IONS - NASDAQ

Good morning, and welcome to Ionis Pharmaceuticals, Inc.'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 Walke, 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 Pharmaceuticals, Inc. website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany today's call. With me on the call this morning are Brett Monia, our Chief Executive Officer; Kyle Jenne, Chief Global Product Strategy Officer; Richard Geary, Chief Development Officer; and Beth Hougen, 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. 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. And 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 Pharmaceuticals, Inc. 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. And Tringolza is just the beginning. We are on track to deliver three additional independent launches over the next three years: Donidalorsen, a potential treatment for hereditary angioedema later this year; a second indication for olezarsen in severe hypertriglyceridemia, or SHTG, a large patient population with high unmet need; and

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 the 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 the 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 are 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 experienced 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 a 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 Pharmaceuticals, Inc. 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 Pharmaceuticals, Inc. 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 and the services that they are experiencing from the program. Our market access and reimbursement teams have been actively engaged with a broad set of US 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 omnichannel 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 olezarsen, 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 olezarsen could offer people with SHTG. Today, the team is focused on pre-commercialization activities ahead of an anticipated launch next year. With Astra

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 Pharmaceuticals, Inc. 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 US, the positive data from the phase three BALANCE study formed the basis for Tringolza's approval. In the BALANCE study, Tringolza at 80 milligrams demonstrated substantial and sustained triglyceride reductions, clinically meaningful reductions in acute pancreatitis, a substantial reduction in all-cause hospitalizations, 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 ESSENCE, our supportive safety exposure study, first, with data expected in mid this year. ESSENCE is being conducted primarily in patients with triglyceride levels between 150 and 500 mg/dL who are not at high risk for acute pancreatitis. This is not the patient population we are targeting commercially. Rather, the ESSENCE 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 olezarsen profile in SHTG. These studies are evaluating olezarsen in our target patient population who have triglycerides greater than 500 mg/dL. 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. 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 olezarsen could be the standard of care for both diseases. Following closely behind Tringolza is Donidalorsen, a potential advance for patients with hereditary angioedema. We are pleased that Donidalorsen is now under regulatory review in both the US and EU. Our regulatory submissions were based on positive data generated from our phase two and phase three studies, including a separate switch study. In the phase three program, long-term Donidalorsen 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 Donidalorsen from prior prophylactic treatment showed a further reduction in HAE attack rates from baseline, with nearly 85% of the patients surveyed preferring Donidalorsen. 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 Ionis Pharmaceuticals, Inc.-owned late-stage pipeline is

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, SPINRA

Thank you, Beth. Becoming a fully integrated commercial-stage biotechnology company required the commitment and hard work of all Ionis Pharmaceuticals, Inc. employees, and we expect great progress as we enter this next exciting chapter for Ionis Pharmaceuticals, Inc. Innovation has always been a key differentiator for Ionis Pharmaceuticals, Inc., 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: Qalsody for SOD1 ALS, WAYLIVRA for ATTR polyneuropathy, and now Tringolza for FCS. And a fourth FDA approval anticipated later this year, Donidalorsen for HAE. We've also achieved several important approvals outside the US, 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 three 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 Tringolza 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 top-line revenue growth. It sets us up to deliver accelerating value for all Ionis Pharmaceuticals, Inc. 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 withdraw your question, please press star then two. 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 Ulz with Morgan Stanley. Please go ahead.

Hey, guys. Thanks for taking the question. And congratulations on all the progress. Maybe just one on olezarsen and SHTG, just given the ESSENCE study is supposed to read out sort of midyear ahead of the CORE studies, and I realize it's more of a safety study and you're enrolling a different population. But, you know, 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 above. So it is a safety study, as you say, Mike. As for read-through, safety will certainly be a key read-through to demonstrate and we think confirm further validate the safety that we've seen in the FCS patient population. So that's very important, as well as the APOC3 reductions that we expect in that study. We, of course, will 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 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 Fye with JPMorgan. 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 ATTR polyneuropathy market. For example, what portion of new starts do you think you're capturing there? Thank you.

