs, the advocacy groups, payers, et cetera, have been very, very positive about Tringosa. They are really excited to have a treatment option when they've never had a treatment option before. In terms of execution around this plan, we had product and channel before the end of the year. We launched in 2024, and everything that we've been trying to do to be able to deliver treatment to these patients is going very well. Now, of the 3,000 patients, there are several hundred right now that are currently identified, and they are continuing to come in, as I mentioned, and become diagnosed formally and get prescriptions written for. So we've got some time in terms of the momentum in the launch ramp here. On the metrics, we're not disclosing too many metrics. Obviously, this is a competitive market that we're in, but what we're really encouraged by right now is the number of physicians that we've seen identifying and prescribing. So we've got a good breadth of prescribers. We are seeing a mix of specialties prescribing as well. Also, we have endocrinologists and cardiologists, those that have an interest in lipids and also pancreatology, are prescribing Tringolza, which was to be expected. The other thing that we're keeping an eye on is time to prescription and how long it takes to go from prescription to actually getting the drug filled into the patient. And that's going very, very quickly, faster than we had expected here early on. And what that's telling us is that the FCS diagnosis, if it's either clinical or genetic, is confirming these patients and physicians are working through the medical exception process in order to justify the prescription and getting these patients on treatment quickly. The final thing I'll say is our Ionis Every Step program is executing very well, and that allows us to interact directly with patients and do disease education and product education and support them through the reimbursement process. And patients are giving us very positive feedback about the ability to self-administer with an auto-injector on a monthly basis. And the profile of the drug is playing out very positively here in the first couple of weeks of launch. So thanks for asking.

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

Hi, this is Chi on for Jason. Thanks for taking a question. I guess I would like to follow up Tringolza launch in FCS. Thanks for all the commentary on early launch experience so far. I'm curious, based on early launch experience, what insurance company you think are requiring in terms of documentation for reimbursement consideration? We've done some doc checks, and one thing that we have heard is that genetic confirmation is the most straightforward documentation to get insurance company on board. Somewhat a bit of a gray area when it comes to clinical diagnosis. Part of it is the lack of consensus, diagnosis criteria. Some of it is what insurance company accept as clinical diagnosis criteria. Can you talk about that? And when you talk about several hundred patients currently identified and become formally diagnosed, how many of those are getting genetically confirmed? How many of those are getting clinically diagnosed? And if you can talk about that mix within that 3,000 patients, U.S. prevalence that you have estimated, that would be great as well. Thanks so much.

Yeah, thanks, Chi. First, let me just touch on the insurance process. The first three to six months, as is typical, is going to go through a medical exception process. So, you know, there are really, there are very few plans so far that have established formal criteria to say this is what's absolutely required. So then the question becomes, what is the history of the patient? What steps has the physician gone through to actually substantiate or validate that this truly is an FCS patient so that they can get the coverage by the plan and ultimately get the drug approved? The most straightforward is a genetic confirmation. I think that's the easiest one. However, we have seen both clinically and genetically diagnosed patients work through the medical exception process very efficiently with justification about patient triglyceride levels, the history of the patient, age of diagnosis, symptomatology, right, abdominal pain, acute pancreatitis potentially in their history. So there are a lot of other things to unpack in terms of the patient presentation that ultimately will justify or qualify that patient for an approval from the health plan. And as I mentioned as well, we're seeing this through both the commercial and Medicare segments of the business. So, you know, what we're most optimistic about is that physicians are doing this the right way. They're identifying FCS patients. They're justifying it through one of those two means and supporting that patient through the process very quickly. I don't have a number that I can share with you in terms of how many have been clinically versus genetically confirmed at this point that have gone through our process. But obviously both are being approved in terms of getting that approval. The lack of consensus we have not heard yet. You know, using the NAFCS scoring tool that Dr. Hegley published at the end of last year seems to be a pretty straightforward tool for them to be able to use and substantiate and validate for these patients is what we're seeing based on the fact that it has been published. So, you know, not to break out the mix, but other than that, I'm very encouraged here early on at the coverage. There's more to learn in terms of coverage and then payers will be establishing criteria, you know, throughout the first six months or so. And we're working directly with the payers in order to make sure that there's a reasonable path forward for these patients to be able to have access to Tringulza.

Thanks, Kyle. And just very much. Two points that I'll just add to that, Chi. We're very pleased with the speed to genetic diagnosis that we're experiencing so far, one to two weeks to the genetic diagnosis when we go that route. And I also think it's reasonable to assume that any aspect of diagnosis that physicians are unfamiliar with today, they will become more familiar with as time goes on. And we're driving a lot of that work, especially utilizing the North American FCS diagnosis criteria to build that familiarity with physicians. So expect that to improve as

we go forward. Great. Thanks so much.

The next question comes from David Lebowitz with CIDI. Please go ahead.