Yeah. Thanks, Jessica. As Beth communicated earlier, we're so excited about the continued progress here with the launch of WAYLIVRA in ATTR 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 WAYLIVRA. 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. You know, we're seeing not only centers of excellence but also community physicians begin prescribing. So the expansion, neuros and cardiologists are both prescribing, and we're still seeing a mix of naive switches as well as combination treatment for WAYLIVRA. So 2025 is really setting up, I think, to be a very strong year for WAYLIVRA to see the continued growth that we saw in 2024 quarter over quarter. Thank you.

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

Hey. Thanks so much. Can you talk a little more about your design for SHTG, the phase three? I mean, you've mentioned previously the enrollment rate in that trial is ten times that of FCS. What does that imply for the effect size you 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 are a few things there to unpack. Very important questions, but then also, Eugene can jump in. So our study, our SHTG phase three study CORE and CORE2 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 SHTG CORE studies, 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's a very small study. The higher the triglycerides in patients, the greater the risk of acute pancreatitis. That's obvious and well-established. The SHTG 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 ten times the number of patients in our CORE studies, 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'd be difficult to power a study on reduction of AP in SHTG, certainly the BALANCE FCS data lends us some confidence that we'll see a significant or a meaningful signal in acute pancreatitis in SHTG. Eugene, would you like to add anything to that?

Oh, not really. There was another question about clinical meaningfulness of reduction. Of course, as Brett 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, as Brett 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

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 WAYLIVRA polyneuropathy, 84% quarter-over-quarter growth. How much of that growth is driven by switching? Because I did hear there are both naive patients and switching patients, but I'm wondering how much of a force is the switch from siRNA. And my main question, I think Biogen announced a couple of updates to some new neurology collaboration programs. Could you provide a little more color on what's the plan for those programs? Thank you.

Sure. The growth, as we know in this market, less than 20% of the patients currently being treated in the polyneuropathy space with 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 Astra

And regarding the other part of your question, Yanan, 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 two development for multiple system atrophy, and the LRRK2 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're thrilled to have full control of this very important drug going forward. The LRRK2 program was a very small study, 12 weeks of treatment. Obviously, you're not going to have any clinical data, meaningful data, you know, 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. Well, we're very pleased with the magnitude of LRRK2 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, LRRK2 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 an R&D prioritization decision by Biogen.

Great. Thanks for all the color.

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 Tringolza, I think you mentioned 3,000 patients in the US. 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 Tringolza? Thank you.

Yeah. Thanks, Jay. I can't be more excited than to talk about Tringolza. 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 the 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 Tringolza for clinically or genetically diagnosed patients. We have AP in the label demonstrating substantial reductions in acute pancreatitis. 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 onto Tringolza very quickly. The feedback that we're receiving already is that all of the stakeholders, be it patients, HCPs, the advocacy groups, payers, etc., have been very, very positive about Tringolza. 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 us. So we've got some time in terms of the momentum and 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. So we have endocrinologists and cardiologists, those that have an interest in lipids, 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. And the final thing I'll say is our Ionis Pharmaceuticals, Inc. Every Step program is executing very well, and that allows us to interact directly with patients and do disease education and product education. 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.

Hey. This is Chi on for Jason. Thanks for taking our question. I guess I would like to follow up on Tringolza's launch in the FDA. 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, you know, for reimbursement consideration. We've done some doc tests, 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 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 clean 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 US prevalence that you have estimated, that'll be great as well. Thanks so much.

Yeah. Thanks, Chi. First, let me just touch on the insurance process. You know, the first three to six months, as is typical, is going to go through a medical exception process. So, you know, there are really very few plans so far that have established formal criteria to say this is what's absolutely required. 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, you know, by 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, you know, 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. Hegele 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 Tringolza.

Thanks, Kyle. And just to 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 if you want to 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.

Thanks so much.

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

Hi. This is Ike Lee on for David Lebowitz. Thanks for taking the question. I also have one on the SHTG readout. It's regarding the one-time point in the trials on the primary. So we know that these SHTG patients, they're going to be coming in with much lower TG levels than in FCS and likely different rates of APs at baseline as well. 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.