Hi, this is Ike Lee-Aung for David Lebowitz. Thanks for taking the question. I also have one on the SHTG readout. It's regarding the 12-month time point in the trials on the primary. So we know that these SHTG patients, they're going to be coming in lower, with much lower TG levels than in FCS and likely different rates of APs at baseline as well. And so I'm wondering if there's no clinical consensus on how much TG lowering is actually beneficial, as you said. Just wondering what the reasoning was behind the selection of that 12-month timeline and just overall, what is our understanding in this population so far as to what they need. Thanks.

So thank you for the question. And Richard, follow up with anything that you want to touch on after my comments. So the primary endpoint is triglyceride lowering at six months. The full study readout is at 12 months. So the primary endpoint is at six months on TGs. We have a very rapid response on ApoC3 reductions, substantial lowering of ApoC3, substantial and rapid lowering of triglycerides based on our previous clinical data for Tringolza as well as our balance FCS data. So we strongly believe we were very well powered on the primary endpoint. Regarding acute pancreatitis, as I mentioned earlier, although the rate of AP in SHTG patients is not well documented in the literature, it will be after our phase three outcome. We believe that we're in a good position based on our FCS data as a read through to show clinically meaningful reductions in acute pancreatitis in this study. And that's based on what we saw in balance. I think that's driving a lot of that, don't you, Richard? Yes,

and I would also say that we see events being adjudicated by our independent adjudication committee and the events are accruing over the course of this study and it's looking very good. The other thing I would say about triglycerides and clinically meaningful, that has been determined by the regulatory agencies. Certainly the FDA has said significant risk occurs above 500 and it increases as the triglyceride levels increase. So by decreasing triglyceride levels, by whatever the amount is, you're decreasing the risk for these patients having an acute pancreatitis. So I think that's the primary goal of the study, obviously, is to reduce their triglyceride and risk for acute pancreatitis and we'll be able to monitor that and see the results very soon.

Yeah, and let me add to that from a commercial viewpoint. You know, currently patients with severely elevated triglycerides are on, you know, fibroids and fish oils and other things, statins to try to reduce their triglycerides. And cardiologists and endocrinologists are not getting these patients low enough. They need a better, more effective triglyceride lowering treatment in order to meet the established guidelines that are already in place. So the guidelines are there already that say you need to be below 500 in order to get out of risk, as Richard was talking about from a regulatory standpoint, but most importantly from a commercial standpoint. We know that physicians are trying to get there and they're treating hundreds of thousands of patients already and they're just unfortunately not able to do so because they don't have a therapy that's sufficient in order to accomplish that. And that's what we hope to be able to bring to the market here shortly with an approval and .T.G. with Olisarsin.

Exactly. Yeah, I think it's also important to emphasize that this .T.G. is not a asymptomatic disease. It's a very serious symptomatic disease that in addition to acute pancreatitis, these patients suffer from serious cognitive, often serious cognitive impairment, serious body pains, nausea and so forth and often land in a hospital even without a treatment. They're not an AP event because they are in such fear of having an AP event because of the body pain. And we think that that'll go a long way in the success, commercial success

of Tringosa in .T.G.

The next question is from Gary Nachman with Raymond James. Please go ahead.

Hi, thanks and my congrats as well on the progress. So as you prepare for new launches for Donnie and .A.E. and Olisarsin and .T.G., just talk about how you're scaling the commercial organization following the FCF launch. What's in place versus what you need to add specifically in terms of reps for those other programs? And then just for the Angelman program, just what's your expectations for enrollment timing given the competitive dynamics there? Thank you.

Yeah, Gary, thanks for the question. I'll start. This is Kyle. You know, fortunately with the co-commercialization on WANUA, then we were able to build towards our FCS readiness internally. So, you know, we've got teams around commercial operations and our market access group. We have our capability with our IONIS Every Step patient support program. Those are kind of the core fundamental foundational components to the commercial team that we've got in place and they're ready to go that allow us to scale accordingly whenever we add on new commercial therapies into the mix, such as Donnie Doloreson later this year and .T.G. to follow. Where we're at right now, for example, with Donnie Doloreson is we've hired the vice president of sales. We will build out our regional director team and ultimately our customer facing field teams from there. And that is in time and in sequence with what we're doing for the regulatory process for the anticipated approval on August 21st. So, I mean, I think right now as we build, it's been a sequential build over time and it's been a purposeful build and it's been an intentional build as well to make sure that we're building the right capabilities at the right time and also investing the right amount within those respective functions. When we get to .T.G., it will grow exponentially as you would expect based on the size of the market that we'll be entering into. But we'll be able to add our customer facing and field teams at the right time. And I'm just excited about the talent and the tremendous accomplishments that we've already had with our teams that are in place and the good product that we have within the commercial group overall. And Gary,

on the Angelman's enrollment, so we are still well on track to initiate our Phase 3 study in the first half of this year. Things are going well. We've also established internal metrics to achieve with respect to enrollment this year by our team that sets us up for completing enrollment in 2026 next year. We do not believe that this trial will be difficult to enroll. There's pent up demand. We're really encouraged by the enthusiasm by the community, inquiring about our program, when they will be able to enlist enroll in the study. And this is a relatively large patient population with tremendous unmet needs. So that's our

expectations for enrollment. Great. Thank you.