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, you know, we strongly believe we're 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 are in a good position based on our FCS read data as a read-through to show clinically meaningful reductions in acute pancreatitis in this study, and that's, you know, based on what we saw in BALANCE. Richard, do you want to add anything?

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 variation.

Yeah. And let me add to that from a commercial viewpoint. You know, currently, patients with severely elevated triglycerides are on, you know, fibrates 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 on SHTG with olezarsen.

Exactly.

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

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 Donidalorsen in HAE and olezarsen in SHTG, just talk about how you're scaling the commercial organization following the Tringolza 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 WAYLIVRA, 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 Pharmaceuticals, Inc. 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 Donidalorsen later this year and SHTG to follow. Where we're at right now, for example, with Donidalorsen is we've hired the vice president of sales. We, you know, 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 SHTG, 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 have already had with our teams that are in place and the good product that we have within the commercial group overall.

And, Gary, the Angelman's enrollment, so we are still well on track to initiate our phase three study in the first half of this year. Things are going well. And 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 enthusiasm by the community, inquiring about our program, when they will be able to enlist, enroll in somebody. And this is a relatively large patient population with tremendous unmet needs. So those are our expectations for enrollment.

Great. Thank you.

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

Yeah. Hey. Thanks for taking my question. I have a quick question also. As you think about WAYLIVRA, if you think about how do you power the Angelman phase three study, I know you haven't announced the full trial design yet, but unexpected communications. And then maybe just for Beth, as you think about revenue, as you mentioned, more second-half weighted. Are there particular milestones we need to keep in mind that are driving that? Thank you.

Yeah. Sure. So as you know, our primary endpoint is expressive communication as assessed by Bayley-4. There's quite a bit of natural history data available utilizing a slightly older version of Bayley, 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 kind of an unknown primary deficiency in this population. They have little to no expressive communication. So that combined with our phase two of very encouraging phase two data really allowed us to make assumptions on the treatment effect size that we're expecting to see in a placebo-controlled setting for phase three.

Are both doses powered against placebo?

Yes. So 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 HALOS study, both of which showed really, really encouraging evidence of efficacy across all domains that we examined using all instruments, whether it be Bayley-4, Vineland, Saff CGI, etc., at Orca. And as a reminder, expressive communication uniformly demonstrated the greatest best outcome in our phase two HALOS study, which that combined with the fact that this endpoint is part of the Angelman's phenotype is the most burdensome on families. That coupled with that's where we saw the greatest magnitude is why we settled on the expressive communication in our phase study, and that certainly was very important along with the natural history data that Eugene mentioned in the power in our powering assumptions for our study, which is well, nearly 300 patients, three cohorts, in the base for each study design. Does randomized one to one to one or two to one when you look at on treatment versus placebo. But Beth, you had a question from Yaron.

Yep. Yep. So on our revenue guidance for this year, I think just to reemphasize, we really anticipate a shift to commercial revenue this year with SPINRA

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

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

Hi. This is Jake on for Myles. Thank you much for taking my question. A couple for you. The first is on SHTG. We were wondering if we could get some color on your plans for potential ex-US 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 Donidalorsen. And then second, we wanted any updates you have on the next-generation Lp(a) targeting asset with Novartis and whether clinical development or clinical entry is contingent on a positive readout from the HORI

Thanks, Jake. So before we get into ex-US SHTG, let me start with FCS. For both FCS, and then subsequently SHTG, we're planning to secure an OUS commercial partner like we did for Donidalorsen. Discussions are progressing very nicely. And it's consistent with our commercial strategy that we laid out five years ago. That initially will focus on the US market and secure OUS 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 US market, but today, we will secure an OUS partner to commercialize Tringolza for FCS and SHTG outside the US. I really do not have much to offer with respect to whether or not Novartis will wait for the pelacarsen readout before initiating clinical testing for our follow-on molecule that we provided to them and they licensed last year. It's a great-looking molecule, as is pelacarsen, 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 pelacarsen isn't that far away, first half of next year. And the follow-on molecule for Lp(a) CVD that we provided is starting IND supporting toxicology study now. So it now has to run its course through there and then prepare for clinical testing. So that's really a question more specifically that's best suited for Novartis. But 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.