The next question comes from Yaron Werber with TD Cohen. Please go ahead.

Yeah. Yeah. Hey, thanks for taking my question. I have a quick question also. If you think about how do you power the Angelman Phase 3 study? I know you haven't announced the full trial design yet, but on expressive communications. And then maybe just for Beth, as you think about revenue, as you mentioned, it's more second half weighted. Are there particular milestones we need to keep in mind that are driving that?

Thank

you.

Eugene, would you comment on the powering?

Of course, Richard, jump into. Yeah, sure. So as you know, our primary endpoint is expressive communication as assessed by Bailey for. There is quite a bit of natural history data available utilizing slightly older version of Bailey, but nonetheless, we are able to see and kind of make estimates on how the patients are expected to progress with regard to their ability to communicate, which is. Unfortunately, and unknown primary deficiency in this population, they have little to no expressive communication. So that combined with our phase two, very encouraging case to data really allowed us to make some assumptions on the treatment effect size that we're expecting to see in a placebo controlled setting for phase three. As you know, we're also testing to two dose levels. So again, it's a two to one randomization, but essentially that that and the knowledge of natural history trajectory in this patient population is what we use in our assumptions.

Are they both are both doses powered against placebo? Thank you. Yes,

so our right. Our goal is to see an effectiveness of both doses.

So the two doses are the same two doses that we studied in the phase two halo study, both of which showed really, really encouraging evidence of efficacy across all domains that we examined using all instruments, whether it be Bailey for Vineland, SAF-CGI, etc. Orca. And as a reminder, expressive communication uniformly demonstrated the greatest best outcome in our phase two halo study, which which that combined with the fact that this is this this this end point is this part of the angel wins phenotype is the most burdensome on families that coupled with that's where we sort of even the greatest magnitude is why we settled on the expressive communication in our phase three study. And that and that certainly was very important, along with the natural history data that Eugene mentioned in the power and our powering assumptions for our study, which is what nearly 300 patients, the three cohorts in the Bay Street study design does randomize one to one to one or two to one when you look on treatment versus placebo. That you had a question from your own.

Yes. Yes. So on the on our revenue for for this year, I think just to sort of reemphasize really anticipate a shift to commercial revenue this year with spin raza we knew a continuing to grow your quarter over quarter. The addition of trangolsa revenues and in the back half of the year, the the dining delurcen revenues assuming approval as we think about R and D revenues. As you know, we have lots of different partnerships and lots of medicines in development under those partnerships. No one particular medicine has a very significant milestone. So there's there's no sort of large milestones that I could point to that are going to really be the cornerstone for our revenue this year. A big piece of it will be the continued R and D funding we get from AstraZeneca as we conduct the cardio transform phase three study. We get 55% of those all in costs reimbursed to us from AstraZeneca and that we book as revenue. And then there's a whole host of partnered programs, particularly with by Jim and others with AstraZeneca that as they advance, we would anticipate seeing milestones over the course of the year. With, as I said, much of that being back and loaded.

Thanks, Beth. Thank you, Ron. We have time for one more question.

Today's last question will come from Miles Minter with William Blair. Please go ahead.

Hi, this is Jake on for Miles. Thank you so much for taking my question. A couple for you. The first is on .T.G. We were wondering if we could get some color on your plans for potential -U.S. launch and whether you would be sort of comfortable going in alone or whether you're looking to find a partner in that as you did for Donald Lorson. And then second, we wanted any updates you have on the next generation LPLA targeting asset with Novartis and whether clinical development or clinical entry is contingent on a positive readout from the Horizon study. Thank you.

Thanks, Jake. So before we get into -U.S. .T.G., let me start with .C.S. For both .C.S. and then subsequently .T.G., we're planning to secure a .U.S. commercial partner like we did for Donald Lorson. Discussions are progressing very nicely. And it's consistent with our commercial strategy that we laid out five years ago. That initially we will focus on the U.S. market and secure .U.S. commercial partners for programs we bring to the market ourselves. And that will evolve and that will change in due time. And we're working on that now where we will emerge from the U.S. market. But today we will secure an .U.S. partner to commercialize Tringosa for .C.S. and .T.G. Outside the U.S. I really do not have much to offer with respect to whether or not Nobartis will wait for the Pellicarson readout before initiating clinical testing for our follow on molecule that we provided to them and they licensed them last year. It's a great looking molecule as is Pellicarson. But the follow on really does look like a best in class molecule with respect, you know, as compared to everything that's been publicly disclosed to date. I don't think it matters much on the timing because Pellicarson isn't that far away. So that's really a question more specifically that's best suited for Nobartis. But thank you. Thank you for the questions and thanks to everybody who joined us today and participated in our call. We're really looking forward to an outstanding year ahead and sharing our progress along the way with you. But until then, thanks again and everybody have a great day.

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